AF 2011: Therapeutic Update

Gerald V. Naccarelli M.D.

Research support: Boston-Scientific, sanofi-aventis, Boehringer-Ingelheim, Glaxo-Smith-Kline, Astellas

Consultant: Glaxo-Smith-Kline, Boston-Scientific, Medtronic, Pfizer, sanofi-aventis, Xention, Gilead, Novartis, Astra-Zeneca, Boehringer-Ingelheim, Merck, Bristol Myers Squibb, Otsuka, Blue Ash Therapeutics, St. Jude’s, Cordis-Webster, Ortho-McNeill, Daiichi-Sankyo

Projected Number of Patients with AF by 2050

ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation.Go AS, et al. JAMA. 2001;285(18):2370-2375. Miyasaka Y, et al. Circulation. 2006;114:119-125. Naccarelli GV, et al. Am J Cardiol. 2009;104(11):1534-1539.

Year

2.08 2.442.26

5.1

5.1

0

2

4

6

8

10

12

14

16

1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

Pat

ien

ts w

ith

AF

(m

illio

ns)

3.03

7.56

5.42

11.7

15.2

4.34

9.4

11.7

3.33

7.5

8.9

2.94

6.8

7.7

8.4

10.2

3.804.78

10.3

13.1

5.16

11.1

14.3

5.61

12.1

15.9

5.6

5.9

2.66

6.1

6.7

MarketScan and Thomson Reuters Medicare Databases, 2009

Olmsted County Data, 2006(assuming a continued increase in AF incidence)

ATRIA Study Data, 2000

Olmsted County Data, 2006(assuming no further increase in AF incidence)

AF: Prevalence of Common Co-morbidities

Naccarelli GV, et al. Am J Cardiol 2009; 104:1534-1539

The Consequences of AFThromboembolism

Stroke: 4.5 increased risk Microemboli: reduced

cognitive function Prothrombotic state

Thromboembolism Stroke: 4.5 increased risk

Microemboli: reduced cognitive function

Prothrombotic state

Mortality 2 increased risk independent

of comorbid CV disease Sudden death in HF and HCM

Mortality 2 increased risk independent

of comorbid CV disease Sudden death in HF and HCM

Hospitalizations Most common arrhythmia

requiring hospitalization 2-3 increased risk for

hospitalization

Hospitalizations Most common arrhythmia

requiring hospitalization 2-3 increased risk for

hospitalization

Impaired Hemodynamics Loss of atrial kick

Irregular ventricular contractions HF

Tachycardia-induced cardiomyopathy

Impaired Hemodynamics Loss of atrial kick

Irregular ventricular contractions HF

Tachycardia-induced cardiomyopathy

Reduced QoL Palpitations, dyspnea, fatigue, reduced exercise

tolerance

Reduced QoL Palpitations, dyspnea, fatigue, reduced exercise

tolerance

HCM=hypertrophic cardiomyopathy; QoL=quality-of-life.HCM=hypertrophic cardiomyopathy; QoL=quality-of-life.Van Gelder IC, et al. Van Gelder IC, et al. EuropaceEuropace. 2006;8:943-949; Narayan SM, et al. . 2006;8:943-949; Narayan SM, et al. Lancet.Lancet. 1997;350:943-950; Wattigney WA, 1997;350:943-950; Wattigney WA, et al. et al. CirculationCirculation. 2003;108:711-716; Wyse DG, et al. . 2003;108:711-716; Wyse DG, et al. CirculationCirculation. 2004;109:3089-3095; Favale S, et al. . 2004;109:3089-3095; Favale S, et al. PACEPACE. .

2003;26:637-639.2003;26:637-639.

• AF is an enormous contributor AF is an enormous contributor to the growing cost of medical careto the growing cost of medical care

What Are the Goals of AF Therapy?

• Improve survival

• Reduce sequelae

– Stroke, systemic emboli, heart failure

• Reduce hospitalizations

• Improve symptoms

• Improve QoL

• Restore atrial function/reverse the remodeling process

• Minimize adverse effects of therapies employed

QoL = quality of life.

Cost Increases With Each AF Recurrence, Mainly Driven by Hospital Costs

FRACTAL Registry—Annual Costs of AF-Related Medical Care

0

2,000

4,000

6,000

8,000

10,000

12,000

Permanent AF(n=34)

0(n=620)

1-2(n=286)

≥3(n=33)

Documented Recurrences

$2,372

$3,385

$6,331

$10,312

Cos

t ($)

Outpatient costs

Drug costs

Hospital costs

P<.05

P<.05

Reynolds MR et al. J Cardiovasc Electrophysiol. 2007;18:628-633.

AF: CV Hospitalization Implications

• AF accounts for more hospitalizations than any other arrhythmia1

– 1/3 of hospitalizations for cardiac arrhythmia2

• During the past 20 years hospital admissions for AF have increased by 66%2

• Except cardioversion, hospitalization is motivated by the severity of an AF episode or an AF-related complication such as a cardiovascular event3

• Hospitalization is an important negative determinant of QoL in patients with AF4

• 50 to 70% of the cost of AF management is driven byin-patient care5

• Direct cost of AF in USA: $6.65 billion annually

Adapted from A.J. Camm. 1. Bialy D, et al. J Am Coll Cardiol 1992;19:41A. 2. ACC/AHA/ESC 2006 guidelines Eur Heart J 2006;27:1979–2030. 3. Stewart S, et al. Eur Heart J 2001;22:693-701. 4. Dorian P, et al. Circ Arrhythmia Electrophysiol 2009;218-224. 5. Le Heuzey J.Y.et al. Am. Heart J. 2004; 47 : 121-126. 6. Bajpai A, et al. US Cardiovascular Disease. 2007:14-17.

Guideline-BasedAF Treatment Options

CCB = calcium channel blocker; SR = sinus rhythm; ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; LA = left atrial.Fuster V, et al. J Am Coll Cardiol. 2006;48(4):854-906.

Maintenance of SR

Pharmacologic

Class IA Class ICClass III-blockers

Nonpharmacologic

Catheter ablationPacingSurgery Implantable

devices

Stroke prevention

Pharmacologic• Warfarin• Aspirin +/- clopidogrel• Dabigatran• Factor Xa inhibitorsNonpharmacologic• Removal/isolation

LA appendage

Rate control

Preventremodeling

CCBsACE-Is, ARBs

StatinsFish oil

Pharmacologic• CCBs-blockers• Digitalis• Amiodarone• DronedaroneNonpharmacologic• Ablate and pace

Intermittent AF

Permanent AF

Annual Stroke Rate (%)

AF and Stroke

• AF increases stroke risk 4- to 5-fold

• Stroke is the most common and devastating complication of AF

– Incidence of all-cause stroke in patients with AF is 5%

• AF is an independent risk factor for stroke

– Approximately 15% of all strokes in the United States caused by AF

– Risk for stroke increases with age

• Stroke risk persists even in asymptomatic AF

• Stroke risk persists in patients with a “high-risk” profile despite a strategy of rhythm control (AFFIRM study, RACE study)

RACE II = Rate Control Efficacy in Permanent Atrial Fibrillation.Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Kannel WB, et al. Med Clin North Am. 2008;92(1):17-42. Page RL, et al. Circulation. 2003;107(8):1141-1145. Hart RG, et al. J Am Coll Cardiol. 2000; 35(1):183-187. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123.

LowRiskLowRisk

ModerateRisk

ModerateRisk

HighRiskHighRisk

10

8

6

4

2

0

Stroke Risk Stratification in AFCHADS2 CHA2DS2-VASc

Risk Factor Score

Cardiac failure 1

HTN 1

Age ≥75 y 1

Diabetes 1

Stroke 2

Risk Factor Score

Cardiac failure 1

HTN 1

Age ≥75 y 2

Diabetes 1

Stroke 2

Vasc dz (MI, PAD, aortic ath) 1

Age 65-74 y 1

Sex category (female) 1

Lip GY, Halperin JL. Am J Med. 2010;123(6):484-488.

0 1 2 3 4 5 60

5

10

15

20

Str

oke

Rat

e, %

0 1.3 2.2 3.2 4.06.7

9.8

CHA2DS2-VASc Score

7 8 9

9.6

15.2

6.7

Relationship between CHA2DS2-VASc score and annual risk of stroke

Total Score Annual Risk of Stroke (%)

0 1.9  1 2.8  2 4.0

3 5.9 4 8.5 5 12.5 6 18.2

ESC AF Guidelines EHJ 2010

HAS-BLED Bleeding Risk Score

ESC AF Guidelines EHJ 2010

Approach to Thrombo-prophylaxis in AF

Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13):1449-1457.

AFASAK 27 811

BAATAF 15 922

CAFA 14 478

SPAF 23 508

SPINAF 29 972

Combined 108 3691

100 50 0 -50 -100Warfarin Better Warfarin Worse

No. of Events

Patient-Years Risk Reduction, %

Compared With Control in 5 Studies

Efficacy of Warfarin

62% to 67% RRR with warfarin vs placebo

ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events.ACTIVE Investigators. Lancet. 2006;367:1903-1912. ACTIVE Investigators. N Engl J Med. 2009;360(20):2066-2078.

Antiplatelet Therapy in AF

ACTIVE-W:6706 randomized patients;

trial stopped

6

4

0

2

Ou

tco

me/

Yea

r (%

)

StrokeVascularEvent

MajorBleeding

5

3

1

P = .0003

P = .001 P = .53

Warfarin

Clopidogrel + ASA

ACTIVE-A:7554 randomized patients;

median follow-up of 3.6 years

8

6

4

0

2Ou

tco

me/

Yea

r (%

)

StrokeVascularEvent

MajorBleeding

7

5

3

1

P = .01

P<.001

P<.001

ASA

Clopidogrel + ASA

Potential Advantages of New Oral Anticoagulants

• Oral administration

• Rapid onset of action -- eliminates 2 AC regimen

• Predictable effect with fixed or weight-based dosing -- no monitoring

• Less food/drug interactions

• Short half- life: ease of reversal/ no bridging

• More convenient -- potentially leading to greater use

• More cost effective− No routine monitoring− Fewer ADEs requiring ER visits and hospitalizations

• Possible superior efficacy -- demonstrated for dabigatran• Possible superior safety -- demonstrated for dabigatran

Characteristics of New Oral Anticoagulants1,2

Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban

Mechanism of action

Thrombin inhibitor

FXa inhibitor FXa inhibitor FXa inhibitor FXa inhibitor

Half-life 14-17 h 5-9 h 12 h 19-24 h 6-12 h

Regimen BID QD, BID BID QD QD

Peak to trough ~7x 12x (QD) 3-5x ~3x ~3x

Renal excretion of absorbed drug

~80% 36-45% 25-30% ~15% 35%

Potential for drug interactions

P-glycoprotein inhibitor

CYP3A4 substrate and P-glycoprotein inhibitor

CYP3A4 substrate and P-glycoprotein inhibitor

Not substrate for major CYPs

CYP3A4 substrate and P-glycoprotein inhibitor

1. Usman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5):388-397.2. Piccini JP, et al. Curr Opin Cardiol. 2010;25(4):312-320.

Dabigatran

• Dabigatran etexilate is a pro-drug that undergoes metabolism to dabigatran which is a competitive inhibitor of thrombin that binds clot-bound and free thrombin with high affinity and specificity and also inhibits thrombin-induced platelet aggregation

• Bioavailability 6.5%; low protein binding

• No known food or CYP450 drug interactions

• No need for INR monitoring

• Hepatotoxicity <1%

• Half-life: 8 hours after single dose and 14-17 hours after multiple doses

• BID dosing

• 80% renal excretedUsman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5):388-397

Design of the RE-LY® Trial

Study Parameters• Open label, noninferiority,

intent-to-treat trial

• Blinded adjudication ofoutcome events

• 50% patients VKA-naïve*

• Primary outcome: incidence of stroke (ischemic and hemorrhagic) and systemic embolism in patients withnon-valvular atrial fibrillation

• Primary safety outcome: incidence of major bleeds†

Patient Flow

RandomizedN= 18,113

Blinded to dose

Warfarin(INR 2.0-3.0)

N= 6022

Dabigatran110 mg

twice dailyN= 6015

Dabigatran150 mg

twice dailyN= 6076

Avg CHADS score 2.2, with 32% CHADS 3 or higher

Minimum 1-year follow-up, maximum 3 years, median of 2 years of follow-up. INR: international normalized ratio; VKA: vitamin K antagonist.*Total lifetime exposure of < 2 months.

†Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial

bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention, Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

Connolly SJ, Ezekowitz MD et al. N Engl J Med. 2009;361:1139-1151.

Minimum 1-year follow-up, maximum 3 years, median of 2 years of follow-up. INR: international normalized ratio; VKA: vitamin K antagonist.*Total lifetime exposure of < 2 months.

†Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial

bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention, Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

Connolly SJ, Ezekowitz MD et al. N Engl J Med. 2009;361:1139-1151.

*Noninferiority; †SuperiorityMI = myocardial infarction; RE-LY = Randomized Evaluation of Long-term Anticoagulation Therapy. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

Stroke Prevention in AFDabigatran Etexilate vs Warfarin (RE-LY)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Stroke/Systemic Embolism

Major Bleed IntracranialHemorrhage

Per

cen

t/Y

ear Dabigatran 110 mg is not FDA approved for

this indication; for informational purposes only

MI

Dabigatran 150 mg

Warfarin INR 2.0-3.0

Dabigatran 110 mgP = .003

†P<.001

*P<.001

P<.001

P<.001

P<.048

Avg TTR: 67%

Dabigatran: DC Cardioversion

N (Pts/CV) CVA/SEE

Dabigatran 110 mg 409/647 5 (0.8%)

Dabigatran 150 mg 415/672 2 (0.3%)

Warfarin 431/664 4 (0.6%)

Nagarakanti R, et al. Circulation 2011:123:131-136

ROCKET AF Trial: Rivaroxaban1,2

1. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347.e1.2. ClinicalTrials.gov identifier: NCT00403767.

Warfarin target INR, 2.5 (INR range, 2.0-3.0)

N =14,264

Nonvalvular AF, history of stroke, TIA, or embolism,

or at least 2 of the following: heart

failure, hypertension, age 75 y, or diabetes

mellitus

Nonvalvular AF, history of stroke, TIA, or embolism,

or at least 2 of the following: heart

failure, hypertension, age 75 y, or diabetes

mellitus

Day 1Day 1

Rivaroxaban 20 mg once dailyRivaroxaban 20 mg once daily

Rivaroxaban 15 mg once daily (CrCL 30-49 mL/min at entry)Rivaroxaban 15 mg once daily (CrCL 30-49 mL/min at entry)

Day 30 after last dose

Day 30 after last dose

Treatment period 12-32 monthsTreatment period 12-32 months

• In AF patients with a moderate to high risk of stroke, does rivaroxaban reduce the risk of major vascular events compared with warfarin?

• 10 study end point: composite of all-cause stroke and non-CNS systemic embolism

• 20 end points: composite of transient ischemic attack, all-cause death, vascular death, and MI

• 10 safety end point: composite of major and clinically relevant nonmajor bleeding events

• Randomization completed in June 2009; follow-up completed 2010

• Follow-up: up to 4 years (until 405 primary outcome events have been observed)

End

of

trea

tmen

t

Fol

low

-up

R

  Rivaroxaban* Warfarin    Event Rate

Event Rate

HR(95% CI) P-value

On TreatmentN= 14,143

1.70 2.15 0.79 (0.65,0.95)  0.015

ITTN= 14,171

2.12 2.42 0.88 (0.74,1.03)  0.117

Rivaroxabanbetter

Warfarinbetter

ROCKET AF: Primary Efficacy OutcomeStroke and non-CNS Embolism

*Rivaroxaban is not FDA approved.Event Rates are per 100 patient-years

Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

TTR 57.8%

Avg CHADS score 3.7

Rivaroxaban Warfarin

Event Rate Event Rate HR (95% CI) P-value

Vascular Death, Stroke, Embolism

4.51 4.81 0.94 (0.84, 1.05) 0.265

Stroke Type Hemorrhagic Ischemic Unknown Type

0.261.620.15

0.441.640.14

0.58 (0.38, 0.89)0.99 (0.82, 1.201.05 (0.55, 2.01)

0.0120.9160.871

Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308

Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464

All Cause Mortality Vascular Non-vascular Unknown Cause

4.522.911.150.46

4.913.111.220.57

0.92 (0.82, 1.03)0.94 (0.81, 1.08)0.94 (0.75, 1.18)0.80 (0.57, 1.12)

0.1520.3500.6110.195

ROCKET AF: Key Secondary Efficacy Outcomes

Event Rates are per 100 patient-yearsBased on Intention-to-Treat Population

ROCKET AF Compared With RE-LYROCKET AF1 RE-LY2

N 14,171 18,000

VKA naive 37% 50%

Design Randomized, double-blind, double-dummy study

PROBE design

Treatment Rivaroxaban

1 dose (with dose adaptation for moderate renal impairment)

Dabigatran

2 doses

Regimen Once daily Twice daily

Primary outcome

Efficacy: Composite of all-cause stroke and non-CNS systemic embolism

Safety: Composite of major and clinically relevant nonmajor bleeding events

Efficacy: Incidence of stroke (including hemorrhagic) and systemic embolism

Safety: Major bleeding events

Secondary outcome

Each category of bleeding events, and adverse events

Composite of TIA, all-cause death, vascular death, and MI

Incidence of stroke (including hemorrhagic), systemic embolism, all death, pulmonary embolism, MI, TIA, vascular deaths (including deaths from bleeding), and hospitalizations

1. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347. 2. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

ROCKET AF Compared With RE-LYROCKET AF1 RE-LY2

TTR (median)

58% 67%

CHADS2 (mean)

3.7 2.1

Previous TIA/CVA

55% 20%

Primary outcome HR

0.79 0.66 (150 dose)

Hem CVA rate

0.24 0.24 (150 dose)

Ischemic CVA: HR

0.99 0.75 (150 dose)

Major Bleeding rate

3.6% 3.3% (150 dose)

1. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347. 2. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

AVERROES Trial1,2

ASA(81-324 mg daily; up to 36 mo/end of study)

Apixaban(5 mg twice daily; 2.5 mg in selected patientsa; up to 36 mo/end of study)

E

Unsuitable for warfarin therapy

N= 5600

Double-blind

AVERROES, Apixaban Versus ASA to Reduce the Risk Of Stroke.1. Eikelboom JW, et al. Am Heart J. 2010;159(3):348-353.e1.2. ClinicalTrials.gov identifier: NCT00496769. http://www.theheart.org/article/1087291.do.

a At least 2 of: age 80 y, weight 60 kg, or serum Cr 1.5 mg/dL

a At least 2 of: age 80 y, weight 60 kg, or serum Cr 1.5 mg/dL

• Is apixaban more effective than ASA in preventing stroke and systemic embolism in moderate to high-risk (stroke; at least 1 risk factor) AF patients?

• 10 efficacy end point: confirmed ischemic or hemorrhagic stroke or systemic embolism

• 20 study end points: as above, including MI or vascular death

• 10 safety end point: major bleeding

• Study period: until 226 primary outcome events have been observed

• In June 2010, BMS-Pfizer announced that the study had been stopped early because a predefined interim analysis revealed clear evidence of a clinically important reduction in stroke and systemic embolism. Results presented at ESC 2010, Stockholm, Sweden.

R

Cu

mu

lativ

e R

isk

0.0

0.01

0.03

0.05

0 3 6 9 12 18 21

ASA

Apixaban*

No. at RiskASA

Apix

2791 2720 2541 2124 1541 626 329

2809 2761 2567 2127 1523 617 353

Months

RR=0.4595% CI, 0.32-0.62

P<.001

AVERROES: Stroke or Systemic Embolic Event

Connolly S., et al N Engl J Med 2011

*Apixaban is not FDA approved.

Cu

mu

lati

ve R

isk

0.0

0.00

50.

010

0.01

50.

020

0 3 6 9 12 18 21

ASA

Apixaban

No. at Risk

ASA

Apix

2791 2744 2572 2152 1570 642 340

2809 2763 2567 2123 1521 622 357

Months

RR=1.1395% CI, 0.74-1.75

P=.57

AVERROES: Major Bleeding

28

Connolly S, et al. N Engl J Med 2011

ARISTOTLE Trial: Apixaban1,2

Double-blind

1. Lopes RD, et al. Am Heart J. 2010;159(3):331-339.2. ClinicalTrials.gov identifier: NCT00412984.

AF or atrial flutter18,206 randomizedAF or atrial flutter

18,206 randomized

Warfarin INR, 2.0-3.0

Apixaban(5 mg twice daily; 2.5 mg twice daily in selected patientsa)

a At least 2 of: age 80 y, weight 60 kg, or serum Cr 1.5 mg/dL

a At least 2 of: age 80 y, weight 60 kg, or serum Cr 1.5 mg/dL

• Is apixaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (stroke; at least 1 risk factor) AF patients?

• 10 efficacy end point: confirmed ischemic or hemorrhagic stroke, or systemic embolism

• 20 efficacy end points: composite of confirmed ischemic or hemorrhagic stroke, systemic embolism, and all-cause death

• 10 safety end point: time to first occurrence of confirmed major bleeding

• Treatment period: up to 4 years (until 448 primary outcome events have been observed — >90% power to demonstrate noninferiority);

– Stratified by warfarin-naïve status

E R

ENGAGE AF–TIMI 48: Edoxaban

Warfarin INR, 2.0-3.0

Edoxaban(60 mg vs 30 mg qd)

Double-blind

AF>20,000 pts

AF>20,000 pts

• Is edoxaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (CHADS2 score ≥2) AF patients?

• 10 efficacy end point: composite primary end point of stroke and systemic embolic events

• 20 efficacy end points: composite clinical outcome of stroke, systemic embolic events, and all-cause mortality; also major bleeding events

• Treatment period: up to 2 years

3 treatment arms

ClinicalTrials.gov identifier NCT00781391.

RE

CVA = cerebrovascular accident; LV = left ventricular; RHD = rheumatic heart disease.Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

Anticoagulation in AF

• Anticoagulation is needed in patients at increased thromboembolic risk

– CHADS2: Age ≥75 years, prior CVA/TIA, diabetes, HTN, LV dysfunction. Highest risk: RHD

– Anticoagulation usually should be continued chronically

• Drugs, herbals, diet, genetic patterns, generics must all be considered in choosing and during anticoagulation

• Warfarin has been more effective than ASA in all comparative studies, without excess risk; dabigatran 150 mg bid is superior to warfarin

• Anticoagulation is necessary prior to cardioversion of nontransient (>48 hours) AF

• New oral direct thrombin inhibitors and factor Xa drugs may replace warfarin in the future for many/most patients with AF

Favors Rate Control Favors Rhythm Control

Persistent AF Paroxysmal AF

Newly Detected AF

Less Symptomatic More Symptomatic

>65 years of age < 65 years of age

Hypertension No Hypertension

No History of Congestive Heart Failure Congestive Heart Failure clearly

exacerbated by AF

Previous Antiarrhythmic Drug Failure No Previous Antiarrhythmic Drug Failure

Canadian Cardiovascular Society Recommendations

Canadian Cardiovascular Society AF Guidelines. http://www.ccsguidelineprograms.ca/index.php. Accessed January 25, 2011.

Hynes BJ, et al. Future Cardiol. 2005;1(2):135-144.

Dronedarone

• Amiodarone-like compound lacking the iodine moiety

• Similar electrophysiologic properties to amiodarone

– Low propensity to cause TDP

• 13 to 30-hour T½, but administered as bid regimen

• Food effect (2x-3x increase in levels)

• Extensive first-pass hepatic metabolism through CYP4503A4 system

– Only 15% bioavailability

– Elevates serum creatinine 10% to 15% without a change in glomerular filtration rate

• Drug interactions similar to amiodarone, except no significant interaction with warfarin

• No evidence of thyroid or pulmonary toxicity but rare cases of serious hepatotoxicity

Amiodarone Dronedarone

Iodine moiety Yes No

T½ 53 days 14-30 hours

Blocks IKr; IKs; B1; ICa; Ito; INa Yes Yes

Dosing Daily after loading bid with meals

Food effect Yes Yes

CYP4503A4 metabolism No Yes

Inhibits tubular secretion of creatinine Yes Yes

Increase QT but low TDP Yes Yes

Efficacy in suppressing AF 65% 50%

Efficacy in suppressing ventricular tachyarrhythmias YesNot well studied

Decreases CV hospitalization No Yes

Warfarin interaction Yes No

Pulmonary/thyroid toxicity Yes No

Safety concerns in CHF SCD-HEFT NYHA III ANDROMEDA

SCD-HEFT = Sudden Cardiac Death in Heart Failure Trial.Wolbrette DL, et al. Vasc Health Risk Manag. 2010;(6):517-523.

Clinical Profiles forAmiodarone and Dronedarone

Months

0

10

20

40

50

30

6 12 18 24 300

HR = 0.76

P<.001

24% reductionin relativerisk

ATHENA = A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation. Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.

ATHENA: Primary Endpoint(CV Hospitalization or Death)

Dronedarone

Placebo

Cu

mu

lati

ve In

cid

ence

(%

)

4628 patients with paroxysmal or persistent AF were randomized if they met the following: ≥75 years of age with or without additional risk factors or ≥70 years of age and ≥1 risk factor (HTN, diabetes, prior stroke/TIA, LA diameter ≥50 mm, LVEF ≤0.40)

Outcome Placebo(N = 2327)

Dronedarone(N = 2301)

HR 95% CI P Value

Primary Endpoint

First CV hospitalization or death 917 (39.4%) 734 (31.9%) 0.76 0.69-0.84 <.001

First CV hospitalization 859 (36.9%) 675 (29.3%) 0.74 0.67-0.82 <.001

First hospitalization for AF 510 (21.9%) 335 (14.6%) 0.63 0.55-0.72 <.001

Secondary Endpoints

Death from any cause 139 (6.0%) 116 (5.0%) 0.84 0.66-1.08 .18

Death from non-CV causes 49 (2.1%) 53 (2.3%) 1.10 0.74-1.62 .65

Death from CV causes 90 (3.9%) 63 (2.7%) 0.71 0.51-0.98 .03

Cardiac nonarrhythmic death 18 (0.8%) 17 (0.7%) 0.95 0.49-1.85 .89

Cardiac arrhythmic death 48 (2.1%) 26 (1.1%) 0.55 0.34-0.88 .01

Any CV hospitalization or death 1668 (71.7%) 1253 (54.5%) 0.76 0.68-0.84 <.001

In a post-hoc analysis, dronedarone was also associated with a 34% reduction in relative risk of stroke, HR 0.66 (95% CI 0.46-0.96), P = .027.

Adapted from Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678. Connolly SJ, et al. Circulation. 2009;120(13):1174-1180.

ATHENA: Primary and Secondary Endpoints

ATHENA: Stroke IncidencePost-Hoc Analysis

Mean follow-up 21 ± 5 months

0

1

2

3

4

5

230122752266

22202223

15981572

618 608

6 4

2327

Placebo

PlaceboDronedarone

Months

Dronedarone

0 6 12 18 24 30

Cu

mm

ula

tive

Inci

de

nce

(%

) HR=0.66

p=0.027

Connolly SJ, et al. Circulation. 2009;120(13):1174-1180

*Limited interpretation; hospitalization was not reported in the same way in ATHENA, AFFIRM, and AF-CHF trials. NA = not applicable. Wyse DG, et al. N Engl J Med. 2002;347(23):1825-1833. Roy D, et al. N Engl J Med. 2008;358(25):2667-2677. Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678. Torp-Pedersen C, et al. Circulation. 2008;118:S828. Connolly SJ, et al. Circulation. 2009;120(13):1174-1180.

CV Outcome Benefits:Amiodarone and Dronedarone in Large AF Trials

ATHENAAF-CHFAFFIRM

None82% of patients63% of patientsAmiodarone use

P<.001P = .06P<.001Hospitalization*

P = .03NACV mortality

P = .027Stroke

P = .08Total mortality

ATHENA Post-Hoc Analysis Risk of unplanned CV hospitalization or death in

"permanent" AF patients

Months

10

20

40

50

30

Cum

ula

tive

Inc

iden

ce (

%)

6 12 18 24 300

Placebo on top of standard therapy

DR 400mg bid on top of standard therapy

Placebo 295 244 224 151 60 0

DR 400mg bid 178 160 150 110 47 1

26% reductionin relativerisk

Patients at risk:

0

HR=0.74p=0.096

Mean follow-up 21 ±5 months. Page R, et al. AHA Scientific Sessions 2008.Page R, et al. Circulation. 2008;118:S_827.

Any unplanned hospitalisation (i.e., admission with an overnight stay in the hospital) was classified by the investigator as a hospitalisation due to either CV or non-CV causes

Patients with AF/AFL at each ECG recording were classified as having "permanent AF"

PALLASStudy Design

• Co-primary Endpoints

•• Composite endpoint of first stroke, systemic arterial embolism, myocardial infarction or cardiovascular death

•• Composite endpoint of first unplanned cardiovascular hospitalization or death from any cause

Dronedarone 400 mg BID

Placebo BID

R

Patients with permanent AF and additional risk factors*

Event-Driven N~10800

On top of Standard of Care

*Patients aged 65 years or older with at least one of the following risk factors or combination of risk factors:Coronary artery disease

Prior strokeSymptomatic heart failure

Left ventricular ejection fraction less than or equal to 0.40Peripheral arterial occlusive disease

Aged 75 years or older with both hypertension and diabetes mellitus

Køber L, et al. N Engl J Med. 2008;358(25):2678-2687.

ANDROMEDA: Study Primary Endpoint and Results

• Primary endpoint

– The primary composite endpoint was all-cause mortality or hospitalization for HF vs placebo

• Results Analysis Up to Study Discontinuation

Placebo(n = 317)

Dronedarone 800 mg/day(n = 310)

Number of patients who died 12 25

Relative risk (relative to placebo) 2.13

95% CI 1.07, 4.25

P value .03

Tschuppert Y, et al. Br J Clin Pharmacol. 2007;64:785-791. US Food and Drug Administration (FDA). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM136957.pdf. Accessed July 9, 2010.

Dronedarone Safety Profile

• Safety profile of dronedarone has been established in >6700 patients

– Low risk of extracardiac toxicities (<0.1%) (thyroid, pulmonary, dermatologic)

– Low risk of proarrhythmia (<0.1%)

– Most frequently reported adverse events

• Gastrointestinal effects (24% vs 21% for placebo)

• General disorders and administration site conditions (16% vs 15% for placebo)

• Serum creatinine increase without indications of renal toxicity (4% vs 1% for placebo)

• Rare cases of serious hepatotoxicity were reported in 2010 within 6 months of beginning therapy, two required transplantation

FDA = US Food and Drug Administration; AFL = atrial flutter.Multaq [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2009.

Dronedarone Indication

• Approved by the FDA in July 2009 to

– Reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL, and 1 or more associated CV risk factors

• Age >70

• HTN

• Diabetes

• Prior CVA

• LA diameter ≥50 mm or LVEF <40%

– Treat patients who are in SR, or who will be cardioverted

• Contraindicated in class IV HF or lesser HF with recentdecompensation

Efficacy of AADs in AF Trials

*At 6 months; †Mean follow-up 7 months. CTAF = Canadian Trial of Atrial Fibrillation; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial; DAFNE = Dronedarone Atrial Fibrillation Study after Electrical Cardioversion; EURIDIS = European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm; ADONIS = American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter for the Maintenance of Sinus Rhythm; DIONYSOS = Randomized, Double-blind Trial to Evaluate the Efficacy and Safety of Dronedarone vs Amiodarone for at Least 6 Months for the Maintenance of Sinus Rhythm in Patients with AF. Courtesy of G Naccarelli, MD. Roy D, et al. Am J Cardiol. 1997;80:464-468. Singh BN, et al. N Engl J Med. 2005;352(18):1861-1872. AFFIRM Investigators. J Am Coll Cardiol. 2003;42:20-29. Touboul P, et al. Eur Heart J. 2003;24:1481-1487. Singh BN, et al. N Engl J Med. 2007;357(10):987-999. Le Heuzey JY, et al. J Cardiovasc Electrophysiol. 2010;21:597-605.

Dronedarone

Sotalol

Amiodarone

Class IC

Placebo

100

80

60

40

20

0

Pat

ien

ts in

SR

at

1 Y

ear

(%)

CTAF SAFE-T AFFIRM DAFNE* EURIDIS* ADONIS EURIDIS/ADONIS Pooled

DIONYSOS†

A Safety-Driven Approach

*Within each box, drugs are listed alphabetically and not in order of suggested use. HTN = hypertension; CAD = coronary artery disease; HF = heart failure; CHF = congestive heart failure.Wann LS, et al. Circulation. Published online Dec 20, 2010. Camm AJ, et al. Eur Heart J. Published online August 29, 2010.

2011 ACCF/AHA/HRS Guidelines:Antiarrhythmic Approaches to Maintain SR in Patients with Recurrent

PAF or Persistent AF*

HF

AmiodaroneDofetilide

Maintenance of SR

AmiodaroneDofetilide

Catheterablation

DronedaroneFlecainide

PropafenoneSotalol

No (or minimal)heart disease

DronedaroneFlecainide

PropafenoneSotalol

Amiodarone

No Yes

AmiodaroneDofetilide

Catheterablation

Catheterablation

HTN

Substantial LVH

CAD

Catheterablation

Amiodarone Catheterablation

DofetilideDronedrone

Sotalol

2010 ESC Guidelines – Dronedarone recommended for patients with LVH and stable NYHA I/II CHF

In AF In NSR

Hospital Outpatient Hospital Outpatient

IA* X X

IC* X† X†

Sotalol X X X‡

Dofetilide X X

Dronedarone X X

Amiodarone X X

*After rate control; †No SHD or sinus node/conduction abnormalities; ‡No risk factors for TDP (QT <450 ms, normal electrolytes).TDP = Torsades de pointes.Fuster V, et al. Circulation. 2006;114:e257-e354. Multaq [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2009.

Outpatient vs Inpatient Initiation of Antiarrhythmics for AF

ACE-Is/ARBs Statins Glucocorticoids Physical activity Omega-3 fatty acids

Inflammation Oxidative stress RAAS activity Endothelial function

Autonomic nervous system activityPlaque stability Atrial remodeling

Stabilize LA endocardium

AF

To date, large prospective trials have not confirmedbenefit of upstream therapies in suppressing AF

RAAS = renin-angiotensin-aldosterone system.Courtesy of CJ Pepine, MD.

Possible “Upstream” Treatments and Mechanisms for AF Prevention

PUFA = polyunsaturated fatty acid; CABG = coronary artery bypass graft.Mozaffarian D, et al. Circulation. 2004;110(4):368-373. Calo L, et al. J Am Coll Cardiol. 2005;45(10):1723-1728.

35

25

10

0

5PU

FA

fo

r P

reve

nti

on

of

AF

Post-Op AF (%) Hospital Days (n)

Control

PUFA

AF Post-CABG

20

15

30

P = .013

P = .017

Fish Oil/n-3 PUFA for Prevention of AF

• Prospective cohort of 4815 adults with 12-year follow-up

– People who consumed tuna or other broiled/baked fish 1-4 times/week had 28% lower risk of AF (P = .005) compared to <1 time/month

• Randomized controlled trial of 160 patients treated pre- and post-bypass surgery

(2 g PUFA/day)

OM 8: Primary Endpoint: Time to First Recurrence of Symptomatic AF/Flutter (PAF)

HR: 1.15CI: (0.90, 1.46)P value: 0.263

PLA: 129/269 (48%)

P-OM3: 135/258 (52%)

Analysis based on Cox model: log (HR)=treatment+region+ACE/ARB+StatinKowey PR, et al. JAMA 2010;302(21):2363-2372

ACE-Is and ARBs reduced the RR of AF by 28% (P = .0002)

Reduction in AF was similar with ACE-Is (28%, P = .01) and ARBs(29%, P = .00002)

Effect was most pronounced in HF and only significant in HTN when associated with LVH

RR = relative risk. Healey JS, et al. J Am Coll Cardiol. 2005;45(11):1832-1839.

RR (95% CI)

0.0 0.5 1.0 1.5 2.0

Total

ARBs

ACE-Is

Favors Treatment Favors Control

ACE-Is and ARBsReduce the Risk of AF

• Meta-analysis: 11 studies (N = 56,308)

• 4 in HF, 3 in HTN, 2 in patients following cardioversion for AF, and 2 in patients after MI

0

12

Pro

bab

ility

of

Fir

st R

ecu

rren

ce o

f A

F Valsartan

Placebo

Log-rank testP = .829

Patients at Risk

0 1 2 3 4 5 6 7 8 9 10 11

Time since Randomization (months)

ValsartanPlacebo

722720

586589

524520

491484

465454

445435

423407

398387

383377

368359

356344

343334

260254

0.1

0.2

0.3

0.4

0.5

0.6

Valsartan: 371/722 (51.4%)Placebo: 375/720 (52.1%)

Adjusted HR 0.9796% CI 0.83-1.14P = .73

The GISSI-AF Investigators. N Engl J Med. 2009;360:1606-1617.

GISSI-AFStudy Results: Probability of First Recurrence of AF

CS = coronary sinus; RA = right atrium.Haissaguerre M, et al. N Engl J Med. 1998;339(10):659-666. Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

Triggers of AF: Focal Firing and Interplay with Reentrant Rotors

SVC

IVC

PVs

611

1731

Septum

Fossa Ovalis

CS

RA LA

Extension of muscular fibers into PV

Ganglia noted in yellow

Large and small reentrant wavelets that play a role in initiating andsustaining AF

Common locations of PV (purple) and common sites of origin of non-PVtriggers (black)

Composite of anatomic and arrhythmic mechanisms of AF

LSPV

LIPV

RSPV

IVC

RIPV

SVC

LSPV

LIPV

RSPV

IVC

RIPV

SVC

LSPV

LIPV

RSPV

IVC

SVC

RIPV

LSPV

LIPV

RSPV

IVC

RIPV

SVC

Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

Anatomy of PVs

A.Circumferential ablation around left and right PV antra

B.and C. Additional linear lesion sets for the roof, mitral isthmus, carinae, SVC, and cavotricuspid isthmus

D.Targeting fractionated electrograms and/or ganglionic plexi

SVC = superior vena cava; PV = pulmonary vein; LSPV = left superior pulmonary vein; RSPV = right superior pulmonary artery; LIPV = left inferior pulmonary vein; RIPV = right inferior pulmonary vein; IVC = inferior vena cava.Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

Common Lesions Performed in AF Ablation

A. B.

LSPV

LIPV

RSPV

IVC

RIPV

LSPV

LIPV

RSPV

IVC

RIPV

LSPV

LIPV

RSPV

IVC

RIPV

SVC

C. D.

LSPV

LIPV

RSPV

IVC

RIPV

SVC

SVCSVC

0

10

20

30

40

50

60

70

80

90

100

0-3 4-6 7-9 10-12 13-18 19-24 >24

Rat

es (

%)

Range of Follow-Up (months)

Cappato R, et al. Circulation. 2005;111:1100-1105.

Success Rates with Ablation: Worldwide Survey

Success with AADs

Overall Success

Success without AADs

Additional recent studies suggest 5 yr success rates are <50%; LA size and function may not normalize despitecontrol of the arrhythmia, and new MRI detected embolic CNS lesions occur in >10% of subjects

Jeevanantham et al. AJC 2010; 105:1317-26* Ouyang et al. Circuation 2010;122:2368-77 ** Weerasooriya et al. JACC 2011

*** Gaita F, et al. Circulation 2010; 122:1667-73 **** Schwarz et al. Heart Rhythm 2010; 7:1761-67

Type of Complication Number of Patients Rate (%)

Death 25 0.15

Tamponade 215 1.31

Pneumo/hemo thorax 19 0.11

Sepsis, abscesses, or endocarditis 2 0.01

Permanent diaphragmatic paralysis 28 0.17

Femoral pseudoaneurysm/AV fistula 152/88 0.93/0.54

Valve damage/requiring surgery 11/7 0.07

Atrium-esophageal fistulae 3 0.02

Stroke/TIA 37/115 0.23/9.71

PV stenoses requiring intervention 49 0.29

TOTAL 741 4.54

Heart Rhythm Society. Lessons from the Second International Ablation Registry Update. http://www.hrsonline.org/education/selfstudy/webcasts/af/ablationregistry/. Accessed February 2010.

Risks of AF Ablation:The Second International AF Ablation Registry

Iatrogenic atrial flutter occurred in 8.3% of patients

Additional Ablation Data

• Longer term success (5 yr):

– With a single procedure, sinus rhythm has been maintained at 5 yrs in just under 46.6% of pts in 1 study and just 29% in another* **

• Recently appreciated additional embolic events:

– Gaita et al *** studied 232 consecutive patients with PAF or persistent AF who underwent ablation (PVI +/- additional lesions). Standard anticoagulation was employed. All pts underwent preprocedural and postablation cerebral MRIs.

• A periprocedural symptomatic CVA occurred in 1 pt (0.4%). Postablation MRIs, Postablation MRIs,

however, were positive for new lesions in 33 pts (14%).however, were positive for new lesions in 33 pts (14%).

– Schwarz et al **** studied 23 pts in a similar study.

• 14.3% had new ischemic lesions on post-procedure imaging, and, compared to 23

controls, the ablation pts showed neuropsychological decline

* Ouyang et al. Circuation 2010;122:2368-77 ** Weerasooriya et al. JACC 2011

*** Gaita F, et al. Circulation 2010; 122:1667-73 **** Schwarz et al. Heart Rhythm 2010; 7:1761-67

Additional Ablation Data Cont’d

• Atrial size and function post ablation:

– 17 studies enrolling 869 pts provided adequate data on LA size and function after RFA.

– Compared to pre-ablation values, there were significant decreases in LA diameter and volumes at post-ablation follow up.

– Decreases remained significant in those without AF recurrence but not in those with recurrent AF.

– Compared to pre-ablation values, however, there were no improvements in LA EF or LA active emptying fraction, and LA size did not routinely decrease to normal.

• LAEF and LA emptying remained unchanged in pts without AF recurrence but decreased further in those with recurrent AF.

Jeevanantham et al. AJC 2010; 105:1317-26

Minnesota Living with HF Questionnaire

6-Minute Walk

Dis

tan

ce (

m) 360

320

340

300

280

260

00 3 6

Months

P = .003P<.001

Eje

ctio

nF

ract

ion

(%

) 37

3335

3129

2527

00 3 6

Months

Ejection Fraction

P = .03P<.001

PVI = pulmonary vein isolation; CRT = cardiac resynchronization therapy; BiV = biventricular pacing.Khan MN, et al. N Engl J Med. 2008;359(17):1778-1785.

PVI Is Superior to AVN Ablation/CRT in CHF Patients with Drug-Refractory AF

Months

Sco

re

100

60

80

40

20

00 6

P<.001

AVN Ablation + BiV

PVI

Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

Indications for Catheter AF Ablation

• Symptomatic AF refractory or intolerant to at least 1 class I or III AAD

• Selected symptomatic patients with HF and/or reduced ejection fraction

• As an alternative to device implantation to support AAD therapy in bradycardic patients

• Presence of an LA thrombus is a contraindication to catheter ablation of AF

• Discontinuation of anticoagulation is not an indication for ablation

Circ.AHAjournals.org Dec 20, 2010

AF: atrial fibrillation; CV: cardiovascular; INR: international normalized ratio; LAA: left atrial appendage.

Holmes DR, et al. Lancet. 2009;374:534-542.

LAA Device for AFPROTECT-AF Study

• 707 patients with nonvalvular AF randomized to LAA device + 45 days of warfarin vs warfarin vs warfarin alone

• Primary efficacy end point of stroke, CV death, or systemic embolism was 3.0% (1.9-4.5) with device and 4.9% (2.8-7.1) with warfarin; [RR 0.62, 95% CI (0.35-1.25)]

• Primary safety end point of excessive bleeding, serious pericardial effusion, device embolization, or procedure-related stroke was 7.4% with device and 4.4% with warfarin; [RR 1.69, 95% CI (1.01-3.19)]

Outcome Parameters for Trials in AFRecommendations from a consensus conference

organized by the German AF Competence NETwork(AFNET) and the EHRA

EHRA = European Heart Rhythm Association.Kirchof P, et al. Europace. 2007;9(11):1006-1023.

AF Trial Endpoints

• Symptoms

• QoL

• Recurrence of AF

• LV function

• Exercise tolerance

• Major adverse cardiac events

• All hospitalizations

• CV hospitalizations

• CV, all-cause mortality

• Thromboembolism

NIH = National Institutes of Health.Calkins H, et al. Heart Rhythm. 2007;4(6):816-861. Marrouche NF, et al. Pacing Clin Electrophysiol. 2009;32(8):987-994.

Ongoing Ablation Trials

CABANA: Catheter Ablation vs AAD for AF

– NIH/industry-cooperative, 5-year study to investigate if mortality is improved with ablation compared to drug therapy (rate or rhythm control)

CASTLE-AF: Catheter Ablation vs Standard Conventional Treatment in Patients with LV Dysfunction and AF

– Time to first event of death or hospitalization for HF

• Comprehensive management of AF should address its multiple impacts

• In addition to stroke prevention and reduction of AF burden,* successful management of AF should also aim at further reducing hospitalizations and costs, as well as CV morbidity and mortality

Preventionof

thrombo-embolism

Reductionof

AF burden*

QoL Symptoms

Reduction inthe risk ofCV events

andhospitalizations

andcosts

Reductionin

mortality

*Total percentage of time a patient has AF as determined by the number and duration of AF episodes.Wolf PA, et al. Stroke. 1991;22:983-988. Singh SN, et al. J Am Coll Cardiol. 2006;48:721-730. Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(Suppl 2):S7-S10. Hohnloser S, et al. J Cardiovasc Electrophysiol. 2008;19:69-73. Camm AJ, et al. Eur Heart J Suppl. 2008;10(Suppl H):H55-H78.

New Goals of AF Management

Summary

• AF is a common disease that is increasing in prevalence

• For any patient with AF, decisions need to be made regarding antithrombotic therapy, rate control, and/or rhythm control

• Guidelines provide recommendations for the management of patients with AF

• Anticoagulation is essential in AF patients with risk markers, regardless of any restoration of SR

• New agents and procedures may provide antiarrhythmic and antithrombotic options with improved outcomes for managing AF