David J. Cohen, M.D., M.Sc. On behalf of The PARTNER Investigators 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) David J. Cohen, M.D., M.Sc. On behalf of The PARTNER Investigators Saint Luke’s Mid-America Heart Institute Harvard Clinical Research Institute University of Missouri-Kansas City Harvard Medical School Kansas City, Missouri Boston, MA TCT 2011 | San Francisco | November 7, 2011

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

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

PARTNER Study Design High-Risk Inoperable N = 699 N = 358 Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened N = 179 N = 358 Inoperable 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) 1:1 Randomization VS Yes No Total = 1,057 patients High-Risk N = 699 2 Parallel Trials: Individually Powered ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR AVR Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) TA TAVR VS N = 248 N = 104 N = 103 N = 244

Methods: Quality of Life Instrument Description/Role Kansas City Cardiomyopathy Questionnaire (KCCQ) Heart failure-specific QOL Domains: symptoms, physical limitations, quality of life, social limitations Scores: 0-100 (higher = better) WNA The total number of pairs is 179×179 = 32041. If the analysis had been based on survival only, then 71.7% (22964/32041) of the possible pairs could be compared. Such an analysis would be equivalent to the Gehan-Wilcoxon test. The addition of the rehospitalization component allows for an additional 16.6% (5324/32041) percent of the pairs to be compared. It is this increased comparison that gives the Finkelstein-Schoenfeld method increased power over the log-rank or Gehan-Wilcoxon test. There are three situations where a pair could not be compared on survival Both patients are censored. One patient died and the other was censored, with the days to death greater than the days to censoring. Both patients died, with the days to death equal. If the patients cannot be compared on survival, then the time to first rehospitalization is compared. The same principles apply. 6

Methods: Quality of Life Instrument Description/Role Kansas City Cardiomyopathy Questionnaire (KCCQ) Heart failure-specific QOL Domains: symptoms, physical limitations, quality of life, social limitations Scores: 0-100 (higher = better) SF-12 General physical and mental health Scores standardized such that mean = 50, standard deviation = 10 (higher = better) WNA The total number of pairs is 179×179 = 32041. If the analysis had been based on survival only, then 71.7% (22964/32041) of the possible pairs could be compared. Such an analysis would be equivalent to the Gehan-Wilcoxon test. The addition of the rehospitalization component allows for an additional 16.6% (5324/32041) percent of the pairs to be compared. It is this increased comparison that gives the Finkelstein-Schoenfeld method increased power over the log-rank or Gehan-Wilcoxon test. There are three situations where a pair could not be compared on survival Both patients are censored. One patient died and the other was censored, with the days to death greater than the days to censoring. Both patients died, with the days to death equal. If the patients cannot be compared on survival, then the time to first rehospitalization is compared. The same principles apply. 7

Methods: Quality of Life Instrument Description/Role Kansas City Cardiomyopathy Questionnaire (KCCQ) Heart failure-specific QOL Domains: symptoms, physical limitations, quality of life, social limitations Scores: 0-100 (higher = better) SF-12 General 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) WNA The total number of pairs is 179×179 = 32041. If the analysis had been based on survival only, then 71.7% (22964/32041) of the possible pairs could be compared. Such an analysis would be equivalent to the Gehan-Wilcoxon test. The addition of the rehospitalization component allows for an additional 16.6% (5324/32041) percent of the pairs to be compared. It is this increased comparison that gives the Finkelstein-Schoenfeld method increased power over the log-rank or Gehan-Wilcoxon test. There are three situations where a pair could not be compared on survival Both patients are censored. One patient died and the other was censored, with the days to death greater than the days to censoring. Both patients died, with the days to death equal. If the patients cannot be compared on survival, then the time to first rehospitalization is compared. The same principles apply. Assessments performed by self-administered questionnaires at baseline and at 1, 6, and 12 months 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 life Social 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 This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Green CP, et al. JACC. 2000;35:1245-55. Soto G, et al. Circulation. 2004;110:546-51. 9 9

KCCQ: Interpretation 546 outpts with HF Change in KCCQ-Overall Summary Score 546 outpts with HF KCCQ assessed at baseline and 5 weeks Extent of deterioration or improvement assessed by physician based on sx and exam and correlated with KCCQ-Overall Summary Clinically Important Change Small = 5 points Moderate = 10 points Large = 20 points Large Medium Small Small Medium Large No Change Deterioration Improvement Am Heart J. 2005;150:707-15.

Analytic Approach Analytic Population Primary QOL Endpoint 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

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

Baseline Characteristics TAVR (n = 328) AVR (n = 300) Age (yrs) 84  7 84  6 Male gender 57.6% 56.7% STS risk score 11.8  3.4 11.5  3.2 Prior MI 27.4% 27.7% Prior CABG 42.7% 45.0% Cerebrovascular Dz 26.8% 24.7% COPD (O2 dependent) 9.1% 7.3% Frailty 15.4% 17.1% P = NS for all comparisons

QOL Compliance ITT Population * Among pts eligible for QOL assessment

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

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

KCCQ Subscales TF Subgroup Physical Limitations Symptom Score D = 10.9 P = 0.001 D = -0.5 P = NS D = 2.3 P = NS D = 6.6 P = 0.006 D = -2.1 P = NS D = -1.1 P = NS Quality of Life Social Limitations D = 9.8 P < 0.001 D = 0.3 P = NS D = -1.9 P = NS D = 10.6 P = 0.006 D = -2.9 P = NS

Generic QOL and Utilities TF Subgroup SF-12 Physical SF-12 Mental D = 2.0 P = 0.04 D = -0.9 P = NS D = -0.4 P = NS D = 5.4 P < 0.001 D = 1.2 P = NS D = 0.4 P = NS EQ-5D Utilities D = 0.061 P = 0.008 D = 0.012 P = NS D = 0.028 P = NS

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

KCCQ Subscales TA Subgroup Physical Limitations Symptom Score D = -5.8 P = NS D = -9.6 P = 0.04 D = -4.1 P = NS D = -5.1 P = NS D = -13.2 P < 0.001 D = -2.3 P = NS Quality of Life Social Limitations D = -4.7 P = NS D = -8.4 P = 0.06 D = 4.8 P = NS D = -5.8 P = NS D = -3.8 P = NS D = 6.1 P = NS

Generic QOL and Utilities TA Subgroup SF-12 Physical SF-12 Mental D = 0.3 P = NS D = -3.3 P = 0.05 D = 0.2 P = NS D = -4.3 P = 0.02 D = -2.5 P = NS EQ-5D Utilities D = -0.057 P = NS D = -0.065 P = 0.05 D = -0.051 P = NS

Overall Clinical Status TF Subgroup P = NS KCCQ Categories 1 month 6 months 1 year *P-values from ordinal logistic regression

Overall Clinical Status TA Subgroup P = NS P = NS P = NS KCCQ Categories 1 month 6 months 1 year *P-values from ordinal logistic regression

KCCQ-Summary: Substantial Improvement* TF Subgroup P = NS P = NS P = 0.008 * Improvement ≥ 20 points vs. baseline among patients with available QOL data

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

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

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 ~ 25-30 points (MCID = 5) SF-12 Physical ~ 6 points (MCID = 2) SF-12 Mental ~ 5 points (MCID = 2)

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

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