Transcatheter Aortic Valve Implantation in Inoperable Patients with Severe Aortic Stenosis

1. Transcatheter Aortic Valve Implantation in Inoperable Patients with Severe Aortic Stenosis Press Conference Martin B. Leon, MD on behalf of the PARTNER Investigators TCT 2010; Washington, DC; September 23, 2010

2. PARTNER Study Design Total = 1058 patients n=358 n= 700 2 Parallel Trials: Individually Powered High Risk Inoperable ASSESSMENT: Transfemoral Access ASSESSMENT: Transfemoral Access High Risk TA High Risk TF 1:1 Randomization 1:1 Randomization 1:1 Randomization Not In Study TAVI Trans femoral Surgical AVR Standard Therapy (usually BAV) TAVI Trans femoral Surgical AVR TAVI Trans femoral VS VS VS Primary Endpoint: All Cause Mortality (1 yr)(Non-inferiority) Primary Endpoint: All Cause Mortality over length of trial (Superiority) Symptomatic Severe Aortic Stenosis ASSESSMENT: High Risk AVR Candidate 3105 Total Patients Screened

3. Primary and Co-Primary Endpoints PRIMARY: All-cause mortality over the duration of the study Superiority test (two-sided), 85% power to detect a difference, α = 0.05, sample size = 350 total patients CO-PRIMARY: Hierarchical composite of all-cause mortality and repeat hospitalization Non-parametric method described by Finkelstein and Schoenfeld (multiple pair-wise comparisons) > 95% power to detect a difference, α = 0.05 Positive study if both endpoints P < 0.05, or if either endpoint is < 0.025

4. Study Devices Edwards-SAPIEN THV Retroflex 1 23mm and 26mm valve sizes 22F and 24F sheath sizes

5. Inclusion Criteria Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cm2(EOA index <0.5cm2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s NYHA functional class II or greater Risk of death or serious irreversible morbidity as assessed by cardiologist and two surgeons must exceed 50%

6. Standard Rx TAVI All Cause Mortality • HR [95% CI] =0.54 [0.38, 0.78] • P (log rank) < 0.0001 All-cause mortality (%) Months

7. All Cause Mortality Standard Rx • ∆ at 1 yr = 20.0%NNT = 5.0 pts TAVI 50.7% All-cause mortality (%) 30.7% Months

8. Compare, at random, every TAVI patient with every Standard Rx patient; 179 x 179 (32,041) patient pairs, which did better? #1, compare “time to death” 72% chance that we know who died first If so, 63% chance that Standard Rx patient died first and 37% chance that TAVI patient died first #2, if necessary, compare “time to repeat hospitalization” 17% chance that we know who had repeat hosp first If so, 75% chance that Standard Rx patient had repeat hosp first and 25% chance that TAVI patient had repeat hosp first Finklestein & Schoenfeld Analysis(hierarchical multiple pair-wise comparison) FS Method Produces a P-value < 0.0001

9. Clinical Outcomes at 30 Days & 1 Year

10. Clinical Outcomes at 30 Days & 1 Year

11. Six-Minute Walk Tests Walking Distance P = 0.002 P = 0.67 P = 0.004 P = 0.55 Walking distance (meters) Baseline 1 Year 30 Days

12. Percent TAVI Standard Rx TAVI Standard Rx TAVI Standard Rx TAVI Standard Rx Treatment Visit Baseline 30 Day 6 Month 1 Year NYHA Class Over TimeSurvivors • P = 0.68 • P < 0.0001 • P < 0.0001 • P < 0.0001 I II III IV

13. Standard Rx 70 TAVI 44.6 44.4 60 39.5 50 33.0 40 Mean Gradient (mm Hg) 30 43.2 12.1 11.3 10.8 20 10 0 Mean Gradients Over Time P < 0.0001 6 Months N=100 1 Year N=89 Baseline N=163 30 Day N=143 • Error bars = ± 1 Std Dev

14. Paravalvular Regurgitation: TAVI 30 Day 6 Month 1 Year No changes over time None/Trace Moderate Mild Severe

15. Conclusions - 1 In patients with severe AS and symptoms, who are not suitable candidates for surgery… • Standard therapy (including BAV in 83.8% of pts) did not alter the dismal natural history of AS; all-cause and cardiovascular mortality at 1 year was 50.7% and 44.6% respectively • Transfemoral balloon-expandable TAVI, despite limited operator experience and an early version of the system, was associated with acceptable 30-day survival (5% after randomization in the intention-to-treat population)

16. Conclusions - 2 • TAVI was superior to standard therapy, markedly reducing the rate of… • all-cause mortality by 46%, P < 0.0001, NNT = 5.0 pts • cardiovascular mortality by 61%, P < 0.0001, NNT = 4.1 pts • all-cause mortality and repeat hospitalization • hierarchical (FS method), P < 0.0001 • non-hierarchical (KM analysis) by 54%, P < 0.0001, NNT = 3.4 pts

17. Conclusions - 3 • TAVI improved cardiac symptoms (NYHA class, P < 0.0001) and six minute walking distance (P = 0.002), after 1-year follow-up • TAVI resulted in more frequent complications at 30 days, including… • major vascular complications, 16.2% vs. 1.1%, P < 0.0001 • major bleeding episodes, 16.8% vs. 3.9%, P < 0.0001 • major strokes, 5.0% vs. 1.1%, P = 0.06

18. Conclusions - 4 • Serial echocardiograms in TAVI patients indicated… • reduced mean gradients (P < 0.0001) which were unchanged during 1-year FU • frequent paravalvular AR, which was usually trace or mild (~90%), remained stable during 1-year FU, and rarely required further Rx.

19. Clinical Implications • Balloon-expandable TAVI should be the new standard of care for patients with aortic stenosis who are not suitable candidates for surgery! • Next generation devices (e.g. SAPIEN XT) may help to reduce the frequency of procedure-related complications in the future. • The ultimate value of TAVI will depend on careful assessment of bioprosthetic valve durability, which will mandate obligatory long-term clinical and echocardiography FU of all TAVI patients.

20. September 22, 2010 on NEJM.org