History and Future of Aortic Valve Implantation

1. History and Future of Aortic Valve Implantation OTTAVIO ALFIERI S.Raffaele University Hospital Milano

2. Aetiologies of Single Valvular Heart Diseases in the Euro Heart Survey 43% 13% 32% 12% (Iung. Eur Heart J 2003;24:1244-53)

3. Aortic Stenosis: Survival Onset of symptoms 97.2% alive Surgery 45% alive % Survival Failure Syncope Angina 3 15 Years NEJM 1997;337;32-41 and UK Heart Valve Registry

4. Patient Characteristics in the Euro Heart Survey (Iung. Eur Heart J 2003;24:1244-53)

5. Surgical Risk vs. Benefit Limited Value Surgical Risk Optimum Value • Poor value: • Patient • Purchaser • Physician ? Clinical Benefit Increasing age

6. 22 centres, 67,764 patients, 4,743 octogenarians Central Cardiac Audit Database, UK

7. Survival after Isolated Aortic Surgeryin patients aged 80+: Influence of pulmonary disease Central Cardiac Audit Database, UK

8. Survival after Isolated Aortic Surgery in patients aged 80+: Influence of peripheral vascular disease Central Cardiac Audit Database, UK

9. Not surprisingly…. One third of patients did not undergo surgery because of age, comorbidities or LV dysfunction

10. Aortic Stenosis  75 years N=408 No Severe AS (n=114) Severe AS (n=284) NYHA III :106 NYHA IV : 36 No Symptoms N=68 Symptoms N=216 Angina : 148 No Intervention N=72 (33%) Intervention N=144 (67%) Severe symptomatic AS Severe AS : Valve Area ≤ 0.6 cm²/m² BSA or Mean Gradient  50 mmHg Symptomatic AS : NYHA Class III or IV or Angina (Iung. Eur Heart J 2005;26:2714-20)

11. At least 30-40% of Cardiologists’ AS Patients Go Untreated Severe Symptomatic Aortic StenosisPercent of Cardiology Patients Treated No AVR AVR Under-treatment especially prevalent among patients managed by Primary Care physicians • 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 • 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 Journal2003;24:1231-1243 (*includes both Aortic Stenosis and Mitral Regurgitation patients) • Pellikka, Sarano et al. Outcome of 622 Adults with Asymptomatic, Hemodynamically Significant Aortic Stenosis During Prolonged Follow-Up. Circulation 2005 • Charlson E et Decision-making and outcomes in severe symptomatic aortic stenosis al.. J Heart Valve Dis2006;15:312-321

12. Aortic Valve ImplantationThe Evolving Process Conventional midline sternotomy Surgical through Minimal Incision On pump, arrested heart sutureless valve replacement Transaortic, beating heart delivery Transapical delivery Percutaneous - antegrade or retrograde Invasiveness

13. Sept 1985 F.I.M.: 20mm Balloon THE LANCET, JANUARY 11, 1986 1985 F.I.M. Balloon Aortic Valvuloplasty 200 BAV 100 0 • First attempt of treating • non surgical AS patients • Thousand of cases performed worldwide • Hemodynamic / symptomatic improvement • No effect on patient’s survival • ONE MAIN LIMITATION • Early valve restenosis: 80% at one year

14. THE GOAL…. “Observational Study in Cadavers Hearts- PHV Implantation/Retention Force”, February 24, 2002.

15. CE mark commercialization 2007 International TF Feasibility Studies 2005-07 2004 First in Man Corevalve 25 F 2002-03 Feasibility Studies (antegrade) 2002 20 years F.I.M. PHV implantation 2000-02 Large series of animal implantation 2000 First animal implantation(self exp) 1999 1989 « Percutaneous Valve Technology » (prototypes) 1987 First animal implantation (balloon exp) in pig Post mortem studies of intra-valvular stenting 1985 Concept of« stented valve », to rule out post-BAV valvular restenosis F.I.M. Balloon Aortic Valvuloplasty

16. The pioneers • Henning Andersen (May 1st 1989) • First successful pig implant • Granted with 2 patents • Alain Cribier (April 16, 2002) • Parallel research and proof of concept • Implanted first percutaneous aortic valve on a patient via an antegrade approach

17. 8 days post-implantation F.I.M Alain Cribier 2002

18. F.I.M. and Feasibility Studiespre CE approvalRESULTS • Procedural success about 90% • Mortality at 30 days ranges from 5 to 18% • Acute myocardial infarction in 2 to 11% • Severe AR in about 5% • Vascular complications in 10 to 15% • Stroke in 3 to 9% • AV bock in 4 to 20% • Survival :70 to 80% at 2 y.

19. CE-MARKED DEVICES Core Valve Edwards SAPIEN (Transfemoral / Transapical) (Transfemoral / Transaxillary)

20. CoreValve evolution Generation 1 25Fr Endovascular Generation 2 21Fr Endovascular 14 patients 2004-2005 Generation 3 18Fr Percutaneous 65 patients 2005-2006 >3000 patients May 2006 *

21. 18 French Procedural Progress Evolution to a « real cath lab procedure » within the first 40 Patients of 18 Fr study • Pre-closing with ProStar™ • Local Anesthesia • Beating heart • Valve delivery without rapid pacing • No cardiac assistance Oct. 2006 Nov. 2006 General anesthesia Surgical cutdown/repair Ventricular assistance Dec. 2006

22. Developments and Improvments Edwards SAPIEN Untreated Equine Tissue Treated Bovine Tissue Low profile Cobalt-chrome Edwards SAPIEN™ THV II 23mm, 26mm Cribier-Edwards™ THV 23mm Edwards SAPIEN™ THV 23mm, 26mm Ascendra Introducer Sheath 26Fr. RetroFlex II Heamodynamic Performance Durability Profile – Ease of Use

23. Edwards SAPIEN evolution RETROFLEX DELIVERY SYSTEM Stainless Steel Braid – BETTER TORQUE Front end rotational grip – SINGLE HANDED ARTICULATION

25. INDICATION TAVI is reserved to pts. with severe AS and symptoms who are inoperable or at high risk for surgery

26. STEPS OF PTS. SELECTION -Confirmation of severity of AS -Evaluation of symptoms-QoL -Analysis of surgical risk -Evaluation of life expectancy -Assessment of feasibility and exlusion of contraindications

27. Severity of aortic stenosis • Gradients and Valve Area • ECHO TT and TEE • Hemodynamics • CT • MRI • D obutamine testing

28. Aortic valve area assessmentMDCT vs MRI vs TEE vs TTE MDCT MRI TEE Pouleur AC , et al, Radiology, 2007;244: 745-754

29. Analysis of surgical risk • Logistic Euroscore > 20 • STS Score > 10 (new M & M) • Parsonnet • Ambler • Mini Nutritional Assesment (Geriatric Version)

30. Contraindicatios (general) • Aortic annulus (too small or to large) • Bicuspid valve ( ? ) • Asymmetric heavy valvular calcification • Aortic root dilatation (for self-expandable) • Presence of LV thrombus

31. Annular measurements TT<TEE<CT

32. Anulus measurements

33. Calcium distribution Risk of embolism Risk of coronary occlusion Prosthesis selection

34. Contraindications for TF approach • Iliac arteries severe calcification tortuosity,small diameter;previous ao-fem.by-pass • Aorta:severe atheroma of the arch,coartation,aneurysm with protruding thrombus…. • Bulky atherosclerosis of the asc. aorta • Transverse asc.aorta

35. Access • Size • Calcifications • Tortuosity • Stenosis • Degree • lenght • Atheromatous disease

37. Calcifications

38. Tortuosity Insertion of Amplatz Ultra stiff 0,35 Cook Wire

39. Contraindications for TA approach • Previous surgery of the LV (Dor) • Calcified pericardium • Severe respiratory insufficiency • Dislocated LV apex

40. Teamwork The procedure requires the close cooperation of a team of specialists in valve disease, including clinical cardiologists, echocardiographists, interventional cardiologists, cardiac surgeons, and anaesthesiologists. 40

41. Appropriate environment • Hybrid room • Cath lab • Operating room • NO COMPROMISES • Imaging quality • Sterility • Instrumentation • Ergonomics • Device availability

42. POST CE MARK RESULTS (from registries)

43. Edwards THV Clinical Studies Program

44. Methods 34 Centres Initially Participating in Commercial Launch 1123 patients • Excluded: • 2 Centres / 85 Patients • Unable to obtain Ethic Cte approval • Unable to secure administrative support • One missing patient due to admin. error Included: 32 Centres 1038 Patients The SOURCE Registry has 100% procedure data 98% 30 day data All consecutively enrolled Source Registry

45. Baseline Demographics and Risk Factors

46. Risk Analysis: Logistic EuroSCORE 49% 48% 37% 30% 16% 12% 6% 3% As EuroSCORE gets higher, ratio of TA to TF is greater

47. 1 0.95 0.9 0.85 Survival 0.8 0.75 < 20 >= 20 0.7 0.65 0.6 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Fraction of Months post Procedure SOURCE 30 Day All Cause Mortality -- Transfemoral Approach Stratified by Logistic EuroSCORE SOURCE 30 Day All Cause Mortality -- Transapical Approach Stratified by Logistic EuroSCORE p=0.068 < 20 >= 20 Survival 1 0.95 0.9 0.85 Survival 0.8 0.75 0.7 0.65 0.6 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Fraction of Months post Procedure Survival of TA pts with ES< and >20 are significantly different (93.4 vs. 88.1) (p=0.067)

48. Procedure Complications (<30 Days)

49. Major Complications (< 30 Days)

50. Major Vascular / Access Complications TF : 10.6 % (not significant predictor of 30 d. survival) TA: 2.4 % (significant predictor of 30 d. survival)