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

Medtronic CoreValve

US Pivotal Trial:Design Considerations and Perspectives:

Nitinol: Selected for its shape recovery after

percutaneous delivery chronic outward force for

stabilization and conformability to anatomy

Nitinol Characterization:

Specifications and Testing

• Radial Force, Fatigue

Physiology: Understanding the in-vivo

Environment

• Aortic compliance

• In-vivo pressures

FEA Modeling And Device Design:

Functional and Safety Verification

• Operational Stresses

• Fatigue and Durability

Frame Durability Proof Test

CoreValve Global Clinical Experience

18 Fr. CVSS&E Study

CE Marking

EER

(Post-CE

Mark)

Australia

New Zealand

Trial

Published Single-

Center Experience

Munich

(Lange)1

Siegburg

(Grube)2

Dates 5/06 – 6/07 4/08 – 11/08 4/07 – 12/08 8/08 - Ongoing 6/07 – 8/08 5/06 – 3/08

Patients (n) 112 14[a] 1,424 Up to 150 137 102

Logistic

EuroSCORE23.1 13.4 25.7 17.1 22.6 13.9 17.6 13.3 24.3 14.9 24.5 15.4

STS Score Not collected 17.7 12.3 Not collected Being collected 23.4 10.1 8.6 4.7

Adjudicated Yes Yes No Yes No No

1. Bleiziffer, et al. Eur J Cardiothorac Surg 2009 Apr;35(4):615-20

2. Grube, et al. Circ Cardiovas Intervent. 2008;1:167-175

Is percutaneous AVR comparable to surgical AVR in

“high-risk” patients Requires RCTs

18F Safety/Efficacy: Long-Term Survival

28.2% 12 Mo Mortality

15.2% 30 Day Mortality

Serruys TCT 2009

What is the mortality risk for

surgical outcome in comparable

“high-risk” patients?

No.

Pts

Included

CABG

30 Day

Mortality MI Stroke

Reop for

Bleeding PPM

Pulm

Compls

Renal

Failure LOS, d

Prior CABG

Akins , 2004 89 Yes 6.7% 1.1% 4.5% 5.6% 4.5% 9% 11.2% 8

Byrne , 2002 94 Yes 6.4% 7% 11% 3% 7% 7% 2% NR

Fighali , 1995 104 Yes 14% 13% 11% 28% NR NR 11% NR

Elderly (≥ 80 years)

Chiappini , 2004 115 Yes 8.5% 3.8% 1% NR 3.4% NR NR NR

Collart , 2005 215 Yes 8.8% NR NR 6% 6.0% 10.7% 8.8% 14

De Vincentiis ,2008 345 Yes 8.5% NR NR 2% NR 2.7% 4% NR

Gilbert , 1999 103 Yes 18.4% NR 17% 4% 11% NR 12% NR

Kolh , 2007 220 Yes 13% 4% 2% 4% 5% 21% 5% 17.6

Melby , 2007 245 Yes 9% 1% 3% 9% NR 22% 12% 9

Sundt , 2000 133 Yes 11.1% < 1% 3.8% 10.5% NR 26.3% 11.3% 14.7

Thourani , 2008 88 No 5.7% 0 3.4% 6.8% 2.3% NR 4.6% 9.8

“High-Risk” Surgical AVR OutcomesCoreValve

US Pivotal

No.

Pts

Include

CABG

30 Day

Death MI Stroke

Reop for

Bleeding PPM

Pulm

Compls

Renal

Failure LOS, d

Elderly ≥ 70 yr

Tseng, 1997 247 No 6.1% < 1% 2.0% 3.2% NR NR 2.0% 15.1

Bloomstein,2001 180 No 16.7% NR NR NR NR NR NR NR

Euroscore >7

Grossi, 2008 731 No 7.8% 0 3.7 3.6 NR 10.8% 4.2% NR

Reduced LVEF

Powell, 2000† 55 Yes 18% NR NR NR NR NR NR NR

Connolly, 2000†† 52 Yes 21% NR NR NR NR NR NR NR

Tarantini, 2003†† 52 Yes 8% NR NR NR NR NR NR NR

Clavel 2008†††† 44 Yes 18% NR NR NR NR NR NR NR

“High-Risk” Surgical Outcomes

† LVEF < 30% †† LVEF < 35% †††† LVEF <% 40

CoreValveUS Pivotal

sAVR Outcomes in High Risk Patients

30-Day

MortMI Stroke

Bleeding

Re-opPPI

Pulm

Comp.

Renal

FailureLOS, d

Mean 11.3% 5.0% 5.7% 7.1% 5.6% 13.7% 7.3% 12.6

High 5.7 1.0 2.0 2.0 2.3 2.7 2.0 8.0

Low 21.0 13.0 11.0 28.0 11.0 26.3 12.0 17.6

sAVR in high risk patients:Prior CABG, > 80 yrs, > 70 yrs, high-risk, and LEVF < 40%.

Mortality # 6 mo 12 mo 18 mo 24 mo 36 mo 60 mo To, 2008 26 22% 36% 62%* 69%

Sack, 2008 75 30% 40%

Shareghi, 2007 80 25%* 44% 66% 63%* 71%

Klein, 2006 78 62% 69% 69% 80% 86%

Agarwal, 2005 212 36% 48% 53% 72% 86%

Lieberman, 1995 165 39% 45% 59% 75%

Otto, 1993 674 45% 65% 77%

Kuntz, 1992 219 16%* 25% 33%* 40% 43%*

O'Neill, 1991 492 44%* 36%

Kuntz, 1991 205 17%* 25% 34%* 40% 47%*

Ferguson, 1990 68 17% 30%** 33%* 37%*

Brady, 1989 26 32%

Berland, 1989 55 30% 40% 45%

Sherman, 1989 36 28% 55%

Safian, 1988 170 29% 36%

Block, 1988 90 28%

Meta-analytic

mortality rate2671 21.1% 37.4% 42.9% 56.1% 69.6% 86%

Inoperable: Mortality Following BAVCoreValve

US Pivotal

Survival following BAV100%

72%

63%57%

44%36%

30%25%

21%17% 14%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 6 12 18 24 30 36 42 48 54 60

Month from BAV

Cu

mu

lati

ve

surv

iva

lMeta-analysis: Mortality Following BAV

Novack V HCRI Analysis 2009

CoreValveUS Pivotal

1 Year Mortality: 37%

2 Year Mortality: 56%

3 Year Mortality: 70%

5 Year Mortality: 86%

Ongoing Design Discussions

Disclaimer: Discussions are ongoing with the

FDA relating to the final trial CoreValve US

Pivotal trial design.

The purpose of this presentation is to outline the

ongoing considerations for evaluation of the

Medtronic CoreValve device in patients with

severe aortic stenosis who are at “high-risk” or

inoperable for conventional aortic valve

replacement surgery

CoreValveUS Pivotal

DEVICE

DESCRIPTION

The CoreValve ReValvingTM System is an 18F percutaneous

aortic valve consisting of a porcine pericardial valve constructed

on a self-expanding Nitinol frame housed within a percutaneous

delivery catheter.

SPONSOR Medtronic CardioVascular, , Mounds View, MN

STUDY DESIGN Subjects will be randomized to either percutaneous aortic valve

replacement (PAVR) with the study device or to surgical aortic

valve replacement (SAVR).

STUDY

PURPOSE

To evaluate the safety and efficacy of the CoreValve ReValving

System in the treatment of severe symptomatic aortic stenosis

in subjects who have a predicted high risk for heart surgery.

INDICATIONS

FOR USE

The CoreValve ReValving™ System is indicated for use in

subjects with Aortic Stenosis (AS) necessitating valve

replacement who are considered poor surgical candidates with

high surgical risk (STS score ≥ 8 and/or elevated perioperative

mortality risk of ≥15%).

Study ObjectivesCoreValve

US Pivotal

CoreValve sAVR

PI: Jeffrey J. Popma, MD; David Adams, MD

~30-50 sites

United States

Primary Endpoint: 12 month all cause mortality

30d 6mo 4yr3yr2yr9mo 12mo8mo 5yr

All Cause Mortality

Symptomatic patients with severe aortic

stenosis deemed “high risk” for sAVR

Proposed “High-Risk” Randomized ArmCoreValve

US Pivotal

• Subject has senile symptomatic (NYHA Functional Class ≥ II)

degenerative aortic valve stenosis with mean gradient > 40 mmHg

and/or jet velocity greater than 4.0 m/s, or an initial aortic valve

area of ≤ 0.8 cm2 (or AVA index ≤ 0.5 cm2/M2) by echocardiogram

• Subject must have co-morbidities such his/her predicted high risk

for surgery as determined by an STS score ≥ 8%, or have

predicted peri-operative mortality risk of ≥ 15% determined by two

independent cardiac surgeons

• The subject or the subject's legal representative has been

informed of the nature of the study, agrees to its provisions and

has provided written informed consent

“High Surgical Risk”: Inclusion CriteriaCoreValve

US Pivotal

• Evidence of an acute myocardial infarction ≤ 30 days before the

intended treatment.

• Any percutaneous coronary interventional procedure performed

within 30 days prior to the index procedure with bare metal stents

and 6 months with drug eluting stents.

• Blood dyscrasias as defined: leukopenia (WBC < 1000mm3),

thrombocytopenia (platelet count <50,000 cells/mm3), history of

bleeding diathesis or coagulopathy, or hypercoagulable states.

• Untreated clinically significant coronary artery disease requiring

revascularization.

• Cardiogenic shock manifest by low cardiac output, pressure

dependent, or mechanical hemodynamic support.

“High-Risk” Clinical Exclusion CriteriaCoreValve

US Pivotal

• Need for emergency surgery for any reason.

• Severe ventricular dysfunction with LVEF < 20%.

• Subject has been offered surgery but declined.

• Recent (within 6 months) cerebrovascular accident (CVA) or

transient ischemic attack (TIA).

• End stage renal disease requiring chronic dialysis or creatinine

clearance < 15 cc/min.

• Active peptic ulcer or GI bleeding within the past 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.

“High-Risk” Clinical Exclusion CriteriaCoreValve

US Pivotal

• Subject refuses a blood transfusion.

• Life expectancy < 12 months due to associated non-cardiac co-

morbid conditions.

• Other medical, social, or psychological conditions that in the

opinion of an Investigator precludes the subject from appropriate

consent.

• Currently participating in an investigational drug or another

device study.

“High-Risk” Clinical Exclusion CriteriaCoreValve

US Pivotal

• Access Site– Artery diameter– Tortuosity– Lesions– Calcification

• Abdominal and thoracic aorta

• Native valve anatomy– Annulus diameter – Valve/Aorta angulation– Valve Calcifications – Sinus dimensions– Sino-tubular junction– Ascending aorta

“High Risk” Anatomic Exclusion CriteriaCoreValve

US Pivotal

• Native aortic annulus size ≤ 20 mm or > 27 mm

• Pre-existing prosthetic mitral/aortic mechanical heart valve

• Mixed aortic valve disease (aortic stenosis and aortic regurgitation

with predominant aortic regurgitation > 3+).

• Moderate-or severe mitral or severe tricuspid insufficiency.

• Hypertrophic obstructive cardiomyopathy.

• Evidence of intracardiac mass, thrombus or vegetation.

• Severe LV hypertrophy (wall thickness > 1.7cm)

• Coronary ostia (from native leaflet) < 14 mm with severe Ca+< 13;

mm with moderate Ca+; < 10 mm without Ca+

• Annulus-to-aorta (angle) > 70

• Ascending aorta diameter > 43 mm.

“High Risk” Anatomic Exclusion CriteriaCoreValve

US Pivotal

• Severe aortic or severe iliofemoral disease with iliac and

femoral vessels (diameter) < 6 mm.

• 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.

• Subjects with either:

“High Risk” Vascular Exclusion Criteria

1. Bi-lateral femoral or aortic vascular conditions (e.g.,

stenosis, tortuousity), that make insertion and

endovascular access to the aortic valve impossible.

2. Symptomatic carotid or vertebral artery disease.

CoreValveUS 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 morbidity exceeds the probability of meaningful

improvement. Specifically, the probability of death or serious,

irreversible morbidity should exceed 50% at 12 months.

• Subject has senile degenerative aortic valve stenosis with mean

gradient > 40 mmHg and/or jet velocity greater than 4.0 m/s, or

an initial aortic valve area of < 0.8 cm2 by echocardiogram.

“Inoperable” Inclusion Criteria

Study Design Pending Discussion with FDA

CoreValveUS Pivotal

Study

Endpoints

CoreValve

US Pivotal

• High Risk Surgical

– Freedom from all cause mortality

compared to sAVR at 12 months

• High Risk Inoperable Study

– Freedom from all cause mortality

Primary Trial EndpointsCoreValve

US Pivotal

• Time: 24 hours, 30 days (or in-hospital), 12+ months

• Place: OR, in Hospital, Post-discharge

• Type: Cardiac, vascular, non cardiovascular, valve

related

All Cause Mortality preferred but

Our study population is by definition “high-risk” with

severe co-morbidities that predispose to non-cardiac

mortality at one year – there are challenges in identifying

the specific effect of the valve treatment vs the “noise” of

the co-morbidities in these high risk populations

CoreValveUS Pivotal

• Evidence of prosthetic valve dysfunction (hemolysis, infection,

thrombosis, or migration) at 30 days, 6 months and 12 months.

• Device success (successful delivery and deployment of the device

and retrieval of the delivery catheter resulting in AVA greater than

0.9cm2 and <3+ aortic regurgitation (AR).

• Procedural success, defined as device success and absence of in-

hospital MACCE.

• Major adverse cardiovascular and cerebrovascular events

(MACCE), including all cause death, MI, stroke, or re-intervention

at 30 days, 6 months and 12 months.

• Improvement in NYHA class at 30 days, 6 months and 12 months.

• in distance walked during 6-minute walk test (6MWT) from

baseline to 12 months.

Secondary Endpoints-ICoreValve

US Pivotal

• Quality of Life (QOL) change from baseline at 30 days, 6 months

and 12 months.

• Length of index hospital stay and repeat hospitalization.

• Discharge, 30 day, 6 month and 12 month echocardiographic

assessment of aortic valve function by using the following

measures:

- Transvalvular peak and mean gradient transvalvular gradient

- Effective orifice area

- AV performance index

- Cardiac output

- Aortic or mitral regurgitation, or mitral regurgitation.

Secondary Endpoints-IICoreValve

US Pivotal

5 Year+ Long-Term Durability Studies

Absence of Fracture Absence of Migration

CoreValveUS Pivotal

Unique Design of CoreValve Frame

18Fr SE Feasibility Study Re-Adjudication

CoreValve US Pivotal Study

“High Risk” Study Cohort

Non Operable Cohort

Clinical Endpoints (VARC Study Group)

Next Steps (Soon)

Closing CommentsCoreValve

US Pivotal