tct 2012 | miami, fl | october 24, 2012 three-year outcomes of transcatheter aortic valve...

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

• Samir Kapadia – No financial disclosures

– Member of PARTNER Trial steering committee

• Murat Tuzcu– No financial disclosures

– Member of PARTNER Trial executive committee

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.

Background (2)

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.

PARTNER Study Design

n = 358Inoperable

StandardTherapyn = 179

ASSESSMENT: Transfemoral

Access

TF TAVRn = 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.

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 or 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%.

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

n = 358Randomized Inoperable

n = 179TAVR

n = 179Standard Therapy

124/124 patients100% followed at 1 Yr

124/124 patients100% followed at 1 Yr

85/85 patients100% followed at 1 Yr

85/85 patients100% followed at 1 Yr

101/102 patients*99.0% followed at 2 Yr

101/102 patients*99.0% followed at 2 Yr

46/46 patients100% followed at 2 Yr

46/46 patients100% followed at 2 Yr

Study FlowInoperable 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

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

19/19 patients100% followed at 3 Yr

19/19 patients100% followed at 3 Yr

Cross over 11 pts

Cross over 9 pts

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).

Patient Characteristics (1)

Characteristic TAVRn = 179

Standard Rxn = 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 (%)

7.892.2

6.193.9

0.680.68

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.

Patient Characteristics (2)

Characteristic TAVRn = 179

Standard Rxn = 179

p value

PVD (%) 30.3 25.1 0.29

COPD Any (%) O2 dependent (%)

41.321.2

52.525.7

0.040.38

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.

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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

30.7%

50.8%

43.0%

68.0%

54.1%

80.9%

All

Cau

se M

orta

lity

(%)

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 RxTAVR

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Cardiovascular Mortality (ITT)Crossover Patients Censored at Crossover

20.5%

44.6%

30.7%

62.4%

41.4%

74.5%

Car

diov

ascu

lar

Mor

talit

y (%

)

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 RxTAVR

0%

20%

40%

60%

80%

100%

MonthsNumbers at Risk

Standard Rx 179 121 85 62 46 27 17

TAVR 179 138 124 110 101 88 70

0 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

Cau

se M

orta

lity

(%)

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 RxTAVR

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 360%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Repeat Hospitalization (ITT)

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 7TAVR 179 115 100 89 77 64 49 179 115 100 89 77 64 49

Months Months

Reh

ospi

taliz

atio

n (%

)

Mor

talit

y or

Reh

ospi

taliz

atio

n (%

)

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 pts37.6%

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

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

NYHA Class Over Time (ITT)

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%

0%

10%

20%

30%

40%

50%

0 6 12 18 24 30 36

All Stroke (ITT)

5.5%

11.2%

5.5%

13.7%

5.5%

15.7%Str

oke

(%)

Months

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

∆ = 5.7%

NNT = 17.5 ptsNNT = 12.2 pts

NNT = 9.8 pts

∆ = 8.2%∆ = 10.2%

Standard RxTAVR

Numbers at Risk

TAVR 179 128 116 105 96 82 65

Standard Rx 179 118 84 62 46 27 17

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Numbers at Risk

Standard Rx 179 118 84 62 46 27 17

TAVR 179 128 116 105 96 82 65

Mortality or Stroke (ITT)

51.3%

35.2%

45.8%

57.5%

68.0%

80.9%

Mor

talit

y or

Str

oke

(%)

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 RxTAVR

44.2

10.211.0 10.9 10.8 11.3

0.6

1.5

1.6 1.6 1.6 1.5

0

0.5

1

1.5

2

2.5

0

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 & Valve AreaM

ean

Gra

dien

t (m

mH

g)

EOAMean Gradient

Val

ve A

rea

(cm

²)

N =

Error bars = ± 1 Std Dev

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

Paravalvular LeakP

erce

nt o

f eva

luab

le e

chos

N =

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 360%

20%

40%

60%

80%

100%

0 6 12 18 24 30 360%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Mortality Stratified by STS Score (ITT)

Mor

talit

y (%

)

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 0 123 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%

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 BRandomized 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

Primary Outcome (Composite)All Cause Mortality

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.

Conclusions (2)

• Survival benefit of TAVR is dependent on the presence of comorbid illness.

• Without TAVR, mortality is similar irrespective of comorbid illness.

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.

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

Backup Slides

n = 358Randomized Inoperable

n = 179TAVR

n = 179Standard Therapy

124/124 patients100% followed at 1 Yr

124/124 patients100% followed at 1 Yr

85/85 patients100% followed at 1 Yr

85/85 patients100% followed at 1 Yr

101/102 patients*99.0% followed at 2 Yr

101/102 patients*99.0% followed at 2 Yr

56/56 patients100% followed at 2 Yr

56/56 patients100% followed at 2 Yr

Study FlowInoperable 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

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

34/34 patients100% followed at 3 Yr

34/34 patients100% followed at 3 Yr

Survival of Crossover Patients

1-2 yearn = 11

2-3 yearn = 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

Survival of Crossover Patients

Crossover Patients n 30 Day MortalityEvents (%)

1 Year MortalityEvents (%)

Last Follow-Up MortalityEvents (%)

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

0%

20%

40%

60%

80%

100%

Cardiovascular Mortality (ITT)Landmark Analysis

20.5%

44.6%

12.7%

32.1%

15.1%

32.2%

Car

diov

ascu

lar

Mor

talit

y (%

)

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

0 6 12 18 24 30 36

Months

Standard RxTAVR

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

NYHA Class Over Time (ITT)Survivors

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 = NSp = NS p < 0.0001 p < 0.0001

Adverse EventsBetween 2 and 3 years (ITT)

3 Yearn = 179

2-3 Yearn = 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)

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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

30.7%

26.6%

44.6%

34.4%

56.0%

45.6%

Months

Mor

talit

y (%

)

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-SevereNone-Trace

Echo Analysis PV Leak Changes 30 Days Compared to 3 Years

16.0% Progressed31.8% Improved 52.3% Unchanged

3 Year

30 Day None Trace Mild Moderate

None 7 3 0 0

Trace 5 5 2 0

Mild 5 1 11 2

Moderate 0 1 2 0

Of the 44 patients alive with data at both 30 days and 3 years:

Patients With Data at Both Time Points

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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)

10.7%

47.4%

30.1%

21.6%

60.5%

42.5%

33.2%

65.8%

55.2%

Mor

talit

y (%

)

5 - 15> 15

< 5

Months

p (log rank) = 0.0503

Patient Characteristics (1)Pooled

Characteristic TAVRn = 229

Standard Rxn = 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

Patient Characteristics (2)Pooled

Characteristic TAVRn = 229

Standard Rxn = 220

p value

PVD (%) 24.9 30.0 0.2

COPD Any (%) O2 dependent (%)

72.924.7

64.322.0

0.10.8

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

Primary Outcome (Composite)Functional Status

Primary Outcome (Composite)Mean Gradient & AVA

Univariate and Multivariate Predictors of 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

Pooled Randomized

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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 RandomizedCrossover Patients Censored at Crossover

31.4%

45.5%

44.8%

64.3%

54.9%

78.0%

All

Cau

se M

orta

lity

(%)

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 RxTAVR

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Cardiovascular Mortality (ITT)Pooled RandomizedCrossover Patients Censored at Crossover

21.0%

38.4%

31.2%

56.9%

41.4%

70.2%

Car

diov

ascu

lar

Mor

talit

y (%

)

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 RxTAVR

0%

20%

40%

60%

80%

100%

All Cause Mortality (ITT)Pooled Randomized – Landmark Analysis

31.4%

45.5%

19.6%

34.4%

18.3%

38.5%

All

Cau

se M

orta

lity

(%)

MonthsNumbers 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 RxTAVR

0 6 12 18 24 30 36

0%

20%

40%

60%

80%

100%

Cardiovascular Mortality (ITT)Pooled Randomized – Landmark Analysis

21.0%

38.4%

12.9%

30.1%

14.8%

30.9%

Car

diov

ascu

lar

Mor

talit

y (%

)

MonthsNumbers 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

0 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 RxTAVR

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 360%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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

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 pts31.5%

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

Reh

ospi

taliz

atio

n (%

)

Mor

talit

y or

Reh

ospi

taliz

atio

n (%

)

Months Months

Standard Rx

TAVR

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

NYHA Class Over Time (ITT)Pooled Randomized

Baseline 1 Year 2 Year 3 Year

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

60.2%

90.5%

47.9%

75.9%

35.1%

54.9%

44.1% 46.7%

N =

0%

20%

40%

60%

80%

100%

TAVR

220

StandardRx

229

TAVR

145

Standard Rx

113

TAVR

111

Standard Rx

49

TAVR

81

Standard Rx

17

IV

III

II

I

NYHA Class Over Time (ITT)Pooled Randomized (Survivors)

Baseline 1 Year 2 Year 3 Year

25.9%

41.2%

18.0%

53.1%

23.4%

61.9%

92.7% 94.3%

p = NSp = NS

N =

p < 0.0001 p < 0.0001

0%

10%

20%

30%

40%

50%

0 6 12 18 24 30 36

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

4.2%

10.5%

4.2%

12.7%

4.2%

14.4%Str

oke

(%)

Months

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

∆ = 6.3%

NNT = 15.9 ptsNNT = 11.8 pts

NNT = 9.8 pts

∆ = 8.5% ∆ = 10.2%

Standard RxTAVR

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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

45.9%

35.5%

47.1%

57.8%

64.2%

78.0%

Mor

talit

y or

Str

oke

(%)

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 RxTAVR

Months

43.6

10.210.7 10.7 10.9 11.6

0.6

1.6

1.6 1.6 1.5 1.5

0

0.5

1

1.5

2

2.5

0

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 & Valve AreaPooled Randomized

Mea

n G

radi

ent (

mm

Hg)

EOAMean Gradient

Val

ve A

rea

(cm

²)

N =

Error bars = ± 1 Std Dev

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

Paravalvular LeakPooled Randomized

Per

cent

of e

valu

able

ech

os

N =

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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

32.5%

24.7%

48.1%

33.6%

59.0%

43.0%

Months

Mor

talit

y (%

)

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-SevereNone-Trace

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Mortality Stratified by Paravalvular Leak (ITT)Pooled Randomized – Valve Implant Patients

Numbers at Risk

Mod.-Severe 33 25 22 20 15 14 9Mild 90 70 61 52 47 40 26None-Trace 81 65 61 55 51 46 29

24.7%

33.3%

32.2%

33.6%

47.8%

49.5%

43.0%

60.4%

58.7%

Mor

talit

y (%

)

Months

HR [95% CI] = 1.18 [0.92, 1.51]p (log rank) = 0.3517

None-TraceMildModerate-Severe

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

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

9.4%

46.8%

31.2%25.4%

63.8%

42.8%

35.9%

68.1%

54.8%

Mor

talit

y (%

)

Months

p (log rank) = 0.01685 - 15> 15

< 5

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 360%

20%

40%

60%

80%

100%

0 6 12 18 24 30 360%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Mortality Stratified by STS Score (ITT)Pooled Randomized

Mor

talit

y (%

)

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 0 154 113 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

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

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36

Numbers at Risk

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

Mortality Stratified by Paravalvular LeakValve Implant Patients

26.6%

30.8%

30.4%

34.4%

43.5%

44.9%

45.6%

55.7%

57.0%

None-TraceModerate-SevereMild

Mor

talit

y (%

)

Months

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