Transcatheter versus Surgical Aortic Valve Replacement in High Risk Patients with Severe Aortic Stenosis: Results From

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Transcatheter versus Surgical Aortic Valve Replacement in High Risk Patients with Severe Aortic Stenosis: Results From The PARTNER Trial Craig R. Smith, MD in the interest 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 support (Edwards LifeSciences ) repays standard travel and different costs

Background Surgical aortic valve substitution (AVR) is the standard of tend to treating patients with symptomatic aortic stenosis who are possibility for operation. In spite of the fact that transcatheter aortic valve substitution (TAVR) diminishes mortality in patients who can't have AVR, there have been no randomized trials contrasting TAVR with AVR in patients who are at high-chance for operation.

Purpose To look at the wellbeing and viability of TAVR (either transfemoral or transapical ) to surgical AVR in high-hazard, operable patients with symptomatic, extreme aortic stenosis .

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

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

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

Primary Endpoint All-cause mortality at one year Analysis by plan to-treat Event rates by Kaplan-Meier gauges Crossovers allowed just when doled out treatment unsuccessful All patients took after for ≥ one year

Other Important Endpoints (1) Safety: Neurologic occasions Prospective: Stroke and stroke in addition to TIA (all neuro occasions) Retrospective: Major stroke (changed Rankin Score ≥ 2 @ ≥ 30 days) Major vascular entanglements (VARC definition) Major dying (adjusted VARC definition) Repeat hospitalization New pacemakers and new-onset atrial fibrillation (ECG center lab) Procedural occasions (allocated treatment prematurely ended or changed over to AVR, different valves, and so on.) Surgical difficulties (re-operation for dying, sternal contamination, and so forth.)

Other Important Endpoints (2) Clinical Effectiveness and Valve Performance: NYHA manifestations Six-minute walk tests Quality-of-life measures and cost-viability (center lab) Echocardiography appraisal of valve execution (center lab) Peak and mean inclinations Effective opening zone Bioprosthetic valve disgorging (esp. para-valvular ) Other: LV discharge part, MR, LV mass, proof of auxiliary valve disintegration

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. Associated

Executive Committee Craig Miller Lars Svensson Michael Mack Jeff Moses Murat Tuzcu Marty Leon John Webb Craig Smith

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

High-Risk Enrollment by Site

High-Risk Enrollment by Site

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

TAVR Transfemoral and Transapical Transfemoral

Inclusion Criteria • Severe AS: Echo-inferred AVA < 0.8 cm 2 ( or AVA list < 0.5 cm 2/m 2 ) and mean AVG > 40 mm Hg or pinnacle fly speed > 4.0 m/s • Cardiac Symptoms: NYHA Functional Class ≥ II High surgical hazard: Predicted danger of agent mortality ≥ 15% (controlled by site specialist and cardiologist); rule = STS score ≥ 10

Key Exclusion Criteria (1) Anatomic: Bicuspid or non-calcified aortic valve Aortic annulus distance across (resound estimation) < 18 mm or > 25 mm Aortic dismemberment or iliac-femoral measurements or malady blocking safe sheath addition (esp. calcification) Severe LV brokenness (LVEF < 20%) Untreated CAD requiring revascularization Severe AR or MR (> 3+) or prosthetic valve (any area)

Key Exclusion Criteria (2) Clinical: Serum Cr > 3.0 mg/dL or dialysis subordinate Acute MI inside 1 month Upper GI seep inside 3 months CVA or TIA inside 6 months Any heart strategy, other than BAV, inside 1 month or inside 6 months for DES Hemodynamic precariousness (e.g. requiring inotropic bolster)

Statistical Analysis Plan Primary speculation is non-mediocrity of test (TAVR) versus control (AVR) for all-cause mortality at 1 year Non-substandard in the event that uneven 95% upper certainty restrain for the treatment distinction is < 7.5% ( α =0.05) Primary Endpoint: All TF and TA patients Assuming genuine 1-year mortality 32% after AVR and 29% after TAVR Intended example estimate = 650 patients for ≥ 85% power Powered Secondary Endpoint: Only TF patients Assuming genuine 1-year mortality 35% after AVR and 25% after TAVR Intended specimen measure = 450 patients for ≥ 85% power

Study Methodology Preliminary qualification dictated by webpage agents Every case explored by online telephone call before enlistment Randomized to TF-TAVR versus AVR, or TA-TAVR versus AVR, to be dealt with inside 2 weeks Intent-to-treat (ITT) investigation for the essential and most auxiliary endpoints; characterized as the season of randomization As-treated (AT) examination for some procedural endpoints and for reverberate evaluations; characterized as the season of procedural anesthesia enlistment

Study Flow Randomized = 699 patients Transfemoral n = 492 Transapical n = 207 TF = 492 TA = 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 (73) Dead = 26 Withdrawal = 0 LTFU = 1 Year (68) Dead = 20 Withdrawal = 3 LTFU = 1 Year (189) Dead = 46 Withdrawal = 1 Year (168) Dead = 47 Withdrawal = 8 42 Patients not regarded as allocated

Reasons for Non-treatment ITT = 699 patients │ AT = 657 patients NOTE: Time from randomization to treatment = TAVR 10.6 [SEM 0.7] days versus AVR 15.6 [SEM 1.1] days; P <0.001

Patient Characteristics (1) 5.7 6.0 Cerebrovascular illness - %

Patient Characteristics (2) 0.94 43.0

Baseline Echocardiography

Procedural Outcomes - TAVR versus AVR TAVR 3 fizzled get to 2 new TEE discoveries 2 kicked the bucket Aborted technique - no. (%) *Converted to transapical TAVR because of porcelain aorta

Procedural Outcomes - TAVR versus AVR TAVR 5 valve embolization 3 annulus estimate on TEE 1 extensive sigmoid septum 5 changed over to AVR 2 valve-in-valve 2 not treated Converted to AVR - no. (%) Valve embolization - no. (%) *Converted to transapical TAVR because of 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 24.2 0.2 0.1 0 6 12 18 24 No. at Risk Months TAVR AVR

Primary Endpoint: All-Cause Mortality at 1 Year TAVR (N = 348) 24.2% AVR (N = 351) 26.8% Dif