1. Jeffrey W. Moses, MD Columbia University Medical Center Cardiovascular Research Foundation New York City The State of TAVR -PARTNER: From Concept to Mortality Benefit

2. Presenter Disclosure Information for U Minn Grand Rounds; Jeffrey W. Moses, M.D. Equity Relationship: Equity Relationship: Claret Claret Equity Relationship: Equity Relationship: Claret Claret

3. At Least 30% of Patients with Severe Symptomatic AS are “Untreated”! Severe Symptomatic Aortic Stenosis Percent of Cardiology Patients Treated 1.Bouma B J et al. To operate or not on elderly patients with aortic stenosis: the decision and its consequences. Heart 1999;82:143-148 2.Iung B et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. European Heart Journal 2003;24:1231-1243 (*includes both Aortic Stenosis and Mitral Regurgitation patients) 3.Pellikka, Sarano et al. Outcome of 622 Adults with Asymptomatic, Hemodynamically Significant Aortic Stenosis During Prolonged Follow-Up. Circulation 2005 4.Charlson E et al. Decision-making and outcomes in severe symptomatic aortic stenosis. J Heart Valve Dis2006;15:312-321 AVR No AVR Under-treatment especially prevalent among patients managed by Primary Care physicians

4. SEVERE AORTIC STENOSIS AORTIC VALVE REPLACEMENT SURGERY BALLOON AORTIC VALVULOPLASTY PT. REFUSALS NOT REFERRED ? ASYMPTOMATIC Potential Patients for Transcatheter Aortic Valve Therapy HIGH-RISK PATIENTS PATIENTS

5. Technology Review TAVR 2011

6. Early Catheter-Based AV Designs The Davis valve (1965) The Andersen valve (1992)

7. Diastole Systole 1 2 3 Alain Cibier Sketches (1990)

8. First generation – polyurethane Second generation – bovine pericardium PVT-Edwards Percutaneous Heart Valve Cribier-Edwards Device Cribier-Edwards Device equine pericardial valve equine pericardial valve stainless steel stent stainless steel stent 23mm and 26mm diameters 23mm and 26mm diameters balloon-expandable balloon-expandable AVA = 1.7-1.9 cm 2 AVA = 1.7-1.9 cm 2

9. Dr. Alain Cribier First-in-Man PIONEER April 16, 2002 Percutaneous Transcatheter Implantation of an Aortic Valve Prosthesis for Calcific Aortic Stenosis First Human Case Description Alain Cribier, MD; Helene Eltchaninoff, MD; Assaf Bash, PhD; Nicolas Borenstein, MD; Christophe Tron, MD; Fabrice Bauer, MD; Genevieve Derumeaux, MD; Frederic Anselme, MD; Fran ç ois Laborde, MD; Martin B. Leon, MD AHA; Nov, 2002 Conclusions— Nonsurgical implantation of a prosthetic heart valve can be successfully achieved with immediate and midterm hemodynamic and clinical improvement.

10. Sapien XT + NovaFlex Delivery System 18 Fr profile

11. Transfemoral Transapical Transcatheter AVR Trans-apical Access Route

12. The PARTNER Trial TAVR 2011

13. Published on-line September 22, 2010 @ NEJM.org and print October 21, 2010 On behalf of the Executive Committee, the Investigator Sites, and the courageous patients who participated in the PARTNER trial!

14. N = 179 N = 358 Inoperable Standard Therapy Standard Therapy ASSESSMENT: Transfemoral Access Not In Study TF TAVR Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) 1:1 Randomization VS Yes No N = 179 TF TAVR AVR Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) TA TAVR AVR VS N = 248N = 104N = 103N = 244 PARTNER Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Total = 1,057 patients 2 Parallel Trials: Individually Powered N = 699 High Risk ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No

15. Executive Committee Executive Committee Michael MackJohn Webb Murat TuzcuCraig Miller Marty LeonJeff Moses Craig Smith Lars Svensson

16. Transcatheter AVR Hybrid OR-Cath Lab A unique collaborative experience!

17. Inoperable: Patient Characteristics - 1 CharacteristicTAVIn=179 Standard Rx n=179 P value Age - yr 83.1 ± 8.683.2 ± 8.30.95 Male sex (%)45.846.90.92 STS Score 11.2 ± 5.812.1 ± 6.10.14 Logistic EuroSCORE26.4 ± 17.230.4 ± 19.10.04 NYHA I or II (%) III or IV (%) 7.8 92.2 6.1 93.9 0.68 CAD (%)67.674.30.20 Prior MI (%)18.626.40.10 Prior CABG (%)37.445.60.17 Prior PCI (%)30.524.80.31 Prior BAV (%)16.224.40.09 CVD (%)27.427.51.00

18. Characteristic TAVI TAVI n= 179 Standard Rx Standard Rx n=179 P value PVD (%) 30.325.10.29 COPD Any (%) Any (%) O2 dependent (%) O2 dependent (%) 41.3 21.2 52.5 25.7 0.04 0.38 Creatinine >2mg/dL (%) 5.69.60.23 Atrial fibrillation (%) 32.948.80.04 Perm pacemaker (%) 22.919.50.49 Pulmonary HTN (%) 42.443.80.90 Frailty (%) 18.128.00.09 Porcelain aorta (%) 19.011.20.05 Chest wall radiation (%) 8.98.41.00 Chest wall deformity (%) 8.45.00.29 Liver disease (%) 3.4 1.00 Inoperable: Patient Characteristics - 2

19. 1 ry Endpt - All Cause Mortality Numbers at Risk Numbers at Risk TAVI TAVI1791381226726 Standard Rx Standard Rx179121 83 834112 All-cause mortality (%) Months HR [95% CI] = 0.54 [0.38, 0.78] P (log rank) < 0.0001 Standard Rx TAVI

20. Numbers at Risk Numbers at Risk TAVI TAVI1791381226726 Standard Rx Standard Rx179121 83 834112 Standard Rx TAVI All-cause mortality (%) Months ∆ at 1 yr = 20.0% NNT = 5.0 pts 50.7% 30.7% 1 ry Endpt - All Cause Mortality

21. Outcome 30 Days n=179 TAVI Standard Rx P-value 1 Year 1 Yearn=179 TAVI Standard Rx P-value Clinical Outcomes at 30 Days & 1 Year Myocardial infarction All (%)00.0.6 1.00 Peri-procedural (%00.00. Stroke or TIA All (%)6.71.70.0310.64.50.04 TIA (%)00.0.601.00 Minor stroke (%)1.70.60.622.20.60.37 Major stroke (%)5.01.10.067.83.90.18 Death (all) or major stroke (%)8.43.90.1233.050.30.001 Repeat hospitalization (%)5.610.10.1722.344.1<.0001 Death (all) or repeat hosp (%)10.612.30.7442.570.4<.0001 Death All (%)5.02.80.4130.749.70.0004 Cardiovascular (%)4.51.70.2219.641.9<.0001

22. Outcome 30 Days n=179 TAVI Standard Rx P-value 1 Year 1 Yearn=179 TAVI Standard Rx P-value Clinical Outcomes at 30 Days & 1 Year Acute kidney injury Creatinine >3 mg/dL (%)011.001.12.80.45 RRT (%)1.11.71.001.73.40.50 Cardiac re-intervention BAV (%)0.61.11.00.636.9<.0001 Re-TAVI (%)1.7na1.7na AVR (%)01.70.251.19.5<.0001 Endocarditis (%)00.1.10.60.31 Vascular complications All (%)30.75.0<.000132.47.3<.0001 Major (%)16.21.1<.000116.82.2<.0001 Bleeding - major (%)16.83.9<.000122.311.20.007 Arrhythmias New atrial fibrillation (%)0.61.11.000.61.70.62 New pacemaker (%)3.45.00.604.57.80.27

23. NYHA Class Over Time Survivors P = 0.68P < 0.0001 IIIIIIIV TAVI Standard RxTAVIStandard RxTAVIStandard RxTAVIStandard Rx Percent TreatmentVisit Baseline 30 Day 6 Month 1 Year

25. PARTNER QOL Analyses TAVI not only adds years to life, but also, adds life to years! adds life to years! TAVI not only adds years to life, but also, adds life to years! adds life to years!

26. $50,000 per LY  Cost = $79,837  LE = 1.59 years ICER = $50,212/LYG  Cost = $79,837  LE = 1.59 years ICER = $50,212/LYG $100,000 per LY Cost-Effectiveness of TAVR vs. Control Lifetime Results

27. Main Outcomes: High Risk TAVR 2011

28. 0 0.1 0.2 0.3 0.4 0.5 06121824 TAVR AVR Months 34829826014767 35125223613965 No. at Risk TAVR AVR 26.8 24.2 Primary Endpoint: All-Cause Mortality at 1 Year HR [95% CI] = 0.93 [0.71, 1.22] P (log rank) = 0.62

29. All-Cause Mortality Transfemoral (N=492) Months 24421518811959 24818016810956 No. at Risk TAVR AVR 26.4 22.2 HR [95% CI] = 0.83 [0.60, 1.15] P (log rank) = 0.25

30. 1048372288 1037268309 29.0 27.9 TAVR AVR MonthsNo. at Risk All-Cause Mortality Transapical (N=207) HR [95% CI] = 1.22 [0.75, 1.98] P (log rank) = 0.41

31. PARTNER 1A :30 Day Outcomes (AT) TransfemoralTransapical 3.7 P=0.045 TFAVR Death 8.2 AVRTF Major Stroke 2.5 1.4 P=0.09 TFAVR Death Stroke 5.4 9.5 8.7 TAAVR Death 7.6 AVRTA Major Stroke 7.0 4.4 TAAVR Death Stroke 15.4 10.9 0 2 4 6 8 10 12 14 16 18

32. NYHA Functional Class Baseline1 Year6 Months30 Days Patients Surviving, % IIIIIIIV P = 1.00P < 0.001P = 0.05P = 0.75

33. Mean Gradient - AVR Mean Gradient - TAVR Peak Gradient - AVR Peak Gradient - TAVR Mean and Peak Gradient As-Treated Trial Arms (mmHg) 50 40 30 20 60 70 10 0 8080 Baseline30 Days6 Months1 Year TAVR n = 327 AVR n = 301 TAVR n = 287 AVR n = 231 TAVR n = 246 AVR n = 170 TAVR n = 227 AVR n = 159 Echo Findings Aortic Valve Gradients

34. Paravalvular Aortic Regurgitation P < 0.001 1 Year6 Months30 Days Patients, % NoneTraceMildModerate Severe

35. TAVR - The Future My Rosey Prophecy Surgery – The “PAST” TAVR – The “Future” In 5-10 years, most patients with severe AS requiring AVR will be treated using TAVR!