Samir R. Kapadia, MD On behalf of The PARTNER Trial Investigators

1. Five-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 • TCT 2014 | September 13, 2014

2. Background • Transcatheter aortic valve replacement (TAVR) is the recommended treatment for “inoperable” patients with severe aortic stenosis (AS). • Long term clinical benefit and valve performance in this population remain unknown.

3. PARTNER Study Design Symptomatic Severe Aortic Stenosis Inoperable N = 358 Severe Symptomatic AS with AVA< 0.8 cm2 (EOA index < 0.5 cm2/m2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s Inoperable defined as risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons exceeding 50%. ASSESSMENT: Transfemoral Access 1:1 Randomization TF TAVR n = 179 Standard Therapy n = 179 VS Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) • Primary endpoint evaluated when all patients reached one year follow-up. • After primary endpoint analysis reached, patients were allowed to cross-over to TAVR.

4. Key End-Points for 5 Year Analysis • All-Cause Mortality • Cardiac Mortality • Re-hospitalization • Stroke • NYHA functional class • Echo-derived valve areas, transvalvular gradients, and paravalvular leak. • Mortality outcomes stratified by STS score, paravalvular leak and age.

5. Study FlowInoperable Cohort N = 358 Randomized Inoperable N = 179 Standard Therapy N = 179 TAVR 10 Patients Withdrew 85 / 85 patients 100% followed at 1 Yr 124 / 124 patients 100% followed at 1 Yr Cross Over 11 pts 19 / 19 patients 100% followed at 3 Yrs 81 / 83 patients 97.6% followed at 3 Yrs Cross Over 9 pts 6 / 6 patients 100% followed at 5 Yrs* 50 / 51 patients 98.0% followed at 5 Yrs* * ± 2 months follow-up window

6. Patient Characteristics

7. All-Cause Mortality (ITT) Crossover Patients Censored at Crossover Standard Rx (n = 179) TAVR (n = 179) 93.6% 87.5% 80.9% 68.0% 71.8% 50.8% 64.1% All-Cause Mortality (%) 53.9% 43.0% 30.7% • HR [95% CI] = 0.50 [0.39, 0.65] • p (log rank) < 0.0001 Months * In an age and gender matched US population without comorbidities, the mortality at 5 years is 40.5%.

8. Median Survival 11.1 Months • p (log rank) < 0.0001 29.7 Months Months

9. All-Cause Mortality (ITT)Landmark Analysis Standard Rx (n = 179) TAVR (n = 179) • HR [95% CI] = 0.50 [0.39, 0.65] • p (log rank) < 0.0001 • HR [95% CI] = 0.46 [0.32, 0.66] • p (log rank) < 0.0001 • HR [95% CI] = 0.47 [0.24, 0.94] • p (log rank) = 0.028 66.7% 0-1 Year 1-3 Years 61.1% 3-5 Years 50.8% All-Cause Mortality (%) 38.9% 33.4% 30.7% Months

10. Cardiovascular Mortality (ITT)Crossover Patients Censored at Crossover Standard Rx (n = 179) TAVR (n = 179) 85.9% 80.6% 74.5% 62.4% 44.6% Cardiovascular Mortality (%) 57.3% 47.6% 41.2% 30.7% • HR [95% CI] = 0.41 [0.31, 0.55] • p (log rank) < 0.0001 20.5% Months

11. Causes of Death 18% vs 34% 48% vs 33% Percent Patients n=179 n=179

12. All-Cause Mortality Stratified by STS Score (ITT) Standard Rx (n = 12) Standard Rx (n = 123) Standard Rx (n = 43) TAVR (n = 28) TAVR (n = 113) TAVR (n = 38) STS < 5 STS 5-15 STS > 15 • p (log rank) = 0.0012 • p (log rank) = 0.0002 • p (log rank) = 0.0749 100% 93.4% 93.3% 75.2% 73.7% 55.9% Mortality (%) Months Months Months

13. Cardiovascular Mortality Stratified by STS Score (ITT) Standard Rx (n = 12) Standard Rx (n = 123) Standard Rx (n = 43) TAVR (n = 28) TAVR (n = 113) TAVR (n = 38) STS < 5 STS 5-15 STS > 15 • p (log rank) < 0.0001 • p (log rank) < 0.0001 • p (log rank) = 0.0098 100% 91.8% 82.4% 61.6% 57.8% Mortality (%) 41.1% Months Months Months

14. Repeat Hospitalization (ITT) Standard Rx (n = 179) TAVR (n = 179) 87.3% 83.0% 75.7% 72.5% 53.9% Rehospitalization (%) 47.6% 46.3% 43.1% 34.9% 27.0% • HR [95% CI] = 0.40 [0.29, 0.55] • p (log rank) < 0.0001 Months

15. NYHA Class Over Time (ITT)Survivors p = NS p = NS p = NS p < 0.0001 14.3% 23.7% 30.0% 40.0% 50.0% 60.8% 92.2% 93.9% N = Baseline 1 Year 3 Years 5 Years

16. Competing Risks Analysis (ITT)Death and Stroke Incidence (%) 14.6% 5.7% Months

17. Paravalvular Leak (AT) Percent of Evaluable Echocardiograms N =

18. Mortality by Paravalvular Leak None-Mild (n = 142) None-Mild (n = 142) Moderate-Severe (n = 23) Moderate-Severe (n = 23) All-Cause Mortality Cardiovascular Mortality 78.3% 74.6% 69.2% 51.3% • p (log rank) = 0.510 • p (log rank) = 0.043

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

20. Mean Gradient & Valve Area (AT) Restricted to Patients with 5 Year Data EOA Mean Gradient • Error bars = ± 1 Std Dev Mean Gradient (mmHg) Valve Area (cm²) N =

21. Subgroup AnalysisAll-Cause Mortality

22. TAVR Mortality Stratified by Age (ITT) 96.0% 91.8% 73.5% 70.4% Mortality (%) Months

23. Clinical Observations • Mortality benefit was similar in elderly (>85 yr) patients compared to those ≤85 years. • Cardiovascular mortality and all-cause mortality benefit was seen even in patients with high STS score. • Patients with O2 dependent COPD may have less mortality benefit. • Beyond early procedural risk of stroke there was no persistent risk over 5-year follow up. • Moderate and severe paravalvular leak is associated with higher cardiovascular mortality particularly in patients with less comorbidities.

24. Main Conclusions • At 5 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.

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