1. TCT 2012 | Miami, FL | October 24, 2012 Three-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) inInoperable Patients With Severe Aortic Stenosis: The PARTNER Trial Samir R. Kapadia, MD On behalf of The PARTNER Trial Investigators

2. Samir Kapadia –No financial disclosures – Member of PARTNER Trial steering committee Murat Tuzcu –No financial disclosures – Member of PARTNER Trial executive committee

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

4. Background (2)

5. Objectives To evaluate the clinical outcomes of TAVR compared to standard therapy at 3 years ininoperable aortic stenosis patients.To evaluate the clinical outcomes of TAVR compared to standard therapy at 3 years ininoperable aortic stenosis patients. To assess valve hemodynamics and durability using echocardiography.To assess valve hemodynamics and durability using echocardiography. To perform subgroup analyses to better define the impact of co-morbidities on outcomes.To perform subgroup analyses to better define the impact of co-morbidities on outcomes.

6. PARTNER Study Design n = 358 Inoperable Standard Therapy n = 179 Standard Therapy n = 179 ASSESSMENT: Transfemoral Access TF TAVR n = 179 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.Primary endpoint evaluated when all patients reached one year follow-up. After primary endpoint analysis reached, patients were allowed to cross-over to TAVR.After primary endpoint analysis reached, patients were allowed to cross-over to TAVR.

7. Inclusion Criteria Severe calcific aortic stenosis defined as echo derived valve area of 40 mmHg or jet velocity > 4.0 m/s.Severe calcific aortic stenosis defined as echo derived valve area of 40 mmHg or jet velocity > 4.0 m/s. NYHA functional class IINYHA functional class II Inoperable defined as risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons exceeding 50%.Inoperable defined as risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons exceeding 50%.

8. Key End-Points for 3 Year Analysis All cause mortalityAll cause mortality Cardiac mortalityCardiac mortality RehospitalizationRehospitalization Adverse outcomes including stroke, bleeding, renal failure, and MIAdverse outcomes including stroke, bleeding, renal failure, and MI NYHA functional classNYHA functional class Days alive and out of hospitalDays alive and out of hospital Echo-derived valve areas, transvalvular gradients, and paravalvular aortic regurgitationEcho-derived valve areas, transvalvular gradients, and paravalvular aortic regurgitation Mortality outcomes stratified by STS scoreMortality outcomes stratified by STS score

9. n = 358 Randomized Inoperable n = 358 Randomized Inoperable n = 179 TAVR n = 179 TAVR n = 179 Standard Therapy n = 179 Standard Therapy 124/124 patients 100% followed at 1 Yr 124/124 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 101/102 patients* 99.0% followed at 2 Yr 101/102 patients* 99.0% followed at 2 Yr 46/46 patients 100% 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*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**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-upNo 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 patients 100% followed at 3 Yr 19/19 patients 100% followed at 3 Yr Cross over 11 pts Cross over 9 pts

10. Statistical Method Primary analysis was by intention-to-treat (ITT).Primary analysis was by intention-to-treat (ITT). Clinical outcomes were analyzed by ITT with censoring of Standard Rx cross-over patients.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.Additional analysis of death was performed by following cross-over patients with their randomized trial arms. Event rates are given as Kaplan-Meier estimates.Event rates are given as Kaplan-Meier estimates. Core lab echo results are presented from the valve implant population (valve retained in position).Core lab echo results are presented from the valve implant population (valve retained in position).

11. Patient Characteristics (1) CharacteristicTAVR n = 179 Standard Rx n = 179 p value Age – yr 83.1 ± 8.683.2 ± 8.30.95 Male sex (%) 45.846.90.92 STS Score 11.2 ± 5.812.1 ± 6.10.14 NYHA I or II (%) I or II (%) III or IV (%) III or IV (%) 7.8 92.2 6.1 93.9 0.68 CAD (%) 67.674.30.20 Prior MI (%) 18.626.40.10 Prior CABG (%) 37.445.60.17 Prior PCI (%) 30.524.80.31 Prior BAV (%) 16.224.40.09 CVD (%) 27.427.51.00 Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

12. Patient Characteristics (2) Characteristic TAVR n = 179 Standard Rx n = 179 p value PVD (%) 30.325.10.29 COPD Any (%) Any (%) O 2 dependent (%) O 2 dependent (%) 41.3 21.2 52.5 25.7 0.04 0.38 Creatinine > 2 mg/dL (%) 5.69.60.23 Atrial fibrillation (%) 32.948.80.04 Perm. pacemaker (%) 22.919.50.49 Pulmonary HTN (%) 42.443.80.90 Frailty (%) 18.128.00.09 Porcelain aorta (%) 19.011.20.05 Chest wall radiation (%) 8.98.41.00 Chest wall deformity (%) 8.45.00.29 Liver disease (%) 3.4 1.00 Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

13. Numbers at Risk Standard Rx 179121 85 85 62 62 46 462717 TAVR1791381241101018870 All Cause Mortality (ITT) Crossover Patients Censored at Crossover 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

14. Cardiovascular Mortality (ITT) Crossover Patients Censored at Crossover 20.5% 44.6% 30.7% 62.4% 41.4% 74.5% Cardiovascular Mortality (%) Numbers at Risk Standard Rx 179121 85 85 62 62 46 462717 TAVR1791381241101018870 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

15. Months Numbers at Risk Standard Rx 179121 85 85 62 62 46 462717 TAVR1791381241101018870 0612 1824 3036 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

16. 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 86 49 49301911 7179 86 86 49 49301911 7 TAVR1791151008977644917911510089776449 Months Rehospitalization (%)Mortality or Rehospitalization (%) Rehospitalization MortalityorRehospitalization 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]

17. NYHA Class Over Time (ITT) Baseline1 Year2 Year3 Year p < 0.0001 N = p = NS p < 0.0001 58.8% 91.1% 45.7% 76.9% 34.7% 59.3% 43.6% 45.3%

18. All Stroke (ITT) 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 TAVR179128116105968265 Standard Rx Standard Rx179118 84 84 62 62462717

19. Numbers at Risk Standard Rx Standard Rx179118 84 84 62 62462717 TAVR TAVR179128116105968265 Mortality or Stroke (ITT) 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

20. Mean Gradient & Valve Area Mean Gradient (mmHg) EOA Mean Gradient Valve Area (cm²) N = Error bars = ± 1 Std Dev

21. Paravalvular Leak Percent of evaluable echos N =

22. Mortality Stratified by STS Score (ITT) Mortality (%) Months STS: 0 - 4.9 STS: 5.0 - 14.9 STS 15 Standard Rx TAVR = 66.8% NNT = 1.5 ptsNNT = 4.5 ptsNNT = 4.8 pts = 20.8% = 22.3% Numbers at Risk Standard Rx 1287653012386614433191343271712854 TAVR2826252421191611384797065554438282016151410 100% 33.2% 86.6% 65.8% 55.2% 77.5%

23. Non-Randomized Continued Access Cohort B: 235 Patients Non-Randomized Continued Access Cohort B: 235 Patients Randomized PARTNER Cohort A: 699 Patients Randomized PARTNER Cohort A: 699 Patients May 2007 – September 2009 PARTNER Secondary Analysis Pooled Cohort (ITT) Randomized PARTNER Cohort B: 358 Patients Randomized PARTNER Cohort B: 358 Patients 200720082009 Randomized PARTNER Cohort B Randomized Continued Access: 91 Patients 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 Non-Randomized Continued Access Cohort A: 1,833 Patients September 2009 – July 2011

24. Primary Outcome (Composite) All Cause Mortality

25. Conclusions (1) At 3 years follow-up benefits of TAVR were sustained as measured by: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.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.Detailed analysis of all randomized inoperable patients showed consistent results for all outcomes.

26. Conclusions (2) Survival benefit of TAVR is dependent on the presence of comorbid illness.Survival benefit of TAVR is dependent on the presence of comorbid illness. Without TAVR, mortality is similar irrespective of comorbid illness.Without TAVR, mortality is similar irrespective of comorbid illness.

27. 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.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.These data underscore the importance of patient selection before TAVR and the need for aggressive management of illnesses after TAVR.

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

30. Backup Slides

31. n = 358 Randomized Inoperable n = 358 Randomized Inoperable n = 179 TAVR n = 179 TAVR n = 179 Standard Therapy n = 179 Standard Therapy 124/124 patients 100% followed at 1 Yr 124/124 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 101/102 patients* 99.0% followed at 2 Yr 101/102 patients* 99.0% followed at 2 Yr 56/56 patients 100% 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*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**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-upNo 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 patients 100% followed at 3 Yr 34/34 patients 100% followed at 3 Yr

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) 522 ± 129323 ± 248469 ± 178110 ± 11 No patients crossed over after three yearsNo patients crossed over after three years

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) All20 0 (0) 3 (15) 5 (20) Follow-up of surviving patients = 497 ± 150 days

34. Cardiovascular Mortality (ITT) Landmark Analysis 20.5% 44.6% 12.7% 32.1% 15.1% 32.2% Cardiovascular Mortality (%) Numbers at Risk Standard Rx 179121 85 85 62 62 46 462717 TAVR1791381241101018870 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 061218243036 Months Standard Rx TAVR

35. NYHA Class Over Time (ITT) Survivors Baseline1 Year2 Year3 Year N = 29.0% 50.0% 17.7% 56.1% 23.7% 60.8% 92.2% 93.9% p = NS p < 0.0001

36. Adverse Events Between 2 and 3 years (ITT) 3 Year n = 179 2-3 Year n = 179 OutcomeTAVR Standard Rx TAVR 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) AVR, % (n)0.9 (1)8.9 (11)0 (0) Endocarditis, % (n) 2.3 (3)0.8 (0)0 (0) New pacemaker, % (n) 7.6 (11)8.6 (14)1.2 (1)0 (0)

37. Numbers at Risk Mild-Severe101787062564835 None-Trace 64 64514743413729 Mortality Stratified by Paravalvular Leak Valve Implant Patients 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

38. Echo Analysis PV Leak Changes 30 Days Compared to 3 Years 16.0% Progressed 31.8% Improved 52.3% Unchanged 3 Year 30 Day NoneTraceMildModerate None7300 Trace5520 Mild51112 Moderate0120 Of the 44 patients alive with data at both 30 days and 3 years: Patients With Data at Both Time Points

39. Numbers at Risk > 15 > 15 38 38282016151410 5 - 15 5 - 15113847970655544 < 5 < 5 28 28262524211916 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% Mortality (%) 5 - 15 > 15 < 5 Months p (log rank) = 0.0503

40. Patient Characteristics (1) Pooled CharacteristicTAVR n = 229 Standard Rx n = 220 p value Age – yr (SD) 83.2 (8.5) 83.0 (8.5) 0.8 Male sex (%) 48.547.70.9 STS Score (SD) 12.2 (5.4) 11.4 (6.0) 0.1 NYHA III or IV (%) 94.392.70.6 CAD (%) 73.865.90.08 Prior MI (%) 28.422.30.1 Prior CABG (%) 42.431.80.02 Prior PCI (%) 22.725.90.4 Prior BAV (%) 21.413.60.04 CVD (%) 25.826.80.6

41. Patient Characteristics (2) Pooled Characteristic TAVR n = 229 Standard Rx n = 220 p value PVD (%) 24.930.00.2 COPD Any (%) Any (%) O 2 dependent (%) O 2 dependent (%)72.924.764.322.00.10.8 Creatinine > 2 mg/dL (%) 8.85.50.2 Atrial fibrillation (%) 26.620.80.2 Perm. pacemaker (%) 19.720.50.9 Pulmonary HTN (%) 50.747.70.6 Frailty (%) 25.617.80.1 Porcelain aorta (%) 11.818.60.049 Chest wall radiation (%) 7.97.71.0 Chest wall deformity (%) 6.17.70.6 Liver disease (%) 3.55.00.4

42. Primary Outcome (Composite) Functional Status

43. Primary Outcome (Composite) Mean Gradient & AVA

44. 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

45. Pooled Randomized

46. Numbers at Risk Standard Rx Standard Rx229163118 77 77 56 56 33 3317 TAVR TAVR22016915113311710370 All Cause Mortality (ITT) Pooled Randomized Crossover Patients Censored at Crossover 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

47. Cardiovascular Mortality (ITT) Pooled Randomized Crossover Patients Censored at Crossover 21.0% 38.4% 31.2% 56.9% 41.4% 70.2% Cardiovascular Mortality (%) Numbers at Risk Standard Rx Standard Rx229163118 77 77 56 56 33 3317 TAVR TAVR22016915113311710370 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

48. All Cause Mortality (ITT) Pooled Randomized – Landmark Analysis 31.4% 45.5% 19.6% 34.4% 18.3% 38.5% All Cause Mortality (%) Months Numbers at Risk Standard Rx 229163118 77 77 56 56 33 3317 TAVR22016915113311710370 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 ptsNNT = 6.8 ptsNNT = 5.0 pts Standard Rx TAVR 061218243036

49. Cardiovascular Mortality (ITT) Pooled Randomized – Landmark Analysis 21.0% 38.4% 12.9% 30.1% 14.8% 30.9% Cardiovascular Mortality (%) Months Numbers at Risk Standard Rx 229163118 77 77 56 56 33 3317 TAVR22016915113311710370 = 17.4% = 17.2% = 16.1% NNT = 5.7 pts NNT = 5.8 pts NNT = 6.2 pts 061218243036 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

50. Repeat Hospitalization (ITT) Pooled Randomized Numbers at Risk Standard Rx 229120 74 74 43 432614 7229120 74 74 43 432614 7 TAVR220142122106877349220142122106877349 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 MortalityorRehospitalization Mortality or Rehospitalization Rehospitalization (%)Mortality or Rehospitalization (%) Months Standard Rx TAVR

51. NYHA Class Over Time (ITT) Pooled Randomized Baseline1 Year2 Year3 Year p < 0.0001p = NS p < 0.0001 60.2% 90.5% 47.9% 75.9% 35.1% 54.9% 44.1% 46.7% N =

52. NYHA Class Over Time (ITT) Pooled Randomized (Survivors) Baseline1 Year2 Year3 Year 25.9% 41.2% 18.0% 53.1% 23.4% 61.9% 92.7% 94.3% p = NS N = p < 0.0001

53. All Stroke (ITT) Pooled Randomized Numbers at Risk Standard Rx Standard Rx22916011777563317 TAVR TAVR2201581421271129765 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

54. Mortality or Stroke (ITT) Pooled Randomized Numbers at Risk Standard Rx Standard Rx22916011777563317 TAVR TAVR2201581421271129765 45.9% 35.5% 47.1% 57.8% 64.2% 78.0% Mortality or Stroke (%) 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 Months

55. Mean Gradient & Valve Area Pooled Randomized Mean Gradient (mmHg) EOA Mean Gradient Valve Area (cm²) N = Error bars = ± 1 Std Dev

56. Paravalvular Leak Pooled Randomized Percent of evaluable echos N =

57. Mortality Stratified by Paravalvular Leak (ITT) Pooled Randomized – Valve Implant Patients Numbers at Risk Mild-Severe123958372625435 None-Trace81656155514629 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

58. Mortality Stratified by Paravalvular Leak (ITT) Pooled Randomized – Valve Implant Patients Numbers at Risk Mod.-Severe3325222015149 Mild90706152474026 None-Trace81656155514629 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

59. Mortality Stratified by STS Score (ITT) Pooled Randomized Numbers at Risk > 15 > 1547332520171610 5 - 15 5 - 151411069785776644 < 5 < 532302928232116 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

60. Mortality Stratified by STS Score (ITT) Pooled Randomized Mortality (%) Months STS: 0 - 4.9 STS: 5.0 - 14.9 STS 15 = 64.1% NNT = 1.6 ptsNNT = 5.1 ptsNNT = 6.7 pts = 15.0% = 19.6% Numbers at Risk Standard Rx 1611965301541138456412413583925151064 TAVR32302928232116141106978577664447332520171610 100% 35.9% 83.1% 68.1% 54.8% 74.4% Standard Rx TAVR

61. Stroke – Between year 2-3 ITT arm Age Days post randomization DescriptionComorbidity Procedure related* Device related* Comments TAVR97879Ischemic Blood stream infection, Right carotid stenosis (80%) NoNo Cerebellar infarct; Linear echodensity on mitral valve, Ao valve: Mild AI TAVR87837 Acute infarct with surrounding intraparenchymal bleed Atrial Fibrillation not on warfarin NoNo Cerebellar infarct/ hemorrhage; Ao valve: Ok *CEC adjudicated

62. Numbers at Risk Mild78615447433626 Mod.-Severe231716151312 9 None-Trace64514743413729 Mortality Stratified by Paravalvular Leak Valve Implant Patients 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