Types of AVR Examples of replacement aortic valves: a) shows an aortic homograft, b) and c) show a...

Types of AVRTypes of AVR

Examples of replacement aortic valves: a) shows an aortic homograft, b) and c) show a xenograft, d) shows a ball and

cage valve, e) shows a tilting-disk valve, f) shows a bi-leaflet valve

Elderly PatientsElderly PatientsPts >80years, operative mortality as high

as 30%.

Percutaneous aortic balloon valvuloplasty is an alternative to valve replacement introduced in ‘80s.

Inflating one or more large balloons across the aortic valve from a percutaneous route, a modest decrease in gradient and improvement in symptoms

Balloon ValvuloplastyBalloon ValvuloplastyFollow-up has demonstrated a high rate

of re-stenosis (>60% at 6 months and nearly 100% at 2 years), with no decrease in mortality rate after procedure

Therefore, now only has a role in critically ill elderly pts who are not candidates for surgery or as a “bridge” in critically ill pts before AV replacement

Building on 50 Years of Proven Building on 50 Years of Proven Valve ExpertiseValve Expertise

Aortic stenosis is life threatening and progresses rapidly

– Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1

– “Surgical intervention [for severe AS] should be performed promptly once even…minor symptoms occur”1

Helping to Solve a Grave Helping to Solve a Grave Problem Problem

Latent Period(Increasing Obstruction,Myocardial Overload)

Su

rviv

al, %

100

80

60

40

20

0 40 50 60 70 80Age, y

Onset Severe Symptoms

AnginaSyncope

Average Survival, y

Failure

0 2 4 6

At least 40% of patients with severe aortic stenosis (AS) do not have an AVR2-8

Addressing a Serious Addressing a Serious Unmet NeedUnmet Need

1999 2006 2006 20092005 2010

Pati

ents

, %

Aortic Valve Replacement (AVR) No AVR

2009

4657

40 39

26

48

31

54 43 60 61 74 52 69

0

20

40

60

80

100

Boum

a

Pellikk

a

Charls

on

Varad

araja

n Jan

Bach

Freed

For inoperable patients with severe symptomatic native aortic valve stenosis

Edwards SAPIEN Transcatheter Edwards SAPIEN Transcatheter Heart Valve Heart Valve With the RetroFlex 3 Transfemoral With the RetroFlex 3 Transfemoral System System

Patient-Focused Patient-Focused Multidisciplinary Multidisciplinary Heart Team ApproachHeart Team Approach

Multidisciplinary in all aspects:Patient selectionProcedure planningPatient treatmentPost-operative care

The PARTNER Trial The PARTNER Trial ProtocolProtocol

Not in StudyNot in Study

AssessmentTransfemoral Access

AssessmentTransfemoral AccessYesYes NoNo

Primary Endpoint: All-Cause Mortality OverLength of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)

Primary Endpoint: All-Cause Mortality OverLength of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)

TFTAVR

(n = 179)

TFTAVR

(n = 179)

Standard Therapy(Control)(n = 179)

Standard Therapy(Control)(n = 179)

vsvs

1:1 Randomization



TF(n = 492)

TF(n = 492)

TA(n = 207)

TA(n = 207)

YesYes NoNo

Primary Endpoint: All-Cause Mortality (1 yr)(Non-inferiority)

Primary Endpoint: All-Cause Mortality (1 yr)(Non-inferiority)

TFTAVR

(n = 244)

TFTAVR

(n = 244)

AVR(Control)(n = 248)


vsvs

1:1 Randomization

TATAVR

(n = 104)

TATAVR

(n = 104)



vsvs

1:1 Randomization

Cohort ACohort ACohort A(n = 699)

Cohort B(n = 358)

2 CohortsIndividually Powered

(N = 1,057)

2 CohortsIndividually Powered

(N = 1,057)

TA, transapical; TF, transfemoral.

AssessmentOperability

AssessmentOperability

NoNoYesYes

Severe Symptomatic Native Aortic Valve StenosisSevere Symptomatic Native Aortic Valve Stenosis

A Seminal Date in A Seminal Date in Cardiovascular Medicine Cardiovascular Medicine

September 22, 2010 on NEJM.org

Absolute Reduction in Mortality Absolute Reduction in Mortality Continues to Diverge at 2 YearsContinues to Diverge at 2 Years

∆ at 1 yr = 20.0%

NNT = 5.0 pts

All-

Cause

Mort

alit

y, %

50.7%

30.7%

HR [95% CI] = 0.57 [0.44, 0.75]P (log rank) < .0001

Numbers at Risk

Edwards SAPIEN THV

179 138 124 110 83

Standard Therapy 179 121 85 67 51

Months

0

20

40

60

80

100Edwards SAPIEN THV

Standard Therapy

67.6%

∆ at 2 yr = 24.3%

NNT = 4.1 pts

43.3%

Edwards SAPIEN THV Edwards SAPIEN THV Delivered Delivered QOL BenefitsQOL Benefits

MCID, minimum clinically important difference.

60

40

20

0

80

100

0 4 6 8 10 122

Standard Therapy

Edwards SAPIEN THV

∆ = 13.9P < .001

∆ = 24.5P < .001

KC

CQ

Sco

re (

Mean)

MCID = 5 points

Months

Improvement in quality

of life

At 30 days, TAVR resulted in more frequent strokes, major vascular complications, and bleeding events than standard therapyAll strokes, 7.3% vs 1.7%, P = .02

Major vascular complications, 16.8% vs 1.1%, P < .0001

Bleeding events, 16.2% vs 2.2%, P < .0001

Peri-procedural Peri-procedural HazardsHazards

Sobering PerspectiveSobering Perspective

* National Institutes of Health. National Cancer Institute. Surveillance Epidemiology and End Results. Cancer Stat Fact Sheets.http://seer.cancer.gov/statfacts/. Accessed November 16, 2010. † Using constant hazard ratio. Data on file, Edwards Lifesciences LLC. Analysis courtesy of Murat Tuczu.

5-Year Survival

Surv

ival, %

†**

* * *

23

4

12

3028

30

5

10

15

20

25

30

35

BreastCancer

Lung Cancer ColorectalCancer

ProstateCancer

OvarianCancer

SevereInoperable

AS

Advancing the Science Advancing the Science of TAVR of TAVR

TCT 2011 | San Francisco, CA | November 10, 2011TCT 2011 | San Francisco, CA | November 10, 2011

Two-Year Outcomes of Transcatheter Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in Aortic Valve Replacement (TAVR) in “Inoperable” Patients With Severe “Inoperable” Patients With Severe Aortic Stenosis: Aortic Stenosis: The PARTNER The PARTNER TrialTrial

Raj R. Makkar, MDRaj R. Makkar, MDOn behalf of The PARTNER Trial On behalf of The PARTNER Trial InvestigatorsInvestigators

Background (1)Background (1)Transcatheter aortic valve replacement (TAVR)

is the recommended treatment for “inoperable” patients with severe aortic stenosis (AS), based upon 1-year results of The PARTNER Trial which demonstrated reduced mortality and improved quality of life.

However, whether clinical benefit and valve performance are sustained beyond one year is unknown and longer term outcomes will importantly alter clinical practice decisions.

ObjectivesObjectivesTo evaluate the clinical outcomes of TAVR

compared to standard therapy at 2 years in “inoperable” aortic stenosis patients.

To assess valve hemodynamics and durability using echocardiography.

To perform subgroup analyses to better define the impact of co-morbidities on outcomes.

Inclusion CriteriaInclusion CriteriaSevere calcific aortic stenosis defined as echo

derived valve area of < 0.8 cm2 (EOA index < 0.5 cm2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s.

NYHA functional class II or greater.Risk of death or serious irreversible morbidity

of AVR as assessed by cardiologist and two surgeons must exceed 50%.

Surgeons must agree and attest that before PARTNER these patients would not have received AVR treatment!

Key End-Points for 2 Year Key End-Points for 2 Year AnalysisAnalysisAll cause mortalityAll cause mortalityCardiac mortalityCardiac mortalityRehospitalizationRehospitalizationStrokeStrokeNYHA functional classNYHA functional classDays alive and out of hospitalDays alive and out of hospitalEcho-derived valve areas, transvalvular Echo-derived valve areas, transvalvular

gradients, paravalvular aortic regurgitationgradients, paravalvular aortic regurgitationMortality outcomes stratified by STS scoreMortality outcomes stratified by STS score

n = 358Randomized Inoperable

n = 358Randomized Inoperable

n = 179TAVR

n = 179TAVR

n = 179Standard therapy

n = 179Standard therapy

124/124 patients100% followed at 1

Yr

124/124 patients100% followed at 1

Yr

85/85 patients100% followed at 1 Yr


99/102 patients*97.1% followed at 2

Yr

99/102 patients*97.1% followed at 2

Yr



Study Flow - Study Flow - Inoperable Inoperable CohortCohort

• 5 withdrawals in the first year in Standard Rx arm• *3 patients followed outside of protocol window in TAVR group• No patients were lost to follow-up

Patient Characteristics Patient Characteristics (1)(1)

CharacteristicCharacteristic TAVRTAVRn = 179n = 179

Standard RxStandard Rxn = 179n = 179

p valuep value

Age – yrAge – yr 83.1 ± 8.683.1 ± 8.6 83.2 ± 8.383.2 ± 8.3 0.950.95

Male sex (%)Male sex (%) 45.845.8 46.946.9 0.920.92

STS ScoreSTS Score 11.2 ± 5.811.2 ± 5.8 12.1 ± 6.112.1 ± 6.1 0.140.14

NYHANYHA I or II (%)I or II (%) III or IV (%)III or IV (%)

7.87.892.292.2

6.16.193.993.9

0.680.680.680.68

CAD (%)CAD (%) 67.667.6 74.374.3 0.200.20

Prior MI (%)Prior MI (%) 18.618.6 26.426.4 0.100.10

Prior CABG (%)Prior CABG (%) 37.437.4 45.645.6 0.170.17

Prior PCI (%)Prior PCI (%) 30.530.5 24.824.8 0.310.31

Prior BAV (%)Prior BAV (%) 16.216.2 24.424.4 0.090.09

CVD (%)CVD (%) 27.427.4 27.527.5 1.001.00

Patient Characteristics Patient Characteristics (2)(2)

CharacteristicCharacteristic TAVRTAVRn = 179n = 179

Standard RxStandard Rxn = 179n = 179

p valuep value

PVD (%)PVD (%) 30.330.3 25.125.1 0.290.29

COPDCOPD Any (%)Any (%) OO2 2 dependent (%)dependent (%)

41.341.321.221.2

52.552.525.725.7

0.040.040.380.38

Creatinine > 2 mg/dL (%)Creatinine > 2 mg/dL (%) 5.65.6 9.69.6 0.230.23

Atrial fibrillation (%)Atrial fibrillation (%) 32.932.9 48.848.8 0.040.04

Perm. pacemaker (%) Perm. pacemaker (%) 22.922.9 19.519.5 0.490.49

Pulmonary HTN (%)Pulmonary HTN (%) 42.442.4 43.843.8 0.900.90

Frailty (%)Frailty (%) 18.118.1 28.028.0 0.090.09

Porcelain aorta (%)Porcelain aorta (%) 19.019.0 11.211.2 0.050.05

Chest wall radiation (%)Chest wall radiation (%) 8.98.9 8.48.4 1.001.00

Chest wall deformity (%)Chest wall deformity (%) 8.48.4 5.05.0 0.290.29

Liver disease (%)Liver disease (%) 3.43.4 3.43.4 1.001.00

All Cause Mortality All Cause Mortality (ITT)(ITT)Crossover Patients Followed

Numbers at RiskNumbers at Risk

TAVRTAVR 179179 138138 124124 110110 8383 Standard Standard RxRx 179179 121121 8585 6767 5151

All

Cause

Mort

alit

y (

%)

Standard Rx

TAVR

∆ at 2 yr = 24.3%NNT = 4.1 pts

67.6%

43.3%

∆ at 1 yr = 20.0%NNT = 5.0 pts

50.7%

30.7%

Months

HR [95% CI] =0.57 [0.44, 0.75]

p (log rank) < 0.0001

All Cause Mortality (ITT)All Cause Mortality (ITT)Landmark AnalysisLandmark Analysis

All

Cause

Mort

alit

y (

%)

Months

Mortality 0-1 yr Mortality 1-2yr

Standard Rx TAVR

HR [95% CI] =0.57 [0.44, 0.75]

p (log rank) < 0.0001

HR [95% CI] =0.58 [0.37, 0.92]

p (log rank) = 0.019450.7%

30.7%

35.1%

18.2%


TAVRTAVR179179 138138 124124 110110 88

33 Standard Standard RxRx 179179 121121 8585 6262 44

22

Cardiovascular Mortality Cardiovascular Mortality (ITT)(ITT)Crossover Patients CensoredCrossover Patients Censored



Card

iovasc

ula

r M

ort

alit

y (

%) Standard Rx

TAVR

∆ at 2 yr = 31.4%NNT = 3.2 pts

62.4%

31.0%

∆ at 1 yr = 24.1%NNT = 4.1 pts 44.6%

20.5%

Months

HR [95% CI] =0.44 [0.32, 0.60]

p (log rank) < 0.0001

Repeat Hospitalization Repeat Hospitalization (ITT)(ITT)



Repeat

Hosp

italiz

ati

on (

%) Standard Rx

TAVR

∆ at 2 yr = 37.5%NNT = 2.7 pts

72.5%

35.0%

∆ at 1 yr = 26.9%NNT = 3.7 pts

53.9%

27.0%

Months

HR [95% CI] =0.41 [0.30, 0.58]

p (log rank) < 0.0001

Hospitalization Through Hospitalization Through 2 Years2 Years

TAVRTAVR Standard Standard TxTx p valuep value

Repeat Hospitalizations Repeat Hospitalizations (No.)(No.) 7878 151151 <.0001<.0001

Repeat Hospitalizations Repeat Hospitalizations (%)(%) 35.0%35.0% 72.5%72.5% <.0001<.0001

Days Alive Out of Days Alive Out of Hospital Median [IQR]Hospital Median [IQR]

699 [201-699 [201-720]720] 355 [116-712]355 [116-712] .0003.0003

Perc

ent

Treatment Treatment VisitVisit

Baseline 1 Year 2 Year

p = 0.61 p < 0.0001 p < 0.0001

92.2%

57.5%

16.9%23.7%

60.8%

93.9%

NYHA Class Over TimeNYHA Class Over TimeSurvivorsSurvivors

All Stroke (ITT)All Stroke (ITT)



Inci

dence

(%

)

Months

Standard Rx

TAVR

∆ at 2 yr = 8.3%

5.5%

13.8%

∆ at 1 yr = 5.7%

5.5%

11.2%

HR [95% CI] =2.79 [1.25, 6.22]

p (log rank) = 0.009

All Cerebrovascular All Cerebrovascular Events (%)Events (%)

≤ ≤ 30 Days30 Days 31 Days – 1 Year31 Days – 1 Year 1 Year – 2 Years1 Year – 2 Years

All CVA p = 0.010 p = 0.387 p = 0.028

Ischemic Stroke p = 0.017 p = 0.155 p = 0.083

Hemorrhagic Stroke p = 0.316 p = 0.121 p = 0.415

Even

ts

Note: Percents are of patients in the trial (n/179).

Mortality or Stroke (ITT)



All

Cause

Mort

alit

y o

r Str

oke

(%

)

Months

Standard Rx

TAVR

∆ at 2 yr = 21.9%NNT = 4.6 pts

68.0%

46.1%

∆ at 1 yr = 16.1%NNT = 6.2 pts 51.3%

35.2%

HR [95% CI] =0.64 [0.49, 0.84]

p (log rank) = 0.0009

1 Year1 Yearn = 179n = 179

OutcomeOutcomeTAVRTAVR StandarStandar

d Rxd Rx P valueP value

2 Year 2 Year n = 179n = 179

TAVRTAVR Standard Standard RxRx P valueP value

Acute kidney injuryAcute kidney injury

Creatinine > 3 mg/dL, % Creatinine > 3 mg/dL, % (n)(n) 1.1 (2)1.1 (2) 2.8 (5)2.8 (5) 0.4490.449 1.1 (2)1.1 (2) 2.8 (5)2.8 (5) 0.4490.449

Renal failure (CEC), % (n)Renal failure (CEC), % (n) 2.3 (4)2.3 (4) 4.7 (7)4.7 (7) 0.2570.257 3.2 (5)3.2 (5) 7.6 (9)7.6 (9) 0.1490.149

Cardiac re-interventionCardiac re-intervention

BAV, % (n)BAV, % (n) 1.1 (2)1.1 (2) 82.3 (138)82.3 (138) <.0001<.0001 2.8 (4)2.8 (4) 85.3 85.3 (140)(140) <.0001<.0001

Re-TAVR, % (n)Re-TAVR, % (n) 1.7* (3)1.7* (3) NANA -- 1.7* (3)1.7* (3) NANA --

AVR, % (n)AVR, % (n) 0 (0)0 (0) 7.6 (10)7.6 (10) 0.0020.002 0.9 (1)0.9 (1) 8.9 (11)8.9 (11) 0.0050.005Endocarditis, % (n)Endocarditis, % (n) 1.4 (2)1.4 (2) 0.8 (1)0.8 (1) 0.6180.618 2.3 (3)2.3 (3) 0.8 (1)0.8 (1) 0.3160.316

Bleeding – major, % (n)Bleeding – major, % (n) 24.2 24.2 (42)(42) 14.9 (21)14.9 (21) 0.0380.038 28.9 (48)28.9 (48) 20.1 (25)20.1 (25) 0.0930.093

New pacemaker, % (n)New pacemaker, % (n) 4.7 (8)4.7 (8) 8.6 (14)8.6 (14) 0.1490.149 6.4 (10)6.4 (10) 8.6 (14)8.6 (14) 0.4690.469

Myocardial infarctionMyocardial infarction

All, % (n)All, % (n) 0.8 (1)0.8 (1) 0.7 (1)0.7 (1) 0.9060.906 1.6 (2)1.6 (2) 2.5 (2)2.5 (2) 0.6940.694

Clinical Outcomes1 Year and 2 Year (ITT)

Mean G

radie

nt

(mm

Hg)

Error bars = ± 1 Std DevError bars = ± 1 Std Dev

EOA

Mean Gradient

N = 158

N = 162

N = 137

N = 143

N = 84

N = 89

N = 65

N = 65

N = 9

N = 9

AV

A (cm

²)

Mean Gradient & Valve Mean Gradient & Valve AreaArea


None to MildNone to Mild 147147 118118 107107 9595 7272 Moderate or Moderate or SevereSevere 1717 1212 1111 1010 88

Death

Inci

dence

(%

)

Months

Moderate or Severe

None to Mild

41.2%

40.5%

35.3%

27.2%

Mortality Stratified by Paravalvular Mortality Stratified by Paravalvular Leak (ITT)Leak (ITT)Starting at DischargeStarting at Discharge

p (log rank) = 0.891

2828 2626 2525 2424 1616108108 8080 7676 6767 5252

4343 3232 2323 1919 1515

Death

Inci

dence

(%

)

Months

STS <5STS <5 STS 5-STS 5-14.914.9

Months

STS ≥15STS ≥15

p value (log rank) = 0.012

p value (log rank) = 0.676

1212 88 77 66 55119119 8484 5959 4242 2929

4747 2929 1919 1414 88

Mortality Stratified by STS Mortality Stratified by STS Score (ITT)Score (ITT)

TAVRTAVRStandard RxStandard Rx


Conclusions (1)Conclusions (1)At 2 years, in patients with symptomatic

severe ASwho are not suitable candidates for surgery…TAVR remained superior to standard therapy

with incremental benefit from 1 to 2 years, markedly reducing the rates of… All cause mortality Cardiovascular mortality Repeat hospitalization• TAVR improved NYHA functional status and

decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001).

Conclusions (2)Conclusions (2)At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery…

There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients.

After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR patients.

A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is in patients without extreme clinical co-morbidities.

Conclusions (3)Conclusions (3)At 2 years, in patients with symptomatic At 2 years, in patients with symptomatic severe AS who are not suitable candidates for severe AS who are not suitable candidates for surgery…surgery…

TAVR hemodynamics by echo showed durable TAVR hemodynamics by echo showed durable improvements in AVA and mean gradients up to improvements in AVA and mean gradients up to 3 years after implantation.3 years after implantation.

Moderate or severe paravalvular AR in the TAVR Moderate or severe paravalvular AR in the TAVR patients did not influence 2-year survival and there patients did not influence 2-year survival and there was a trend towards reduced paravalvular AR was a trend towards reduced paravalvular AR between 1 and 2 years.between 1 and 2 years.

Clinical Implications Clinical Implications • Two year data continues to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.

The ultimate value of TAVR in “inoperable” patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR and render the intervention futile.

QUESTIONS?QUESTIONS?

Types of AVR Examples of replacement aortic valves: a) shows an aortic homograft, b) and c) show a...

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