Transcatheter Aortic Valve Replacement: Expanding to “Intermediate Risk” Patients Jeffrey J. Popma, MD Director, Interventional Cardiology Clinical Services Beth Israel Deaconess Medical Center Associate Professor of Medicine Harvard Medical School Boston, MA

Jeffrey J. Popma, MD Contracted Research / Grant Support: Abbott Vascular Abiomed, Inc. Atrium Medical Corporation Boston Scientific Corporation Cordis Corporation IDEV Technologies, Inc. Medtronic, Inc.

Consulting Fees: Abbott Vascular Boston Scientific Corporation My presentation will include off label discussions: Percutaneous aortic valves

Conflict of Interest Statement Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below. Physician Name Company/Relationship Jeffrey J. Popma, MD Research Grants: Cordis, Boston Scientific, Medtronic, Abbott-Guidant, eV3, LabCoat Medical Advisory Board: Cordis, Boston Scientific, Abbot Vascular

Better TAVR Outcomes in Lower Risk Patients N=420 patients (105 per quartile) Quartile 1 Quartile 4 Age, years 81.1 years 78.9 years Logistic Euroscore, % 25.4% 17.8% STS-PROM, % 7.13% 4.8% Crude 30 day Mortality, % 11.4% 3.8% Lange JACC 2012;59:280–7

European ‘’On-Label’’ and ‘’Off-Label ’’ Use Piazza Heart 2010;96:19–26.

European ‘’On-Label’’ and ‘’Off-Label ’’ Use Better Survival in “Off-Label” No Change in Stroke But at an increased risk of bleeding (5% on-label; 14% off label) Piazza Heart 2010;96:19–26.

Intermediate Populations “Risk Creep” Favors TAVR Preferentially

“Risk Creep” Favors TAVR Preferentially Bern Windecker

Expanding Into Risk Populations Top 33% Surgical Risk STS ≥ 4 Top 7% Surgical Risk STS > 8 “Cohort C” Two-thirds of patients will remain optimal surgical candidates Extreme Risk Surgical Aortic Valve Replacements 70-90,000 yearly PARTNER IIA SURTAVI Intermediate ≈ 26% STS PROM < 4% 30-Day Mortality < 2-4% CoreValve Extreme Risk PARTNER B CoreValve High Risk PARTNER A Inoperable 20-50K

Patient Selection Presented By Prof. Patrick Serruys, MD on behalf of

SURTAVI Trial Leadership Chairmen: Prof. P.W. Serruys (Chair) Dr. N. van Mieghem (Deputy Chair) Principal Investigators: Prof. S. Windecker Prof. A.P. Kappetein Prof. R. Lange Prof. T. Walther Dr. J. Popma Dr. D. Adams Dr. M. Reardon Serruys SURTAVI TCT2011

Identifying Intermediate Risk Patients Serruys SURTAVI TCT2011

Identifying Intermediate Risk Patients Serruys SURTAVI TCT2011

Operability is a Risk Continuum TAVR or AVR ¿ Surgery (AVR) Low Risk Intermed Risk High Risk 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) OR risk < 5% 5-15% >15% % patients ~65-70% ~20-25% ~10% Serruys SURTAVI TCT2011 15

STS ≥ 3 46% STS ≥ 4 33% STS ≥ 5 25% STS PROM (2006-2010) Leon PARTNERII A TCT2011

BERMUDA Results Serruys SURTAVI TCT2011

Heart Team Assesment May Vary From STS Serruys SURTAVI TCT2011

BERn – MUnich – rotterDAm Registry 3666 patients enrolled TAVI – 782 SAVR – 2884 2882 patients excluded based on propensity scores 784 matched patients TAVI – 392 SAVR - 392 510 matched patients (STS scores 3-8%) 274 patients excluded based on STS score <3% and >8% TAVI 255 patients analyzed SAVR Serruys SURTAVI TCT2011

BERn – MUnich – rotterDAm Registry Matched Cohort STS <3 n=184 STS 3-8 n=510 STS >8 n=90 Age (years) 77.3 (4.7) 80.1(5.3) 81.7 (5.3) Logistic ES (%) 13.5 (8.4) 17.6 (10.5) 25.1(17.1) TAVI vs. SAVR 92 vs. 92 255 vs. 255 45 vs. 45 Serruys SURTAVI TCT2011

BERn – MUnich – rotterDAm Registry One Year Outcome In Intermediate Risk Patients Serruys SURTAVI TCT2011

SURTAVI: Primary Objective Evaluate in a prospective randomized fashion whether TAVI is non-inferior to SAVR with respect to the event free survival of the combined endpoint of all-cause mortality and major stroke at 24 months in patients with symptomatic severe aortic stenosis and at intermediate surgical risk. Serruys SURTAVI TCT2011

SURTAVI: Study Design Patient population Symptomatic severe aortic stenosis Intermediate surgical risk, defined by Society of Thoracic Surgeons (STS) mortality risk: ≥ 3% and ≤ 8-10% (OUS) ≥ 4% and ≤ 8-10% (US) Long-term follow-up through 5 years Enrollment phase ~ 20 months Trial duration ~ 7 years Serruys SURTAVI TCT2011

SURTAVI: Inclusion Criteria Subject must have STS mortality risk score ≥ 3% and ≤ 8% (in United States, STS mortality risk score ≥4% and ≤8%) Heart Team consisting of at least one interventional cardiologist and one cardiac surgeon agree on indication, treatment proposal, and eligibility for randomization based on their clinical judgment Critical aortic valve area defined as an initial aortic valve area of ≤1.0 cm2 or aortic valve area index < 0.6 cm2/m2

SURTAVI: Inclusion Criteria In presence of normal LV function: mean gradient > 40mmHg OR Vmax > 4m/sec . In the presence of reduced LV function and a mean gradient < 40 mmHg AND Vmax < 4 m/sec, dobutamine stress echo may be give to increase the mean gradient >40mmHg or Vmax < 4 m/sec Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater

SURTAVI: Exclusion Criteria Active Gastrointestinal (GI) bleeding within the past 3 months Subject refuses a blood transfusion Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits) Multivessel coronary artery disease with a Syntax score >22

SURTAVI: Exclusion Criteria True porcelain aorta Extensive mediastinal radiation Liver failure (Child-C) Reduced ventricular function with left ventricular ejection fraction (LVEF) <30% as measured by resting echocardiogram Uncontrolled atrial fibrillation Pregnancy or intent to become pregnant prior to completion of all protocol follow-up requirements End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min

SURTAVI: Exclusion Criteria Native aortic annulus size < 20 mm or > 29 mm Pre-existing prosthetic heart valve in any position Mixed aortic valve disease [AS and AR with predominant AR (3-4+)] Severe mitral or severe tricuspid regurgitation Severe mitral stenosis Hypertrophic obstructive cardiomyopathy Echocardiographic or Multislice Computed Tomography (MSCT) evidence of intracardiac mass, thrombus or vegetation Ascending aorta diameter > 43 mm unless the aortic annulus is 20-23 mm in which case the ascending aorta diameter > 40 mm

Neurological Assessments SURTAVI: Study Design OUS STS mortality risk ≥3% and ≤8% US STS mortality risk ≥4% and ≤8% Heart Team Evaluation including assessment for significant CAD with determination of need for revascularization Meet I/E Criteria and eligible for SAVR and TAVI QoL Questionnaire Randomization with 5 year follow up Neurological Assessments Presence of significant CAD with intended revascularization No intended revascularization TAVI + PCI SAVR + CABG TAVI SAVR

PARTNER II – Intermediate Risk Symptomatic Severe Aortic Stenosis ASSESSMENT by Heart Valve Team Intermediate Risk Inoperable 2 Parallel RCTs: Individually Powered TF TAVR Sapien ASSESSMENT: Transfemoral Access Not In Study Sapien XT Primary Endpoint: All-Cause Mortality + Major Stroke + Repeat Hospitalization at One Year (Non-inferiority) 1:1 Randomization VS Yes No ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR Sapien XT AVR Primary Endpoint: All-Cause Mortality + Major Stroke at Two Years (Non-inferiority) TA TAVR Ascendra 2 VS

PARTNER II – Intermediate Risk Severe, symptomatic calcific AS (echo criteria) Intermediate risk = STS score ≥ 4% OR specific qualifying intermediate risk criteria Includes AS patients with CAD requiring treatment… AS + CAD patients substratified to compared (TAVR + PCI vs. AVR + CABG) “Complex” CAD excluded (unprotected LM lesions, MVD with Syntax score ≥ 33) All CAD treatment patients reviewed by EC sub-committee for study inclusion Less aggressive complete revascularization acceptable (both for TAVR and AVR) TF-TAVR includes vascular anatomy appropriate for lower profile Sapien XT + Novaflex system

PARTNER II – Intermediate Risk Non-inferiority of TAVR-Sapien XT vs. sAVR for the primary endpoint for the duration of the study (all patients followed for at least 2 years) Primary endpoint is a nonhierarchical composite of all- cause mortality and major stroke (mRankin score ≥ 2 at 90 days) Non-inferior if one-sided 95% upper confidence limit for the treatment difference (∆) is < 20% of control; α =0.05 and power = 80% Based on PARTNER 1 High-risk study results in AVR control arm (death + stroke at 1-year = 28%); assumed event rate for primary endpoint in control 30% (discounted for intermediate risk and adjusted for longer 2-year FU)

PARTNER II – Intermediate Risk 1:1 randomization between TAVR (Sapien XT) vs. AVR Estimated sample size = 1744 patients (872 patients per arm); study sample size = 2,000 patients to account for lost-to-FU, withdrawals, and other study contingencies; (? mid-course pre-specified adjustment in final SAP)

PARTNER II – Intermediate Risk FDA approved for enrollment Nov 4, 2011 Up to 50 study sites (all U.S.) VARC definitions More intense neurologic assessments (100% qualified neurology pre- and post-evaluations) and neurocognitive function substudies Detailed frailty assessments Incorporate TAVR Best Clinical Practices, including adjunctive pharmacology regimens (anti-platelet and anti-thrombin therapy) ? Incorporate cerebral embolic protection (later portion of study)

Intermediate Risk Populations: Summary Outcomes will definitely be better with TAVI in lower risk populations, but so will the outcomes in patients undergoing sAVR Two big concerns: Perivalvular AR and Stroke Aim to lower PPM rate with good implantation technique Randomized trials are essential