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Vinod H. Thourani, MD on behalf of The PARTNER Trial Investigators

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1 Vinod H. Thourani, MD on behalf of The PARTNER Trial Investigators
SAPIEN 3 Transcatheter Aortic Valve Replacement Compared with Surgery in Intermediate-Risk Patients: A Propensity Score Analysis Vinod H. Thourani, MD on behalf of The PARTNER Trial Investigators ACC 2016 | Chicago | April 3, 2016

2 Disclosure Statement of Financial Interest
Vinod H. Thourani, MD Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Grant/Research Support Consulting Fees/Honoraria Major Stock Shareholder/Equity Boston Scientific, Claret Medical, Edwards Lifesciences, Medtronic, St. Jude Medical Abbott Vascular, Edwards Lifesciences, St. Jude Medical None

3 Background The 3rd generation SAPIEN 3 transcatheter heart valve has demonstrated improved clinical outcomes in high-risk patients at 1 year. The 30-day outcomes in intermediate-risk patients treated with SAPIEN 3 in PARTNER 2 were… All-cause Mortality: 1.1% Disabling Stroke: 1.0% PVL > Moderate: 3.8% There is a paucity of longer-term data in intermediate-risk patients with SAPIEN 3 and there have been no rigorous comparisons with surgery in intermediate-risk patients.

4 Purpose To evaluate the 1-year clinical and echo outcomes of SAPIEN 3 TAVR in intermediate-risk patients. To compare these intermediate-risk patient outcomes using SAPIEN 3 TAVR with surgery results in similar intermediate-risk patients from the PARTNER 2A trial using a rigorous pre-specified propensity score analysis.

5 The PARTNER 2A and S3i Trials Study Design
Intermediate Risk Symptomatic Severe Aortic Stenosis Intermediate Risk ASSESSMENT by Heart Valve Team P2 S3i n = 1078 ASSESSMENT: Optimal Valve Delivery Access TA/TAo TAVR SAPIEN 3 Transapical / Transaortic (TA/TAo) TF TAVR Transfemoral (TF) P2A n = 2032 ASSESSMENT: Transfemoral Access Transapical / TransAortic (TA/TAo) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR SAPIEN XT Surgical AVR VS TA/Tao TAVR SAPIEN 3

6 The PARTNER 2A and S3i Trials Study Design
Intermediate Risk Symptomatic Severe Aortic Stenosis Intermediate Risk ASSESSMENT by Heart Valve Team TF TAVR SAPIEN 3 TA/TAo TAVR P2 S3i n = 1078 ASSESSMENT: Optimal Valve Delivery Access Transapical / Transaortic (TA/TAo) Transfemoral (TF) Surgical AVR P2A n = 2032 ASSESSMENT: Transfemoral Access Transapical / TransAortic (TA/TAo) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR SAPIEN XT VS TA/Tao TAVR SAPIEN 3 Primary Endpoint: All-Cause Mortality, All Stroke, or Mod/Sev AR at One Year (Non-inferiority Propensity Score Analysis)

7 SAPIEN Platforms in PARTNER Device Evolution
Valve Technology SAPIEN SAPIEN XT SAPIEN 3 Sheath Compatibility Available Valve Sizes 23 mm 26 mm 20 mm 29 mm 22-24F 16-20F 14-16F 29 mm 23 mm 26 mm

8 The PARTNER 2A and S3i Trials Inclusion Criteria
• Severe AS: Echo-derived AVA ≤ 0.8 cm2 (or AVA index < 0.5 cm2/m2) and mean AVG > 40 mmHg or peak jet velocity > 4.0 m/s • Cardiac Symptoms: NYHA Functional Class ≥ II Intermediate Risk: Determined by a multi-disciplinary Heart Team Using a guideline STS between 4-8%*, and Adjudicated by case review committee * PARTNER 2A used guideline STS ≥ 4%

9 The PARTNER 2A and S3i Trials Key Exclusion Criteria
Anatomic: Aortic annulus diameter < 18 mm or > 28 mm (echo or CT) Bicuspid AV or predominant AR (> 3+) Severe LV dysfunction (LVEF < 20%) Untreated CAD requiring revascularization with either unprotected LM coronary disease or Syntax score > 32 Pre-existing surgical valve in any position Clinical: Serum Cr > 3.0 mg/dL or dialysis dependent Acute MI within 1 month CVA or TIA within 6 months Hemodynamic instability Life expectancy < 24 months

10 The PARTNER 2A and S3i Trials Primary Endpoint
Non-hierarchical composite of all-cause mortality, all stroke, or ≥ moderate aortic regurgitation at one year Propensity score analysis of the valve implant (VI) populations from S3i compared to the surgical arm of the PARTNER 2A trial All patients followed for at least 1 year Event rates by Kaplan-Meier estimates Non-inferiority trial design followed by superiority testing for the primary endpoint and components

11 Other Important Endpoints VARC 2 Definitions
SAFETY EFFICACY Cardiac mortality Major vascular complications All strokes and TIAs Repeat hospitalizations Peri-procedural MIs Acute kidney injury Life-threatening or disabling bleeding New permanent pacemakers New onset atrial fibrillation Repeat AV intervention Endocarditis NYHA class QOL instruments 6-minute walk test Days alive out-of-hospital ICU and index hospital LOS ECHO VALVE PERFORMANCE Mean AV gradient Effective orifice area (and index) LV function (ejection fraction) Paravalvular AR

12 Study Methodology Every patient reviewed (including imaging studies) by multi-disciplinary Heart Team AND case review committee Systematic assessment by neurologists before and after index procedures for ascertainment of neurologic events MDCT evaluation of annulus dimensions for all TAVR S3i patients (with core laboratory analyses) In patients with CAD requiring revascularization: treatment (PCI or CABG) allowed (unless unprotected left main disease or Syntax score > 32) at the discretion of the Heart Team CEC adjudication of major clinical events (VARC 2 definitions whenever possible)

13 Baseline Patient Characteristics Demographics (AT)
TAVR (n = 1077) Surgery (n = 944) p-value Age - yrs 81.9 ± 6.6 81.6 ± 6.8 0.23 Male - % 61.7 55.0 0.002 BMI - kg/m2 28.7 ± 6.1 28.4 ± 6.2 0.32 Median STS Score - % 5.2 [4.3, 6.3] 5.4 [4.4, 6.7] 0.0002 NYHA Class III or IV - % 72.5 76.1 0.07 mean ± SD, median [IQR]

14 Baseline Patient Characteristics Other Co-morbidities (AT)
TAVR (n = 1077) Surgery (n = 944) p-value CAD 69.6 66.5 0.14 Previous CABG 27.9 25.7 0.27 Cerebrovascular Disease 9.0 10.3 0.36 PVD 28.2 32.2 0.05 COPD 30.0 30.2 0.92 Cr level > 2 mg/dL 7.5 5.4 0.06 Atrial Fibrillation 36.0 34.9 0.61 Permanent Pacemaker 13.2 12.0 0.42 15 ft Walk Test > 7s 41.3 45.7

15 Statistical Analysis Plan - 1
Pre-specified propensity score analysis of SAPIEN 3 TAVR vs. P2A surgery for the composite primary endpoint (all- cause mortality, all stroke, or total AR ≥ moderate at 1 year). The analysis incorporated 22 pre-specified baseline characteristics that were factored through a logistic regression into a propensity score. Patient population was divided into quintiles based on propensity scores. Quintile stratification (unlike patient matching) allows for the use of data from all patients, minimizing selection bias.

16 Statistical Analysis Plan - 2
The primary hypothesis was non-inferiority of SAPIEN 3 vs. surgery from P2A for the primary endpoint at 1 year. Non-inferiority: One-sided alpha: 0.05 Hypothesis testing: upper bound of the one-sided 95% CI of the primary weighted difference of proportions endpoint (weighted avg test - control) < 7.5% Superiority: Two-sided alpha: 0.05 Hypothesis testing: upper or lower bound of the two-sided 95% CI of the primary weighted difference of proportions endpoint (weighted avg test - control) < 0 for TAVR and > 0 for surgery

17 Quintile Propensity Score Analysis: Primary Endpoint
Surgery TAVR # Patients Mortality, Stroke, AR > Mod 191 28.3% 138 13.8% Proportional Difference -14.5% Weighting 0.14 175 22.9% 171 9.9% -12.9% 0.18 147 19.7% 197 10.7% 147 19.7% 197 10.7% -9.1% -9.1% 0.20 0.20 126 23.0% 219 14.6% -8.4% 0.23 108 19.4% 238 15.1% -4.3% 0.25 Overall weighted difference of proportions - 9.2% [-12.4%,-6.0%] two-sided 90% CI

18 Primary Endpoint - Non-inferiority Death, Stroke, or AR ≥ Mod at 1 Year (VI)
Weighted Difference % Upper 1-sided 95% CI -6.0% Non-Inferiority p-value < 0.001 Pre-specified non-inferiority margin = 7.5% -10 -8 -6 -4 -2 2 4 6 8 10 Favors TAVR Favors Surgery Primary Non-Inferiority Endpoint Met

19 Weighted Difference -9.2% Superiority Testing p-value < 0.001
Primary Endpoint - Superiority Death, Stroke, or AR ≥ Mod at 1 Year (VI) Weighted Difference % Upper 2-sided 95.0% CI -5.4% Superiority Testing p-value < 0.001 -10 -8 -6 -4 -2 2 4 6 8 10 Favors TAVR Favors Surgery Superiority Achieved

20 Superiority Analysis Components of Primary Endpoint (VI)
Favors TAVR Favors Surgery Weighted Difference % Upper 2-sided 95% CI -2.4% Superiority Testing p-value < 0.001 Mortality -10 -8 -6 -4 -2 2 4 6 8 10 Weighted Difference % Upper 2-sided 95% CI -1.1% Superiority Testing p-value = 0.004 Stroke -10 -8 -6 -4 -2 2 4 6 8 10 Weighted Difference % Lower 2-sided 95% CI +0.2% Superiority Testing p-value = AR > Moderate -10 -8 -6 -4 -2 2 4 6 8 10

21 Unadjusted Clinical Events At 30 Days and 1 Year (AT)
TAVR Surgery Death All-cause 1.1 4.0 7.4 13.0 Cardiovascular 0.9 3.1 4.5 8.1 Neurological Events Disabling Stroke 1.0 4.4 2.3 5.9 All Stroke 2.7 6.1 4.6 8.2 All-cause Death and Disabling Stroke 2.0 8.0 8.4 16.6

22 Unadjusted Time-to-Event Analysis All-Cause Mortality and All Stroke (AT)
10 20 30 40 P2A Surgery SAPIEN 3 TAVR 18.8% All-Cause Mortality / Stroke Rate (%) 10.8% 9.7% 3.7% 3 6 9 12 Months from Procedure Number at risk: P2A Surgery 944 805 786 757 743 S3 TAVR 1077 1012 987 962 930

23 Unadjusted Time-to-Event Analysis All-Cause Mortality (AT)
10 20 30 40 P2A Surgery SAPIEN 3 TAVR All-Cause Mortality (%) 13.0% 4.0% 7.4% 1.1% 3 6 9 12 Months from Procedure Number at risk: P2A Surgery 944 859 836 808 795 S3 TAVR 1077 1043 1017 991 963

24 Unadjusted Time-to-Event Analysis All Stroke (AT)
10 20 30 40 P2A Surgery SAPIEN 3 TAVR All Stroke (%) 8.2% 6.1% 4.6% 2.7% 3 6 9 12 Months from Procedure Number at risk: P2A Surgery 944 805 786 757 743 S3 TAVR 1077 1012 987 962 930

25 Other Unadjusted Clinical Outcomes At 30 Days and 1 Year (AT)
Events (%) 30 Days 1 Year TAVR (n = 1077) Surgery (n = 944) Re-hospitalization 4.6 6.8 11.4 15.1 MI 0.3 1.9 1.8 3.1 Major Vascular Complication 6.1 5.4 --- AKI (Stage III) 0.5 3.3 Life-Threatening/Disabling Bleeding 46.7 New Atrial Fibrillation 5.0 28.3 5.9 29.2 New Permanent Pacemaker 10.2 7.3 12.4 9.4 Re-intervention 0.1 0.0 0.6 Endocarditis 0.2 0.8 0.7

26 Paravalvular Regurgitation 3-Class Grading Scheme (VI)
≥ Moderate 1.5% Mild 39.8% No. of echos 30 Days 1 Year P2A Surgery 755 610 S3i TAVR 992 875

27 The PARTNER 2A and S3i Trials Conclusions - 1
In intermediate-risk patients, SAPIEN 3 TAVR resulted in low 1-year rates of all-cause mortality (7.4%), all stroke (4.6%), and moderate or severe aortic regurgitation (1.5%)

28 The PARTNER 2A and S3i Trials Conclusions - 2
A rigorous propensity score analysis comparing SAPIEN 3 TAVR with surgery from PARTNER 2A in intermediate-risk patients at 1 year demonstrated: Non-inferiority for the primary endpoint (composite of all-cause mortality, all stroke, or AR ≥ moderate) Superiority of SAPIEN 3 TAVR for the primary endpoint, all-cause mortality, and all stroke Superiority of surgery for AR ≥ moderate Time-to-event analyses indicated that the benefits of SAPIEN 3 TAVR occurred in the first few months, suggesting procedure-related effects

29 The PARTNER 2A and S3i Trial Clinical Implications
The conclusions from the PARTNER 2A randomized trial and this propensity score analysis provide strong evidence that in intermediate-risk patients with severe aortic stenosis, SAPIEN 3 TAVR compared with surgery improves clinical outcomes and is the preferred therapy.

30 The PARTNER 2A and S3i Trial Lancet On-line
Special thanks to the PARTNER sites and patients, the clinical research teams, and the writing group!

31 The PARTNER 2A and S3i Trial Lancet On-line

32 The PARTNER 2A and S3i Trial Lancet On-line

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