1. Martin B. Leon, MD Columbia University Medical Center Cardiovascular Research Foundation New York City Study Design for the PARTNER 3 Low-Risk Trial Study Design for the PARTNER 3 Low-Risk Trial 5 mins

2. Disclosure Statement of Financial Interest TVT 2016, Chicago, IL; June 15-18, 2016 Martin B. Leon, 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. Grant / Research Support / SAB Consulting Fees / Honoraria Shareholder / Equity Abbott, Boston Scientific, Edwards Lifescience, Medtronic None Claret, GDS, Mitralign, Valve Medical Affiliation / Financial RelationshipCompany

3. 2014 ACC/AHA Valve Guidelines TIMING of Intervention (AVR) for AS Summary: 8 class I or IIa indications for AVR; LOE either B or C; no RCTs, supported by few small studies (100’s pts) or N/A; not based on age or risk stratification (100’s pts) or N/A; not based on age or risk stratification TAVR should be available for every clinical indication approved for surgery!

4. 79.9% 13.9% High risk (STS > 8%) Intermediate risk (STS 4-8%) Low risk (STS <4%) 6.2% STS database 2002-2010 (141,905 pts) Courtesy of N. Piazza

5. TAVR is now the dominant therapy in inoperable and high-risk AS patients; recent data shows clear benefits in intermediate-risk patients as well! TAVR is now the dominant therapy in inoperable and high-risk AS patients; recent data shows clear benefits in intermediate-risk patients as well! As complications continue to decline and the procedure is further simplified, there are clear secondary benefits associated with TAVR – reduced ICU and hospital LOS, more rapid QOL recovery, lower frequency of AKI, bleeding, and post-operative AF, and improved valve hemodynamics. As complications continue to decline and the procedure is further simplified, there are clear secondary benefits associated with TAVR – reduced ICU and hospital LOS, more rapid QOL recovery, lower frequency of AKI, bleeding, and post-operative AF, and improved valve hemodynamics. TAVR should now be introduced to low-risk AS patients in thoughtful randomized clinical trials! TAVR should now be introduced to low-risk AS patients in thoughtful randomized clinical trials! TAVR in Low-Risk Patients

6. The PARTNER 3 Trial Study Design 1:1 Randomization (n=1228) TF - TAVR (SAPIEN 3) TF - TAVR (SAPIEN 3) Surgery (Bioprosthetic Valve) Surgery (Bioprosthetic Valve) Follow-up: 30 days, 6 mos, 1 year and annually through 10 years CT Imaging Sub-Study (n=200) Low Risk ASSESSMENT by Heart Team (STS < 4%, TF only) Low Risk ASSESSMENT by Heart Team (STS < 4%, TF only) Symptomatic Severe Calcific Aortic Stenosis PRIMARY ENDPOINT: Composite of all-cause mortality, all strokes, or re-hospitalization at 1 year post-procedure PRIMARY ENDPOINT: Composite of all-cause mortality, all strokes, or re-hospitalization at 1 year post-procedure Bicuspid Valves (n=100) Bicuspid Valves (n=100) ViV (AV and MV) (n=100) ViV (AV and MV) (n=100) PARTNER 3 Registries Alternative Access (n=100) (TA/TAo/Subclavian) Actigraphy/QoL Sub-Study (n=200) CT Imaging Sub-Study (n=200) Actigraphy/QoL Sub-Study (n=200)

7. Bovine pericardial tissue Scalloped leaflet shape CE ThermaFix* process is intended to minimize the risk of calcification Outer skirt PET outer skirt designed to reduce paravalvular leak Low frame height Respects the cardiac anatomy Frame design Enhanced frame geometry for low delivery profile High radial strength for circularity Inner Skirt Polyethylene terephthalate (PET) SAPIEN 3 THV

8. SAPIEN 3 Sizing Guidelines Specifications20 mm23 mm26 mm29 mm Native Valve Annulus Size (CT) Area273–345 mm 2 338–430 mm 2 430–546 mm 2 540–683 mm 2 Area Derived Diameter 18.6–21 mm20.7–23.4 mm23.4–26.4 mm26.2–29.5 mm Native Valve Annulus Size TEE16–19 mm18–22 mm21–25 mm24–28 mm 273 - 345 mm 2 23 mm 26 mm 29 mm 338 – 430 mm 2 430 – 546 mm 2 540 – 683 mm 2 20 mm 23 or 26 mm?26 or 29 mm?20 or 23 mm? 3D Annular Area

9. SAPIEN 3 Commander Delivery System Distinguishing Features Accurate positioning Accurate positioning Fine control of valve positioning Distal flex SAPIEN 3 Valve Size 20 mm 23 mm 26 mm 29 mm Expandable Sheath14F 16F Minimum Access Vessel Diameter5.5 mm 6.0 mm Improved coaxial alignment Improved coaxial alignment

10. The PARTNER 3 Trial Key Inclusion Criteria Severe, calcific aortic stenosis Severe, calcific aortic stenosis  AVA ≤ 1.0 cm 2 or AVA index ≤ 0.6 cm 2 /m 2  Mean gradient ≥ 40 mmHg or jet velocity ≥ 4.0 m/sec Symptom status Symptom status  NYHA Functional Class ≥ 2, or  Exercise test with reduced exercise capacity, abnormal BP response, or arrhythmias, or  Asymptomatic with LVEF < 50% Heart Team agrees patient is low operative risk and STS < 4% Heart Team agrees patient is low operative risk and STS < 4% Informed consent in all patients Informed consent in all patients

11. The PARTNER 3 Trial Key Exclusion Criteria (1) Aortic annulus size suitable for Sapien 3 valves (20, 23, 26, and 29mm; CT annulus area 270 cm 2 – 680 cm 2 ) Aortic annulus size suitable for Sapien 3 valves (20, 23, 26, and 29mm; CT annulus area 270 cm 2 – 680 cm 2 ) Iliofemoral vessels without sufficient size and morphology (esp. Ca+) suitable for appropriate sheaths (TF only) Iliofemoral vessels without sufficient size and morphology (esp. Ca+) suitable for appropriate sheaths (TF only) Bicuspid aortic valve Bicuspid aortic valve Severe AR (> 3+) or MR (> 3+) Severe AR (> 3+) or MR (> 3+) LVEF < 30% LVEF < 30% Complex CAD requiring revascularization (unprotected LMCA, Syntax score > 32, or Heart Team assessment that optimal revascularization cannot be performed) Complex CAD requiring revascularization (unprotected LMCA, Syntax score > 32, or Heart Team assessment that optimal revascularization cannot be performed) CKD – eGFR < 30 ml/min CKD – eGFR < 30 ml/min

12. The PARTNER 3 Trial Key Exclusion Criteria (2) MI within 30 days, stroke/TIA within 90 days MI within 30 days, stroke/TIA within 90 days Severe lung disease (FEV1 < 50% predicted) or home oxygen Severe lung disease (FEV1 < 50% predicted) or home oxygen Significant frailty as determined by the Heart Team (after objective assessments) Significant frailty as determined by the Heart Team (after objective assessments) Hemodynamic or respiratory instability requiring inotropic support or mechanical ventilation within 30 days Hemodynamic or respiratory instability requiring inotropic support or mechanical ventilation within 30 days

13. The PARTNER 3 Trial Primary Endpoint Composite (non-hierarchical) of death (all-cause), strokes (all) or rehospitalization (valve-related or procedure-related and including heart failure) at 1-year post-procedure Composite (non-hierarchical) of death (all-cause), strokes (all) or rehospitalization (valve-related or procedure-related and including heart failure) at 1-year post-procedure Assumptions: Assumptions:  Event rate for surgery 16.6% and TAVR 14.6%  One-sided alpha 0.025 and relative non-inferiority margin 0.35  For 85% power, sample size 1,068 patients  Due to event rate uncertainty, sample size increased 15% = 1,228 patients  Primary analysis population = as-treated patients Safety and Effectiveness

14. The PARTNER 3 Trial Key Secondary Endpoints Death (all-cause and CV) at 30 days and 1-yearDeath (all-cause and CV) at 30 days and 1-year Strokes (with and without disability) at 30 days and 1-yearStrokes (with and without disability) at 30 days and 1-year Death (all) or strokes (all) at 30 days and 1-yearDeath (all) or strokes (all) at 30 days and 1-year Death (all) or strokes with disability at 30 days and 1-yearDeath (all) or strokes with disability at 30 days and 1-year Rehospitalization at 30 days and 1-yearRehospitalization at 30 days and 1-year Vascular complications, bleeding, AKI, new-onset AF, new permanent pacemakersVascular complications, bleeding, AKI, new-onset AF, new permanent pacemakers Six-minute walk distance, QOL assessment (KCCQ scores), and NYHA Functional Class at 30 days and 1-yearSix-minute walk distance, QOL assessment (KCCQ scores), and NYHA Functional Class at 30 days and 1-year Length of stay (ICU and hospitalization) and days alive out- of-hospitalLength of stay (ICU and hospitalization) and days alive out- of-hospital

15. The PARTNER 3 Trial Substudies and Registries (1) CT sub-study (leaflet thickening/mobility/thrombosis) CT sub-study (leaflet thickening/mobility/thrombosis)  400 evaluable randomized patients (1:1 TAVR vs. surgery) from ~20 centers with required time-resolved 3D-MDCT imaging capabilities  Studies at 1 month and 1 year  Exclude patients with oral AC therapy Actigraphy/QOL sub-study (cw KCCQ and 6MWT) Actigraphy/QOL sub-study (cw KCCQ and 6MWT)  200-400 evaluable randomized patients (1:1 TAVR vs. surgery) from ~20 centers  Wearable actigraphy monitors at baseline and for 4-8 weeks post-procedure

16. The PARTNER 3 Trial Substudies and Registries (2) Alternative access registry Alternative access registry  100 low-risk patients with unfavorable TF access  Treated by TA, direct Ao, or other access routes (e.g. subclavian, carotid) Bicuspid AS registry Bicuspid AS registry  100 patients with severe AS and bicuspid AV disease from ~25 centers  TF only, “favorable” anatomy for TAVR, all risk categories Sapien 3 Aortic and Mitral Valve-in-Valve registry Sapien 3 Aortic and Mitral Valve-in-Valve registry  150 patients; 75 aortic and 75 mitral with bioprosthetic valve failure from ~25 centers (all risk categories)

17. The PARTNER 3 Trial Special Considerations Up to 60 study sites (U.S. and Canada)Up to 60 study sites (U.S. and Canada) 10-year FU for all randomized patients (valve durability echocardiography assessments)10-year FU for all randomized patients (valve durability echocardiography assessments) Young age not an exclusion criteriaYoung age not an exclusion criteria Careful neurology evaluations to ascertain stroke endpointsCareful neurology evaluations to ascertain stroke endpoints In patients with concomitant CAD, revascularization based on Heart Team assessment (within protocol guidelines)In patients with concomitant CAD, revascularization based on Heart Team assessment (within protocol guidelines) CTAs in all patients; optimal valve sizing for both TAVR and surgery patientsCTAs in all patients; optimal valve sizing for both TAVR and surgery patients Case review calls to adjudicate clinical and anatomic entry criteriaCase review calls to adjudicate clinical and anatomic entry criteria

18. The PARTNER 3 Trial Summary “Real World” low-risk AS study population – few exclusions“Real World” low-risk AS study population – few exclusions Rigorous trial design with meaningful 1 ry endpoint and numerous important 2 ry endpoints (including QOL and health economics) – VARC II and III definitionsRigorous trial design with meaningful 1 ry endpoint and numerous important 2 ry endpoints (including QOL and health economics) – VARC II and III definitions Politically more challenging (surgeons “sweet spot”), so can’t predict enrollment cadencePolitically more challenging (surgeons “sweet spot”), so can’t predict enrollment cadence 10-year FU to address valve durability issues10-year FU to address valve durability issues Important substudies and registries – serial CTAs (valve leaflet thickening/motion), actigraphy wearables (new QOL methods), bicuspid valve disease, and aortic/mitral ViVImportant substudies and registries – serial CTAs (valve leaflet thickening/motion), actigraphy wearables (new QOL methods), bicuspid valve disease, and aortic/mitral ViV