CoreValve US Pivotal Trial Extreme Risk Iliofemoral Study Results

1. CoreValve US Pivotal TrialExtreme Risk IliofemoralStudy Results Jeffrey J. Popma, MD On Behalf of the CoreValve US Clinical Investigators

2. Conflict of Interest Within the past 12 months, I have had a financial interest/arrangement or affiliation with the organization(s) listed below. Physician NameCompany/Relationship Jeffrey J. Popma, MD Research Grants: Cordis, Boston Scientific, Medtronic, Abbott, Abiomed,Covidien, eV3, Medical Advisory Board: Cordis, Boston Scientific, Covidien

3. CoreValve Bioprosthesis OutflowOrientation Maximizes Flow Constrained Portion Valve Function Supra-annular leaflet function Designed to avoid coronaries Inflow PortionSealing Intra-annular anchoring Mitigates paravalvular aortic regurgitation Extreme Risk Study |Iliofemoral Pivotal

4. Pivotal Trial Design CoreValve US Pivotal Trials Extreme Risk High Risk Iliofemoral Access > 18 Fr Sheath Randomization 1:1 CoreValve Iliofemoral Versus No Yes CoreValve CoreValve Non-Iliofemoral SAVR N=147 N=487 Extreme Risk Study |Iliofemoral Pivotal

5. Study Purpose Study Purpose: To evaluate the safety and efficacy of the CoreValve THV for the treatment of patients with symptomatic severe aortic stenosis in whom the predicted risk of operative mortality or serious, irreversible morbidity was 50% or greater at 30 days Risk Determined by: Two Clinical Site Cardiac Surgeons and One Interventional Cardiologist Risk Confirmed by: Two Screening Committee Cardiac Surgeons and One Interventional Cardiologist Primary Endpoint: All Cause Mortality or Major Stroke at 12 Months Extreme Risk Study |Iliofemoral Pivotal

6. Co-Principal Investigators Jeffrey Popma, BIDMC, Boston David Adams, Mt. Sinai, New York Steering Committee CS’s: Michael Reardon, G. Michael Deeb, Joseph Coselli, David Adams, Tom Gleason IC’s: James Hermiller, Steven Yakubov, Maurice Buchbinder, Jeffrey Popma Consultants: Blasé Carabello, Patrick Serruys Data & Safety Monitoring Board Chair: David Faxon, Brigham and Women’s Hospital Echo Core Laboratory Chair: Jae Oh, Mayo Clinic Rotational X-ray Core Laboratory Chair: Philippe Genereux, CRF Study Administration Clinical Events Committee Chair: Donald Cutlip, HCRI ECG Core Laboratory Chair: Peter Zimetbaum, HCRI • Quality of Life and Cost-Effective Assessments • Chair: David J. Cohen, Mid-America Heart Institute • Matt Reynolds, HCRI • Pathology Core LaboratoryChair: RenuVirmani, CV Path • Screening Committee • Chair: Michael Reardon, David Adams, John Conte, G. Michael Deeb, Tom Gleason, Jeffrey Popma, Steven Yakubov • Sponsor Medtronic, Inc. Extreme Risk Study |Iliofemoral Pivotal

7. Inclusion and Exclusion Criteria • Inclusion Criteria: • Severe aortic stenosis: AVA ≤ 0.8 cm2 or AVAI ≤ 0.5 cm2/m2AND mean gradient > 40 mm Hg or peak velocity > 4 m/sec at rest or with dobutamine stress (if LVEF < 50%) • NYHA functional class II or greater • Exclusion Criteria (selected): • Recent active GI bleed (3 mos), stroke (6 mos), or MI (30 days) • Creatinine clearance < 20 mL/min • Significant untreated coronary artery disease • LVEF < 20% • Life expectancy < 1 year due to co-morbidities Extreme Risk Study |Iliofemoral Pivotal

8. Screening Committee • Chairman: Mike Reardon, MD • Twice weekly phone call with a minimum of 2 Cardiac Surgeons and 1 Interventional Cardiologist • Executive Summary to expedite review and document: • STS PROM and incremental factors reviewed • Independent review of transthoracic echocardiogram • Independent review of chest/abdominal CTA findings • Planned access route by clinical team • Case by case telephone discussion with Heart Team Extreme Risk Study |Iliofemoral Pivotal

9. Objective Performance Goal • An objective performance goal (OPG) was used to estimate the risk of all-cause mortality or major stroke in patients treated with standard therapy • OPG constructed from: • Meta-analysis of 5 contemporary balloon valvuloplasty series  random effects meta-analytic all-cause mortality or major stroke rate at 12 months =42.7% (95% CI 34.0%-51.4%) • 12-Month PARTNER B all-cause mortality or major stroke rate of 50.3% with a corresponding 95% lower confidence bound of 43.0% Extreme Risk Study |Iliofemoral Pivotal

10. Sample Size Determination Hypothesis: TAVR with the CoreValve System is superior to standard therapy using an OPG of 12 month rate of all-cause mortality or major stroke: HA: π MCS TAVR < 43% H0: π MCS TAVR> 43% Sample Size Determination: 438 patients π0 = 43% One sided alpha = 0.025 πTAVR = 36.5% Power = 80% Study Size: 487 patients to account for up to 10% drop out rate Extreme Risk Study |Iliofemoral Pivotal

11. Analysis Cohort • Primary Analysis was performed using the “As-Treated” population: all enrolled iliofemoral subjects with a documented attempt for an iliofemoral implant procedure – defined when subject was brought into the procedure room and any of the following have occurred: anesthesia administered, vascular line placed, TEE placed or any monitoring line placed Extreme Risk Study |Iliofemoral Pivotal

12. Participating Sites U of Michigan Ann Arbor, MI Providence Spokane, WA Morristown Morristown, NJ Beth Israel Boston, MA Spectrum Grand Rapids, MI DetroitMedicalCenter Detroit, MI Yale New Haven, CT U of Pitt Pittsburg, PA Aurora St. Lukes Milwaukee, WI St. Francis Roslyn, NY UH Case Cleveland, OH North Shore Manhasset, NY VA Palo Alto VA Palo Alto, CA Loyola Maywood, IL Mount Sinai Lenox Hill Iowa Heart Des Moines, IA OhioState Columbus, OH Saint Vincent Indianapolis, IN RiversideMethodist Columbus, OH El Camino Mountain View, CA U of Kansas Kansas City, KS Geisinger Danville, PA Duke Durham, NC Wake Forest Winston Salem, NC Pinnacle Wormleysburg, PA Vanderbilt Nashville, TN USC Los Angeles, CA Johns Hopkins Baltimore, MD Saint Joseph’s Atlanta, GA Kaiser Permanente Los Angeles, CA Banner Phoenix, AZ Piedmont Atlanta, GA WashingtonHospital Center Washington, DC Baylor Dallas, TX Inova Fairfax Falls Church, VA St. Luke’s Houston, TX Methodist Houston, TX Mount Sinai Miami, FL U of Miami Miami, FL 487 Patients Enrolled at 40 Participating Sites Extreme Risk Study |Iliofemoral Pivotal

13. 16 Clinical Sites Enrolled ≥15 Patients Extreme Risk Study |Iliofemoral Pivotal

14. Study Disposition Screening Committee Approved N=737 Subject Enrolled N=719 N=634 ITT Population Iliofemoral N=487 Subjects Not Enrolled N=18 Roll-in Subjects N=63 23 mm Subjects N=22 ITT Population Non-Iliofemoral N=147 ITT Population Iliofemoral N=487 As Treated Population Iliofemoral N=471 Exited Prior to Procedure N=11 No Iliofemoral Access N=5 Implanted Iliofemoral Population N=470 Implanted Iliofemoral Population N=470 Non Implanted N=1 Per Protocol Population N=455 Per Protocol Population N=455 Did not meet the per-protocol definition N=15 Extreme Risk Study |Iliofemoral Pivotal

15. Study Compliance Clinical Assessments Echocardiographic Assessments 100% Follow-up (n=471/471) 100% Echo Performed (n=471/471) Baseline N=471 98.2% Follow-up (n=427/435) 96.6% Echo Performed (n=420/435) 1-MonthN=435 91.0% Echo Performed (n=323/355) 98.9% Follow-up (n=351/355) 1-Year N=355 Extreme Risk Study |Iliofemoral Pivotal

16. Baseline Demographics Extreme Risk Study |Iliofemoral Pivotal

17. Prohibitive Chest Anatomy *Aorta calcification is measured on screening CT angiogram Extreme Risk Study |Iliofemoral Pivotal

18. Baseline Co-Morbidities • *STS Criteria: Severe = FEV1 < 50% predicted and/or RA pO2 < 60 or pCO2 > 50 **CharlsonScore: = 1 MI, CHF, PVD, CVD, dementia, chronic lung disease, connective tissue disease, ulcer, mild liver disease, DM; = 2 hemiplegia, mod-severe kidney disease, diabetes with end organ damage, leukemia, lymphoma; = 3 moderate or severe liver disease; = 6 metastatic solid tumor, AIDS Extreme Risk Study |Iliofemoral Pivotal

19. Frailty Assessment Extreme Risk Study |Iliofemoral Pivotal

20. Disability Assessment Extreme Risk Study |Iliofemoral Pivotal

21. CoreValve Extreme Risk Iliofemoral Results

22. Primary Endpoint All Cause Mortality or Major Stroke P < 0.0001 Performance Goal = 43% All Cause Mortality or Major Stroke 9.3% [6.7,12.0] 25.5% [21.6,29.4] Months Post-Procedure Extreme Risk Study |Iliofemoral Pivotal

23. 1 Year Mortality All Cause Mortality CardiovascularMortality All Cause Mortality (%) 24.0% 7.9% 7.9% 17.9% Months Post-Procedure Extreme Risk Study |Iliofemoral Pivotal

24. Major Stroke Major Stroke Major Stroke (%) 4.1% 2.4% Months Post-Procedure Extreme Risk Study |Iliofemoral Pivotal

25. Secondary Endpoints • * Percentages obtained from Kaplan Meier estimates Extreme Risk Study |Iliofemoral Pivotal

26. NYHA Class Survivors 90% of Patients Improved at Least 1 NYHA Class by 1 Year 60% of Patients Improved at Least 2 NYHA Classes by 1 Year Percentage of Patients Extreme Risk Study |Iliofemoral Pivotal

27. Echocardiographic Findings Effective Orifice Area, cm2 Mean Gradient, mm Hg Extreme Risk Study |Iliofemoral Pivotal

28. Paravalvular Regurgitation Percentage of Patients Extreme Risk Study |Iliofemoral Pivotal

29. Paravalvular Regurgitation 80% of patients with moderate PVL at one month who survived to one year experienced a reduction in PVL over time Percentage of Patients Extreme Risk Study |Iliofemoral Pivotal

30. Impact of PVL on Late Mortality Extreme Risk Study |Iliofemoral Pivotal

31. Primary Endpoint Predictors-I Extreme Risk Study |Iliofemoral Pivotal

32. Primary Endpoint Predictors-II Extreme Risk Study |Iliofemoral Pivotal

33. Continued Access Study Screening Committee Approved N=737 Continued Access Study Subject Enrolled N=719 ITT Population Iliofemoral N=487 Subject Enrolled N=1158 ITT Population Iliofemoral N=873 ITT Population Iliofemoral N=487 As Treated Population Iliofemoral N= 471 ITT Population Iliofemoral N=487 As Treated Population Iliofemoral N= 830 Implanted Iliofemoral Population N=470 Implanted Iliofemoral Population N=470 Implanted Iliofemoral Population N=825 Implanted Iliofemoral Population N=470 Per Protocol Population N=455 Per Protocol Population N=455 Extreme Risk Study |Iliofemoral Pivotal

34. 6 Month Mortality or Major Stroke All Cause Mortality or Major Stroke 4.8% One Month All Cause Mortality CAS 1.8% One Month Major Stroke CAS 19.5% 16.1% 9.3% 6.0% Extreme Risk Study |Iliofemoral Pivotal

35. Conclusions - I • 471 patients deemed extreme risk for surgical aortic valve replacement by two cardiac surgeons confirmed by external surgical review • Detailed analysis of co-morbidity, frailty, and disability confirmed unsuitability for surgical AVR • The CoreValve Extreme Risk Study achieved its primary endpoint of a reduction in all cause mortality or major stroke at one year compared to a rigorously defined OPG Extreme Risk Study |Iliofemoral Pivotal

36. Conclusions - II • Low rates of major stroke at 1 month and one year • Low rate of moderate/severe aortic regurgitation that improved over time • No association of mild/moderate PVL on late mortality • Improved outcomes in Continued Access Study Extreme Risk Study |Iliofemoral Pivotal

37. Summary • The results from the US CoreValve Extreme Risk Iliofemoral Study support the safety and efficacy of this therapy who are deemed unsuitable for surgical aortic valve replacement Extreme Risk Study |Iliofemoral Pivotal