US Pivotal Trial: Update Medtronic CoreValve US Pivotal Trial: Update 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 Honoraria Boston Scientific Corporation Cordis Corporation Grants/Contracted Research Medtronic, Inc. Abbott Laboratories

I intend to reference off label or unapproved uses of drugs or devices in my presentation. I intend to discuss Transcatheter aortic valves that are not approved in the USA

CoreValve Technology Outflow region orients the system Supra-annular valve function delivers optimal hemodynamics Frame designed to maintain coronary perfusion Intra-annular implantation and sealing skirt mitigates paravalvular leaks Inflow radial force is designed to prevent device migration 4

CoreValve Clinical Experience Study Study Size Number of centers Follow-up to date Status 18 Fr Safety and Efficacy 126 9 2 years Enrollment complete Australia-New Zealand 380 6 months Enrolling REDO 18 4 30 days Advance Study 1000 Up to 50 NA CoreValve US Pivotal >1,300 40 Italian Registry 772 14 1 year Enrollment Complete Belgian Registry 328 (141 CoreValve) 13 (6 CoreValve) Spanish Registry 108 3 French Registry 244 (78 CoreValve) 16 UK Registry 872 (460 CoreValve) 25 German Registry 697 (588 CoreValve) 22 Medtronic Sponsored Studies Independent Studies 5 5

CoreValve US Pivotal Proposed Design Medtronic CoreValve U.S. Pivotal Trial 40 Sites in the US “Extreme Risk” Patient Group 1277 to 1377 “High Risk” Patient Group 790 Iliofemoral access ? No Randomization 1:1 Up to 100 Yes 487 395* 395* CoreValve Observational CoreValve Single Arm CoreValve SAVR * * Includes iliofemoral and non-iliofemoral access patients Note: 3 roll-in patients per study site equates to a maximum of 1,497 patients enrolled

CoreValve US Pivotal Trial: Extreme Risk Medtronic CoreValve U.S. Pivotal Trial Inclusion Criteria Degenerative AS - Mean gradient > 40 mmHg - Jet velocity greater than 4.0 m/s - Initial AVA ≤ 0.8 cm2 - Aortic Valve Area Index ≤ 0.5 cm2/m2 Co-morbidities such as the probability of procedural death or serious, irreversible morbidity should equal or exceed 50% at 30 days. “Extreme Risk” Patient Group Iliofemoral access ? Endpoints: Primary: All-Cause Mortality + Major Stroke at 12 months (compared to Performance Goal) Secondary: MACCE, QoL Long-Term Safety and Durability No Yes CoreValve Observational Up to 100 CoreValve Single Arm N=487

CoreValve US Pivotal Trial: High Risk Inclusion Criteria Degenerative AS - Mean gradient > 40 mmHg - Jet velocity greater than 4.0 m/s - Initial AVA ≤ 0.8 cm2 - Aortic Valve Area Index ≤ 0.5 cm2/m2 Estimated surgical mortality > 15% at 30 days Medtronic CoreValve U.S. Pivotal Trial “High Risk” Patient Group N=790 Endpoints: Primary: All-Cause Mortality at 12 months (non-inferiority) Secondary: Pre-specified Hierarchical Testing Long-Term Safety and Durability Randomization 1:1 CoreValve N=395 SAVR N=395

CoreValve US Pivotal Trial: Alternative Access Extreme Risk Cohort Patients with no appropriate iliofemoral access will be evaluated for alternative access. Those who do have alternative access will be enrolled in an observational arm that will contain up to 100 patients. High Risk Surgical Cohort Those who do have alternative access will be randomized against SAVR and implanted either with SAVR or with TAVI through alternative access These patients will be part of the 790 patients enrolled in the randomized study (maximum 100 patients).

Subclavian-Axillary Access Subclavian-access approach approved patients with prohibitive ileo-femoral disease Laborde JC 2010 TVT Seattle

Direct Transaortic Approach Brushi Journal of Thoracic and Cardiovascular Surgery 2010 ; 140, 3 :715

Difference from other US TAVI trials High Risk Study Inclusion estimated surgical mortality >15% at 30 days All-cause mortality as single endoint Alternative access (e.g. subclavian/axillary) included but no transapical. Extreme Risk Study Single arm with performance goal. All patients enrolled are implanted with 18F CoreValve All-cause mortality + major stroke as single endpoint Alternative access possible (e.g. subclavian/axillary) in observational arm

CoreValve US Pivotal Trial: Current Status 16 Site 40 Sites Trained Roll-ins Ongoing Extreme Risk Registry “High-Risk” RCT We are on our way . . . . .

Interdisciplinary Committees Screening Committee National PIs and designated investigators (voting) as well as non voting CoreValve proctors and analysts Detailed review patient screening and imaging data to determine patient eligibility Establish and maintain consistency in the designation of “Extreme Risk” and “High Risk” patients Minimum of two surgeons and one interventionalist provide a screening committee quorum

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  DSE 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

Screening Committee Considerations Clinical Data Summary Clinical History STS and related Co-Morbidities Frailty Indices: Gait Speed, Grip Strength, ADLs 100% Central Imaging Lab Review (Intelemage) 2 D Echocardiography Coronary and Graft Angiography CTA Chest: Annular dimensions, SOV Dimensions CTA Torso: Peripheral Vessel Diameter, Calcification, Tortuousity

Screening Committee: Demographics

Screening Committee: STS Co-Morbidities

Comparisons of Outcomes with Three Models The STS Risk score underestimated the observed risk (ratio 1.41) whereas the logistic Euroscore overestimated the risk Important co-morbid factors were not included in the STS model for mortality (lung disease, frailty, porcelain aorta) All risk score calibrate risk within their individual score Dewey J Thor CV Surgery 2008; 135:180

Screening Committee: STS “Plus”

Determinants of Surgical Risk Disability: ADL IADLs CoreValve Frailty Score Charlson Co-Morbidities

Quantitating “Frailty” for the CoreValve Pivotal The CoreValve Frailty Index includes measures of nutritional assessment, strength and balance, energy level, average daily living, mental status, and medical co-mordibities. The measures will be collected prospectively to assess the patients overall frailty for this study. Nutritional Assessment Serum Albumin (≤ 3.3 g/dL) Hematocrit (≤ 35%) BMI (< 19) Unintentional Weight Loss Average Daily Living Bathing, Dressing, Toileting, Transferring, Continence, Feeding Charlson Co-morbidity Score Strength and Balance Wheelchair-requirement (0 = No; 1 = Yes) Grip strength adjusted for weight-BMI (kgs) 15-foot walk test (m/s) (Get-Up and Go) Falls (≥ 1 in past 6 mos Energy Level Poor endurance - self report Low activity - kilocalorie expenditure Men (< 383 Kcals/week Women (< 270 Kcal/week)

CoreValve Assessment of Annular Diameter Identify AV annulus hinge points – measure into the calcification 1.0 mm on each side (measured in systole). If TEE, measure into calcification 0.5 mm on each side. Jae Oh Mayo Core Lab Inclusion Criteria: Annular diameter 20-27 mm

CT Measurement of the Aortic Annulus Centralized Screening Will Provide The Answers CT Measurement of the Aortic Annulus (A) Aortic root of the annulus showing its crown-like shape. (B) Short-axis view of the AsAo at the Valsalva level (C) Short-axis view at the level of the basal attachment of the aortic leaflet (red arrows). (D) Measurements of the aortic annulus in the 3-chamber view. Small white arrows represent the hinge point of the leaflet into the aortic wall. Messika-Zeitoun J Am Coll Cardiol 2010;55:186–94

Medtronic Imaging Lab: Confirmation of Sizing 3 Mensio Reconstruction Perimeter Measurements 26 mm CoreValve  81.64 mm 29 mm CoreValve  91.06 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

Medtronic Imaging Lab: Confirmation of Angles Horizontal Heart Alignment of SOV LAO 15 degrees Caudal 5 degrees 65 degrees

US Pivotal Trial: Summary Progressive activation of clinical sites Meticulous oversight by Screening Committee to assess: Patients co-morbidities and surgical risk Echocardiographic-CTA analysis in all patients to confirmed anatomy Surgeon qualification “High-Risk” RCT will likely have lower STS scores but comparable co-mordidities for surgery “Extreme Risk” analysis v. PG