Dr Martyn Thomas Director of Cardiac Services Guys and St Thomas NHS Foundation Trust A Member of Kings Health Partners London

Available systems: Edwards (TA and TF) and Corevalve.

Current Indications The Edwards SAPIEN transcatheter heart valve is indicated for use in patients with symptomatic aortic stenosis (aortic valve area <0.8 cm2) requiring aortic valve replacement who have high risk for operative mortality, or are “non-operable”, as determined by one of the following risk assessments: 1) Logistic EuroSCORE >20% or 2) STS Score>10

Inclusion Criteria (from 18F safety & efficacy study) 1.Aortic valve area: < 1 cm 2 (<0.6 cm 2 /m 2 ) 2.Aortic valve annulus diameter: ≥ 20 mm and ≤ 27 mm 3.Ascending aorta: ≤ 43 mm 4.Iliac/femoral vessel diameter: ≥ 6 mm AND 5c. Age ≥ 65 yrs and 1- 2 comorbidities 5b. Logistic ES ≥ 15% OR 5a. Age ≥ 75 yrs OR

Homograft – 1962 Porcine valve – 1965 Pericardial tissue valve – First CoreValve Transcatheter AVR by Retrograde Approach Laborde, Lal, Grube – July 12, 2004 First PVT Transcatheter AVR by Antegrade Approach Alain Cribier Mechanical heart valve – 1962 Surgery Transvascular Aortic Valve Replacement 2006 First CoreValve PERCUTANEOUS AVR by Retrograde Approach – Oct 12, 2006 Serruys, DeJaegere, Laborde First Edwards/PVT Transapical Beating Heart AVR Webb, Lichtenstein – Nov 29, First PVT animal implantation A. Cribier First Corevalve animal implantation JC. Laborde

First-in-Man RECAST REVIVE REVIVE I REVIVAL I Procedural success in humans Feasibility REVIVE II REVIVAL II IDE TRAVERCE PARTNER EU Demonstrate “reasonable” safety & effectiveness Randomized Control PARTNER IDE Effectiveness vs. control (AVR & medical therapy) Post-Market SOURCE Evaluate transition to commercial use Procedural success & clinical outcomes Edwards SAPIEN™ THV Most recent clinical Results. > 1500 Patients treated with Edwards Valve

*Implant success = Successful device delivery and deployment resulting in an AVA>0.9cm² with AI <2+ PARTNER EU TF: Procedure Outcomes Ventricular embolization (n = 1) Aortic embolization (n=1) 23 mm SAPIEN valve N=25 26 mm SAPIEN valve N=27 Implant failures n = 2 Patients Implanted n = 54 Successful Implants* n = 52 Patients Planned n = 60 Implant aborted n = 6 Vascular access (n = 3) Unsucessfull BAV (n=2) Active endocarditis (n=1) 96.3%

THV Learning Curve Percent Successful Implant %

PARTNER EU TF Vascular Events EventTotal Days to Event Phlebitis and Pulmonary Embolism 111 Iliac Artery Dissection 70 False Aneurysm 11 Wound dehiscence 14 Iliac Perforation 10 Groin Hematoma 2 0, 3 Iliac Occlusion %

Freedom from death at 6M = 90% PARTNER EU TF: primary safety outcome. Freedom from death at 6 months.

PARTNER EU TF Freedom from Stroke Freedom from Stroke at 6 Mo = 95%

PARTNER EU TF: Efficacy endpoints NYHA Class

PARTNER EU TF: Efficacy endpoints Paravalvular Leak

SOURCE Registry Post CE Mark Commercial Experience  Purpose  Evaluate the transition to commercial clinical use under controlled market release conditions with a prescribed training and proctor program  Objective  Multicenter, observational collection of acute and early (30d) procedural success and short term (1 yr)clinical performance outcomes

Procedural Success definition used by Sponsor to assess training success in new commercial sites Defined as successful valve deployment and delivery system removal, AVA > 0.9 cm 2 and AR ≤ 2. The SOURCE Registry & SAPIEN™ THV Commercial Experience Acute Procedural Success Transfemoral Success 96.9% (n=254) Transapical Success 94.9% (n=316)

Aborted Procedure 2.3% Malposition0.3% Valve-in-Valve Bailout 0.7% Pericardial Tamponade 0.7% Coronary Interventions 0.7% Vascular Complications 6.9% (19/273) Intraprocedural Deaths 0.3% (1/273) The SOURCE Registry Procedural Complications Transfemoral

ComplicationTransapical (n = 295) Aborted Procedure 1.0% Malposition0.7% Valve-in-Valve Bailout 2.4% Pericardial Tamponade 0.3% Coronary Interventions 0.3% Vascular Complications Access Injury Access Injury Related to Closure Device Related to Closure Device Aortic Dissections/Perforations Aortic Dissections/Perforations1.0%0%0% 1.0% 1.0% Intraprocedural Deaths 1.7% Hemodynamic Support 3.7% The SOURCE Registry Procedural Complications Transapical

*Population analyzed = Patients with Sapien in place and alive post-procedure (no conversion) < 30 day < 30 dayTransfemoral Survival*(n=204)93.6% NYHA(n=99) Class I: 39.4% Class I: 39.4% Class II: 50.5% Class II: 50.5% Class III: 9.1% Class III: 9.1% Class IV: 1.0% Class IV: 1.0% MI(n=204)1.0% Stroke(n=204)3.4% Vascular Complications (n=204)7.4% The SOURCE Registry 30 Day Results: Trans-femoral

*Population analyzed = Patients with Sapien in place and alive post-procedure (no conversion) < 30 day < 30 dayTransapical Survival*(n=173)89.6% NYHA(n=55) Class I: 38.2% Class I: 38.2% Class II: 56.4% Class II: 56.4% Class III: 5.5% Class III: 5.5% Class IV: 0% Class IV: 0% MI(n=173)1.2% Stroke (n=173) 0.6% Vascular Complications (n=173) 0.6% The SOURCE Registry (TA) 30 Day Results

THV Learning Curve: TF Percent Successful Implant %

Pooled Transfemoral TAVI All Cause Mortality Months Post Procedure Partner Source 90% 93.6%

Generation 1 25F Generation 2 21F CoreValve Self-Expanding ReValving™ System Technological Progress Generation 3 18F 14 patients 65 patients** 124 patients ** including 10 in feasibility study and 2 ReDo > 1600 Cases Post CE Mark Cumulative 18F ReValving PAVR Procedures Updated 01-October-2008: ~100 sites in 20 countries The Corevalve Aortic Valve Replacement Personnal contribution as Proctor Before CE mark : N = 123 Registry period : N = 495

Procedural Results 21F S&E18F S&E18F EE Site reported data only in the case of registry & not monitored

PAVR Cases Post CE Mark 24

Procedural Results In-Training (N = 809) Certified (N = 456) Both (N = 1265) 25

Procedural Complications* *Multiple events in same patients = data not cumulative 21F S&E Study (N = 52) 18F S&E Study (N = 124) 18F EE Registry ≤ 24-Hour Mortality 0.0%3.2%1.5% Aortic dissection 9.6%0.8%0.4% Major bleeding 13.5%8.0%2.3% Cardiac tamponade 5.8%)6.5%2.3% Conversion to surgery 5.8%2.4%0.6% Access site complication 9.6%4.8%1.7% Site reported data only in the case of registry & not monitored

≤ 30-Day Adverse Events* * Multiple events in same patients = data not cumulative † Includes 4 deaths where cause is not known 21F S&E Study (N = 52) 18F S&E Study (N = 124) 18F EE Registry 30-Day All Mortality 15.4% 14.5%9.7% Cardiac Deaths 7.7%11.2%4.9% † Myocardial Infarction 3.8%3.4%0.7% Major Arrhythmias 25.0%18.5%4.9% Pacemaker 17.3%25.8%12.2% Renal Failure 5.8%4.8%1.2% Stroke 17.3%6.5%2.2% TIA 0.0%5.6%0.3% Structural Valve Dysfunction 0.0% Valve Migration 0.0% Site reported data only in the case of registry & not monitored

Paired NYHA Comparison Baseline to 30-Day Follow-up 28

Transfemoral approach 362 Transapical * 5 Left Subclavian Right Subclavian 1 Trans aorta * 2 Personnal contribution as Proctor Registry period 04/01/ /09/08 N = 397 * Out of the Registry PAVR by Femoral vs Subclavian Access

The PARTNER IDE Trial Co-principal Investigators: Martin B. Leon, MD Interventional Cardiology Craig Smith, MD, Cardiac Surgeon Columbia University Population: High Risk/Non- Operable Symptomatic, Critical Calcific Aortic Stenosis No Not in Study No VS Trans apical AVR Control 1:1 Randomization Cohort A TA Powered to be Pooled with TF Yes Cohort B No ASSESSMENT: Operability Cohort A n= up to 690 pts n=350 pts Total n= 1040 ASSESSMENT: Transfemoral Access Trans femoral AVR Control VS Yes 1:1 Randomization Cohort A TF Powered Independently Primary Endpoint: All Cause Mortality (Non-inferiority) Medical Management Control ASSESSMENT: Transfemoral Access VS Trans femoral 1:1 Randomization Yes Primary Endpoint: All Cause Mortality (Superiority) Two Trials: Individually Powered Cohorts (Cohorts A & B)

Conclusions (Personal) Primary success rate is improving and training can “limit” the learning curve of a TAVI device. Patient selection remains a “learning” curve. Technical success but a non-cardiac death at 1 year with not be cost effective. The trans-apical approach is very simple BUT requires a minithoracotomy. The transfemoral approach is technically more difficult but has advantages if the peripheral complication rate can be minimised. This is a major technology breakthrough what, where, why and when remain the questions!!