1. 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

2. 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

3. 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

4. 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;
2Smith N Engl J Med 2011; 364;

5. 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

6. 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
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7. 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)

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

9. 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

10. 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

11. 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

12. 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.

13. 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.

14. 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 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.

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

16. What Kind of Patients are Deemed Extreme Risk?

17. 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

18. “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

19. 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

20. 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

21. 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

22. 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

23. “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%
FEV 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%

24. 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

25. 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

26. 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

27. CT Used to Determine Valve Sizing
3 Mensio Reconstruction
Perimeter Measurements
23 mm CoreValve  mm
26 mm CoreValve  mm
29 mm CoreValve  mm
31 mm CoreVavel  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

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

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

30. 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