CoreValve US Pivotal Study: Update and Design Considerations Jeffrey J. Popma, MD Director, Interventional Cardiology Clinical Services Beth Israel Deaconess Medical Center Associate Professor of Medicine Harvard Medical School Boston, MA

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

US CoreValve Clinical Study: Background US CoreValve clinical program was a later entry The PARTNER Trial design that evaluated patients unsuitable for sAVR had already been negotiated by the FDA to include: Inoperable patients (RCT to medical therapy) High-Risk (RCT to sAVR at high-volume centers) Cardiac surgery involvement was mandatory With PARTNER B results, it was no longer ethical to randomized to medical therapy alone Stroke was a more important outcome than was previously appreciated Alternative access routes were available to test

Comparative Definitions for TAVR Trials Indication PARTNER Sapien US CoreValve “Inoperable” or “Extreme” Risk > 50% risk of either death by 30 days or a serious irreversible condition1 > 50% risk of 30d mortality or irreversible morbidity “High” Risk > 15% risk of 30 day (Guideline STS PROM > 10%) 2 > 15% risk of 30 day mortality (Guideline STS and STS Plus > 15%) 1Leon N Engl J Med 2010; 363; 1597-607 2Smith N Engl J Med 2011; 364; 2187-98

44 Participating Study Sites Activated On a personal note, this is the most talented investigative team with whom I have ever had the opportunity to work. Our national heart surgeons, interventional cardiologists, and proctors work as one integrated team. We learn more every day and everyone teaches what they learn to others. 16 12 17 29 3 41 24 7 19 35 14 40 10 8 4 34 23 31 21 30 5 39 2 9 33 15 18 22 38 26 25 13 32 6 1 28 27 20 37 36 11 High Volume Centers; Multidisciplinary Teams On-line course worked followed by 2 Day Product Training with Procedural Simulation 3 Roll-in Cases; 10 Cases Proctored Per Site

CoreValveUS Pivotal: Study Administration Co-Principle Investigators Jeffrey Popma, BIDMC David Adams, Mt. Sinai Screening Committee Michael Reardon, Stephen Yakubov, Tom Gleason, John Conte, Jeffrey Popma Data & Safety Monitoring Board Chairman: David Faxon Brigham and Women’s Hospital Clinical Events Committee Chairman: Donald Cutlip HCRI EKG Core Laboratory Chairman: Peter Zimetbaum HCRI Echo Core Laboratory Chairman: Jae Oh Mayo Clinic Steering Committee: Cardiac Surgeons: Michael Reardon, Michael Deeb, John Byrne, Joseph Coselli, David Adams Interventionalists: James Hermillar, Stephen Yakubov, William Anderson, Maurice Buchbinder, Jeffrey Popma Consultants: Blasé Carabello, Patrick Serruys Quality of Life and Cost-Effective Assessments Chairman: David J. Cohen Mid-America Heart Inst, KC Sponsor Medtronic: Thomas Armitage, MD 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) 6

CoreValve US Trial: Primary Endpoints CoreValve U.S. Pivotal Trial “Extreme Risk” Patient Group “High Risk” Patient Group N=790 Primary Endpoint: Primary: All-Cause Mortality + Major Stroke (MRS > 1) at 12 months (compared to Objective Performance Criteria) Primary Endpoint: Primary: All-Cause Mortality at 12 months (non-inferiority)

CoreValve US Trial: Jan 2012 In 12 months . . . . Total patients submitted to the Screening Committee     1414 Total patients approved by Screening Committee  1126 Total Number of Subjects Enrolled / Randomized  1082     Total CoreValve cases  877        Roll-In High Risk        69        Roll-In Extreme Risk     58     

CoreValve US Trial: Top Sites The Methodist DeBakey Heart & Vascular Center Texas Heart Institute   St. Vincent Heart Center of Indiana   University of Kansas  Duke University Medical Center Vanderbilt University Medical Center  St. Francis Hospital    Banner Good Samaritan Medical Center   Riverside Methodist Hospital/Ohio Health Research Institute   St. Luke's Medical Center/Aurora Health Care   The Mount Sinai Medical Center  Spectrum Health Hospitals       University of Michigan Health Systems   Detroit Medical Center Cardiovascular Institute Beth Israel Deaconess Medical Center    University of Miami Health System       University of Pittsburgh Medical Center Providence Sacred Heart Medical Center  Highest Enrollment Sites

CoreValve US Trial: Current Status CoreValve U.S. Pivotal Trial “Extreme Risk” (Up to 687) “High Risk” N=790 Completed Enrollment Jan 2012 Iliofemoral access ? Randomization 1:1* No Yes CoreValve Observational Up to 200 CoreValve Single Arm N=487 CoreValve N=395 SAVR N=395

Screening Committee Challenges Patients required to have critical aortic stenosis that is severe enough to impact their chance of survival over the next 12 months. Low-gradient, low-output AS, Valve assessment Patients required to have substantial (> 15%) 30-day surgical mortality risk No minimum STS risk score; new indices for frailty Patients required to have a good likelihood of surviving for the next year after their aortic stenosis has been corrected  Exclude “mortal” co-morbidities

CoreValve Pivotal Trial: Inclusion Criteria Subject has senile degenerative aortic valve stenosis with Mean gradient >40 mm Hg or jet velocity >4.0 m/s by either resting or dobutamine stress echocardiogram AND An initial AVA of ≤0.8 cm2 (or aortic valve area index ≤0.5 cm2/m2) by resting echocardiogram or catheterization Subject is symptomatic from his/her aortic valve stenosis as demonstrated by NYHA class II or greater The subject or the subject's legal representative provided, written informed consent as approved by the IRB The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits Other criteria included1 Subject has senile degenerative aortic valve stenosis with Mean gradient of more than 40 mm Hg or jet velocity of more than 4.0 m/s by either resting or dobutamine stress echocardiogram, or simultaneous pressure recordings at cardiac catheterization (either resting or dobutamine stress) AND An initial aortic valve area of 0.8 cm2 or less (or aortic valve area index of 0.5 cm2/m2 or less) by resting echocardiogram or simultaneous pressure recordings at cardiac catheterization. Subject is symptomatic from his/her aortic valve stenosis as demonstrated by New York Heart Association class II or above. The subject or the subject's legal representative has been informed of the nature of the trial, agrees to its provisions, and has provided written informed consent as approved by the IRB of the respective clinical site. The subject and the treating physician agree that the subject will return for all required postprocedure follow-up visits. Reference: 1. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 7.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2011.

CoreValve® Pivotal: Exclusion Criteria Evidence of AMI ≤30 days before procedure Any procedure performed <30 days prior to procedure Defined blood dyscrasias Untreated clinically significant CAD requiring revascularization Cardiogenic shock Need for emergency surgery for any reason Severe ventricular dysfunction with LVEF <20% Recent CVA or TIA ESRD requiring chronic dialysis or CrCl <20 cc/min Clinical Exclusion Criteria Native aortic annulus size <18 mm or >29 mm Preexisting prosthetic heart valve, any position Mixed aortic valve disease Severe mitral (3 or 4+) or severe tricuspid regurgitation Moderate to severe mitral stenosis Hypertrophic obstructive cardiomyopathy Congenital bicuspid or unicuspid valve verified by echocardiography Anatomical Exclusion Criteria Transarterial access not able to accommodate an 18Fr sheath Vascular Exclusion Criterion Subjects were NOT eligible for trial participation if they met ANY of the clinical, anatomical, or vascular exclusion criteria detailed in the protocol.1 Exclusion criteria included1 Evidence of a heart attack within the last month Any percutaneous coronary or peripheral interventions within the last month; bleeding disorders Untreated significant CAD requiring revascularization Stroke within the last 6 months; active peptic ulcer or gastrointestinal bleeding within the last 6 months Severe kidney disease Severe left ventricular dysfunction with LVEF less than 20% Symptomatic carotid or vertebral artery disease Several other exclusion criteria were evaluated during the screening process according to the protocol.1 AMI=acute myocardial infarction; CAD=coronary artery disease; CrCl=creatinine clearance; CVA=cardiovascular event; ECG=echocardiogram; ESRD=end-stage renal disease; LVEF=left ventricular ejection fraction; TIA=transient ischemic attack. 1. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 7.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2011. Reference: 1. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 7.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2011.

Anatomical and Vascular Exclusion Criteria1,2 Severe basal septal hypertrophy with outflow gradient Aortic root angulation >70°(for femoral and left subclavian access) and >30°(for right subclavian access) Ascending aorta diameter >43 mm unless the aortic annulus is 20-23 mm, in which case the ascending aorta diameter is >40 mm For patients with native coronary artery dependent circulation: Sinus of Valsalva width <29 mm (29 mm Valve) or <27 mm (26 mm Valve) OR Height of the left or right coronary sinus of Valsalva (to the tubular aorta) <15 mm Subjects were NOT eligible for trial participation if they met ANY of the clinical, anatomical, or vascular exclusion criteria detailed in the protocol.1 Exclusion criteria included1 Evidence of a heart attack within the last month Any percutaneous coronary or peripheral interventions within the last month; bleeding disorders Untreated significant coronary artery disease requiring revascularization Stroke within the last 6 months; active peptic ulcer or gastrointestinal bleeding within the last 6 months Severe kidney disease Severe left ventricular dysfunction with left ventricular ejection fraction less than 20% Symptomatic carotid or vertebral artery disease Several other exclusion criteria were evaluated during the screening process according to the protocol.1 1. Medtronic CoreValve® U.S. Pivotal Trial (High Risk Patients). Version 6.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2011. 2. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 7.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2011. Reference: 1. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 7.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2011.

CoreValve: CTA Exclusion Criteria The left to right coronary dimension may be most important to predict coronary occlusion Right Left

What Kind of Patients are Deemed Extreme Risk?

Hostile Mediastinum: Chest Wall Radiation Prior Chest Radiation and Sternal Osteomyelitis Prior Chest Radiation Vahanian ICI 2008 Tel-Aviv Urbanski Ann Thorac Surg 2009;88:987

“Porcelain” Aorta There is an extraordinarily high incidence of stroke after cannulation and clamping of a severe atherosclerotic ascending aorta, with nine (45%) cerebrovascular accidents and four fatal strokes in a series of 20 pts. Mills NL, Everson CT. J Thorac Cardiovasc Surg 1991;102:546–53. Herrmann et al Ann Thorac Surg 2009:998 CoreValve Clinical Trial

Harder to Assess Frailty: Cohort B  C Disability: ADL IADLs Difficulty or dependency in daily living Frailty Impairment in multiple systems that leads to a decline in homeostatic reserve and resiliency Charlson Co-Morbidities Two or more medical conditions

Screening Committee Challenges Patients required to have critical aortic stenosis that is severe enough to impact their chance of survival over the next 12 months. Low-gradient, low-output AS, Valve assessment Patients required to have substantial (> 15%) 30-day surgical mortality risk No minimum STS risk score; new indices for frailty Patients required to have a good likelihood of surviving for the next year after their aortic stenosis has been corrected  Exclude “mortal” co-morbidities

What Defines “High Risk” US CoreValve Pivotal Cohort “Subject must have co-morbidities such that one cardiologist and two cardiac surgeons agree that predicted risk of operative mortality is ≥15% (and predicted operative mortality or serious, irreversible morbidity risk of < 50%) at 30 days” No Minimal STS Risk Score Burden of Proof on Clinical Site Surgeons Consistency Required by Screening Committee For Evaluation of Incremental Risk FDA Guidance: Adjust for Clinical Site O/E

Re: TAVR - STS Incompletely Assesses Better accounting is needed to estimate 30-day surgical risk . . . Top five conditions Severe Pulmonary Disease Severe Liver Disease (MELD, Childs) RV Function and Right Heart Failure Frailty (and Cognitive Dysfunction) Ilio-Femoral Vascular Disease

“STS Plus” Risks Determined by 40 Cardiac Surgeons BNP ≥ 550 pg/mL 3% NT ProBNP ≥ 3200 pg/mL Prohibitive Chest Deformity 5% Hostile Mediastinum 15% Prior Stroke / TIA FEV1 < 750 20% FEV2 750-1000 cc Home (Supplemental) O2 Nocturnal BiPAP 2% Severe Diastolic Dysfunction 4% Δ Risk Liver Disease Childs A 5% Childs B 7% Childs C 25% Pulmonary Hyptension 60-80 mmHg 5 > 80 mmHg 15% Porcelain Aorta 20% Age > 85 and Prior CABG 3% Severe Aortic Calcification Frailty Assessments < 80 Yrs 80-90 Years > 90 Years BMI < 21 4% 5% 6% Albumin < 3.3 7% Wheelchair Bound 8% 10% Does Not Live Independently 9%

Screening Committee Challenges Patients required to have critical aortic stenosis that is severe enough to impact their chance of survival over the next 12 months. Low-gradient, low-output AS, Valve assessment Patients required to have substantial (> 15%) 30-day surgical mortality risk No minimum STS risk score; new indices for frailty Patients required to have a good likelihood of surviving for the next year after their aortic stenosis has been corrected  Exclude “mortal” co-morbidities

Mini-Mental State Examination (MMSE) Category Points Orientation to time 5 Correlated with decline Orientation to place Registration 3 Repeat named prompts Attention and calculation Serial sevens Recall Registration recall Language 2 Name a pencil and watch Repitition 1 Speaking back a phase Complex Commands 6 Drawing figures Score ≥ 25 points (out of 30) is effectively normal (intact). Below this, scores can indicate severe (≤9 points), moderate (10-20 points) or mild (21-24 points) Folstein MF, Folstein SE, McHugh PR (1975). ""Mini-mental state". A practical method for grading the cognitive state of patients for the clinician". Journal of psychiatric research 12 (3): 189–98

US CoreValve : Unique Features 100% independent review of all imaging studies, including echocardiograms, CT angiograms (chest and abdomen/pelvis), and angiograms Movement toward CT annular sizing for device selection to minimize perivalvular leak Expansion of non-iliofemoral registry to 200 patients in the extreme risk groups with increasing experience with direct aortic approach

CT Used to Determine Valve Sizing 3 Mensio Reconstruction Perimeter Measurements 23 mm CoreValve  72.26 mm 26 mm CoreValve  81.64 mm 29 mm CoreValve  91.06 mm 31 mm CoreVavel  97.39 mm 30.1 Major aortic annulus diameter Minor aortic annulus diameter Aortic annulus perimeter Max. ascending Aorta diameter Sinus of Valsalva width Sinus of Valsalva height (All in mm) 25.1 88.5 32 35.3 19

Iliofemoral CT Angiogram Tortuosity, Calcium, Marginal CSA < OD 18Fr 6.93 mm 026-S017

Subclavian and Direct Aortic Approach Represents up to 20% of patients in Extreme Risk

CoreValve US Pivotal Trial: Summary 44 Clinical Sites activated Trial recruitment on track: Extreme Risk: Completed  Continued Access High Risk: Summertime 2012 Screening Committee is essential for detailed case review, surgical risk confirmation, and re- assessment of anatomic considerations Mandates an interdisciplinary approach to case planning and case management