SH-102103- AD- APR 2013 Left Atrial Appendage Closure.
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SH-102103-AD- APR 2013 Left Atrial Appendage Closure
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Transcript of SH-102103- AD- APR 2013 Left Atrial Appendage Closure.
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Left Atrial Appendage Closure
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Disclosure
IMPORTANT INFORMATION These materials are intended to describe common clinical considerations and procedural steps for the on-label use of referenced technologies as well as current standards of care for certain conditions Of course patients and their medical circumstances vary so the clinical considerations and procedural steps described may not be appropriate for every patient or case As always decisions surrounding patient care depend on the physicianrsquos professional judgment in light of all available information for the case at hand
Boston Scientific (BSC) does not promote or encourage the use of its devices outside their approved labeling Boston Scientific does not have an FDA-approved ablation catheter for the treatment of atrial fibrillation
The presenterrsquos experience with BSC products may not be interpreted or relied upon to support clinical claims about BSC devices or product comparison claims regarding BSC and competitive devices The experiences of other users may vary
All case studies presented are not necessarily representative of clinical outcomes in all cases as individual results may vary All material graphs data and charts sourcing is on file with the presenter and are the property of their respective copyright owner
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Disclosure Statement of Financial Interest
bull GrantResearch Supportbull Consulting FeesHonorariabull Major Stock ShareholderEquitybull Royalty Incomebull OwnershipFounderbull Intellectual Property Rightsbull Other Financial Benefit
bull Nonebull Nonebull Nonebull Nonebull Nonebull Nonebull None
Within the past 12 months I or my spousepartner have had a financial interestarrangement or affiliation with the organization(s) listed below
AffiliationFinancial Relationship Company
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Stroke in AF patients
bull People with AF have 5 times the risk of stroke compared to people without AF1
bull Stroke is more severe for patients with AF as they have a 70 chance of death or permanent disability1
bull AF-associated ischemic strokes generally occlude large intracranial arteries depriving a more extensive region of the brain of blood flow2
bull Thirty-day mortality was greater in AF strokes than in non-AF strokes3
bull Compared with non-AF patients AF patients had poorer survival and more recurrences of stroke during the first year of follow-up3
bull The economic burden of stroke will continue to rise globally as the incidence of stroke increases4
1 Holmes DR Seminars in Neurology 201030528ndash5362 Tu HT et al Cerebrovascular Disease 201030(4)389-953 Lin HJ et al Stroke 1996271760-1764 4 Klein A et al Datamonitor July 2011
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91 of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
Fibrillation causes blood to stagnate in the LAA
The stagnant blood becomes an ideal environment for a
thrombus or blood clot to form
The blood clot or portion of it dislodges from the LAA and
travels through arterial system
The embolism lodges itself in the blood vessels of the brain
restricting blood flow and causing a stroke
Images on file at Boston Scientific Corporation
Thrombus in the LAA
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Disclosure
IMPORTANT INFORMATION These materials are intended to describe common clinical considerations and procedural steps for the on-label use of referenced technologies as well as current standards of care for certain conditions Of course patients and their medical circumstances vary so the clinical considerations and procedural steps described may not be appropriate for every patient or case As always decisions surrounding patient care depend on the physicianrsquos professional judgment in light of all available information for the case at hand
Boston Scientific (BSC) does not promote or encourage the use of its devices outside their approved labeling Boston Scientific does not have an FDA-approved ablation catheter for the treatment of atrial fibrillation
The presenterrsquos experience with BSC products may not be interpreted or relied upon to support clinical claims about BSC devices or product comparison claims regarding BSC and competitive devices The experiences of other users may vary
All case studies presented are not necessarily representative of clinical outcomes in all cases as individual results may vary All material graphs data and charts sourcing is on file with the presenter and are the property of their respective copyright owner
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Disclosure Statement of Financial Interest
bull GrantResearch Supportbull Consulting FeesHonorariabull Major Stock ShareholderEquitybull Royalty Incomebull OwnershipFounderbull Intellectual Property Rightsbull Other Financial Benefit
bull Nonebull Nonebull Nonebull Nonebull Nonebull Nonebull None
Within the past 12 months I or my spousepartner have had a financial interestarrangement or affiliation with the organization(s) listed below
AffiliationFinancial Relationship Company
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Stroke in AF patients
bull People with AF have 5 times the risk of stroke compared to people without AF1
bull Stroke is more severe for patients with AF as they have a 70 chance of death or permanent disability1
bull AF-associated ischemic strokes generally occlude large intracranial arteries depriving a more extensive region of the brain of blood flow2
bull Thirty-day mortality was greater in AF strokes than in non-AF strokes3
bull Compared with non-AF patients AF patients had poorer survival and more recurrences of stroke during the first year of follow-up3
bull The economic burden of stroke will continue to rise globally as the incidence of stroke increases4
1 Holmes DR Seminars in Neurology 201030528ndash5362 Tu HT et al Cerebrovascular Disease 201030(4)389-953 Lin HJ et al Stroke 1996271760-1764 4 Klein A et al Datamonitor July 2011
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91 of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
Fibrillation causes blood to stagnate in the LAA
The stagnant blood becomes an ideal environment for a
thrombus or blood clot to form
The blood clot or portion of it dislodges from the LAA and
travels through arterial system
The embolism lodges itself in the blood vessels of the brain
restricting blood flow and causing a stroke
Images on file at Boston Scientific Corporation
Thrombus in the LAA
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Disclosure Statement of Financial Interest
bull GrantResearch Supportbull Consulting FeesHonorariabull Major Stock ShareholderEquitybull Royalty Incomebull OwnershipFounderbull Intellectual Property Rightsbull Other Financial Benefit
bull Nonebull Nonebull Nonebull Nonebull Nonebull Nonebull None
Within the past 12 months I or my spousepartner have had a financial interestarrangement or affiliation with the organization(s) listed below
AffiliationFinancial Relationship Company
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Stroke in AF patients
bull People with AF have 5 times the risk of stroke compared to people without AF1
bull Stroke is more severe for patients with AF as they have a 70 chance of death or permanent disability1
bull AF-associated ischemic strokes generally occlude large intracranial arteries depriving a more extensive region of the brain of blood flow2
bull Thirty-day mortality was greater in AF strokes than in non-AF strokes3
bull Compared with non-AF patients AF patients had poorer survival and more recurrences of stroke during the first year of follow-up3
bull The economic burden of stroke will continue to rise globally as the incidence of stroke increases4
1 Holmes DR Seminars in Neurology 201030528ndash5362 Tu HT et al Cerebrovascular Disease 201030(4)389-953 Lin HJ et al Stroke 1996271760-1764 4 Klein A et al Datamonitor July 2011
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91 of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
Fibrillation causes blood to stagnate in the LAA
The stagnant blood becomes an ideal environment for a
thrombus or blood clot to form
The blood clot or portion of it dislodges from the LAA and
travels through arterial system
The embolism lodges itself in the blood vessels of the brain
restricting blood flow and causing a stroke
Images on file at Boston Scientific Corporation
Thrombus in the LAA
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Stroke in AF patients
bull People with AF have 5 times the risk of stroke compared to people without AF1
bull Stroke is more severe for patients with AF as they have a 70 chance of death or permanent disability1
bull AF-associated ischemic strokes generally occlude large intracranial arteries depriving a more extensive region of the brain of blood flow2
bull Thirty-day mortality was greater in AF strokes than in non-AF strokes3
bull Compared with non-AF patients AF patients had poorer survival and more recurrences of stroke during the first year of follow-up3
bull The economic burden of stroke will continue to rise globally as the incidence of stroke increases4
1 Holmes DR Seminars in Neurology 201030528ndash5362 Tu HT et al Cerebrovascular Disease 201030(4)389-953 Lin HJ et al Stroke 1996271760-1764 4 Klein A et al Datamonitor July 2011
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91 of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
Fibrillation causes blood to stagnate in the LAA
The stagnant blood becomes an ideal environment for a
thrombus or blood clot to form
The blood clot or portion of it dislodges from the LAA and
travels through arterial system
The embolism lodges itself in the blood vessels of the brain
restricting blood flow and causing a stroke
Images on file at Boston Scientific Corporation
Thrombus in the LAA
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91 of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
Fibrillation causes blood to stagnate in the LAA
The stagnant blood becomes an ideal environment for a
thrombus or blood clot to form
The blood clot or portion of it dislodges from the LAA and
travels through arterial system
The embolism lodges itself in the blood vessels of the brain
restricting blood flow and causing a stroke
Images on file at Boston Scientific Corporation
Thrombus in the LAA
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The left atrial appendage is a gestational remnant
bull Forms during the third week of gestation and serves as the left atrium in the fetus
bull LAA is the about the size of a thumb
bull The opening may be a range of sizes ndash 10mm - 40mm
bull LAA also varies in structurebull may be thin or thick-walledbull may have ldquoturnsrdquo or curvesbull may contain multiple ldquohornsrdquo
Images on file at Boston Scientific Corporation
Left Atrial Appendag
e
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The management of AF is aimed at reducing symptoms and minimizing complications
bull American Heart Association and European Society of Cardiology guidelines recommend anticoagulation for AF patients1
bull ESC 2012 Guidelines state that there is no indication for oral anticoagulation or aspirin if the CHA2DS2VASc score is 0 or in women less than 65 years of age without additional risk factors2
bull Treatment options for AF are based on a complex algorithm based on stroke risk
bull What are the goals of therapybull To minimize symptomsbull Control thromboembolic riskbull Ultimately to prolong life
bull Patients need to be well informed to actively and successfully participate in their treatment decisions
1 Camm AJ et al Eur Heart J 2010312369ndash24292 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs253
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Hart et al Ann Intern Med 1999131492-501
Warfarin Better Control Better (placebo)
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
50 -50
Aggregate
Reduction of stroke
RRR 62
Reduction ofall-cause
mortality RRR 26
100 0
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with atrial fibrillation
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
Anticoagulation in AF meta-analysisstroke risk reductions with warfarin
-100
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CHADS2 scores establish risk of stroke
bull CHADS2 developed and validated by Gage et al is a system for establishing the risk of stroke in patients with non-rheumatic atrial fibrillation1
bull Patients are awarded points based on comorbidities
Condition Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 1
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
CHADS2
ScoreTreatment
0 Aspirin
1 Aspirin or warfarin
ge2 Warfarin
European Society of Cardiology Guidelines2
1 Gage BF et al JAMA 20012852864ndash28702 Camm AJ et al Eur Heart J 2010312369ndash2429
Use of aspirin or warfarin is based on additional patient characteristics such as age number of risk factors etc
0 1 2 3 4 5 60
2
4
6
8
10
12
14
16
18
20
23
4
6
9
13
18
Annual Risk of Stroke
CHADS2 Score
Ris
k o
f S
troke
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0 1 2 3 4 5 6 7 8 90
3
6
9
12
15
18
0
12
34
7
10 10
7
152Annual Risk of Stroke
CHA2DS2VASc Score
Ris
k o
f S
troke
European Society of Cardiology Guidelines2
CHA2DS2VASc is a newer scoring systembull CHA2DS2VASc developed by Lip et al is a refinement of the older
CHADS2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor1
1 Lip GY et al Chest 2010137(2)263-722 Camm AJ et al Eur Heart J 2010312369ndash2429
ConditionRisk Factor
Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 2
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
V Vascular disease 1
A Age 65-74 years 1
Sc Sex (female gender) 1
CHA2DS2-VASc Score
Treatment
0 No treatment
1 Aspirin or warfarin or dabigatran
ge2 Warfarin or dabigatran
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How do the two CHADS scores compare
Generally they result in similar treatment recommendations
Where they are the samebull Both CHADS systems assign 1 ldquopointrdquo each for presence of
congestive heart failure (any) hypertension and diabetesbull Both CHADS systems assign 2 points for prior TIA or stroke
Where they differbull CHA2DS2VASc puts greater emphasis on age assigning 1 point
for age between 65-74 years and 2 points for age gt75 years CHADS2 only assigns one point for age gt75 years
bull CHA2DS2VASc adds 1 point each for presence of any vascular disease and female gender which are not included in the CHADS2 score
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Warfarin effective in preventing coagulation but has significant therapeutic limitations
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with AF
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
bull Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range
bull Despite efficacy in stroke prevention warfarin exposes patients to a number of risks (eg intracranial hemorrhage and hemorrhagic stroke)
bull Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery
bull Warfarin has high rates of discontinuation and non-adherence to therapy
bull Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1A need exists for an anti-thrombotic regimen that does not increase rates of
major bleeding does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy
1 Budnitz DS et al NEJM 2011 365 2002-2012
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Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
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bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
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Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
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15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
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119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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3
Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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The management of AF is aimed at reducing symptoms and minimizing complications
bull American Heart Association and European Society of Cardiology guidelines recommend anticoagulation for AF patients1
bull ESC 2012 Guidelines state that there is no indication for oral anticoagulation or aspirin if the CHA2DS2VASc score is 0 or in women less than 65 years of age without additional risk factors2
bull Treatment options for AF are based on a complex algorithm based on stroke risk
bull What are the goals of therapybull To minimize symptomsbull Control thromboembolic riskbull Ultimately to prolong life
bull Patients need to be well informed to actively and successfully participate in their treatment decisions
1 Camm AJ et al Eur Heart J 2010312369ndash24292 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs253
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Hart et al Ann Intern Med 1999131492-501
Warfarin Better Control Better (placebo)
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
50 -50
Aggregate
Reduction of stroke
RRR 62
Reduction ofall-cause
mortality RRR 26
100 0
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with atrial fibrillation
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
Anticoagulation in AF meta-analysisstroke risk reductions with warfarin
-100
SH
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21
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2
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3
CHADS2 scores establish risk of stroke
bull CHADS2 developed and validated by Gage et al is a system for establishing the risk of stroke in patients with non-rheumatic atrial fibrillation1
bull Patients are awarded points based on comorbidities
Condition Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 1
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
CHADS2
ScoreTreatment
0 Aspirin
1 Aspirin or warfarin
ge2 Warfarin
European Society of Cardiology Guidelines2
1 Gage BF et al JAMA 20012852864ndash28702 Camm AJ et al Eur Heart J 2010312369ndash2429
Use of aspirin or warfarin is based on additional patient characteristics such as age number of risk factors etc
0 1 2 3 4 5 60
2
4
6
8
10
12
14
16
18
20
23
4
6
9
13
18
Annual Risk of Stroke
CHADS2 Score
Ris
k o
f S
troke
SH
-10
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- A
PR
2
01
3
0 1 2 3 4 5 6 7 8 90
3
6
9
12
15
18
0
12
34
7
10 10
7
152Annual Risk of Stroke
CHA2DS2VASc Score
Ris
k o
f S
troke
European Society of Cardiology Guidelines2
CHA2DS2VASc is a newer scoring systembull CHA2DS2VASc developed by Lip et al is a refinement of the older
CHADS2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor1
1 Lip GY et al Chest 2010137(2)263-722 Camm AJ et al Eur Heart J 2010312369ndash2429
ConditionRisk Factor
Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 2
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
V Vascular disease 1
A Age 65-74 years 1
Sc Sex (female gender) 1
CHA2DS2-VASc Score
Treatment
0 No treatment
1 Aspirin or warfarin or dabigatran
ge2 Warfarin or dabigatran
SH
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2
01
3
How do the two CHADS scores compare
Generally they result in similar treatment recommendations
Where they are the samebull Both CHADS systems assign 1 ldquopointrdquo each for presence of
congestive heart failure (any) hypertension and diabetesbull Both CHADS systems assign 2 points for prior TIA or stroke
Where they differbull CHA2DS2VASc puts greater emphasis on age assigning 1 point
for age between 65-74 years and 2 points for age gt75 years CHADS2 only assigns one point for age gt75 years
bull CHA2DS2VASc adds 1 point each for presence of any vascular disease and female gender which are not included in the CHADS2 score
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01
3
Warfarin effective in preventing coagulation but has significant therapeutic limitations
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with AF
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
bull Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range
bull Despite efficacy in stroke prevention warfarin exposes patients to a number of risks (eg intracranial hemorrhage and hemorrhagic stroke)
bull Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery
bull Warfarin has high rates of discontinuation and non-adherence to therapy
bull Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1A need exists for an anti-thrombotic regimen that does not increase rates of
major bleeding does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy
1 Budnitz DS et al NEJM 2011 365 2002-2012
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Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
SH
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3
bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
SH
-10
21
03
-AD
- A
PR
2
01
3
Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
SH
-10
21
03
-AD
- A
PR
2
01
3
Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
SH
-10
21
03
-AD
- A
PR
2
01
3
Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
SH
-10
21
03
-AD
- A
PR
2
01
3
Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
SH
-10
21
03
-AD
- A
PR
2
01
3
15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
SH
-10
21
03
-AD
- A
PR
2
01
3
ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
03
-AD
- A
PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
21
03
-AD
- A
PR
2
01
3
0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
21
03
-AD
- A
PR
2
01
3
Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
-10
21
03
-AD
- A
PR
2
01
3
AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
-10
21
03
-AD
- A
PR
2
01
3
Mechanical Approaches for
Stroke Prophylaxis
SH
-10
21
03
-AD
- A
PR
2
01
3
Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
SH
-10
21
03
-AD
- A
PR
2
01
3
Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
SH
-10
21
03
-AD
- A
PR
2
01
3
Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
SH
-10
21
03
-AD
- A
PR
2
01
3
The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
SH
-10
21
03
-AD
- A
PR
2
01
3
The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
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PR
2
01
3
DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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03
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PR
2
01
3
Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Hart et al Ann Intern Med 1999131492-501
Warfarin Better Control Better (placebo)
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
50 -50
Aggregate
Reduction of stroke
RRR 62
Reduction ofall-cause
mortality RRR 26
100 0
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with atrial fibrillation
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
Anticoagulation in AF meta-analysisstroke risk reductions with warfarin
-100
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CHADS2 scores establish risk of stroke
bull CHADS2 developed and validated by Gage et al is a system for establishing the risk of stroke in patients with non-rheumatic atrial fibrillation1
bull Patients are awarded points based on comorbidities
Condition Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 1
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
CHADS2
ScoreTreatment
0 Aspirin
1 Aspirin or warfarin
ge2 Warfarin
European Society of Cardiology Guidelines2
1 Gage BF et al JAMA 20012852864ndash28702 Camm AJ et al Eur Heart J 2010312369ndash2429
Use of aspirin or warfarin is based on additional patient characteristics such as age number of risk factors etc
0 1 2 3 4 5 60
2
4
6
8
10
12
14
16
18
20
23
4
6
9
13
18
Annual Risk of Stroke
CHADS2 Score
Ris
k o
f S
troke
SH
-10
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2
01
3
0 1 2 3 4 5 6 7 8 90
3
6
9
12
15
18
0
12
34
7
10 10
7
152Annual Risk of Stroke
CHA2DS2VASc Score
Ris
k o
f S
troke
European Society of Cardiology Guidelines2
CHA2DS2VASc is a newer scoring systembull CHA2DS2VASc developed by Lip et al is a refinement of the older
CHADS2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor1
1 Lip GY et al Chest 2010137(2)263-722 Camm AJ et al Eur Heart J 2010312369ndash2429
ConditionRisk Factor
Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 2
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
V Vascular disease 1
A Age 65-74 years 1
Sc Sex (female gender) 1
CHA2DS2-VASc Score
Treatment
0 No treatment
1 Aspirin or warfarin or dabigatran
ge2 Warfarin or dabigatran
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How do the two CHADS scores compare
Generally they result in similar treatment recommendations
Where they are the samebull Both CHADS systems assign 1 ldquopointrdquo each for presence of
congestive heart failure (any) hypertension and diabetesbull Both CHADS systems assign 2 points for prior TIA or stroke
Where they differbull CHA2DS2VASc puts greater emphasis on age assigning 1 point
for age between 65-74 years and 2 points for age gt75 years CHADS2 only assigns one point for age gt75 years
bull CHA2DS2VASc adds 1 point each for presence of any vascular disease and female gender which are not included in the CHADS2 score
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Warfarin effective in preventing coagulation but has significant therapeutic limitations
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with AF
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
bull Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range
bull Despite efficacy in stroke prevention warfarin exposes patients to a number of risks (eg intracranial hemorrhage and hemorrhagic stroke)
bull Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery
bull Warfarin has high rates of discontinuation and non-adherence to therapy
bull Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1A need exists for an anti-thrombotic regimen that does not increase rates of
major bleeding does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy
1 Budnitz DS et al NEJM 2011 365 2002-2012
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Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
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bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
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Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
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21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
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2
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3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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-10
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
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PR
2
01
3
Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
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3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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3
CHADS2 scores establish risk of stroke
bull CHADS2 developed and validated by Gage et al is a system for establishing the risk of stroke in patients with non-rheumatic atrial fibrillation1
bull Patients are awarded points based on comorbidities
Condition Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 1
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
CHADS2
ScoreTreatment
0 Aspirin
1 Aspirin or warfarin
ge2 Warfarin
European Society of Cardiology Guidelines2
1 Gage BF et al JAMA 20012852864ndash28702 Camm AJ et al Eur Heart J 2010312369ndash2429
Use of aspirin or warfarin is based on additional patient characteristics such as age number of risk factors etc
0 1 2 3 4 5 60
2
4
6
8
10
12
14
16
18
20
23
4
6
9
13
18
Annual Risk of Stroke
CHADS2 Score
Ris
k o
f S
troke
SH
-10
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- A
PR
2
01
3
0 1 2 3 4 5 6 7 8 90
3
6
9
12
15
18
0
12
34
7
10 10
7
152Annual Risk of Stroke
CHA2DS2VASc Score
Ris
k o
f S
troke
European Society of Cardiology Guidelines2
CHA2DS2VASc is a newer scoring systembull CHA2DS2VASc developed by Lip et al is a refinement of the older
CHADS2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor1
1 Lip GY et al Chest 2010137(2)263-722 Camm AJ et al Eur Heart J 2010312369ndash2429
ConditionRisk Factor
Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 2
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
V Vascular disease 1
A Age 65-74 years 1
Sc Sex (female gender) 1
CHA2DS2-VASc Score
Treatment
0 No treatment
1 Aspirin or warfarin or dabigatran
ge2 Warfarin or dabigatran
SH
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3
How do the two CHADS scores compare
Generally they result in similar treatment recommendations
Where they are the samebull Both CHADS systems assign 1 ldquopointrdquo each for presence of
congestive heart failure (any) hypertension and diabetesbull Both CHADS systems assign 2 points for prior TIA or stroke
Where they differbull CHA2DS2VASc puts greater emphasis on age assigning 1 point
for age between 65-74 years and 2 points for age gt75 years CHADS2 only assigns one point for age gt75 years
bull CHA2DS2VASc adds 1 point each for presence of any vascular disease and female gender which are not included in the CHADS2 score
SH
-10
21
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01
3
Warfarin effective in preventing coagulation but has significant therapeutic limitations
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with AF
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
bull Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range
bull Despite efficacy in stroke prevention warfarin exposes patients to a number of risks (eg intracranial hemorrhage and hemorrhagic stroke)
bull Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery
bull Warfarin has high rates of discontinuation and non-adherence to therapy
bull Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1A need exists for an anti-thrombotic regimen that does not increase rates of
major bleeding does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy
1 Budnitz DS et al NEJM 2011 365 2002-2012
SH
-10
21
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2
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3
Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
SH
-10
21
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PR
2
01
3
bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
SH
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2
01
3
Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
SH
-10
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01
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
SH
-10
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3
Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
SH
-10
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2
01
3
Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
SH
-10
21
03
-AD
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PR
2
01
3
15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
SH
-10
21
03
-AD
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PR
2
01
3
ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
03
-AD
- A
PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
21
03
-AD
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2
01
3
0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
21
03
-AD
- A
PR
2
01
3
Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
-10
21
03
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PR
2
01
3
AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
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Mechanical Approaches for
Stroke Prophylaxis
SH
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21
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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0 1 2 3 4 5 6 7 8 90
3
6
9
12
15
18
0
12
34
7
10 10
7
152Annual Risk of Stroke
CHA2DS2VASc Score
Ris
k o
f S
troke
European Society of Cardiology Guidelines2
CHA2DS2VASc is a newer scoring systembull CHA2DS2VASc developed by Lip et al is a refinement of the older
CHADS2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor1
1 Lip GY et al Chest 2010137(2)263-722 Camm AJ et al Eur Heart J 2010312369ndash2429
ConditionRisk Factor
Points
C Congestive heart failure
1
H Hypertension 1
A Age ge75 years 2
D Diabetes mellitus 1
S2 Previous stroke or TIA 2
V Vascular disease 1
A Age 65-74 years 1
Sc Sex (female gender) 1
CHA2DS2-VASc Score
Treatment
0 No treatment
1 Aspirin or warfarin or dabigatran
ge2 Warfarin or dabigatran
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How do the two CHADS scores compare
Generally they result in similar treatment recommendations
Where they are the samebull Both CHADS systems assign 1 ldquopointrdquo each for presence of
congestive heart failure (any) hypertension and diabetesbull Both CHADS systems assign 2 points for prior TIA or stroke
Where they differbull CHA2DS2VASc puts greater emphasis on age assigning 1 point
for age between 65-74 years and 2 points for age gt75 years CHADS2 only assigns one point for age gt75 years
bull CHA2DS2VASc adds 1 point each for presence of any vascular disease and female gender which are not included in the CHADS2 score
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Warfarin effective in preventing coagulation but has significant therapeutic limitations
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with AF
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
bull Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range
bull Despite efficacy in stroke prevention warfarin exposes patients to a number of risks (eg intracranial hemorrhage and hemorrhagic stroke)
bull Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery
bull Warfarin has high rates of discontinuation and non-adherence to therapy
bull Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1A need exists for an anti-thrombotic regimen that does not increase rates of
major bleeding does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy
1 Budnitz DS et al NEJM 2011 365 2002-2012
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Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
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bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
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Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
SH
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21
03
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
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15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
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3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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3
WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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2
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3
How do the two CHADS scores compare
Generally they result in similar treatment recommendations
Where they are the samebull Both CHADS systems assign 1 ldquopointrdquo each for presence of
congestive heart failure (any) hypertension and diabetesbull Both CHADS systems assign 2 points for prior TIA or stroke
Where they differbull CHA2DS2VASc puts greater emphasis on age assigning 1 point
for age between 65-74 years and 2 points for age gt75 years CHADS2 only assigns one point for age gt75 years
bull CHA2DS2VASc adds 1 point each for presence of any vascular disease and female gender which are not included in the CHADS2 score
SH
-10
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Warfarin effective in preventing coagulation but has significant therapeutic limitations
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with AF
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
bull Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range
bull Despite efficacy in stroke prevention warfarin exposes patients to a number of risks (eg intracranial hemorrhage and hemorrhagic stroke)
bull Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery
bull Warfarin has high rates of discontinuation and non-adherence to therapy
bull Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1A need exists for an anti-thrombotic regimen that does not increase rates of
major bleeding does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy
1 Budnitz DS et al NEJM 2011 365 2002-2012
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-10
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Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
SH
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21
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2
01
3
bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
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-10
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3
Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
SH
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
SH
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
SH
-10
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2
01
3
15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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-10
21
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3
ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
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PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
21
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PR
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01
3
Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
-10
21
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3
AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
-10
21
03
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PR
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01
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Mechanical Approaches for
Stroke Prophylaxis
SH
-10
21
03
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PR
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01
3
Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
SH
-10
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
SH
-10
21
03
-AD
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PR
2
01
3
Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
SH
-10
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3
The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
SH
-10
21
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
21
03
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2
01
3
WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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PR
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01
3
WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
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PR
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01
3
WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
2
01
3
WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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-AD
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PR
2
01
3
Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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3
DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
2
01
3
PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
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3
PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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2
01
3
bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
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Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
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Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Warfarin effective in preventing coagulation but has significant therapeutic limitations
bull Warfarin is a long standing and when taken appropriately effective means of stroke reduction in patients with AF
bull Careful monitoring is required to help ensure that patients remain within the therapeutic range
bull Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range
bull Despite efficacy in stroke prevention warfarin exposes patients to a number of risks (eg intracranial hemorrhage and hemorrhagic stroke)
bull Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery
bull Warfarin has high rates of discontinuation and non-adherence to therapy
bull Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1A need exists for an anti-thrombotic regimen that does not increase rates of
major bleeding does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy
1 Budnitz DS et al NEJM 2011 365 2002-2012
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Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
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bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
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Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
SH
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15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
03
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PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
21
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01
3
Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
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Mechanical Approaches for
Stroke Prophylaxis
SH
-10
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
SH
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21
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
SH
-10
21
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3
Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
SH
-10
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3
The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
SH
-10
21
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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3
WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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2
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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2
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
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Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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3
PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range
bull Warfarin has a narrow range of effectiveness regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR)
bull Effectiveness is influenced by interactions with some foods and medications
bull INR must be checked frequently until the correct dose is determined
bull Once optimal dosing is determined and anticoagulation is stabilized patients generally return for regular INR monitoring monthly
bull Because it is difficult to maintain patients within the narrow therapeutic range many patients spend a significant amount of time either under- or over-anticoagulated
1 Oake N et al Can Med Assoc J 2007176(11)1589minus1594
-5--4--3--2--1
INR
Over-
antico
agu
late
dU
nd
er-
antico
agu
late
d
Therapeutic Range
44 of bleeding events occur in patients above
therapeutic range1
48 of thromboembolic events occur in patients below
therapeutic range1
SH
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bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
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Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
SH
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
SH
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
SH
-10
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PR
2
01
3
15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
SH
-10
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3
ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
03
-AD
- A
PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
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PR
2
01
3
Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
-10
21
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2
01
3
Mechanical Approaches for
Stroke Prophylaxis
SH
-10
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PR
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01
3
Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
SH
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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bull HAS-BLED developed by Pisters et al allows clinicians to assess an individualrsquos risk of bleeding based on comorbidities1
bull In determining when oral anticoagulation is appropriate clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED
bull Unfortunately a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk
HAS-BLED risk of bleeding
HASBLED Risk of major bleeding in patients with AF in the Euro
Heart Survey
1 Pisters R et al Chest 2010138(5)1093-100
Hypertension stroke and age are also variables in the CHADS scores
Condition Points
H Hypertension 1
A Abnormal liver and renal function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INR 1
E Elderly (age gt65) 1
D Drugs or alcohol (1 point each) 1 or 2
Score Bleeds Per 100 Patient
Years
0 113
1 102
2 188
3 374
4 87
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Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
SH
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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01
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
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01
3
15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
SH
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
03
-AD
- A
PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
21
03
-AD
- A
PR
2
01
3
0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
21
03
-AD
- A
PR
2
01
3
Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
-10
21
03
-AD
- A
PR
2
01
3
AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
-10
21
03
-AD
- A
PR
2
01
3
Mechanical Approaches for
Stroke Prophylaxis
SH
-10
21
03
-AD
- A
PR
2
01
3
Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
SH
-10
21
03
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PR
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3
Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
SH
-10
21
03
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PR
2
01
3
Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
SH
-10
21
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3
The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
SH
-10
21
03
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PR
2
01
3
The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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2
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
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01
3
WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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3
Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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3
The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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3
PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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3
Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Warfarin has a high rate of discontinuation and non-adherence to therapy
0
20
40
60
80
100
At discharge At 3 months
Percent of patients taking warfarin following a
stroke1
Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke
1 Bushnell CD et al Archives of Neurology 201067(12)1456-14632 Kimmel SE et al Archives of Internal Medicine 2007167229-235
Perc
ent
of
Pati
ents
174 of patients discontinue warfarin within 3 months following a stroke
bull A study of 2598 stroke patients discovered that 174 had ceased taking warfarin altogether 3 months after being discharged following a stroke1
bull A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92 of warfarin users had at least 1 missed or extra pill bottle opening during a 35 month period which overall translated to a 40 rate of non-adherence with warfarin therapy2
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
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01
3
Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
SH
-10
21
03
-AD
- A
PR
2
01
3
Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
SH
-10
21
03
-AD
- A
PR
2
01
3
15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
SH
-10
21
03
-AD
- A
PR
2
01
3
ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
03
-AD
- A
PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
21
03
-AD
- A
PR
2
01
3
0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
21
03
-AD
- A
PR
2
01
3
Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
-10
21
03
-AD
- A
PR
2
01
3
AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
-10
21
03
-AD
- A
PR
2
01
3
Mechanical Approaches for
Stroke Prophylaxis
SH
-10
21
03
-AD
- A
PR
2
01
3
Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
SH
-10
21
03
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PR
2
01
3
Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
SH
-10
21
03
-AD
- A
PR
2
01
3
Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
SH
-10
21
03
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PR
2
01
3
The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
SH
-10
21
03
-AD
- A
PR
2
01
3
The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
2
01
3
WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
2
01
3
WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
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PR
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01
3
Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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03
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3
DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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03
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PR
2
01
3
The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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3
PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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PR
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3
PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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03
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PR
2
01
3
WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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03
-AD
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01
3
bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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03
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PR
2
01
3
Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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03
-AD
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2
01
3
PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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2
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3
Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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2
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3
PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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2
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3
Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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3
Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Three new oral anticoagulants have recently completed clinical trials
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
RE-LY1 ROCKET-AF2 ARISTOTLE3
Dabigatran Rivaroxaban Apixaban
Comparator Warfarin Warfarin Warfarin
Total Enrolled Subjects 18113 14264 18201
Trial Design
Randomized controlled non-
inferiority (doses of dabigatran
were blinded)
Randomized controlled double-blind non-inferiority
Randomized controlled double-blind non-inferiority
Median Duration of Follow up 2 years 194 years 18 years
Average CHADS2 Score 21 35 21
Results (primary outcome = stroke or systemic embolism)
Reduction in primary outcome compared to
warfarin
Reduction in primary outcome compared
to warfarin
Reduction in primary outcome compared
to warfarin
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
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15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
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119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
SH
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
SH
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
SH
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Major bleeding rates
This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study
Study Treatment Major Bleeding Hemorrhagic
Stroke
RE-LY1
Dabigatran (110 mg) 271 012
Dabigatran (150 mg) 311 010
Warfarin 336 038
ROCKET-AF2
Rivaroxaban 36 05
Warfarin 34 07
ARISTOTLE3
Apixaban 213 024
Warfarin 309 047
1 Connelly SJ et al NEJM 20093611139-51 2 Patel MR et al NEJM 2011365883-913 Granger J et al NEJM 2011365981-92
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Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
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01
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15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
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PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
21
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
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Mechanical Approaches for
Stroke Prophylaxis
SH
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
SH
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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3
Ischemic Stroke Hemorraghic stroke Major Bleeding0
1
2
3
4
134
012
271
092
010
311
120
038
336
Efficacy of dabigatran versus warfarin
dabigatran 110mgdabigatran 150mgwarfarin
Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
bull A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin
bull Dabigatran etexilate (Pradaxareg) is an oral pro-drug that is rapidly converted to dabigatran a direct inhibitor of thrombin
bull Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding
bull 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism though it had a higher bleeding rate than 110 mg (P=0052)
bull 75 mg dose approved in the US although no data in patients are available
076 relative risk compared to
warfarin
Connelly SJ et al NEJM 20093611139-51
Perc
ent
per
year
SH
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2
01
3
15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
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PR
2
01
3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
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Mechanical Approaches for
Stroke Prophylaxis
SH
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PR
2
01
3
Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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15
21
16
21
10
17
0
5
10
15
20
25
At 1 year At 2 years
dabigatran 110mg dabigatran 150mg warfarin
Like warfarin dabigatran has demonstrated high rates of non-adherence to therapy
bull During the RE-LY trial dabigatran demonstrated higher rates of discontinuation than warfarin
bull Dyspepsia a frequent side effect contributed to the high rates of discontinuation
Percent of patients discontinuing therapy1
21 of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years
1 Connelly SJ et al NEJM 20093611139-51
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
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2
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3
119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
SH
-10
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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ROCKET AF the recently completed Phase III clinical trial demonstrated non-inferiority of rivaroxaban to warfarin
bull The ROCKET AF study was a randomized controlled trial of 14264 patientsbull Rivaroxaban (Xareltoreg) is the first oral direct factor Xa inhibitor to the
market once daily dosingbull Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke
and systemic embolismbull In the primary safety analysis there was no significant difference between
rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding
Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin
Efficacy of rivaroxaban versus warfarin
Patel MR et al NEJM 2011365883-91
36
17 19
34
22 22
01234
Major bleeding Stroke or systemic
embolism
Mortality
rivaroxaban
warfarin
Events
10
0 p
t years
SH
-10
21
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2
01
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119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
SH
-10
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
SH
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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01
3
Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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119097
024 009
151
105
047010
0005101520
All Stroke Ischemic or
uncertain type
stroke
Hemorrhagic
Stroke
Systemic
Embolism
apixaban
warfarin
ARISTOTLEA comparison of apixaban to warfarin
bull The ARISTOTLE study was a randomized double blind trial of 18201 patients with a mean CHADS2 score of 21 and mean duration for follow-up of 18 years
bull Apixaban (Eliquisreg) is an oral direct factor Xa inhibitor taken twice dailybull Apixaban demonstrated superiority to warfarin in ldquopreventing stroke or
systemic embolismrdquo as well as in reducing bleeding and cardiac deathbull Apixaban did not demonstrate superiority to warfarin in the prevention of
ischemic or uncertain type strokes or systemic embolization
Events
(
y
r)
Efficacy of apixiban versus warfarin
Granger J et al NEJM 2011365981-92
49 lower risk of
hemorrhagic stroke
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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3
PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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0
2
4bull Stroke or systemic embolism 16year with
apixaban vs 37year with aspirin (Plt0001)
bull Stroke 16year vs 34year (Plt0001)
bull Clinically relevant nonmajor bleeding 31year vs 27year (P=035)
bull Fatal bleeding 01year vs 02year (P=053)
AVERROESA comparison of apixaban to aspirin
Trial Design Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2808) vs aspirin 81-324 mg daily (n=2791)
Results
Conclusionsbull Among patients with AF and elevated risk for
stroke who were not suitable for warfarin therapy apixaban was beneficial
bull Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin without increasing the risk for major bleeding
Connolly SJ et al NEJM 2011364806-17
Plt0001
apixaban aspirin
p
er
year
Stroke or systemic embolism
16
37
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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01
3
00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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Warfarin alternatives exist buthellip
bull Dabigatran rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials
bull However real-world and long-term efficacy and safety and drug interactions have yet to be investigated
bull While new oral anticoagulants may avoid the burden of regular INR monitoring bleeding risks and high rates of non-adherence are still a problem
bull A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
SH
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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AF Treatment Options
BSC currently has no ablation catheters FDA-approved for the treatment of AF
AF
Ablation PacingDrugs for
RhythmRate Control
Embolic Managemen
t
Drugs (warfarin)
Interventions
Surgical Ligation
LAA Clips Endovascular LAA
ANDOR
Drugs (dabigatran rivaroxaban
apixaban)
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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3
WATCHMAN Clinical Evidence Portfolio
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
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WATCHMANSafety Data
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
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WATCHMANEfficacy Data
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
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10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
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bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
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Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
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Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
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Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Mechanical Approaches for
Stroke Prophylaxis
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
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Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Left atrial appendage clot on echo91 of stroke in AF is caused by blood clots formed in the LAA1
Clot
Images on file at Boston Scientific Corporation
1 Blackshear JL Odell JA Annals of Thoracic Surgery 199661755-759
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Invasive procedures can successfully close the LAA
bull Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s
bull LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery
bull Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events
73
23
00
20
40
60
80
bull A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10-731
Excision Ligation w Sutures
Ligation w Staples
1 Dawson AG et al Interact Cardiovasc Thorac Surg 201010306-11 2 Kanderian et al JACC 200852924ndash9
Meth
od o
f Su
ccess
ful
LA
A C
losu
re2
A need exists for a less invasive approach that can consistently close the LAA
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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2
01
3
Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Guidelines on interventional approaches for stroke prevention in non-valvular AF
bull In its August 2012 update of guidelines the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1
bull European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1
bull AHAACCESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2
1 Camm et al Eur Heart J 2012331-29 doi101093eurheartjehs2532 Fuster V et al Circulation 2006114e257-e35
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
bull Based on the Amplatzer septal occluder the ACP received CE mark for use in LAA closure in 2008
bull Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP
bull The ACP data presented is based on inexperienced implanters1
bull A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3
bull Results of a large randomized trial are expected by December 20154
Rates of procedure-related adverse events1
1 Park JW et al Catheter Cardiovasc Interv 2011 77700-7062 Lam YY et al Catheter Cardiovasc Interv 2012 79 794-8003 httpwwwclinicaltrialsgovct2showNCT01118299term=amplatzeramprank=94 httpwwwclinicaltrialsgov NCT01118299 as of 41513
P
roce
dura
l C
om
plic
ati
ons
514321432143
21 21
35
0
1
2
3
4
Ischemic
Stroke
Device
Embolization
Pericardial
Effusion
ACP is an investigational device and not FDA approved
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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The WATCHMANreg product is a device for percutaneous closure of the left atrial appendage
bull Five sizes of device (21 24 27 30 and 33 mm) allow for precise fit within ostium
bull It is implanted via a transseptal approach by use of a catheter-based delivery system
bull The delivery catheter is capable of recapturing the device if necessary
bull Received CE mark in 2005
bull WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover
bull It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA
WATCHMAN reg LAA Closure DeviceImages on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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-10
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03
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PR
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3
Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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WATCHMANreg Device Implant Procedure
bull Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance
bull Access to the left atrium is gained via the femoral vein and transseptal puncture
bull The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure
Transseptal puncture
Placement of WATCHMAN reg in LAA
Images on file at Boston Scientific Corporation
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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01
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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WATCHMANreg Device endothelialization
Canine Model ndash 30 Day
Canine Model ndash 45 Day
Human Pathology - 9 Months Post-implant (Non-device related death)
Images on file at Boston Scientific Corporation Results in animal models may not necessarily be indicative of clinical outcomes
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
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WATCHMANSafety Data
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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WATCHMAN Clinical Evidence Portfolio
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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WATCHMAN Evidence-Based Medicine
2012 ESC Guidelines
amp Expanded Indication
2002 ndash PilotEndpoints Feasibility and SafetyComparison nonrandomzedInclExcl CHADS2ge1 able to tolerate warfarin
2005 ndash PROTECT AFEndpoints Safety and EfficacyComparison warfarinInclExcl CHADS2 ge 1 able to tolerate warfarin
2008 ndash CAP RegistryEndpoints Collect additional safety and efficacy data to be pooled with PROTECT AFInclExcl same as PROTECT AF
2009 ndash ASAPEndpoint EfficacyComparison CHADS2 score expected stroke rate InclExcl intolerant or contra-indicated for warfarin
2010 ndash PREVAILEndpoint Safety and EfficacyComparison warfarinInclExcl CHADS2ge2 some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure
2013 EMEA RegistryEndpoint Additional information in a real-world settingInclExcl All comers
In planning phaseCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Study Patients Sites Comments
Pilot 66 8402 patient years of follow-upgt6 years of follow-up
PROTECT AF 800 591500 patient years of follow-up23 years average follow-up per patient3
CAP (Continued Access Registry )
460 26 Significantly improved safety results1 2
ASAP 150 4 Treat patients contra-indicated for warfarin
EVOLVE 69 3Evaluate design changes of a non-commercialized WATCHMAN device
PREVAIL 453 41Same endpoints as PROTECT AFRevised inclusionexclusion criteriaResults presented in March 2013
CAP2 57 16Prospective multicenter single-arm registry300 patients from 60 sites (PROTECT AF or PREVAIL)4
Total Patients 2055
WATCHMAN Clinical Portfolio~2000 patients and 4000 patient-years of data
1Holmes DR et al Lancet 2009 374 534ndash422Reddy VY et al Circulation 2011123417-4243Reddy VY et al Circulation 2013 127720-7294 As of 21913
bull WATCHMAN is the only device with over 2000 patients studied in multiple randomized trials and registries and 4000 patient-years of follow-up
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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2
01
3
PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
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Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
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LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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DemographicsDevice Patients
CharacteristicPROTECT AF
N=463CAP
N=566PREVAILN=269
P value
Age years717 plusmn 88 (463)
(460 950)
740 plusmn 83 (566)(440 940)
740 plusmn 74 (269)(500 940)
lt0001
Gender (Male) 326463 (704) 371566 (655) 182269 (677) 0252
CHADS2 Score
(Continuous)22 plusmn 12(10 60)
25 plusmn 12(10 60)
26 plusmn 10(10 60)
lt0001
CHADS2 Risk Factors
CHF 124463 (268) 108566 (191) 63269 (234)
Hypertension 415463 (896) 503566 (889) 238269 (885)
Age ge 75 190463 (410) 293566 (518) 140269 (520)
Diabetes 113463 (244) 141566 (249) 91269 (338)
StrokeTIA 82463 (177) 172566 (304) 74269 (275)
Most notable differencesAge Diabetes and Prior StrokeTIA
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT AF and CAP data from Reddy VY et al Circulation 2011123417-424
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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The PROTECT AF trial demonstrated non-inferiority of the WATCHMANreg Device to warfarin in 707 randomized patients
bull PROTECT AF was a prospective randomized multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis
bull 707 patients were randomized to either the WATCHMAN Device or warfarin in a 21 device to therapy ratio 93 roll-in patients
Baseline Risk Factorsbull Patients who received the
WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization
bull Transesophogeal echocardiography was performed at 45 days 6 months and 1 year to check for device placement presence of thrombus and flow
bull Patients received up to 5 years of biannual follow-up Average age for WATCHMANreg
was 717 years plusmn 88 years
Holmes DR et al Lancet 2009374534ndash42
CHADS2WATCHMA
NregWarfarin
1 339 27
2 341 361
3 19 209
4 8 98
5 41 41
6 09 2
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
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Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
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LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PROTECT AFPrimary Safety Results
Device ControlObserved rate
(events per 100 pt-yrs) (95 CrI)
Observed rate (events per 100 pt-yrs
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Primary Safety
55
( 42 71)
36
(22 53)
153
(095 270)
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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3
ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PROTECT AFIschemic and hemorrhagic stroke rates
Holmes DR et al Lancet 2009374534ndash42
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of ischemic stroke over time
Perc
ent
of
pati
en
ts
Perc
ent
of
pati
en
ts
warfarinWatchman
On or before procedure
Days 1-45 After day 450
1
2
3
4
Rate of hemorrhagic stroke over time
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANSafety Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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WATCHMANSafety Data
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
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Patient Populations
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
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Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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bull Both the WATCHMAN Device and warfarin patients experienced adverse events
bull The WATCHMAN Device events were concentrated around the time of the procedure
bull Warfarin events occurred at any time (not shown)From tests for differences across three groups
(early PROTECT AF late PROTECT AF and CAP)
ProcDevice Rel Safety AE win 7
days
Serious PE win 7 days
Proc Rel Stroke 0
2
4
6
8
10
Early (n=271) Late (n=271) CAP (n=460)
P=0006 P=0018 P=0039
WATCHMANreg
Procedure outcomes in WATCHMAN patients
AE=adverse event PE=pericardial effusionReddy VY et al Circulation 2011123417-424
ProcDevice Rel Safety AE
win 7 days
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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01
3
00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Pericardial Effusion Rates
65
44
22
0
2
4
6
8
First 3
patients
Subsequent
patients
CAP
Rates of pericardial effusion within 7 days of
the procedure
bull Pericardial effusion was the most common adverse event in the WATCHMANreg Device group
bull Of patients experiencing pericardial effusion 68 were treated with pericardiocentesis and 32 required surgical intervention
bull Rates of pericardial effusion declined at each center as experience with the procedure increased
Reddy VY et al Circulation 2011123417-424
P
ati
ents
32 reduction in rates of pericardial
effusion as experience increased
PROTECT AF
PROTECT AF
CAP-Continued Access Protocol
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PREVAILStudy Goals and Design
bull Prospective randomized multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device
bull Similar design to PROTECT AF prospective randomized 21 (device control) trial
bull 407 randomized patients from 41 US centersbull Inclusion of new centers and new operators to
show enhancements to the training program are effective
bull Roll-in phase allowed new centers to implant 2 patients prior to randomization phase
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
PROTECT AF Implant Success
909
CAP ImplantSuccess
943
PREVAILImplant Success
950
p = 001
Study Implant Success
Experienced Operators
New Operators
900 920 940 960 980
9500
962
932
of Successful Implants
p = 0282
N= 26
N= 24
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Implant success defined as deployment and release of the device into the left atrial appendage
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PREVAIL First Primary EndpointAcute (7-day) Procedural Safety
bull Acute (7-day) occurrence of death ischemic stroke systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention
bull 6 events in device group = 22 (6269)bull Pre-specified criterion met for first primary endpoint (95
Upper confidence bound lt 267)Results are preliminary final validation not yet complete
267One-sided 95 upper CI
bound for success
20 25 30
Percent of patients experiencing an event
222618
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Additional Safety Analysis7 Day Serious ProcedureDevice Related
1Includes observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleedingPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
Series100
20
40
60
80
10087
41 44
PROTECT AF CAP PREVAIL
o
f Pati
ents
n=39 n=23 n=12
p = 0005
bull Composite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization and other vascular complications1
No procedure-related deaths reported in any of the trials
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Pericardial Effusions Requiring Intervention
16
24
02
12
04
15
00
10
20
30
40
Cardiac perforation requiring
surgical repair
Pericardial effusion with
cardiac tamponade requiring
pericardiocentesis or window
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=7n=1 n=1
n=11
n=7 n=4
PREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0027 p = 0318
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Stroke and Device Embolization
Procedure related strokes were reducedDevice embolizations remained low
11
00 04
00
10
20
30
Procedure Device Related Strokes
o
f Pati
ents
PROTECT AF CAP PREVAIL
n=5n=0 n=1
04 0208
00
10
20
Device Embolizations
o
f Pa
tien
ts
PROTECT AF CAP PREVAIL
n=2 n=1 n=2
1 additional device embolization was reported at 45 daysPREVAIL results from Holmes DR Jr et al CIT 2013PROTECT-AF and CAP data from Reddy VY et al Circulation 2011123417-424
p = 0007
p = 0364
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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01
3
PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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WATCHMANEfficacy Data
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Second Primary EndpointComposite 18-month Efficacy
bull Comparison of composite of stroke systemic embolism and cardiovascularunexplained death
bull 18-month event rates in both control and device groups = 0064bull Upper 95 CI bound slightly higher than allowed to meet success
criterion (lt175)bull Limited number of patients with follow-up through 18 months thus far
(Control = 30 pts Device = 58 pts)
17595 upper CI bound for
non-inferiority
05 10 15
18-month Rate Ratio
20
107
Results are preliminary final validation not yet complete
057 188
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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01
3
ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PREVAIL Control (Warfarin) Group Performance
bull In spite of the high average CHADS2 score of 26 in the control group the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies
bull PREVAIL control group rate = 07 (95 CI 01 51)bull Wide confidence bounds due to small number of
patients with 18-months of follow-up
TrialControl (Warfarin) Group
Stroke Systemic Embolism Rate (Per 100 PY)
PROTECT AF1 16
RE-LY (Dabigatran)2 17
ARISTOTLE (Apixaban)3 16
ROCKET AF (Rivaroxaban)4 22
PREVAIL 07
PREVAIL results from Holmes DR Jr et al CIT 20131 Ischemic stroke rate from Holmes et al Lancet 2009 374534-42 2 Connolly et al N Engl J Med 2009 3611139-51 3 Granger et al NEJM 2011 365981-924 Patel et al NEJM 2011 365883-91
Results are preliminary final validation not yet complete
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Third Primary Endpoint18-month Thrombolic Events
bull Comparison of ischemic stroke or systemic embolism occurring gt7 days post randomization
bull Endpoint success in the presence of an over performing control group
bull Pre-specified non-inferiority criterion met for third primary endpoint (95 CI Upper Bound lt 00275)
0027595 upper CI bound for
non-inferiority
-001 0 001
18-month Rate Difference
002
00051
Results are preliminary final validation not yet complete
-002 003003
-00191 00268
PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PROTECT AFPrimary Efficacy Results
Device ControlPosterior
Probabilities
Observed rate (events per 100 pt-
yrs) (95 CrI)
Observed rate (events per 100 pt-yrs)
(95 CrI)
Rate Ratio InterventionControl
(95 CrI)
Non-inferiority
Superiority
Primary
Efficacy
30
(21 43)
43
(26 59)
071
(044 130)gt099 088
Reddy VY et al Circulation 2013127720-729
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PROTECT AFClinical event rates at 1065 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
323
0703
49
3227
0
Events in PROTECT AF trial at 1065 patient years
bull 38 reduction with WATCHMAN for the composite endpoint for efficacy (including strokes CV or unexplained death and systemic embolism) when compared to warfarin
bull Following the periprocedural period the rate of ischemic stroke with the WATCHMANreg Device was 13 per 100 patient years vs 16 with warfarin
Rate
per
100 p
ati
ent
years
PNI = Posterior Probabilities for non-inferiorityHolmes DR et al Lancet 2009374534ndash42
PNI gt 999 PNI gt 999PNI gt 99
38 lower 29 lower 38 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
SH
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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PROTECT AFClinical event rates at 1500 patient years
Primary Efficacy All Stroke CV or Unexplained Death
Systemic embolism0
1
2
3
4
5
6
7
8
9
10
3
2
103
43
27 28
0
bull WATCHMAN therapy results in a 29 reduction in efficacy events (strokes CV death and systemic embolism) when compared to warfarin therapy
bull In 1500 patient years of follow-up WATCHMAN continues to provide significant reductions in events when compared to warfarin
PNI = Posterior Probabilities for non-inferiorityReddy V et al Circ 2013127720-729
Events in PROTECT AF trial at 1500 patient years
Rate
per
100 p
ati
ent
years
PNI gt 99 PNI gt 999PNI gt 99
29 lower 23 lower 62 lowerWATCHMAN Group
N=463
Warfarin GroupN=244
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Study Objective To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure
Study Design Prospective multicenter
Primary Endpoint Embolic stroke
Patient Population n=66 Mean age=685+8 years Mean CHADS₂ score=18+11
Mean Follow Up 73+25 months
Number of Sites 8 (US and Germany)
Presented by Peter B Sick MD ESC 2012
Sick et al WATCHMAN Pilot data ESC 2012
WATCHMANtrade Pilot Study
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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00
10
20
30
40
50
60
48
05
Expected based on CHADS₂ Score
Observed rate in 6 year follow up
Ischemic Stroke
Isch
em
ic S
troke
Rate
(
pt-
yr)
90 Reduction
One stroke at 2 months and one at 39 months in the setting of severe carotid disease
WATCHMANtrade Pilot StudyLong Term Follow-up
Sick et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
bull 2 embolic strokes over 6 years of follow up
bull A 90 reduction when compared to CHADS₂ expected stroke rate
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
Warfarin Discontinuation
45 days
Reddy VY et al Circulation 2011123417-424
868
Warfarin Discontinuation
6 months
922
Warfarin Discontinuation
12 months
932
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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Patient Populations
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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3
WATCHMANreg PROTECT AFOutcomes in patients with previous stroke
bull Primary efficacy is a composite of stroke cardiovascular death and systemic embolism
bull Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke
bull 47 of AF patients experiencing a stroke will suffer a second stroke within 6 months1
40
82
0
2
4
6
8
10
WATCHMAN warfarin
Primary efficacy in patients with previous stroke2
1 Wolf PA et al Stroke 198314664-6672 Unpublished data on file
reg
51 reduction in stroke cardiovascular death and systemic embolism when used
as secondary prevention
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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21
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-AD
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PR
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ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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21
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-AD
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PR
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PR
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01
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
SH
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
SH
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01
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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2
01
3
ASAP RegistryAspirin and Plavixreg Registry
The ASAP registry a non-randomized feasibility study was designed to determine if the WATCHMANreg Device is a safe and effective treatment for people unable to take warfarin
bull AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis
bull Patients may be treated with aspirin andor clopidogrel this treatment paradigm has a higher stroke risk than warfarin
Annual risk of stroke with secondary
prevention of aspirin or warfarin
7
11
34
0
2
4
6
8
10
12
Prior TIA Prior Stroke
aspirin warfarin
Hart RG et al Stroke 200435948-951
S
troke
ris
k
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
2
01
3
ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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01
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
SH
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01
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
SH
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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3
PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
bull Patients had a history of hemorrhagic amp bleeding tendencies or a hypersensitivity to warfarin
bull 150 patients enrolled at 4 European centers
bull Average CHADS2 = 28
bull Post procedure anti-platelet regimenbull Clopidogrel through 6 monthsbull Aspirin indefinitely
bull Patients were followed for up to 1 yearbull Follow-up 3 6 12 18 amp 24 monthsbull TEE at 3 and 12 months
947 successfully implanted
Rate of Success with implantation in
warfarin contraindicated
patients
Reddy et al JACC 2013 In Press
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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PR
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ASAP RegistryExpected Stroke Rate
Mean CHADS2 Score in ASAP = 28
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
SH
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01
3
00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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-AD
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
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- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
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-AD
- A
PR
2
01
3
00
10
20
30
40
50
60
70
8073
17
Expected based on CHADS₂ Score
Observed rate in ASAP
77 Re-duction
ASAP RegistryEfficacy outcome versus expected
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
SH
-10
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
SH
-10
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
2
01
3
PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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21
03
-AD
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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21
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PR
2
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
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21
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2
01
3
Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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ASAP RegistryEfficacy outcome versus expected
00
10
20
30
40
50
60
70
8073
50
17
Expected based on CHADS₂ Score
Expected if Clopido-grel was used throughout follow-up
Observed rate in ASAP
Isch
em
ic S
troke
Rate
(
pt-
yr)
Ischemic Stroke
77 Reductio
n
64 Reductio
n
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Reddy et al JACC 2013 In Press
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
-10
21
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- A
PR
2
01
3
Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
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- A
PR
2
01
3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
SH
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PR
2
01
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
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2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
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ASAP RegistryEfficacy outcomes with devices
100
10
20
30
40
50
60
70
80 73
17
1-10
00
10
20
30
40
50
60
70
80
66
38
59 Re-duction77
Reduction
ASAP Registry1 PLAATO2
Isch
em
ic S
troke
Rate
(
pt-
yr)
Str
oke
TIA
Rate
(
pt-
yr)
Expected Rate (per CHADS₂) Rate in Device Arm
1 Reddy et al JACC 2013 In Press2 Block PC etal JACC Intervent 20092594-600
PLAATO is an investigational device and not FDA approvedCaution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
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bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
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PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
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PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
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ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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2
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3
PROTECT AF Analysis of Older PatientsMethods
bull In this analysis PROTECT AF trial subjects ge75 years old were compared via proportional hazards models for
bull composite primary efficacy endpoint (stroke systemic embolism and cardiovascularunknown death)
bull strokebull all-cause mortality
bull Outcomes are expressed as a of subjects experiencing the event per year
bull The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
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PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
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Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
-10
21
03
-AD
- A
PR
2
01
3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
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PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
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PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
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PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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3
Warfarin Discontinuation
OVERALL ge75 YEARS
Visit NTotal Implanted
NTotal Implanted
45 day 348401 867 139175 794
6 month 355385 922 133154 864
12 month 345370 932 128142 901
PROTECT AF Analysis of Older PatientsResults
bull Average length of follow-up was 27 monthsbull 190 patients randomized to the device group implantation
was attempted in 183 subjects bull 164183 (88) were successfully implanted
bull Mean CHADS2 Score was 28 (compared to 22 in the Overall patient population)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
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21
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3
PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
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2
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3
PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
-10
21
03
-AD
- A
PR
2
01
3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Analysis of Older PatientsOutcomes ITT Patients ge75 Years
Primary Efficacy All Stroke All-cause Mortality0
2
4
6
8
41
31
52
62
43
57
WATCHMANreg Control
Rate
(Even
tsP
t-yrs
)
163916
162561
123916
112561
214045
152621
Plt001 P=001 P=002
95 of stroke were ischemic non-inferiority P-valuesKar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
-10
21
03
-AD
- A
PR
2
01
3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Analysis of Older PatientsMajor Bleeding in ITT Patients ge75 Years
EVENT
Device (n=190)
Rate (eventspatient-
years)
Control (n=115)
Rate (eventspatient-
years)
Major bleeding 61 (233748) 51 (132528)
Procedure related major bleeding
29 (113859)Or
11 events190 pts (58 pts)
NA
Non procedure-related major bleeding
33 (133933) 51 (132528)
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Kar S et al PROTECT-AF Watchman LAAC in AF Patients ge 75 Years TCT 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
-10
21
03
-AD
- A
PR
2
01
3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
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21
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PR
2
01
3
Study Objective Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke
risk
Study Design PROTECT AF design used CHADS2 scores This
analysis uses the same data replacing the CHADS2
score with the CHA2DS2VASc score
Primary Endpoint Embolic stroke
Patient Population n=463 Mean age=72 Mean CHADS₂ score=22 Mean CHA2DS₂VASc =
35
Total Follow Up 1500 patient years
Number of Sites 59 in the United States and Europe
Presented by Sven Mobius-Winkler ESC 2012Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
SH
-10
21
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-AD
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PR
2
01
3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
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PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
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21
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PR
2
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PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
bull 93 had CHA2DS2VASc score gt2
bull Average CHA2DS2Vasc score 35
bull Expected risk of stroke 3bull Observed stroke rate 2
All stroke
Expected rate based on CHA2DS2VASc score
00
05
10
15
20
25
30
3532
20
WATCHMAN CHA2DS2VASc PROTECT AF Analysis
375 Reductio
n
375 reduction compared to expected
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
Observed Rate
Mobius-Winkler et al WATCHMAN Pilot data ESC 2012
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics AnalysisObjective
bull To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies
bull To estimate the lifetime direct costs amp cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
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PR
2
01
3
PROTECT AF Health Economics Analysis Methods
Analytic Perspectivebull US healthcare provider perspectivebull 2009 US dollars
Approachbull Markov decision analytic model bull Cohort of 65-year-old patients with NVAFbull 6 stroke preventive strategiesbull 8 different health status in each 1 year
Markov cyclebull Time horizon = lifetime (85 years old)
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Results - Cost
TherapyTotal Costs (USD)
Total QALY
gained
Cost per QALY gained (USD)
Aspirin 12877 612 2104
Warfarin 23848 827 2883
Clopidogrel amp aspirin 26287 629 4182
Dabigatran 110mg 42540 877 4850
Dabigatran 150mg 43794 900 4864
LAA closure 47789 1495 3197Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
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PR
2
01
3
PROTECT AF Health Economics Analysis Monte Carlo Simulation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
LAAC was cost-effective gt99 simulations using a cost-effectiveness threshold of US$50000 per QALY gained
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Stroke Risk by CHADS Score
LAA ClosureCHADS Score
0
CHADS Score
1
CHADSScore
2
CHADSScore
3
CHADSScore
ge4
Total Cost 47259 47312 47398 47551 47638
Total QALY Gained 1495 1495 1495 1495 1495
Cost per QALY 3161 3165 3171 3181 3187
ICERQALY gainedcompared to next best alternative
4323 4022 3587 2952 2659
ICERQALY gainedcompared to warfarin
3474 4038 2283 1206 780
Analysisbull Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained bull ICERQALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC amp
other strategies
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
PROTECT AF Health Economics Analysis Conclusions
bull Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone aspirin and clopidogrel warfarin dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation
bull Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke amp younger age of implantation
Yan B et al Cost Effectiveness of LAAO TCT 2012
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
1 Holmes DR et al Lancet 2009374534ndash422 Reddy VY et al Circulation 2013 127720-7293 Sievert H TCT 2011 4 Reddy et al JACC 2013 In Press 5 PREVAIL results from Holmes DR Jr et al CIT 2013
WATCHMANreg Clinical ProgramPROTECT AF1 CAP2 ASAP34 PREVAIL5
Trial Design
Prospective RCT with patients able to take warfarin
Prospective registry with patients able to
take warfarin
Prospective registry with patients contraindicated
for warfarin
Prospective RCT with patients able to take
warfarin
Outcome
WATCHMAN was non-inferior to
warfarin in patients at high-
risk of thromboembolism
Significantly improved safety
results from early PROTECT AF experience
Ischemic stroke rate significantly reduced in
warfarin contra-indicated patients
WATCHMAN device was safely
implanted by new operators
Mean age CHADS2 7222 7424 72428 7426
Total Enrolled Subjects
707 randomized1 93 pts rolled in2 460 150 407
Total Patients Implanted
5422 437 142 269
Implantation Success 8952 950 947 951
Primary Efficacy (all-stroke CVunexplained
death and systemic embolism)
38 reduction vs warfarin
29 reduction vs warfarin
NA
0064Identical 18-month
rates for WATCHMAN and warfarin
All-Stroke29 reduction vs
warfarin23 reduction vs
warfarin77 reduction vs expected
rate per CHADS₂ score Data not yet available
Safety(7 day procedure-related)
875
415
53 reduction vs PROTECT AF
Pericardial effusion with tamponade=13
Major bleeding=27
4449 reduction vs
PROTECT AFComposite of vascular complications includes cardiac perforation pericardial effusion with tamponade ischemic stroke device embolization observed PE not necessitating intervention AV fistula major bleeding requiring transfusion pseudoaneurysm hematoma and groin bleeding
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
SH
-10
21
03
-AD
- A
PR
2
01
3
ConclusionsThromboembolism in AF is a major cause of morbidity and mortality
bull Oral anticoagulation is effective but many cannot tolerate due to bleeding risk
Robust clinical program in place to study WATCHMANreg LAA Closure Device
PROTECT AF bull WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism
with a trend toward improved outcomes
bull Long-term data showed continued significant reductions in events when compared to warfarin1
CAP
bull Comparison of the early PROTECT-AF late PROTECT-AF and CAP results indicated the importance of education for this procedure
ASAP
bull Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient populationrsquos CHADS₂ Score
PREVAIL trial 2
bull Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators
bull WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients
1 Reddy et al Circulation 2013 127720-722 PREVAIL results from Holmes DR Jr et al CIT 2013
Caution In the United States WATCHMAN is an investigational device limited by Federal law and investigational use only Not for sale in the US Prior to use please review device indications contraindications warnings precautions adverse events and operational instructions Only available according to applicable local law CE Mark received in 2005
- Left Atrial Appendage Closure
- Disclosure
- Disclosure Statement of Financial Interest
- Stroke in AF patients
- 91 of stroke in AF is caused by blood clots that form in the l
- The left atrial appendage is a gestational remnant
- The management of AF is aimed at reducing symptoms and minimizi
- Slide 8
- CHADS2 scores establish risk of stroke
- CHA2DS2VASc is a newer scoring system
- How do the two CHADS scores compare
- Warfarin effective in preventing coagulation but has significan
- Warfarin requires regular monitoring to ensure patients stay wi
- HAS-BLED risk of bleeding
- Warfarin has a high rate of discontinuation and non-adherence t
- Three new oral anticoagulants have recently completed clinical
- Major bleeding rates
- Dabigatran demonstrated non-inferiority to warfarin in the RE-L
- Like warfarin dabigatran has demonstrated high rates of non-ad
- ROCKET AF the recently completed Phase III clinical trial dem
- ARISTOTLE A comparison of apixaban to warfarin
- AVERROES A comparison of apixaban to aspirin
- Warfarin alternatives exist buthellip
- AF Treatment Options
- Slide 25
- Left atrial appendage clot on echo 91 of stroke in AF is caus
- Invasive procedures can successfully close the LAA
- Guidelines on interventional approaches for stroke prevention
- The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure
- The WATCHMANreg product is a device for percutaneous closure of t
- WATCHMANreg Device Implant Procedure
- WATCHMANreg Device endothelialization
- Slide 33
- WATCHMAN Evidence-Based Medicine
- WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-yea
- Demographics Device Patients
- The PROTECT AF trial demonstrated non-inferiority of the WATCHM
- PROTECT AF Primary Safety Results
- PROTECT AF Ischemic and hemorrhagic stroke rates
- Slide 40
- Slide 41
- Pericardial Effusion Rates
- PREVAIL Study Goals and Design
- Despite implantation in higher risk patients the WATCHMAN devic
- PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
- Additional Safety Analysis 7 Day Serious ProcedureDevice Relat
- Pericardial Effusions Requiring Intervention
- Stroke and Device Embolization
- Slide 49
- Second Primary Endpoint Composite 18-month Efficacy
- PREVAIL Control (Warfarin) Group Performance
- Third Primary Endpoint 18-month Thrombolic Events
- PROTECT AF Primary Efficacy Results
- PROTECT AF Clinical event rates at 1065 patient years
- PROTECT AF Clinical event rates at 1500 patient years
- WATCHMANtrade Pilot Study
- WATCHMANtrade Pilot Study Long Term Follow-up
- WATCHMANreg PROTECT AF and CAP Warfarin discontinuation
- Slide 59
- WATCHMANreg PROTECT AF Outcomes in patients with previous stroke
- ASAP Registry Aspirin and Plavixreg Registry
- ASAP Registry 150 AF patients contraindicated for long-term wa
- ASAP Registry Expected Stroke Rate
- ASAP Registry Efficacy outcome versus expected
- ASAP Registry Efficacy outcome versus expected (2)
- ASAP Registry Efficacy outcomes with devices
- PROTECT AF Analysis of Older Patients Methods
- PROTECT AF Analysis of Older Patients Results
- PROTECT AF Analysis of Older Patients Outcomes ITT Patients ge7
- PROTECT AF Analysis of Older Patients Major Bleeding in ITT Pa
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis
- WATCHMAN CHA2DS2VASc PROTECT AF Analysis (2)
- PROTECT AF Health Economics Analysis Objective
- PROTECT AF Health Economics Analysis Methods
- PROTECT AF Health Economics Analysis Results - Cost
- PROTECT AF Health Economics Analysis Monte Carlo Simulation
- PROTECT AF Health Economics Analysis Stroke Risk by CHADS Scor
- PROTECT AF Health Economics Analysis Conclusions
- WATCHMANreg Clinical Program
- Conclusions
-
