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

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

Primary and Co-Primary Endpoints PRIMARY: All-cause mortality over the duration of the studyPRIMARY: 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 hospitalizationCO-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 < 0.025Positive study if both endpoints P < 0.05, or if either endpoint is < 0.025

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

Inclusion Criteria Severe calcific aortic stenosis defined as echo derived valve area of 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% Risk of death or serious irreversible morbidity as assessed by cardiologist and two surgeons must exceed 50%

All Cause Mortality Numbers at Risk Numbers at Risk TAVI TAVI Standard Rx Standard Rx All-cause mortality (%) Months HR [95% CI] = 0.54 [0.38, 0.78] P (log rank) < Standard Rx TAVI

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

Compare, at random, every TAVI patient with every Standard Rx patient; 179 x 179 (32,041) patient pairs, which did better?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”#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”#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 <

Outcome 30 Days n=179 TAVI Standard Rx P-value 1 Year 1 Yearn=179 TAVI Standard Rx P-value Clinical Outcomes at 30 Days & 1 Year Myocardial infarction All (%) Peri-procedural (% Stroke or TIA All (%) TIA (%) Minor stroke (%) Major stroke (%) Death (all) or major stroke (%) Repeat hospitalization (%) <.0001 Death (all) or repeat hosp (%) <.0001 Death All (%) Cardiovascular (%) <.0001

Outcome 30 Days n=179 TAVI Standard Rx P-value 1 Year 1 Yearn=179 TAVI Standard Rx P-value Clinical Outcomes at 30 Days & 1 Year Acute kidney injury Creatinine >3 mg/dL (%) RRT (%) Cardiac re-intervention BAV (%) <.0001 Re-TAVI (%)1.7na1.7na AVR (%) <.0001 Endocarditis (%) Vascular complications All (%) < <.0001 Major (%) < <.0001 Bleeding - major (%) < Arrhythmias New atrial fibrillation (%) New pacemaker (%)

Walking Distance P = Walking distance (meters) Baseline 30 Days Six-Minute Walk Tests P = Year P = 0.67 P = 0.55

NYHA Class Over Time Survivors P = 0.68P < IIIIIIIV TAVI Standard RxTAVIStandard RxTAVIStandard RxTAVIStandard Rx Percent TreatmentVisit Baseline 30 Day 6 Month 1 Year

Baseline N= Day N=143 6 Months N=100 1 Year N=89 Mean Gradient (mm Hg) Error bars = ± 1 Std Dev Mean Gradients Over Time P < Standard Rx TAVI

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

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)

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

Conclusions - 3 TAVI improved cardiac symptoms (NYHA class, P < ) 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 <  major bleeding episodes, 16.8% vs. 3.9%, P <  major strokes, 5.0% vs. 1.1%, P = 0.06

Conclusions - 4 Serial echocardiograms in TAVI patients indicated…  reduced mean gradients (P < ) 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.

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.

September 22, 2010 on NEJM.org