TCT 2011 | San Francisco | November 7, 2011

1. 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

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

3. 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

4. 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

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

6. Methods: Quality of Life

7. Methods: Quality of Life

8. Methods: Quality of Life Assessments performed by self-administered questionnaires at baseline and at 1, 6, and 12 months

9. 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 Green CP, et al. JACC. 2000;35:1245-55. Soto G, et al. Circulation. 2004;110:546-51.

10. KCCQ: Interpretation 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.

11. 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

12. 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

13. Baseline Characteristics P = NS for all comparisons

14. 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

15. KCCQ Overall Summary (Primary Endpoint)TF Subgroup D = 9.9P < 0.001 D = -0.5P = NS D =-1.2P = NS P-values are for mean treatment effect of TAVR vs. AVR

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

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

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

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

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

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

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

23. 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

24. 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)

25. 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

26. 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