TCT 2014 | September 13, 2014 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

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

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. Severe Symptomatic AS with AVA 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%.

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

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 81 / 83 patients 97.6% followed at 3 Yrs 81 / 83 patients 97.6% followed at 3 Yrs 19 / 19 patients 100% followed at 3 Yrs 19 / 19 patients 100% followed at 3 Yrs Study Flow Inoperable Cohort 50 / 51 patients 98.0% followed at 5 Yrs* 50 / 51 patients 98.0% followed at 5 Yrs* 6 / 6 patients 100% followed at 5 Yrs* 6 / 6 patients 100% followed at 5 Yrs* Cross Over 11 pts Cross Over 9 pts 10 Patients Withdrew * ± 2 months follow-up window

Patient Characteristics CharacteristicTAVR N = 179 Standard Rx N = 179 p-value Age – yr 83.1 ± ± Male sex (%) STS Score 11.2 ± ± NYHA I or II (%) I or II (%) III or IV (%) III or IV (%) CAD (%) COPD Any (%) Any (%) O 2 dependent (%) O 2 dependent (%) Creatinine > 2 mg/dL (%) Frailty (%) Porcelain aorta (%) Chest wall radiation (%)

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

Median Survival Months 11.1 Months 29.7 Months p (log rank) <

All-Cause Mortality (ITT) Landmark Analysis All-Cause Mortality (%) Standard Rx (n = 179) TAVR (n = 179) 30.7% 50.8% 33.4% 61.1% 38.9% 66.7% HR [95% CI] = 0.47 [0.24, 0.94] p (log rank) = HR [95% CI] = 0.46 [0.32, 0.66] p (log rank) < HR [95% CI] = 0.50 [0.39, 0.65] p (log rank) < Months 0-1 Year3-5 Years1-3 Years

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

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

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

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

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

NYHA Class Over Time (ITT) Survivors Baseline1 Year3 Years5 Years N = 14.3% 40.0% 30.0% 50.0% 23.7% 60.8% 92.2% 93.9% p = NS p < p = NS

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

Paravalvular Leak (AT) Percent of Evaluable Echocardiograms N =

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

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

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

Subgroup Analysis All-Cause Mortality Hazard Ratio [95% CI] Interactionp-value Overall (N=358) 0.50[ ] Age < 85 (N=186) 0.46[ ] 0.40 Age ≥ 85 (N=172) 0.56[ ] Male (N=166) 0.46[ ] 0.34 Female (N=192) 0.55[ ] BMI ≤ 25 (N=170) 0.58[ ] 0.71 BMI > 25 (N=188) 0.44[ ] STS ≤ 11 (N=170) 0.52[ ] 0.65 STS > 11 (N=187) 0.53[ ] EF ≤ 55 (N=173) 0.47[ ] 0.09 EF > 55 (N=171) 0.61[ ] Pulmonary Hypertension No (N=136) No (N=136)0.56[ ] 0.87 Yes (N=103) Yes (N=103)0.51[ ] Mod / Sev MR No (N=261) No (N=261)0.58[ ] 0.03 Yes (N=77) Yes (N=77)0.30[ ] Oxygen Dependent COPD No (N=270) No (N=270)0.46[ ] 0.14 Yes (N=88) Yes (N=88)0.68[ ] Prior CABG or PCI No (N=182) No (N=182)0.55[ ] 0.27 Yes (N=176) Yes (N=176)0.46[ ]

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

Clinical Observations Mortality benefit was similar in elderly (>85 yr) patients compared to those ≤85 years.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.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.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.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.Moderate and severe paravalvular leak is associated with higher cardiovascular mortality particularly in patients with less comorbidities.

Main Conclusions At 5 years follow-up benefits of TAVR were sustained as measured by: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.Valve durability was demonstrated with no increase in transvalvular gradient or attrition of valve area.

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