INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc. 2013. All

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc. 2013 . All Rights Reserved.

UC201105849b EE1P

Medtronic CoreValve® US Pivotal Trial


CoreValve® US Pivotal Trial Study Design1-3

Extreme Risk High Risk

CoreValveObservational

CoreValveSingle Arm

CoreValve SAVR

Iliofemoral Access? Randomization 1:1NoNo

Medtronic CoreValve US Pivotal Trial

45 SitesEstimated Enrollment: ~1,575

YesYes

aIncludes patients with iliofemoral and alternative access.SAVR=surgical aortic valve replacement.

1. Medtronic CoreValve® U.S. Pivotal Trial. US National Institutes of Health Web site. http://clinicaltrials.gov/ct2/results?term=NCT01240902. Accessed 12/2/12.2. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 11.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.3. Medtronic CoreValve® U.S. Pivotal Trial (High Risk Patients). Version 12.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.

Alternative Access


CoreValve® US Pivotal Trial Overview1-3

• Randomized, open-label study

• The trial was conducted at 45 investigational sites in the United States

• Number of trial subjects

– Sample size• Extreme Risk Cohort

– ~500 Medtronic CoreValve System TAVI received 26, 29 or 31mm valve– Up to 20 subjects receiving 23mm valve (either ilio-femoral or non-ilio-

femoral)– ~200 non-ilio-femoral observational arm for 26, 29, and 31mm valves

(direct aortic/subclavian)• High Risk Surgical Cohort

– ~395 Medtronic CoreValve System TAVI– ~395 surgical aortic valve replacementIncludes non-ilio-femoral access (direct aortic/subclavian)– Up to 40 additional subjects (20 receiving TAVI and 23mm valve)

TAVI=transcatheter aortic valve implantation.

1. Medtronic CoreValve® U.S. Pivotal Trial. US National Institutes of Health Web site. http://clinicaltrials.gov/ct2/results?term=NCT01240902. Accessed 12/2/12.2. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 11.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.3. Medtronic CoreValve® U.S. Pivotal Trial (High Risk Patients). Version 12.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.


CoreValve® US Pivotal Trial Patient Populations

Extreme Risk Cohort1 • Subjects with symptomatic severe aortic stenosis,

necessitating aortic valve replacement, with predicted operative mortality or serious, irreversible morbidity risk of ≥50% at 30 days

High Risk Surgical Cohort2

• Subjects with symptomatic severe aortic stenosis, necessitating aortic valve replacement, whose predicted risk of operative mortality is ≥15% (and whose predicted operative mortality or serious, irreversible morbidity risk is <50%) at 30 days

1. Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 11.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.2. Medtronic CoreValve® U.S. Pivotal Trial (High Risk Patients). Version 12.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.


CoreValve® US Pivotal Trial Primary Objective and Endpoint

Extreme Risk Cohort • Primary objective

– Demonstrate the safety and effectiveness of the Medtronic CoreValve System, as measured by a composite of all-cause death or major stroke at 12 months, in subjects necessitating aortic valve replacement with predicted operative mortality or serious, irreversible morbidity risk of ≥50% at 30 days

• Primary endpoint– All-cause death or major stroke at 12 months (compared to

performance goal)

Medtronic CoreValve® U.S. Pivotal Trial (Extreme Risk Patients). Version 11.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.


CoreValve® US Pivotal Trial Primary Objective and Endpoint (Cont.)

High Risk Surgical Cohort• Primary objective

– Demonstrate that the safety and effectiveness of the Medtronic CoreValve System, as measured by all-cause mortality rates at

12 months, is noninferior to surgical aortic valve replacement in the treatment of symptomatic severe aortic stenosis in subjects who have a predicted high risk for aortic valve surgery

• Primary endpoint– All-cause mortality at 12 months

Medtronic CoreValve® U.S. Pivotal Trial (High Risk Patients). Version 12.0. Mounds View, MN: Medtronic, Inc. Clinical Research; 2012.


CoreValve® US Pivotal Trial Secondary Safety Outcomes1,2

• MACCE-free survival at 30 days, 6 months, 12 months, and annually thereafter up to 5 years

– MACCE is defined as a composite of all-cause death, myocardial infarction, all stroke, and reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve)

• Occurrence of individual MACCE components at 30 days, 6 months, 12 months, and annually thereafter up to 5 years

• Conduction disturbance requiring permanent pacemaker implantation at 30 days, 6 months, 12 months, and annually thereafter up to 5 years

• Echocardiographic assessment of prosthetic valve performance at discharge, 30 days, 6 months, 12 months, and annually thereafter up to 5 years

MACCE=major adverse cardiovascular and cerebrovascular event.



CoreValve® US Pivotal Trial Secondary Safety Outcomes1,2 (Cont.)

• Major adverse events (MAEs) at 30 days, 6 months, 12 months, and annually thereafter up to 5 years

• Cardiovascular deaths and valve-related deaths at 30 days, 6 months, 12 months, and annually thereafter up to 5 years

• Strokes (of any severity) and transitory ischemic attacks at 30 days, 6 months, 12 months, and annually through 5 years

• Index procedure–related MAEs

• Evidence of prosthetic valve dysfunction at 30 days, 6 months,12 months, and annually thereafter up to 5 years



CoreValve® US Pivotal Trial Secondary Safety Outcomes1,2 (Cont.)

• Device success defined as follows:– Successful vascular access, delivery, and deployment of the

device, and successful retrieval of the delivery system

– Correct position of the device in the proper anatomical location (placement in the annulus with no impedance on device function)

– Intended performance of the prosthetic valve (aortic valve area >1.2 cm2 for 26, 29 and 31mm valves, > 0.9 cm2 for 23mm valve [by echocardiography using the continuity equation] and mean aortic valve gradient <20 mm Hg or peak velocity <3 m/sec, without moderate or severe prosthetic valve AR)• Assessed acutely in a resting state, either within 24-48 hours after

the index procedure or before hospital discharge

– Only 1 valve implanted in the proper anatomical locationAR=aortic regurgitation.



CoreValve® US Pivotal Trial Secondary Effectiveness Outcomes1,2

• Change in NYHA class from baseline at 30 days, 6 months, 12 months, and annually thereafter through 5 years

• Change in distance walked during 6-minute walk test from baseline to 30 days and baseline to 12 months

• Ratio of days alive out of hospital vs total days alive assessed at 12-month follow-up

• Quality of life (Kansas City Cardiomyopathy Questionnaire,Short Form-12, and EuroQol) change from baseline at 30 days, 6 months, 12 months, and annually thereafter up to 5 years

NYHA=New York Heart Association.



CoreValve® US Pivotal Trial Secondary Effectiveness Outcomes1,2 (Cont.)

• Aortic valve disease–related hospitalization at 30 days, 6 months, 12 months, and annually thereafter up to 5 years

• Length of index procedure hospital stay

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

MACCE=major adverse cardiovascular and cerebrovascular event.



David Adams, MDMount Sinai Medical Center

Jeffrey Popma, MDBeth Israel Deaconess Medical Center

CoreValve® US Pivotal Trial Principal Investigators

1. Medtronic CoreValve® U.S. Pivotal Trial. US National Institutes of Health Web site. http://clinicaltrials.gov/ct2/results?term=NCT01240902. Accessed 6/30/11.


Participating Study Sites

N=1600 estimated enrollment45 investigator sites

19

15 17 33

345279

2239 20

4413

11

53826

35

2434

643

2

12

3718

2125

42

30

29

16

367

1

3231

23

41

4014

8

10

28

4


Banner Good Samaritan Phoenix, AZ Timothy Byrne (IC), Michael Caskey (CS)

Baylor Heart and Vascular Hospital Dallas, TX Robert Hebeler (CS), Robert Stoler (IC)

Beth Israel Deaconess Medical Center Boston, MAKamal Khabbaz (CS), Jeffrey Popma (IC)

Cardiovascular Institute of the SouthHouma, LAPeter Fail (IC), Edgar Feinberg (CS)

Detroit Medical Center Cardiovascular InstituteDetroit, MI Ali Kafi (CS), Theodore Schreiber (IC)

Duke University Medical Center Durham, NC J. Kevin Harrison (IC), G. Chad Hughes (CS)

El Camino Hospital Mountain View, CA Vincent Gaudiani (CS), James Joye (IC)

Fletcher Allen Health CareBurlington, VTHarold Dauerman (IC), Joseph Schmoker (CS)

CS=cardiac surgeon; IC=interventional cardiologist.

CoreValve® US Pivotal Trial Clinical Trial Sites and Principal Investigators

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Geisinger Medical Center Danville, PA Alfred Casale (CS), Kimberly Skelding (IC)

Hartford HospitalHartford, CT Robert Hagberg (CS), Raymond McKay (IC)

Inova Fairfax Hospital/Inova Heart and Vascular InstituteFalls Church, VA Niv Ad (CS), Bryan Raybuck (IC)

Iowa Heart Center Des Moines, IA Atul Chawla (IC), David Hockmuth (CS)

Johns Hopkins Hospital Baltimore, MD John Conte (CS), Jon Resar (IC)

Kaiser Permanente/Los Angeles Medical Center Los Angeles, CA Vicken Aharonian (IC), Thomas Pfeffer (CS)

Lenox Hill Hospital New York, NYGregory Fontana (CS), Chad Kliger (IC)

Loyola University Medical Center Maywood, IL Mamdoh Bakhos (CS), Ferdinand Leya (IC)


CoreValve® US Pivotal Trial Clinical Trial Sites and Principal Investigators

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11

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Morristown Memorial Hospital Morristown, NJ John Brown (CS), Robert Kipperman (IC)

Mount Sinai Medical Center Miami Beach, FL Nirat Beohar (IC), Joseph Lamelas (CS)

North Shore University Hospital Manhasset, NY Alan Hartman (CS), Stanley Katz (IC)

NYU/Langone Medical Center New York, NYAubrey Galloway (CS), James Slater (IC)

Piedmont Heart Institute Atlanta, GA James Kauten (CS), Vivek Rajagopal (IC)

Pinnacle Health Harrisburg, PA Brijeshwar Maini (IC), Mubashir Mumtaz (CS)

Providence Sacred Heart Medical Center Spokane, WA Mike Ring (IC), Leland Siwek (CS)

Riverside Methodist Hospital/Ohio Health Research InstituteColumbus, OH Daniel Watson (CS), Steven Yakubov (IC)

Saint Joseph’s Hospital of Atlanta Atlanta, GA Louis Heller (IC), Steven Macheers (CS)

CoreValve® US Pivotal Trial Clinical Trial Sites and Principal Investigators (Cont.)


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Spectrum Health Hospitals Grand Rapids, MI John Heiser (CS), William Merhi (IC)

St. Francis Hospital Roslyn, NY George Petrossian (IC), Newell Robinson (CS)

St. John Hospital & Medical CenterDetroit, MI Sanjay Batra (IC), Thomas Davis (CS)

St. Luke's Medical Center/Aurora Health CareMilwaukee, WI Tanvir Bajwa (IC), Daniel O'Hair (CS)

St. Vincent Heart Center of Indiana Indianapolis, IN David Heimansohn (CS), James Hermiller (IC)

Texas Heart Institute at St. Luke’s Episcopal Hospital/Baylor College of MedicineHouston, TX Joseph Coselli (CS), Biswajit Kar (IC)

The Methodist DeBakey Heart & Vascular Center, The Methodist HospitalHouston, TX Neal S. Kleiman (IC), Michael Reardon (CS)



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The Mount Sinai Medical Center New York, NY David Adams (CS), Samin Sharma (IC)

The Ohio State University Medical Center/The Richard M. Ross Heart Hospital Columbus, OH John Cheatham (IC), Juan Crestanello (CS)

University Hospitals/Case Medical Center Cleveland, OH Marco Costa (IC), Alan Markowitz (CS)

University of Kansas Hospital Kansas City, KS Peter Tadros (IC), George Zorn (CS)

University of Miami Health SystemMiami, FL Eduardo de Marchena (IC), Tomas Salerno (CS)

University of Michigan Health Systems Ann Arbor, MI Stanley J. Chetcuti (IC), G. Michael Deeb (CS)

University of Pittsburgh Medical Center Pittsburgh, PAThomas G. Gleason (CS), Joon Lee (IC) University of Southern California University HospitalLos Angeles, CA Ray Matthews (IC), Vaughn Starnes (CS)



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VA Palo Alto Health Care System Stanford, CA John Giacomini (IC), Robert Robbins (CS)

Vanderbilt University Medical Center Nashville, TN John Byrne (CS), David Zhao (IC)

Wake Forest University/Baptist Medical Center Winston-Salem, NC Robert Applegate (IC), Neal Kon (CS)

Washington Hospital Center/ Georgetown Hospital Washington, DC Ammar Bafi (CS), Ron Waksman (IC)

Yale New Haven Hospital/Yale University School of MedicineNew Haven, CT John Elefteriades (CS), Craig Thompson (IC)



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CoreValve® US Pivotal Trial Additional Information

• ClinicalTrials.gov identifier: NCT01240902http://www.clinicaltrials.gov/ct2/show/study/NCT01240902?term=CoreValve&rank=4&show_locs=Y#locn

• Medtronic CoreValve US Pivotal Trial site: http://www.medtronic.com/aorticstenosistrial/index.html

CoreValve is a registered trademark of Medtronic CV Luxembourg S.a.r.l. © 2013.

Documents

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc. 2013. All