CoreValve US Pivotal Clinical Trial Update Jeffrey J. Popma, MD Director, Innovations in Interventional Cardiology Senior Attending Physician Beth Israel Deaconess Medical Center Associate Professor of Medicine Harvard Medical School Boston, MA

Jeffrey J. Popma, MD DISCLOSURES Grants/Contracted Research Honoraria Abbott Vascular, Boston Scientific Corporation, Cordis, a Johnson & Johnson company, Medtronic CardioVascular, Inc. Honoraria Abbott Vascular, Boston Scientific Corporation, Cordis, a Johnson & Johnson company I intend to reference unlabeled/unapproved uses of drugs or devices in my presentation. I intend to reference transcatheter aortic valves.

Clinical Trial Overview CoreValve US Pivotal Clinical Trial Overview Overall Trial Design Primary Endpoints Inclusion and Exclusion Criteria Screening Procedures Other Clinical Endpoints Long-Term Follow-up CRT2010 Washington, DC

PARTNER Trial Design: Completed Co-principal Investigators: Martin B. Leon, MD Interventional Cardiology Craig R. Smith, MD, Cardiac Surgeon Columbia University Population: High Risk/Non-Operable Symptomatic, Critical Calcific Aortic Stenosis Yes Cohort B No ASSESSMENT: Operability Cohort A n= up to 690 pts n=350 pts Total n= 1040 ASSESSMENT: Transfemoral Access Trans femoral AVR Control VS Yes 1:1 Randomization Cohort A TF Powered Independently Primary Endpoint: All Cause Mortality (Non-inferiority) Medical Management Control ASSESSMENT: Transfemoral Access VS Trans femoral 1:1 Randomization Yes Primary Endpoint: All Cause Mortality (Superiority) Two Trials: Individually Powered Cohorts (Cohorts A & B) No VS Trans apical AVR Control 1:1 Randomization Cohort A TA Powered to be Pooled with TF No Not in Study Smith TCT2009 San Francisco, DC

Lessons Learned From PARTNERS UNIQUE Clinical Trial Methodology Rare predicate RCTs in severe AS pts Problems of two parallel RCTs Cohort B (non-operable pts) = ethical dilemma Critical illness of these elderly severe AS pts management challenges Rigorous Study Execution Extraordinary commitment to rigorous site training, appropriate case selection, and complete follow-up of all endpoints Dedicated executive-screening committee Collaborations between cardiologists + surgeons Smith TCT2009 San Francisco, DC

Disclaimer The US IDE has not yet been approved for the Medtronic CoreValve US Pivotal Trial. This presentation represents a template clinical trial design, but discussions with the FDA are currently ongoing CRT2010 Washington, DC

Medtronic CoreValve® U.S. Pivotal Trial Trial Design Co-Principal Investigators David Adams, MD Mount Sinai Medical Center Jeffrey Popma, MD Beth Israel Deaconess Medical Center Medtronic CoreValve® U.S. Pivotal Trial Inoperable Patient Population High Risk Patient Population Randomization 2:1 Randomization 1:1 CoreValve® PAV OMM Surgical AVR CRT2010 Washington, DC

Clinical Trial Overview CoreValve US Pivotal Clinical Trial Overview Overall Trial Design Primary Endpoints Inclusion and Exclusion Criteria Screening Procedures Other Clinical Endpoints Long-Term Follow-up CRT2010 Washington, DC

Primary Objective - High Risk Cohort CoreValve US Pivotal Primary Objective - High Risk Cohort Demonstrate that the safety and effectiveness of the Medtronic CoreValve® System as measured by all-cause mortality rates at 12 months, is non-inferior to surgical aortic valve replacement (SAVR) in the treatment of symptomatic severe aortic stenosis in subjects who have a predicted high risk for aortic valve surgery CRT2010 Washington, DC

Primary Objective - Inoperable Cohort CoreValve US Pivotal Primary Objective - Inoperable Cohort Demonstrate that the safety and effectiveness of the Medtronic CoreValve® System (MCS) is superior to optimal medical management (OMM) in the treatment of symptomatic severe aortic stenosis in subjects deemed inoperable for aortic valve surgery as measured by time to all-cause death or hospitalization for heart failure CRT2010 Washington, DC

CoreValve Primary Endpoint High Risk Cohort US Pivotal Primary Endpoint High Risk Cohort All cause mortality at 12 months Inoperable Cohort All cause death or hospitalization for heart failure occurring during at least 12 months of follow-up CRT2010 Washington, DC

Re-Hospitalization for CHF CoreValve US Pivotal Re-Hospitalization for CHF “Hospitalization for worsening heart failure” is defined as an unplanned hospitalization that results in at least one overnight stay (i.e., where the admission date and the discharge date are different) that includes increased signs and/or symptoms of worsening heart failure requiring the administration or augmentation of intravenous heart failure therapy (e.g., inotropes, diuretics, and/or vasodilators). The Clinical Events Committee will adjudicate all primary endpoint events CRT2010 Washington, DC

Clinical Trial Sample Size CoreValve US Pivotal Clinical Trial Sample Size Number of Trial Subjects Sample size 790 total – High Risk Cohort 395 CoreValve® PAVI 395 Surgical Aortic Valve Replacement (SAVR) 398 total – Inoperable Cohort 266 CoreValve® PAVI 132 OMM Proctored cases Minimum of 5 per site Up to 3-5 roll-in cases prior to randomization CRT2010 Washington, DC

Clinical Trial Overview CoreValve US Pivotal Clinical Trial Overview Overall Trial Design Primary Endpoints Inclusion and Exclusion Criteria Screening Procedures Other Clinical Endpoints Long-Term Follow-up CRT2010 Washington, DC

CoreValve Inclusion Criteria High Risk Patients US Pivotal Subject must have co-morbidities such his/her predicted high risk for surgery as determined by an STS (Society of Thoracic Surgeons) score ≥ 8%, or have predicted perioperative mortality risk of ≥ 15% determined by two independent cardiac surgeons, at least one of whom is a member of the Steering Committee CRT2010 Washington, DC

CoreValve Inclusion Criteria Inoperable Cohort US Pivotal Subject must have co-morbidities such that a cardiologist and two cardiac surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious, irreversible morbidity should equal or exceed 50% at 12 months CRT2010 Washington, DC

Inclusion Criteria: Both Cohorts CoreValve US Pivotal Inclusion Criteria: Both Cohorts Symptom Status Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class II or greater Class II: Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. CRT2010 Washington, DC

Inclusion Criteria: Both Cohorts CoreValve US Pivotal Inclusion Criteria: Both Cohorts TTE/TEE/CTA/MRI Assessment of aortic annular sizing Subject has senile degenerative aortic valve stenosis with mean gradient > 40 mmHg and/or jet velocity greater than 4.0 m/s Initial aortic valve area of < 0.8 cm2 (or aortic valve area index < 0.6 cm2/m2) by echocardiogram CRT2010 Washington, DC

Clinical Exclusions: Both Cohorts CoreValve US Pivotal Clinical Exclusions: Both Cohorts Acute Myocardial Infarction < 30 days before intended treatment PCI performed within 30 days prior to the index procedure with bare metal stents and 6 months with drug eluting stents (Cohort A) Untreated clinically significant coronary artery disease requiring revascularization Cardiogenic shock manifested by low cardiac output, pressure dependent, or mechanical hemodynamic support CRT2010 Washington, DC

Clinical Exclusion: Both Cohorts CoreValve US Pivotal Clinical Exclusion: Both Cohorts Need for emergency surgery for any reason Severe ventricular dysfunction: LVEF < 20% Recent (within 6 months) CVA or TIA End stage renal disease requiring chronic dialysis or creatinine clearance < 30 cc/min Active peptic ulcer or GI bleeding < 3 months A known hypersensitivity or contraindication to aspirin, heparin, Nitinol (titanium and nickel alloy), both ticlopidine and clopidogrel, or sensitivity to contrast media, which cannot be adequately pre-medicated CRT2010 Washington, DC

Anatomic Exclusions: Both Cohorts CoreValve US Pivotal Anatomic Exclusions: Both Cohorts Native aortic annulus size < 20 mm or > 27 mm per the baseline diagnostic imaging Pre-existing prosthetic heart valve in mitral or aortic position Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation > 3+) Severe mitral (> 3+) or severe tricuspid insufficiency Hypertrophic obstructive cardiomyopathy Echocardiographic evidence of intracardiac mass, thrombus or vegetation CRT2010 Washington, DC

Anatomical Exclusions: Both Cohorts CoreValve US Pivotal Anatomical Exclusions: Both Cohorts Severe LV hypertrophy (wall thickness > 1.7cm) or basal septal hypertrophy Annulus-to-aorta (angle) > 700 (within the first 7 cm of the ascending aorta versus a perpendicular line across the aortic valve) Ascending aorta diameter > 43 mm Severe mitral annular calcification (circumferential AND heavy concentric calcification extending into the interventricular septum or aortic valvular complex) Bicuspid or unicuspid valve verified by echocardiography CRT2010 Washington, DC

Vascular Exclusion: Both Cohorts CoreValve US Pivotal Vascular Exclusion: Both Cohorts Iliac and femoral vessels (diameter) < 6 mm Subjects with one of the following: Bi-lateral femoral or aortic vascular conditions (e.g., stenosis, tortuousity), that make insertion and endovascular access to the aortic valve impossible Symptomatic carotid or vertebral artery disease Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5 cm or greater; marked tortuosity (hyperacute, bend), severe unfolding and tortuosity of the thoracic aorta CRT2010 Washington, DC

Clinical Trial Overview CoreValve US Pivotal Clinical Trial Overview Overall Trial Design Primary Endpoints Inclusion and Exclusion Criteria Screening Procedures Other Clinical Endpoints Long-Term Follow-up CRT2010 Washington, DC

Screening Procedure: Imaging CoreValve US Pivotal Screening Procedure: Imaging Comprehensive TTE or TEE 2D echocardiogram, including assessment of aortic valve gradients (mean and peak), areas, indices, degree of regurgitation, cardiac output and cardiac index, left ventricle systolic function (global and segmental) < 30 days of submission to the Screening Committee. Screening thoracic and abdominal aortograms or thoracic and abdominal CT angiograms with complete visualization of both iliacs and femorals to the aorta. In the situation where subjects have compromised renal function that precludes contrast media, MR imaging may be used as an alternative. CRT2010 Washington, DC

Clinical Trial Overview CoreValve US Pivotal Clinical Trial Overview Overall Trial Design Primary Endpoints Inclusion and Exclusion Criteria Screening Procedures Other Clinical Endpoints Long-Term Follow-up CRT2010 Washington, DC

Secondary Endpoints (continued) CoreValve US Pivotal Secondary Endpoints (continued) MACCE-free survival at 30 days, 6 months and 12 months and annually thereafter up to 5 years MACCE (major adverse cardiovascular and cerebrovascular events) is defined as a composite of: all-cause death myocardial infarction (MI) (Q-wave and non-Q-wave) stroke, and reintervention (defined as any emergent cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve)

Cerebrovascular Events: Stroke or TIA CoreValve US Pivotal Cerebrovascular Events: Stroke or TIA TIA: Acute focal neurologic defect that resolved completely within 24 hours without positive imaging finding Stroke: Acute neurologic ischemia event of central origin that persists > 24 hours with no alternative cause or < 24 hours with evidence of a structural defect by imaging Easton et al Stroke 2009; 40: 2276-2293

Clinical Trial Overview CoreValve US Pivotal Clinical Trial Overview Overall Trial Design Primary Endpoints Inclusion and Exclusion Criteria Screening Procedures Other Clinical Endpoints Long-Term Follow-up CRT2010 Washington, DC

5 Year+ Long-Term Durability Studies CoreValve US Pivotal 5 Year+ Long-Term Durability Studies Absence of Fracture Absence of Migration CRT2010 Washington, DC

Ongoing and Planned Clinical Study Initiatives CoreValve US Pivotal Ongoing and Planned Clinical Study Initiatives ADVANCE study Post-market study to evaluate clinical outcomes Up to 1000 subjects in Europe and Canada at 90 centers Inoperable and high risk patients Non-randomized, baseline-controlled study design Subjects will be followed up to five years PULSE study Study to examine incidence and causes of new pacing indications after CoreValve implantation Up to 200 subjects in Europe CRT2010 Washington, DC