1. 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

2. 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.

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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)

28. 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:

29. 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

30. 5 Year+ Long-Term Durability Studies
CoreValve
US Pivotal
5 Year+ Long-Term Durability Studies
Absence of Fracture
Absence of Migration
CRT2010 Washington, DC

31. 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