Health-Related Quality of Life After Transcatheter vs. Surgical Aortic Valve Replacement in High-Risk Patients With Severe Aortic Stenosis Results From The PARTNER Trial (Cohort A) TCT 2011 | San Francisco | November 7, 2011 David J. Cohen, M.D., M.Sc. On behalf of The PARTNER Investigators Saint Luke’s Mid-America Heart InstituteHarvard Clinical Research Institute University of Missouri-Kansas CityHarvard Medical School Kansas City, MissouriBoston, MA

Disclosures The PARTNER Trial was funded by a research grant from Edwards Lifesciences, Inc.

Background Transcatheter aortic valve replacement (TAVR) has been developed as a less invasive alternative to surgical valve replacement for high-risk patients with severe aortic stenosis In PARTNER Cohort A, TAVR was found to be non-inferior to surgical AVR for the primary endpoint of 1-year mortality among patients at high surgical risk There were differences in procedure-related complications and valve performance at 1 year – with some endpoints favoring TAVR and others favoring surgical AVR The overall impact of these alternative treatments on health- related quality of life from the patient’s perspective has not yet been reported 3

Study Objectives 1.Compare health-related quality of life outcomes among patients with severe aortic stenosis and high surgical risk treated with either TAVR or surgical AVR 2.Determine whether the QOL benefits of TAVR vs. AVR vary over time 3.Examine whether the QOL benefits of TAVR vs. AVR differ according to access site or other patient characteristics 4

N = 179 N = 358 Inoperable Standard Therapy Standard Therapy ASSESSMENT: Transfemoral Access Not In Study TF TAVR Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) 1:1 Randomization VS Yes No N = 179 TF TAVR AVR Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) TA TAVR AVR VS N = 248N = 104N = 103N = 244 PARTNER Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Total = 1,057 patients 2 Parallel Trials: Individually Powered N = 699 High-Risk ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No

Methods: Quality of Life InstrumentDescription/Role Kansas City Cardiomyopathy Questionnaire (KCCQ) Heart failure-specific QOL Domains: symptoms, physical limitations, quality of life, social limitations Scores: (higher = better) 6

Methods: Quality of Life InstrumentDescription/Role Kansas City Cardiomyopathy Questionnaire (KCCQ) Heart failure-specific QOL Domains: symptoms, physical limitations, quality of life, social limitations Scores: (higher = better) SF-12General physical and mental health Scores standardized such that mean = 50, standard deviation = 10 (higher = better) 7

Methods: Quality of Life Assessments performed by self-administered questionnaires at baseline and at 1, 6, and 12 months InstrumentDescription/Role Kansas City Cardiomyopathy Questionnaire (KCCQ) Heart failure-specific QOL Domains: symptoms, physical limitations, quality of life, social limitations Scores: (higher = better) SF-12General physical and mental health Scores standardized such that mean = 50, standard deviation = 10 (higher = better) EQ-5D (EuroQOL)Generic instrument for assessment of utilities and QALYs Scores: 0-1 (0 = death; 1 = perfect health) 8

KCCQ: Development and Validation 23 items that measure 5 clinically relevant domains of health status from the patient’s perspective –Symptoms Physical limitation –Quality of lifeSocial limitation –Self-efficacy Extensive validation and reliability testing Individual scales combined into a global summary scale (KCCQ Overall Summary) –Independently predictive of mortality and cost among patients with HF Green CP, et al. JACC. 2000;35: Soto G, et al. Circulation. 2004;110:

KCCQ: Interpretation Am Heart J. 2005;150: LargeMediumSmall Deterioration No Change 546 outpts with HF546 outpts with HF KCCQ assessed at baseline and 5 weeksKCCQ assessed at baseline and 5 weeks Extent of deterioration or improvement assessed by physician based on sx and exam and correlated with KCCQ-Overall SummaryExtent of deterioration or improvement assessed by physician based on sx and exam and correlated with KCCQ-Overall Summary Change in KCCQ-Overall Summary Score SmallMediumLarge Improvement Clinically Important Change Small = 5 points Moderate = 10 points Large = 20 points Clinically Important Change Small = 5 points Moderate = 10 points Large = 20 points 10

Analytic Approach Analytic Population All patients with baseline QOL assessment, analyzed by assigned treatment (ITT) Primary QOL Endpoint KCCQ Overall Summary Score All other QOL scales considered secondary endpoints 11

Statistical Methods Scores at each time point compared within treatment group using paired t-tests Scores between groups compared using random effect growth curve models, adjusted for baseline, age, sex, and access site (TA vs. TF) Analytic plan specified that separate analyses would be performed for the TA and TF groups in case of a significant interaction between treatment effect and access site 12

Baseline Characteristics 13 TAVR (n = 328) AVR (n = 300) Age (yrs) 84  7 84  6 Male gender 57.6%56.7% STS risk score 11.8   3.2 Prior MI 27.4%27.7% Prior CABG 42.7%45.0% Cerebrovascular Dz 26.8%24.7% COPD (O 2 dependent) 9.1%7.3% Frailty15.4%17.1% P = NS for all comparisons

Results There were highly significant interactions between treatment effect and access site for the primary endpoint (P = 0.001) and multiple secondary endpoints (P < 0.01) – mainly at the 1 month and 6 month time points Therefore, all QOL analyses were performed separately for TF and TA subgroups 14

KCCQ Overall Summary (Primary Endpoint) TF Subgroup 15 P-values are for mean treatment effect of TAVR vs. AVR  = 9.9 P <  = -0.5 P = NS  =  -1.2 P = NS

KCCQ Subscales TF Subgroup 16 Physical LimitationsSymptom Score Quality of Life Social Limitations  = 10.9 P =  = -0.5 P = NS  = 2.3 P = NS  = 6.6 P =  = -2.1 P = NS  = -1.1 P = NS  = 9.8 P <  = 0.3 P = NS  = -1.9 P = NS  = 10.6 P =  = -2.9 P = NS

Generic QOL and Utilities TF Subgroup 17 SF-12 Physical SF-12 Mental EQ-5D Utilities  = 2.0 P = 0.04  = -0.9 P = NS  = -0.4 P = NS  = P =  = P = NS  = P = NS  = 5.4 P <  = 1.2 P = NS  = 0.4 P = NS

KCCQ Overall Summary (Primary Endpoint) TA Subgroup 18 P-values are for mean treatment effect of TAVR vs. AVR  = -5.8 P = NS  = -7.9 P = 0.04  = 0.8 P = NS

KCCQ Subscales TA Subgroup 19 Physical LimitationsSymptom Score Quality of LifeSocial Limitations  = -5.8 P = NS  = -9.6 P = 0.04  = -4.1 P = NS  = -4.7 P = NS  = -8.4 P = 0.06  = 4.8 P = NS  = -5.1 P = NS  = P <  = -2.3 P = NS  = -5.8 P = NS  = -3.8 P = NS  = 6.1 P = NS

Generic QOL and Utilities TA Subgroup 20 SF-12 Physical SF-12 Mental EQ-5D Utilities  = 0.3 P = NS  = -3.3 P = 0.05  = 0.2 P = NS  = -4.3 P = 0.02  = -2.5 P = NS  = P = NS  = P = 0.05  = P = NS

KCCQ-Summary: Substantial Improvement* TF Subgroup * Improvement ≥ 20 points vs. baseline among patients with available QOL data P = P = NS 21

KCCQ-Summary: Substantial Improvement* TA Subgroup * Improvement ≥ 20 points vs. baseline among patients with available QOL data P = NS at all timepoints 22

Sensitivity Analyses Results similar when: Analysis restricted to patients who underwent attempted valve treatment (“As treated” cohort; n = 607) “Worst case” values (at the 90th percentile) were imputed to all patients with missing data Outcomes analyzed categorically according to either significant improvement (≥ 10-point change from baseline) or a multilevel ordinal outcome 23

Summary-1 Among patients with severe AS who were at high risk for standard valve replacement, both surgical and transcatheter AVR resulted in substantial improvement in disease-specific and generic HRQOL over 1 year follow-up –KCCQ Summary Scale ~ points (MCID = 5) –SF-12 Physical ~ 6 points (MCID = 2) –SF-12 Mental ~ 5 points (MCID = 2) 24

Summary-2 Although the extent of improvement at 1 year was similar with TAVR and AVR, there were important differences in the rate and extent of recovery at the earlier time points For patients eligible for the TF approach, TAVR resulted in substantial QOL benefits compared with AVR at 1 month with similar QOL at later time points For patients eligible only for the TA approach, there was no benefit of TAVR over AVR at any time point, and QOL tended to be better with AVR both at 1 and 6 months 25

Conclusions Taken together with previous data, these findings demonstrate that for patients suitable for a TF approach, TAVR provides meaningful clinical benefits compared with surgical AVR from the patient’s perspective The lack of benefit (and suggestion of worse QOL) among patients ineligible for the TF approach suggests that the TA approach may not be preferable to surgical AVR in such patients Whether further experience and refinements in the TA approach can overcome these limitations should be the subject of future investigation 26