Craig R. Smith, MD on behalf of The PARTNER Trial Investigators Transcatheter vs. Surgical Aortic Valve Replacement in High Risk Patients with Severe Aortic Stenosis: Results From The PARTNER Trial Craig R. Smith, MD on behalf of The PARTNER Trial Investigators ACC 2011 | New Orleans | April 3, 2011

Presenter Disclosure Information for PARTNER at ACC April 3, 2011 Craig R. Smith, MD PARTNER Trial sponsor (Edwards LifeSciences) reimburses customary travel and other expenses

Background Surgical aortic valve replacement (AVR) is the standard of care for treating patients with symptomatic aortic stenosis who are candidates for operation. Although transcatheter aortic valve replacement (TAVR) reduces mortality in patients who cannot have AVR, there have been no randomized trials comparing TAVR to AVR in patients who are at high-risk for operation.

Purpose To compare the safety and effectiveness of TAVR (either transfemoral or transapical) to surgical AVR in high-risk, operable patients with symptomatic, severe aortic stenosis.

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

Inoperable PARTNER Cohort Primary Endpoint: All-Cause Mortality HR [95% CI] = 0.54 [0.38, 0.78] P (log rank) < 0.0001 Standard Rx TAVI ∆ at 1 yr = 20.0% NNT = 5.0 pts 50.7% All-cause mortality (%) 30.7% Months Leon et al, NEJM 2010; 363:1597-1607 Numbers at Risk TAVI 179 138 122 67 26 Standard Rx 121 83 41 12 6

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

Primary Endpoint All-cause mortality at one year Analysis by intent-to-treat Event rates by Kaplan-Meier estimates Crossovers permitted only when assigned therapy unsuccessful All patients followed for ≥ one year

Other Important Endpoints (1) Safety: Neurologic events Prospective: Stroke and stroke plus TIA (all neuro events) Retrospective: Major stroke (modified Rankin Score ≥ 2 @ ≥ 30 days) Major vascular complications (VARC definition) Major bleeding (modified VARC definition) Repeat hospitalization New pacemakers and new-onset atrial fibrillation (ECG core lab) Procedural events (assigned therapy aborted or converted to AVR, multiple valves, etc.) Surgical complications (re-op for bleeding, sternal infection, etc.)

Other Important Endpoints (2) Clinical Effectiveness and Valve Performance: NYHA symptoms Six-minute walk tests Quality-of-life measures and cost-effectiveness (core lab) Echocardiography assessment of valve performance (core lab) Peak and mean gradients Effective orifice area Bioprosthetic valve regurgitation (esp. para-valvular) Other: LV ejection fraction, MR, LV mass, evidence of structural valve deterioration

Study Administration Co-Principal Investigators Martin B. Leon, Craig R. Smith Columbia University Medical Center Executive Committee Martin B. Leon, Michael Mack, D. Craig Miller, Jeffrey W. Moses, Craig R. Smith, Lars G. Svensson, E. Murat Tuzcu, John G. Webb Data & Safety Monitoring Board Chairman: Joseph P. Carrozza Tufts University School of Medicine Clinical Events Committee Chairman: John L. Petersen Duke University Medical Center Echo Core Laboratory Chairman: Pamela C. Douglas Duke University Medical Center Quality of Life and Cost-Effectiveness Chairman: David J. Cohen Mid America Heart Institute, Kansas City Independent Biostatistical Core Laboratory Stuart Pocock, Duolao Wang London School of Hygiene and Tropical Medicine William N. Anderson Publications Committee Co-Chairman: Jeffrey W. Moses Lars G. Svensson Sponsor Edwards Lifesciences: Jodi J. Akin

Executive Committee Lars Svensson Craig Miller Michael Mack Jeff Moses This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Murat Tuzcu Craig Smith John Webb Marty Leon 12

Participating Study Sites St. Paul's Hospital Vancouver, Canada Univ. of Washington Seattle, WA Hospital Laval Quebec City, Canada Toronto Gen. Hospital Toronto, Canada Mayo Clinic Rochester, MN Intermountain Medical Center Salt Lake City, UT Brigham & Women’s Mass General Boston, MA Stanford University Palo Alto, CA Evanston Hospital Northwestern Univ. Chicago, IL Univ. of Penn Phila., PA Columbia University Cornell University New York, NY Cleveland Clinic Cleveland, OH Barnes-Jewish Hospital St. Louis, MO Washington Hosp. Center Wash., DC Cedars-Sinai Medical Center Los Angeles, CA St. Luke’s Hospital Kansas City, MO Univ. of Virginia Charlottesville, VA Scripps Clinic La Jolla, CA Emory University Atlanta, GA Medical City Dallas Dallas, TX Leipzig Heart Center Leipzig, Germany Ochsner Foundation New Orleans, LA Univ. of Miami Miami, FL n = 1,057 patients 26 investigator sites 22 USA, 3 Canada, 1 Germany

High-Risk Enrollment by Site Cedars-Sinai Medical Ctr Los Angeles, CA G. Fontana, R. Makkar 116 Columbia University New York City, NY M. Leon, C. Smith 97 Medical City Dallas Dallas, TX D. Brown, T. Dewey 95 Emory University Atlanta, GA P. Block, R. Guyton 67 University of Pennsylvania Philadelphia, PA J. Bavaria, H. Herrmann 52 Cleveland Clinic Found Cleveland, OH L. Svensson, M. Tuzcu 47 Washington Hospital Ctr District of Columbia P. Corso, A. Pichard 40 University of Miami Miami, FL W. O’Neill, D. Williams 25 Barnes-Jewish Hospital St. Louis, MO R. Damiano, J, Lasala 24 Stanford University Palo Alto, CA C. Miller, A. Yeung 23 Northwestern University Chicago, IL C. Davidson, P. McCarthy 20 St. Paul's Hospital Vancouver, BC, Canada A. Cheung, J. Webb 19

High-Risk Enrollment by Site Mass General Hospital Boston, MA I. Palacios, G. Vlahakis 15 St. Luke’s Hospital Kansas City, MO K. Allen, D. Cohen 13 Universitaire de Quebec Laval, Quebec, CA D. Doyle, J. Rodes-Cabau 8 Scripps Clinic La Jolla, CA S. Brewster, P. Teirstein 7 Herzzentrum Leipzig Leipzig, Germany F. Mohr, G. Schuler Mayo Clinic Rochester, MN C. Rihal, T. Sundt 6 Univ of Washington Seattle, WA M. Reisman, E. Verrier 5 Northshore Univ Health Sys Evanston, IL J. Alexander, T. Feldman 4 University of Virginia Charlottesville, VA I. Kron, S. Lim 3 Brigham & Women’s Hosp Boston, MA M. Davidson, A. Eisenhauer 2 Ochsner Foundation New Orleans, LA E. Parrino, S. Ramee Intermountain Med Center Salt Lake City, UT K. Jones, B. Whisenant 1 Cornell University New York City, NY K. Krieger, C. Wong Toronto General Hospital Toronto, Ontario, CA C. Feindel, E. Horlick

Study Devices Edwards SAPIEN THV RetroFlex Ascendra 23 and 26 mm valves RetroFlex 22 and 24 F sheaths Ascendra 24 and 26 F sheaths

Transfemoral and Transapical TAVR Transfemoral and Transapical Transfemoral Transapical

Inclusion Criteria • Severe AS: Echo-derived AVA < 0.8 cm2 (or AVA index < 0.5 cm2/m2) and mean AVG > 40 mm Hg or peak jet velocity > 4.0 m/s • Cardiac Symptoms: NYHA Functional Class ≥ II High surgical risk: Predicted risk of operative mortality ≥ 15% (determined by site surgeon and cardiologist); guideline = STS score ≥ 10

Key Exclusion Criteria (1) Anatomic: Bicuspid or non-calcified aortic valve Aortic annulus diameter (echo measurement) < 18 mm or > 25 mm Aortic dissection or iliac-femoral dimensions or disease precluding safe sheath insertion (esp. calcification) Severe LV dysfunction (LVEF < 20%) Untreated CAD requiring revascularization Severe AR or MR (> 3+) or prosthetic valve (any location)

Key Exclusion Criteria (2) Clinical: Serum Cr > 3.0 mg/dL or dialysis dependent Acute MI within 1 month Upper GI bleed within 3 months CVA or TIA within 6 months Any cardiac procedure, other than BAV, within 1 month or within 6 months for DES Hemodynamic instability (e.g. requiring inotropic support)

Statistical Analysis Plan Primary hypothesis is non-inferiority of test (TAVR) vs. control (AVR) for all-cause mortality at 1 year Non-inferior if one-sided 95% upper confidence limit for the treatment difference is < 7.5% (α =0.05) Primary Endpoint: All TF and TA patients Assuming true 1-year mortality 32% after AVR and 29% after TAVR Intended sample size = 650 patients for ≥ 85% power Powered Secondary Endpoint: Only TF patients Assuming true 1-year mortality 35% after AVR and 25% after TAVR Intended sample size = 450 patients for ≥ 85% power

Study Methodology Preliminary eligibility determined by site investigators Every case reviewed by web-based conference call before enrollment Randomized to TF-TAVR vs. AVR, or TA-TAVR vs. AVR, to be treated within 2 weeks Intent-to-treat (ITT) analysis for the primary and most secondary endpoints; defined as the time of randomization As-treated (AT) analysis for some procedural endpoints and for echo assessments; defined as the time of procedural anesthesia induction

42 Patients not treated as assigned Study Flow Randomized = 699 patients Transfemoral n = 492 TF = 492 TA = 207 Transapical n = 207 TAVR (244) AVR (248) TAVR (104) AVR (103) 30 Days (236) Dead = 8 Withdrawal = 0 30 Days (223) Dead = 15 Withdrawal = 10 30 Days (100) Dead = 4 Withdrawal = 0 30 Days (92) Dead = 7 Withdrawal = 4 1 Year (189) Dead = 46 Withdrawal = 1 1 Year (168) Dead = 47 Withdrawal = 8 1 Year (73) Dead = 26 Withdrawal = 0 LTFU = 1 1 Year (68) Dead = 20 Withdrawal = 3 LTFU = 1 42 Patients not treated as assigned

Reasons for Non-treatment ITT = 699 patients │ AT = 657 patients Reason TAVR (N = 348) AVR (N = 351) Died before treatment - no. (%) 2 (0.6) 5 (1.4) Deterioration before treatment - no. (%) 1 (0.3) Refusal - no. (%) 17 (4.8) Withdrawal - no. (%) 11 (3.1) Total – no. (%) 4 (1.1) 38 (10.8) NOTE: Time from randomization to treatment = TAVR 10.6 [SEM 0.7] days vs. AVR 15.6 [SEM 1.1] days; P <0.001

Patient Characteristics (1) TAVR (N = 348) AVR (N = 351) p-value Age (yr) 83.6 ± 6.8 84.5 ± 6.4 0.07 Male sex - % 57.8 56.7 0.82 STS Score 11.8 ± 3.3 11.7 ± 3.5 0.61 Logistic EuroSCORE 29.3 ± 16.5 29.2 ± 15.6 0.93 NYHA II - % III or IV - % 94.3 94.0 0.79 CAD - % 74.9 76.9 0.59 Previous MI - % 26.8 30.0 0.40 Prior CV Intervention - % 72.1 71.6 Prior CABG - % 42.6 44.2 0.70 Prior PCI - % 34.0 32.5 0.68 Prior BAV - % 13.4 10.2 0.24 29.3 27.4 0.60 5.7 6.0 Cerebrovascular disease - %

Patient Characteristics (2) TAVR (N = 348) AVR (N = 351) p-value Peripheral vascular disease - % 43.0 41.6 0.76 COPD Any 43.4 Oxygen dependent 9.2 7.1 0.34 Creatinine > 2mg/dL - % 11.1 7.0 0.06 Atrial fibrillation - % 40.8 42.7 0.75 Permanent pacemaker - % 20.0 21.9 0.58 Pulmonary hypertension - % 42.4 36.4 0.15 Frailty - % 15.6 17.6 Porcelain aorta - % 0.6 1.1 0.69 Chest wall radiation - % 0.9 1.00 Liver disease - % 2.0 2.6 0.80 43.0 0.94

Baseline Echocardiography Echo Findings TAVR (N = 348) AVR (N = 351) p-value AVA - cm2 0.7 ± 0.2 0.6 ± 0.2 0.13 AVG - mm Hg 42.7 ± 14.6 43.5 ± 14.3 0.45 Mean LVEF - % 52.5 ± 13.5 53.3 ± 12.8 Moderate or severe MR - % 19.8 21.3 0.63

Procedural Outcomes - TAVR vs AVR Anesthesia time - min 330 Total procedure time - min 230 Aborted procedure - no. (%) Reoperation for bleeding - no. (%) 12 (3.4) Intra-procedural death - no. (%) 1 (0.3) Aortic perforation - no. (%) Aortic dissection - no. (%) 3 (0.9) Median ICU stay (days) 5.0 Anesthesia time - min 236 Total procedure time - min 133 Aborted procedure - no. (%) 7 (2.0) Reoperation for bleeding - no. (%) 2 (0.6) Intra-procedural death - no. (%) 3 (0.9) Aortic perforation - no. (%) Aortic dissection - no. (%) Median ICU stay (days) 3.0 3 failed access 2 new TEE findings 2 died Aborted procedure - no. (%) *Converted to transapical TAVR due to porcelain aorta

Procedural Outcomes - TAVR vs AVR Sternal wound infection - no. (%) 7 (2.0) Total cross clamp time - min 74 Pump time - min 105 Access site infection - no. (%) 7 (2.0) Fluoroscopy time - min 31 Converted to AVR - no. (%) 9 (2.6) Multiple (≥2) valves - no. (%) Valve embolization - no. (%) 5 valve embolization 3 annulus size on TEE 1 large sigmoid septum Converted to AVR - no. (%) 5 converted to AVR 2 valve-in-valve 2 not treated Valve embolization - no. (%) *Converted to transapical TAVR due to porcelain aorta

Primary Endpoint: All-Cause Mortality at 1 Year HR [95% CI] = 0.93 [0.71, 1.22] P (log rank) = 0.62 0.5 TAVR AVR 0.4 26.8 0.3 0.2 24.2 0.1 6 12 18 24 No. at Risk Months TAVR 348 298 260 147 67 351 252 236 139 65 AVR

Primary Endpoint: All-Cause Mortality at 1 Year AVR (N = 351) 26.8% TAVR (N = 348) 24.2% Primary Non-Inferiority Endpoint Met Non-inferiority P value = 0.001 Difference -2.6% Upper 1-sided 95% CI 3.0% Zone of non-inferiority pre-specified margin = 7.5% Non-inferior -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 % Upper one-sided 95% CI

All-Cause Mortality Transfemoral (N=492) HR [95% CI] = 0.83 [0.60, 1.15] P (log rank) = 0.25 26.4 22.2 No. at Risk Months TAVR 244 215 188 119 59 248 180 168 109 56 AVR

Powered Secondary Endpoint (ITT): TF All-Cause Mortality at 1 Year TAVR (N = 248) 22.2% AVR (N = 244) 26.4% Difference -4.2% Upper 1-sided 95% CI 2.3% Non-inferiority P value = 0.002 Zone of non-inferiority pre-specified margin = 7.5% Non-inferior -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 % Upper one-sided 95% CI Secondary TF Non-Inferiority Endpoint Met

All-Cause Mortality Transapical (N=207) HR [95% CI] = 1.22 [0.75, 1.98] P (log rank) = 0.41 29.0 27.9 No. at Risk Months TAVR 104 83 72 28 8 103 68 30 9 AVR

Surgical AVR Outcomes Using an established predictive risk model (STS), the expected (“E”) 30-day mortality after AVR was 11.8%. The observed (“O”) 30-day mortality in the as-treated AVR control group was 8.0%. O:E = 0.68 indicates better than predicted surgical outcomes in the control AVR patients. There were no significant site or surgeon differences. 35

All-Cause Mortality at 30 Days and 1 Year ITT and ATT by Subgroup All Patients no. of patients ( %) TF Patients no. of patients ( %) TA Patients   TAVR AVR p-value ITT 12 (3.4) 22 (6.5) 0.07 8 (3.3) 15 (6.2) 0.13 4 (3.8) 7 (7.0) 0.32 AT 18 (5.2) 25 (8.0) 0.15 9 (3.7) 18 (8.2) 0.05 9 (8.7) 7 (7.6) 0.79 All-Cause Mortality at 1 Year All Patients no. of patients ( %) TF Patients no. of patients ( %) TA Patients   TAVR AVR p-value ITT 84 (24.2) 89 (26.8) 0.44 54 (22.2) 62 (26.4) 0.29 30 (29.0) 27 (27.9) 0.85 AT 81 (23.7) 78 (25.2) 0.64 51 (21.3) 55 (25.2) 0.33 30 (29.1) 23 (25.3) 0.55

Clinical Outcomes at 30 Days and 1 Year All Patients (N=699)   30 Days 1 Year Outcome TAVR (N = 348) AVR (N = 351) p-value TAVR (N = 348) All mortality – no. (%) 12 (3.4) 22 (6.5) 0.07 84 (24.2) 89 (26.8) 0.44 Cardiac mortality – no. (%) 11 (3.2) 10 (3.0) 0.90 47 (14.3) 40 (13.0) 0.63 Rehospitalization – no. (%) 15 (4.4) 12 (3.7) 0.64 58 (18.2) 45 (15.5) 0.38 Death or rehosp – no. (%) 25 (7.2) 33 (9.7) 0.24 120 (34.6) 119 (35.9) 0.73 MI – no. (%) 2 (0.6) 0.16 1 (0.4) 0.69 Acute kidney inj* – no. (%) 10 (2.9) 0.95 18 (5.4) 20 (6.5) 0.56 * Renal replacement therapy

Clinical Outcomes at 30 Days and 1 Year All Patients (N=699)   30 Days 1 Year Outcome TAVR (N = 348) AVR (N = 351) p-value TAVR (N = 348) Vascular complications All – no. (%) 59 (17.0) 13 (3.8) <0.01 62 (18.0) 16 (4.8) Major – no. (%) 38 (11.0) 11 (3.2) 39 (11.3) 12 (3.5) Major bleeding – no. (%) 32 (9.3) 67 (19.5) 49 (14.7) 85 (25.7) Endocarditis – no. (%) 0 (0.0) 1 (0.3) 0.32 2 (0.6) 3 (1.0) 0.63 New AF – no. (%) 30 (8.6) 56 (16.0) < 0.01 42 (12.1) 60 (17.1) 0.07 New PM – no. (%) 12 (3.6) 0.89 19 (5.7) 16 (5.0) 0.68 NOTE: Original idea was to create TWO OPTIONS – HOWEVER, given the amount of content – Option 2 would take a total of 4 slides. I can create these slides easily, but wanted you to review Option 1 before investing time in the creation of those slides. Here’s the original discussion: Clinical Outcomes @ 30 Day & 1 year: Table 2 from Pages 30 & 31 of Manuscript Option 1 = Both 30 Day & 1 Year side-by-side in 1 slide Option 2 = 1 slide for 30 Day / 1 slide for 1 Year 38

Neurological Events at 30 Days and 1 Year All Patients (N=699)   30 Days 1 Year Outcome TAVR (N = 348) AVR (N = 351) All Stroke or TIA – no. (%) 19 (5.5) 8 (2.4) 0.04 27 (8.3) 13 (4.3) TIA – no. (%) 3 (0.9) 1 (0.3) 0.33 7 (2.3) 4 (1.5) 0.47 All Stroke – no. (%) 16 (4.6) 0.12 20 (6.0) 10 (3.2) 0.08 Major Stroke – no. (%) 13 (3.8) 7 (2.1) 0.20 17 (5.1) 0.07 Minor Stroke – no. (%) 0.34 2 (0.7) 0.84 Death/maj stroke – no. (%) 24 (6.9) 28 (8.2) 0.52 92 (26.5) 93 (28.0) 0.68 p-value p-value

All-Cause Mortality or Stroke All Patients (N=699) HR [95% CI] = 0.95 [0.73, 1.23] P (log rank) = 0.70 28.0 26.5 No. at Risk Months TAVR 348 289 252 143 65 351 247 232 138 63 AVR

NYHA Functional Class Patients Surviving, % P = 1.00 P < 0.001 Baseline 30 Days 6 Months 1 Year I II III IV

Six-Minute Walk Test All Patients (N=699) Median Distance, meters

Subgroup Analyses of Treatment Effect All-Cause Mortality at 1 Year TAVR (%) n=348 AVR (%) n=351 RR (95% CI) P-value for interaction Overall 24.1 25.4 0.95(0.73-1.23) Age <85 >85 21.6 27.0 24.9 26.1 0.87(0.60-1.27) 1.03(0.72-1.47) 0.52 Sex Male Female 28.4 18.4 24.2 27.2 1.17(0.84-1.63) 0.045 BMI <26 >26 27.3 21.0 27.4 23.8 0.68(0.44-1.04) 0.99(0.71-1.40) 0.66 STS score <11 >11 19.9 28.1 21.7 29.3 0.88(0.59-1.31) 0.92(0.61-1.38) 0.87 LV ejection fraction <55 >55 26.2 22.4 27.7 22.1 0.96(0.69-1.34) 1.01(0.68-1.50) 0.80 TAVR better AVR better 0.5 1 2

Subgroup Analyses of Treatment Effect All-Cause Mortality at 1 Year TAVR (%) n=348 AVR (%) n=351 RR (95% CI) P-value for interaction Pulmonary hypertension No Yes 21.3 27.4 21.7 29.9 0.98(0.64-1.50) 0.92(0.66-1.28) 0.80 Mitral regurgitation 24.6 24.2 22.1 35.2 1.11(0.82-1.52) 0.69(0.41-1.17) 0.12 Prior CABG 22.2 25.9 30.7 19.1 0.72(0.52-1.01) 1.35(0.88-2.08) 0.02 Peripheral vasc disease 22.4 26.4 25.1 25.4 0.89(0.63-1.27) 1.04(0.70-1.54) 0.57 Cohort TA TF 28.8 26.2 25.0 1.10(0.71-1.71) 0.89(0.64-1.22) 0.43 TAVR better AVR better 0.5 1 2

Echo Findings Aortic Valve Gradients Mean and Peak Gradient As-Treated Trial Arms (mmHg) 50 40 30 20 60 70 10 80 Mean Gradient - AVR Mean Gradient - TAVR Peak Gradient - AVR Peak Gradient - TAVR Baseline 30 Days 6 Months 1 Year TAVR n = 327 AVR n = 301 TAVR n = 287 AVR n = 231 TAVR n = 246 AVR n = 170 TAVR n = 227 AVR n = 159

Echo Findings Hemodynamic Assessments   30 Days 1 Year Finding TAVR AVR AVG – mmHg 9.9 ± 4.8 10.8 ± 5.0 0.04 10.2 ± 4.3 11.5 ± 5.4 0.008 AVA - cm2 1.7 ± 0.5 1.5 ± 0.4 0.001 1.6 ± 0.5 1.4 ± 0.5 0.002 LVEF - % 55.5 ± 11.4 56.0 ± 11.4 0.63 56.6 ± 10.5 57.1 ± 10.3 0.64 p-value p-value

Paravalvular Aortic Regurgitation Patients, % 30 Days 6 Months 1 Year None Trace Mild Moderate Severe

Study Limitations 8% of the control (AVR) group withdrew or refused assigned therapy 5% of patients randomized to TAVR did not receive assigned therapy (procedure aborted or converted to AVR) Significantly longer interval between randomization and treatment in controls (AVR) An early version large TAVR delivery system was used Most sites had no previous TAVR experience - learning curve impact inherent in TAVR, but not in AVR Insufficient statistical power to compare TA to either AVR or TF Long-term follow-up not available to assess TAVR durability This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 48

Conclusions (1) The primary endpoint of the trial was met: In patients with aortic stenosis at high risk for operation, TAVR was non-inferior to AVR for all-cause mortality at 1 year (24.2% vs. 26.8%, p=0.001 for non inferiority) Transfemoral TAVR subgroup was also non-inferior to AVR (p=0.002 for non-inferiority) Death at 30 days was lower than expected in both arms of the trial: TAVR mortality (3.4%) was the lowest reported in any series, despite an early generation device and limited previous operator experience AVR mortality (6.5%) was lower than the expected operative mortality (11.8%) This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 49

Conclusions (2) Both TAVR and AVR were associated with important but different peri-procedural hazards: Major strokes at 30 days (3.8 vs. 2.1%, p=0.20) and one year (5.1% vs. 2.4%, p=0.07) and major vascular complications were more frequent with TAVR (11.0% vs. 3.2%, p<0.001) Major bleeding (9.3% vs. 19.5%, p<0.001) and new onset atrial fibrillation (8.6% vs. 16.0%, p<0.001) were more frequent with AVR TAVR and AVR are both acceptable therapies in these high-risk patients; differing peri-procedural hazards should influence case-based decision-making This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 50

Conclusions (3) Symptom improvement (NYHA class and 6-min walk distance) favored TAVR at 30 days and was similar to AVR at one year Echo findings indicate: Small hemodynamic benefit with TAVR vs. AVR at 1 year (mean gradient p=0.008, AVA p=0.002) Increased para-valvular regurgitation associated with TAVR (p<0.001) Preliminary subgroup analyses should be interpreted cautiously: Possible TAVR benefit in women and patients without prior CABG This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 51

Implications A multidisciplinary valve team approach benefits patients and is recommended for all future valve centers. TAVR is already the standard-of-care for inoperable patients with severe aortic stenosis. These results indicate that TAVR is an acceptable alternative to AVR in selected high-risk operable patients. Future randomized studies should focus on lower risk patients who are candidates for operation.

Back-up Slides

PARTNER Comparison of Outcomes High-Risk vs. Inoperable Patients Per Cent (%) 11.0 5.0

Neurological Events and Mortality at 30 Days and 1 Year (as treated)   TAVR AVR Complication With Without Stroke or TIA All Patients – no. 31 313 16 297 Died ≤ 30 days – no. (%) 2 (6.5) 16 (5.1) 1 (6.3) 24 (8.1) Died ≤ 1 year – no. (%) 10 (32.3) 71 (22.8) 3 (18.8) 75 (25.6) Major Stroke 18 326 11 302 2 (11.1) 16 (4.9) 1 (9.1) 24 (8.0) 9 (50.0) 72 (22.2) 3 (27.3) 75 (25.1)

Vascular/Bleeding Events and Mortality at 30 Days and 1 Year (as treated)   TAVR AVR Complication With Without Major Vascular All Patients – no. 38 306 11 302 Died ≤ 30 days – no. (%) 6 (15.8) 12 (3.9) 2 (19.2) 23 (7.6) Died ≤ 1 year – no. (%) 14 (37.3) 67 (22.0) 5 (49.5) 73 (24.4) Major Bleeding 52 292 88 225 2 (3.8) 16 (5.5) 15 (17.1) 10 (4.5) 16 (31.1) 65 (22.3) 36 (41.3) 42 (18.9)

All-Cause Mortality (As Treated TAVR Trial Arm) Stratified by Major Stroke Months

All-Cause Mortality (As Treated TAVR Trial Arm) Stratified by Major Vascular Event Months

All-Cause Mortality (As Treated TAVR Trial Arm) Stratified by Major Bleed Months

All-Cause Mortality (As Treated AVR Trial Arm) Stratified by Major Stroke Months

All-Cause Mortality (As Treated AVR Trial Arm) Stratified by Major Bleed Months

All-Cause Mortality (As Treated AVR Trial Arm) Stratified by New Atrial fibrillation Months

All-Cause Mortality (As Treated) Pooled Implant Approaches (N= 657) HR [95% CI] = 1.02 [0.77, 1.36] P (log rank) = 0.88 25.2 23.7 No. at Risk Months TAVR 344 291 258 139 64 313 243 226 128 60 AVR

Primary Endpoint: (As Treated) All-Cause Mortality at 1 Year TAVR (N = 344) 23.6% AVR (N = 313) 25.2% Difference -1.6% Upper 1-sided 95% CI 4.0% Non-inferiority P value = 0.004 Zone of non-inferiority pre-specified margin = 7.5% Non-inferior -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 % Upper one-sided 95% CI Primary Non-Inferiority Endpoint Met

All-Cause Mortality (As Treated) Transfemoral (N=461) HR [95% CI] = 0.90 [0.64, 1.26] P (log rank) = 0.53 25.2 21.3 No. at Risk Months TAVR 240 209 186 112 58 221 172 161 100 53 AVR

Powered Secondary Endpoint (AT): TF All-Cause Mortality at 1 Year TAVR (N =240 ) 21.3% AVR (N = 221) 25.2% Difference -3.9% Upper 1-sided 95% CI 2.6% Non-inferiority P value = 0.002 Zone of non-inferiority pre-specified margin = 7.5% Non-inferior -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 % Upper one-sided 95% CI Secondary TF Non-Inferiority Endpoint Met

All-Cause Mortality (As Treated) Transapical (N=196) HR [95% CI] = 1.36 [0.82, 2.26] P (log rank) = 0.23 29.1 25.3 No. at Risk Months TAVR 104 82 72 27 6 92 71 65 28 7 AVR

All-Cause Mortality Stratified by ITT Trial Arm and Patient Gender

All-Cause Mortality Stratified by ITT Trial Arm and Prior CABG

All-Cause Mortality Stratified by ITT Trial Arm and Prior CABG

All-Cause Mortality Stratified by ITT trial arm and Moderate/Severe MR

Echo Findings Valvular Regurgitation   30 Days 1 Year Finding – no. (%) TAVR AVR Transvalv. Regurg. Mod/Severe 3 (1.0) 2 (0.9) <.0001 0 (0.0) Paravalv. Regurg. 35 (12.2) 15 (6.8) 3 (1.9) All Regurg. 21 (7.7) 4 (1.7) <0.001 12 (5.5) p-value p-value

Echo Findings Paravalvular Regurgitation   30 Days 1 Year Finding – no. (%) TAVR AVR None 65 (22.6) 168 (73.7) <.0001 73 (32.9) 123 (77.8) Trace/Mild 187 (65.2) 58 (25.4) 134 (60.4) 32 (20.3) Mod/Severe 35 (12.2) 2 (0.9) 15 (6.8) 3 (1.9) p-value p-value

Aortic Valve Area As Treated Trial Arms Valve Area, cm2 AVR TAVR TAVR n = 319 AVR n = 297 TAVR n = 279 AVR n = 228 TAVR n = 235 AVR n = 165 TAVR n = 219 AVR n = 155