Inoperable Patients With Severe Aortic Stenosis: The PARTNER Trial [PDF]

SLIDE 1

TCT 2012 | Miami, FL | October 24, 2012

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

Samir R. Kapadia, MD

On behalf of The PARTNER Trial Investigators

SLIDE 2

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 two years is unknown and longer term outcomes will importantly alter clinical practice decisions.

SLIDE 3

Background (2)

SLIDE 4

Objectives

To evaluate the clinical outcomes of TAVR

compared to standard therapy at 3 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.

SLIDE 5

PARTNER Study Design

n = 358 Inoperable

Standard Therapy n = 179

ASSESSMENT:

Transfemoral Access

TF TAVR n = 179 Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) 1:1 Randomization VS

Symptomatic Severe Aortic Stenosis

Primary endpoint evaluated when all patients reached one year follow-up.
After primary endpoint analysis reached, patients were allowed to cross-over to TAVR.

SLIDE 6

Inclusion Criteria

Severe calcific aortic stenosis defined as echo

derived valve area of < 0.8 cm2 (EOA index < 0.5 cm2/m2), and mean gradient > 40 mmHg

r jet velocity > 4.0 m/s.
NYHA functional class ≥ II
Inoperable defined as risk of death or serious

irreversible morbidity of AVR as assessed by cardiologist and two surgeons exceeding 50%.

SLIDE 7

Key End-Points for 3 Year Analysis

All cause mortality
Cardiac mortality
Rehospitalization
Adverse outcomes including stroke, bleeding,

renal failure, and MI

NYHA functional class
Days alive and out of hospital
Echo-derived valve areas, transvalvular gradients,

and paravalvular aortic regurgitation

Mortality outcomes stratified by STS score

SLIDE 8

n = 358 Randomized Inoperable n = 179 TAVR n = 179 Standard Therapy 124/124 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 101/102 patients* 99.0% followed at 2 Yr 46/46 patients 100% followed at 2 Yr

Study Flow

Inoperable Cohort

*One TAVR patient was alive and censored prior to the window
**Two TAVR patients were alive and censored prior to the window (including the one

in the same status at 2 years); one TAVR patient withdrew between 2 and 3 years

No patients were lost to follow-up

80/82 patients** 97.6% followed at 3 Yr 19/19 patients 100% followed at 3 Yr

Cross over 11 pts Cross over 9 pts

SLIDE 9

Statistical Method

Primary analysis was by “intention-to-treat” (ITT).
Clinical outcomes were analyzed by ITT with

censoring of Standard Rx cross-over patients.

Additional analysis of death was performed by

following cross-over patients with their randomized trial arms.

Event rates are given as Kaplan-Meier estimates.
Core lab echo results are presented from

the valve implant population (valve retained in position).

SLIDE 10

Patient Characteristics (1)

Characteristic TAVR

n = 179

Standard Rx

n = 179

p value

Age – yr 83.1 ± 8.6 83.2 ± 8.3 0.95 Male sex (%) 45.8 46.9 0.92 STS Score 11.2 ± 5.8 12.1 ± 6.1 0.14 NYHA I or II (%) III or IV (%) 7.8 92.2 6.1 93.9 0.68 0.68 CAD (%) 67.6 74.3 0.20 Prior MI (%) 18.6 26.4 0.10 Prior CABG (%) 37.4 45.6 0.17 Prior PCI (%) 30.5 24.8 0.31 Prior BAV (%) 16.2 24.4 0.09 CVD (%) 27.4 27.5 1.00

Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

SLIDE 11

Patient Characteristics (2)

Characteristic TAVR

n = 179

Standard Rx

n = 179

p value

PVD (%) 30.3 25.1 0.29 COPD Any (%) O2 dependent (%) 41.3 21.2 52.5 25.7 0.04 0.38 Creatinine > 2 mg/dL (%) 5.6 9.6 0.23 Atrial fibrillation (%) 32.9 48.8 0.04

Perm. pacemaker (%)

22.9 19.5 0.49 Pulmonary HTN (%) 42.4 43.8 0.90 Frailty (%) 18.1 28.0 0.09 Porcelain aorta (%) 19.0 11.2 0.05 Chest wall radiation (%) 8.9 8.4 1.00 Chest wall deformity (%) 8.4 5.0 0.29 Liver disease (%) 3.4 3.4 1.00

Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

SLIDE 12

Numbers at Risk Standard Rx 179 121 85 62 46 27 17 TAVR 179 138 124 110 101 88 70

All Cause Mortality (ITT)

Crossover Patients Censored at Crossover

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

30.7% 50.8% 43.0% 68.0% 54.1% 80.9%

All Cause Mortality (%) Months

HR [95% CI] = 0.53 [0.41, 0.68] p (log rank) < 0.0001

20.1% 25.0% 26.8% NNT = 5.0 pts NNT = 4.0 pts NNT = 3.7 pts

Standard Rx TAVR

SLIDE 13

Cardiovascular Mortality (ITT)

Crossover Patients Censored at Crossover

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

20.5% 44.6% 30.7% 62.4% 41.4% 74.5%

Cardiovascular Mortality (%)

Numbers at Risk Standard Rx 179 121 85 62 46 27 17 TAVR 179 138 124 110 101 88 70

Months

HR [95% CI] = 0.41 [0.30, 0.56] p (log rank) < 0.0001

24.1% 31.7% 33.1% NNT = 4.1 pts NNT = 3.2 pts NNT = 3.0 pts

Standard Rx TAVR

SLIDE 14

0% 20% 40% 60% 80% 100%

Months

Numbers at Risk Standard Rx 179 121 85 62 46 27 17 TAVR 179 138 124 110 101 88 70 6 12 18 24 30 36

All Cause Mortality (ITT)

Landmark Analysis

30.7% 50.8% 17.8% 35.1% 19.3% 40.3%

All Cause Mortality (%)

HR [95% CI] = 1.90 [1.05, 3.43] p (log rank) = 0.03 HR [95% CI] = 2.03 [1.36, 3.04] p (log rank) = 0.0005 HR [95% CI] = 0.53 [0.41, 0.68] p (log rank) < 0.0001 ∆ = 20.1% ∆ = 17.3% ∆ = 21.0% NNT = 5.0 pts NNT = 5.8 pts NNT = 4.8 pts

Standard Rx TAVR

SLIDE 15

Repeat Hospitalization (ITT)

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

53.9% 27.0% 72.5% 34.9% 75.7% 42.3% 71.6% 44.1% 88.0% 56.5% 93.1% 66.3% Numbers at Risk

Standard Rx 179 86 49 30 19 11 7 179 86 49 30 19 11 7 TAVR 179 115 100 89 77 64 49 179 115 100 89 77 64 49

Months Months Rehospitalization (%) Mortality or Rehospitalization (%)

Rehospitalization Mortality or Rehospitalization

Standard Rx TAVR 33.4% HR [95% CI] = 0.39 [0.28, 0.54] p (log rank) < 0.0001 NNT = 3.7 pts NNT = 2.7 pts NNT = 3.0 pts NNT = 3.6 pts NNT = 3.2 pts NNT = 3.7 pts 37.6% 26.9% 26.8% 31.5% 27.5% HR [95% CI] = 0.46 [0.36, 0.58] p (log rank) < 0.0001

TAVR 944 [233-1096] Standard Rx 368 [147-1096]

p <.0001 Days Alive Out of Hospital Median [IQR]

SLIDE 16

NYHA Class Over Time (ITT)

0% 20% 40% 60% 80% 100% TAVR 179 Standard Rx 179 TAVR 173 Standard Rx 167 TAVR 173 Standard Rx 160 TAVR 165 Standard Rx 146 Dead IV III II I

Baseline 1 Year 2 Year 3 Year

p < 0.0001

N =

p = NS p < 0.0001 p < 0.0001

58.8% 91.1% 45.7% 76.9% 34.7% 59.3% 43.6% 45.3%

SLIDE 17

All Stroke (ITT)

0% 10% 20% 30% 40% 50% 6 12 18 24 30 36

5.5% 11.2% 5.5% 13.7% 5.5% 15.7%

Stroke (%) Months

HR [95% CI] = 2.77 [1.24, 6.19] p (log rank) = 0.0094

∆ = 5.7% NNT = 17.5 pts NNT = 12.2 pts NNT = 9.8 pts ∆ = 8.2% ∆ = 10.2%

Standard Rx TAVR

Numbers at Risk TAVR 179 128 116 105 96 82 65 Standard Rx 179 118 84 62 46 27 17

SLIDE 18

Stroke – Between year 2-3

ITT arm Age Days post randomization Description Comorbidity Procedure related* Device related* Comments TAVR 97 879 Ischemic Blood stream infection, Right carotid stenosis (80%) No No Cerebellar infarct; Linear echodensity on mitral valve, Ao valve: Mild AI TAVR 87 837 Acute infarct with surrounding intraparenchymal bleed Atrial Fibrillation not on warfarin No No Cerebellar infarct/ hemorrhage; Ao valve: Ok

*CEC adjudicated

SLIDE 19

Numbers at Risk Standard Rx 179 118 84 62 46 27 17 TAVR 179 128 116 105 96 82 65

Mortality or Stroke (ITT)

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

51.3% 35.2% 45.8% 57.5% 68.0% 80.9%

Mortality or Stroke (%) Months

HR [95% CI] = 0.60 [0.46, 0.77] p (log rank) < 0.0001

16.1% 22.2% 23.4% NNT = 6.2 pts NNT = 4.5 pts NNT = 4.3 pts

Standard Rx TAVR

SLIDE 20

Mean Gradient & Valve Area

44.2 10.2 11.0 10.9 10.8 11.3 0.6 1.5 1.6 1.6 1.6 1.5

0.5 1 1.5 2 2.5 10 20 30 40 50 60 70

Baseline 159 30 Day 137 6 Month 96 1 Year 86 2 Year 70 3 Year 43

Mean Gradient (mmHg)

EOA Mean Gradient

Valve Area (cm²)

N =

Error bars = ± 1 Std Dev

SLIDE 21

Paravalvular Leak

0% 20% 40% 60% 80% 100% 30 Day 44 6 Month 45 1 Year 44 2 Year 45 3 Year 46

Valve Implant Patients

(restricted to patients with 3 year values) Severe Moderate Mild Trace None

Percent of evaluable echos

N =

SLIDE 22

Numbers at Risk Mild 78 61 54 47 43 36 26 Mod.-Severe 23 17 16 15 13 12 9 None-Trace 64 51 47 43 41 37 29

Mortality Stratified by Paravalvular Leak

Valve Implant Patients

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

26.6% 30.8% 30.4% 34.4% 43.5% 44.9% 45.6% 55.7% 57.0% None-Trace Moderate-Severe Mild

Mortality (%) Months

HR [95% CI] = 1.09 [0.82, 1.45] p (log rank) = 0.8059

SLIDE 23

Mortality Stratified by

STS Score (ITT)

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

Mortality (%) Months Months Months

STS: 0 - 4.9 STS: 5.0 - 14.9 STS ≥ 15

Standard Rx TAVR ∆ = 66.8% NNT = 1.5 pts NNT = 4.5 pts NNT = 4.8 pts ∆ = 20.8% ∆ = 22.3%

Numbers at Risk Standard Rx

12 8 7 6 5 3 123 86 61 44 33 19 13 43 27 17 12 8 5 4

TAVR

28 26 25 24 21 19 16 113 84 79 70 65 55 44 38 28 20 16 15 14 10

100% 33.2% 86.6% 65.8% 55.2% 77.5%

SLIDE 24

Non-Randomized Continued Access

Cohort B:

235 Patients Randomized PARTNER

Cohort A: 699 Patients

May 2007 – September 2009

PARTNER Secondary Analysis Pooled Cohort (ITT)

Randomized PARTNER

Cohort B: 358 Patients

2007 2008 2009

Randomized PARTNER

Cohort B

Randomized Continued Access: 91 Patients May 2007 – March 2009 March 2009 – September 2009 September 2009 – January 2012 Non-Randomized Continued Access

Cohort A:

1,833 Patients September 2009 – July 2011

SLIDE 25

Primary Outcome (Composite)

All Cause Mortality

SLIDE 26

Conclusions (1)

At 3 years follow-up benefits of TAVR were

sustained as measured by:

– All cause mortality – Cardiovascular mortality – Repeat hospitalization – Functional status

Valve durability was demonstrated with no increase

in transvalvular gradient or attrition of valve area.

Detailed analysis of all randomized inoperable

patients showed consistent results for all outcomes.

SLIDE 27

Conclusions (2)

Survival benefit of TAVR is dependent on the

presence of comorbid illness.

Without TAVR, mortality is similar irrespective
f comorbid illness.

SLIDE 28

Clinical Implications

Three year data continue to support the role of

TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.

These data underscore the importance of patient

selection before TAVR and the need for aggressive management of illnesses after TAVR.

SLIDE 29

Thank You to the Dedicated Study Teams at All PARTNER Investigational Sites

SLIDE 30

Backup Slides

SLIDE 31

n = 358 Randomized Inoperable n = 179 TAVR n = 179 Standard Therapy 124/124 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 101/102 patients* 99.0% followed at 2 Yr 56/56 patients 100% followed at 2 Yr

Study Flow

Inoperable Cohort – Crossover Patients Followed in Standard Therapy Arm

*One TAVR patient was alive and censored prior to the window
**Two TAVR patients were alive and censored prior to the window (including the one

in the same status at 2 years); one TAVR patient withdrew between 2 and 3 years

No patients were lost to follow-up

80/82 patients** 97.6% followed at 3 Yr 34/34 patients 100% followed at 3 Yr

SLIDE 32

Survival of Crossover Patients

1-2 year

n = 11

2-3 year

n = 9

Alive, n (%) Dead, n (%) Alive, n (%) Dead, n (%) 8 (72%) 3 (28%) 7 (77%) 2 (22%) Crossover Follow-up (days) Crossover Follow-up (days) 522 ± 129 323 ± 248 469 ± 178 110 ± 11

No patients crossed over after three years

SLIDE 33

Survival of Crossover Patients

Crossover Patients n 30 Day Mortality Events (%) 1 Year Mortality Events (%) Last Follow-Up Mortality Events (%) 1-2 year 11 0 (0) 1 (9) 3 (27) 2-3 year 9 0 (0) 2 (22) 2 (22) All 20 0 (0) 3 (15) 5 (20)

Follow-up of surviving patients = 497 ± 150 days

SLIDE 34

Cardiovascular Mortality (ITT)

Landmark Analysis

0% 20% 40% 60% 80% 100%

20.5% 44.6% 12.7% 32.1% 15.1% 32.2% Cardiovascular Mortality (%)

Numbers at Risk

Standard Rx

179 121 85 62 46 27 17 TAVR 179 138 124 110 101 88 70 HR [95% CI] = 0.41 [0.30, 0.56] p (log rank) < 0.0001 HR [95% CI] = 2.48 [1.56, 3.95] p (log rank) < 0.0001 HR [95% CI] = 2.09 [1.05, 4.16] p (log rank) = 0.0314 ∆ = 24.1% ∆ = 19.4% ∆ = 17.1% NNT = 4.1 pts NNT = 5.2 pts NNT = 5.8 pts 6 12 18 24 30 36

Months

Standard Rx TAVR

SLIDE 35

NYHA Class Over Time (ITT)

Survivors

0% 20% 40% 60% 80% 100% TAVR 179 Standard Rx 179 TAVR 118 Standard Rx 79 TAVR 96 Standard Rx 41 TAVR 69 Standard Rx 14 IV III II I

Baseline 1 Year 2 Year 3 Year N =

29.0% 50.0% 17.7% 56.1% 23.7% 60.8% 92.2% 93.9%

p = NS p = NS p < 0.0001 p < 0.0001

SLIDE 36

Adverse Events

Between 2 and 3 years (ITT)

3 Year

n = 179

2-3 Year

n = 179

Outcome TAVR Standard Rx TAVR Standard Rx Myocardial infarction All, % (n) 4.0 (4) 2.5 (2) 2.4 (2) 0 (0) Acute kidney injury Renal failure (CEC), % (n) 3.2 (5) 11.1 (10) 0 (0) 3.7 (1) Bleeding – major, % (n) 32.0 (51) 32.9 (28) 3.4 (3) 13.0 (3) Cardiac re-intervention BAV, % (n) 3.8 (5) 85.3 (140) 1.0 (1) 4.7 (2) TAVR, % (n) 1.7 (3) 4.5 (4) 0 (0) 0 (0) AVR, % (n) 0.9 (1) 8.9 (11) 0 (0) 0 (0) Endocarditis, % (n) 2.3 (3) 0.8 (0) 0 (0) 0 (0) New pacemaker, % (n) 7.6 (11) 8.6 (14) 1.2 (1) 0 (0)

SLIDE 37

Numbers at Risk Mild-Severe 101 78 70 62 56 48 35 None-Trace 64 51 47 43 41 37 29

Mortality Stratified by Paravalvular Leak

Valve Implant Patients

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

30.7% 26.6% 44.6% 34.4% 56.0% 45.6%

Months Mortality (%)

HR [95% CI] = 1.15 [0.76, 1.74] p (log rank) = 0.5114

∆ = 10.4% NNT = 24.4 pts NNT = 9.8 pts NNT = 9.6 pts ∆ = 4.1% ∆ = 10.2%

Mild-Severe None-Trace

SLIDE 38

Echo Analysis PV Leak Changes

30 Days Compared to 3 Years

16.6% Progressed 31.0% Improved 52.4% Unchanged 3 Year 30 Day None Trace Mild Moderate

None 7 3 Trace 5 5 2 Mild 5 1 11 2 Moderate 1 2

Of the 42 patients alive with data at 3 years: Patients With Data at Both Time Points

SLIDE 39

Numbers at Risk > 15 38 28 20 16 15 14 10 5 - 15 113 84 79 70 65 55 44 < 5 28 26 25 24 21 19 16

TAVR Mortality Stratified by STS Score (ITT)

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

10.7% 47.4% 30.1% 21.6% 60.5% 42.5% 33.2% 65.8% 55.2%

Mortality (%)

5 - 15 > 15 < 5

Months

p (log rank) = 0.0503

SLIDE 40

Patient Characteristics (1)

Pooled

Characteristic TAVR

n = 229

Standard Rx

n = 220

p value

Age – yr (SD)

83.2 (8.5) 83.0 (8.5) 0.8

Male sex (%)

48.5 47.7 0.9

STS Score (SD)

12.2 (5.4) 11.4 (6.0) 0.1

NYHA III or IV (%)

94.3 92.7 0.6

CAD (%)

73.8 65.9 0.08

Prior MI (%)

28.4 22.3 0.1

Prior CABG (%)

42.4 31.8 0.02

Prior PCI (%)

22.7 25.9 0.4

Prior BAV (%)

21.4 13.6 0.04

CVD (%)

25.8 26.8 0.6

SLIDE 41

Patient Characteristics (2)

Pooled

Characteristic TAVR

n = 229

Standard Rx

n = 220

p value

PVD (%) 24.9 30.0 0.2 COPD Any (%) O2 dependent (%) 72.9 24.7 64.3 22.0 0.1 0.8 Creatinine > 2 mg/dL (%) 8.8 5.5 0.2 Atrial fibrillation (%) 26.6 20.8 0.2

Perm. pacemaker (%)

19.7 20.5 0.9 Pulmonary HTN (%) 50.7 47.7 0.6 Frailty (%) 25.6 17.8 0.1 Porcelain aorta (%) 11.8 18.6 0.049 Chest wall radiation (%) 7.9 7.7 1.0 Chest wall deformity (%) 6.1 7.7 0.6 Liver disease (%) 3.5 5.0 0.4

SLIDE 42

Primary Outcome (Composite)

Functional Status

SLIDE 43

Primary Outcome (Composite)

Mean Gradient & AVA

SLIDE 44

Univariate and Multivariate Predictors

f Mortality after TAVR

Univariate Predictors Hazard Ratio p value

BMI > 26 0.58 (0.39 – 0.86) 0.007 Peripheral Vascular Disease 1.67 (1.13 – 2.47) 0.01 Oxygen dependent COPD 1.62 (1.05 -2.49) 0.03 History of Stroke or TIA 3.19 (1.28 – 7.92) 0.01 History of CABG 0.64 (0.42 – 0.98) 0.04

Multivariate Predictors Hazard Ratio p value

BMI > 26 0.47 (0.31 – 0.70) 0.02 Peripheral Vascular Disease 1.59 (1.07 – 2.38) 0.02 Oxygen dependent COPD 1.83 (1.17 – 2.85) 0.008 Moderate or Severe MR 0.56 (0.33 – 0.94) 0.03

SLIDE 45

Pooled Randomized

SLIDE 46

Numbers at Risk Standard Rx 229 163 118 77 56 33 17 TAVR 220 169 151 133 117 103 70

All Cause Mortality (ITT)

Pooled Randomized Crossover Patients Censored at Crossover

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

31.4% 45.5% 44.8% 64.3% 54.9% 78.0%

All Cause Mortality (%) Months

HR [95% CI] = 0.60 [0.47, 0.76] p (log rank) < 0.0001

14.1% 19.5% 23.1% NNT = 7.1 pts NNT = 5.1 pts NNT = 4.3 pts

Standard Rx TAVR

SLIDE 47

Cardiovascular Mortality (ITT)

Pooled Randomized Crossover Patients Censored at Crossover

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

21.0% 38.4% 31.2% 56.9% 41.4% 70.2%

Cardiovascular Mortality (%)

Numbers at Risk Standard Rx 229 163 118 77 56 33 17 TAVR 220 169 151 133 117 103 70

Months

HR [95% CI] = 0.47 [0.36, 0.63] p (log rank) < 0.0001

17.4% 25.7% 28.8% NNT = 5.7 pts NNT = 3.9 pts NNT = 3.5 pts

Standard Rx TAVR

SLIDE 48

All Cause Mortality (ITT)

Pooled Randomized – Landmark Analysis

0% 20% 40% 60% 80% 100%

31.4% 45.5% 19.6% 34.4% 18.3% 38.5%

All Cause Mortality (%) Months

Numbers at Risk Standard Rx 229 163 118 77 56 33 17 TAVR 220 169 151 133 117 103 70 HR [95% CI] = 1.94 [1.09, 3.45] p (log rank) = 0.0223 HR [95% CI] = 1.94 [1.33, 2.83] p (log rank) = 0.0004 HR [95% CI] = 0.60 [0.47, 0.76] p (log rank) < 0.0001 ∆ = 14.1% ∆ = 14.8% ∆ = 20.2% NNT = 7.1 pts NNT = 6.8 pts NNT = 5.0 pts

Standard Rx TAVR

6 12 18 24 30 36

SLIDE 49

Cardiovascular Mortality (ITT)

Pooled Randomized – Landmark Analysis

0% 20% 40% 60% 80% 100%

21.0% 38.4% 12.9% 30.1% 14.8% 30.9% Cardiovascular Mortality (%) Months

Numbers at Risk Standard Rx 229 163 118 77 56 33 17 TAVR 220 169 151 133 117 103 70 ∆ = 17.4% ∆ = 17.2% ∆ = 16.1% NNT = 5.7 pts NNT = 5.8 pts NNT = 6.2 pts 6 12 18 24 30 36 HR [95% CI] = 0.47 [0.36, 0.63] p (log rank) < 0.0001 HR [95% CI] = 2.44 [1.57, 3.78] p (log rank) < 0.0001 HR [95% CI] = 2.13 [1.09, 4.16] p (log rank) = 0.0229

Standard Rx TAVR

SLIDE 50

Repeat Hospitalization (ITT)

Pooled Randomized

Numbers at Risk Standard Rx 229 120 74 43 26 14 7 229 120 74 43 26 14 7 TAVR 220 142 122 106 87 73 49 220 142 122 106 87 73 49 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

47.4% 26.4% 66.5% 35.0% 71.4% 42.4% 65.4% 44.6% 83.8% 58.5% 90.6% 67.5% HR [95% CI] = 0.45 [0.33, 0.61] p (log rank) < 0.0001 29.0% NNT = 4.8 pts NNT = 3.2 pts NNT = 3.4 pts NNT = 4.8 pts NNT = 4.0 pts NNT = 4.3 pts 31.5% 21.0% 23.1% 25.3% 20.8% HR [95% CI] = 0.54 [0.44, 0.68] p (log rank) < 0.0001

Rehospitalization Mortality or Rehospitalization

Rehospitalization (%) Mortality or Rehospitalization (%) Months Months

Standard Rx TAVR

SLIDE 51

NYHA Class Over Time (ITT)

Pooled Randomized

0% 20% 40% 60% 80% 100% TAVR 220 Standard Rx 229 TAVR 214 Standard Rx 213 TAVR 209 Standard Rx 187 TAVR 201 Standard Rx 169 Dead IV III II I

Baseline 1 Year 2 Year 3 Year

p < 0.0001 p = NS p < 0.0001 p < 0.0001

60.2% 90.5% 47.9% 75.9% 35.1% 54.9% 44.1% 46.7%

N =

SLIDE 52

NYHA Class Over Time (ITT)

Pooled Randomized (Survivors)

0% 20% 40% 60% 80% 100% TAVR 220 Standard Rx 229 TAVR 145 Standard Rx 113 TAVR 111 Standard Rx 49 TAVR 81 Standard Rx 17 IV III II I

Baseline 1 Year 2 Year 3 Year

25.9% 41.2% 18.0% 53.1% 23.4% 61.9% 92.7% 94.3%

p = NS p = NS

N =

p < 0.0001 p < 0.0001

SLIDE 53

All Stroke (ITT)

Pooled Randomized

Numbers at Risk Standard Rx 229 160 117 77 56 33 17 TAVR 220 158 142 127 112 97 65

0% 10% 20% 30% 40% 50% 6 12 18 24 30 36

4.2% 10.5% 4.2% 12.7% 4.2% 14.4%

Stroke (%) Months

HR [95% CI] = 3.33 [1.51, 7.35] p (log rank) = 0.0016

∆ = 6.3% NNT = 15.9 pts NNT = 11.8 pts NNT = 9.8 pts ∆ = 8.5% ∆ = 10.2%

Standard Rx TAVR

SLIDE 54

Mortality or Stroke (ITT)

Pooled Randomized

Numbers at Risk Standard Rx 229 160 117 77 56 33 17 TAVR 220 158 142 127 112 97 65 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

45.9% 35.5% 47.1% 57.8% 64.2% 78.0%

Mortality or Stroke (%) Months

HR [95% CI] = 0.67 [0.53, 0.85] p (log rank) = 0.0008

10.4% 17.1% 20.2% NNT = 9.6 pts NNT = 5.8 pts NNT = 5.0 pts

Standard Rx TAVR

SLIDE 55

Mean Gradient & Valve Area

Pooled Randomized

43.6 10.2 10.7 10.7 10.9 11.6 0.6 1.6 1.6 1.6 1.5 1.5

0.5 1 1.5 2 2.5 10 20 30 40 50 60 70

Baseline 196 30 Day 168 6 Month 120 1 Year 107 2 Year 82 3 Year 49

Mean Gradient (mmHg)

EOA Mean Gradient

Valve Area (cm²)

N =

Error bars = ± 1 Std Dev

SLIDE 56

Paravalvular Leak

Pooled Randomized

0% 20% 40% 60% 80% 100% 30 Day 50 6 Month 50 1 Year 50 2 Year 51 3 Year 52

Valve Implant Patients

(restricted to patients with 3 year values)

Severe Moderate Mild Trace None

Percent of evaluable echos

N =

SLIDE 57

Mortality Stratified by Paravalvular Leak (ITT)

Pooled Randomized – Valve Implant Patients

Numbers at Risk Mild-Severe 123 95 83 72 62 54 35 None-Trace 81 65 61 55 51 46 29 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

32.5% 24.7% 48.1% 33.6% 59.0% 43.0%

Months Mortality (%)

HR [95% CI] = 1.32 [0.90, 1.94] p (log rank) = 0.1483

∆ = 16.0% NNT = 12.8 pts NNT = 6.9 pts NNT = 6.3 pts ∆ = 7.8% ∆ = 14.5%

Mild-Severe None-Trace

SLIDE 58

Mortality Stratified by Paravalvular Leak (ITT)

Pooled Randomized – Valve Implant Patients

Numbers at Risk Mod.-Severe 33 25 22 20 15 14 9 Mild 90 70 61 52 47 40 26 None-Trace 81 65 61 55 51 46 29 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

24.7% 33.3% 32.2% 33.6% 47.8% 49.5% 43.0% 60.4% 58.7%

Mortality (%) Months

HR [95% CI] = 1.18 [0.92, 1.51] p (log rank) = 0.3517 None-Trace Mild Moderate-Severe

SLIDE 59

Mortality Stratified by STS Score (ITT)

Pooled Randomized

Numbers at Risk > 15 47 33 25 20 17 16 10 5 - 15 141 106 97 85 77 66 44 < 5 32 30 29 28 23 21 16 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

9.4% 46.8% 31.2% 25.4% 63.8% 42.8% 35.9% 68.1% 54.8%

Mortality (%) Months

p (log rank) = 0.0168

5 - 15 > 15 < 5

SLIDE 60

Mortality Stratified by STS Score (ITT)

Pooled Randomized

0% 20% 40% 60% 80% 100% 6 12 18 24 30 36 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36 0% 20% 40% 60% 80% 100% 6 12 18 24 30 36

Mortality (%) Months Months Months

STS: 0 - 4.9 STS: 5.0 - 14.9 STS ≥ 15

∆ = 64.1% NNT = 1.6 pts NNT = 5.1 pts NNT = 6.7 pts ∆ = 15.0% ∆ = 19.6%

Numbers at Risk Standard Rx

16 11 9 6 5 3 154 113 84 56 41 24 13 58 39 25 15 10 6 4

TAVR

32 30 29 28 23 21 16 141 106 97 85 77 66 44 47 33 25 20 17 16 10

100% 35.9% 83.1% 68.1% 54.8% 74.4% Standard Rx TAVR