Hospital Israelita Albert Einstein São Paulo São Paulo SBHCI 2010 Belo Horizonte, MG; July 23, 2010 Update on TAVI Studies: Edwards SAPIEN® Transcatheter Heart Valve Adriano Caixeta, MD, PhD

None Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse partner have had a financial Interest /arrangement or affiliation with the organization (s) listed below

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

Lessons Learned… TAVI in … 2. … 3. … 4. … 5. … 6. … 7. … 8. …

1. The “high risk” severe AS patients are “under-treated” and are excellent candidates for TAVI procedures Lessons Learned… TAVI in 2010

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: 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: (*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 Charlson E et al. Decision-making and outcomes in severe symptomatic aortic stenosis. J Heart Valve Dis2006;15: AVR No AVR Under-treatment especially prevalent among patients managed by Primary Care physicians

2. The Edwards technology platform has achieved excellent prosthetic valve hemodynamic results  Both acute and mid-term valve performance has surpassed expectations; equivalent to surgical valve implants  Striking improvements in system characteristics (and performance) over a short time! Lessons Learned… TAVI in 2010

The Current Generation Edwards – SAPIEN THV Current Skirt Height Untreated Equine Tissue [ ] Edwards-SAPIEN THV New Skirt Height Bovine Tissue ThermaFix Treatment Pericardial Mapping Leaflet Deflection Proprietary Processing Cribier-Edwards THV

Edwards Sapien XT THV Cobalt Frame & New Leaflet Geometry Tissue Attachment Leaflet Matching & ThermaFix Finite Element Analysis Partially Closed Design Sapien XT

Sapien XT + NovaFlex Delivery System 18 Fr profile

Transfemoral Transapical Transcatheter AVI Transapical Access Route

PrePost Mean Gradient (mm Hg) AVA (cm²) p = ,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 2 PrePost Cribier – Early PHV Experiences Procedural Results (n=16)

3. The Edwards technology platform has also achieved acceptable early and mid-term clinical outcomes  Clinical outcomes are improving, perhaps due to better patient selection, device and procedure enhancements, and “learning curve” issues Lessons Learned… TAVI in 2010

Edwards TAVI Clinical Data Sources CANADA multi-center (6) (TF=167 pts, TA=172 pts) CANADA multi-center (6) (TF=167 pts, TA=172 pts) PARIS single center (TF=51 pts, TA=24 pts) PARIS single center (TF=51 pts, TA=24 pts) VANCOUVER single center (TF=164 pts, TA=86 pts) Other Studies TOTAL = 664 PTS PARTNER FDA (US/OUS, TF/TA ~1400 pts) PARTNER FDA (US/OUS, TF/TA ~1400 pts) PIVOTAL RCT POSTCE-APPROVAL PARTNER EU (OUS, TF/TA 130 pts) SOURCE (OUS, TF/TA, 1123 pts) PARTNER EU (OUS, TF/TA 130 pts) SOURCE (OUS, TF/TA, 1123 pts) FEASIBILITY(CE-APPROVAL) REVIVE (OUS, TF, 106 pts) TRAVERCE (OUS, TA, 172 pts) REVIVAL (US, TF/TA, 95 pts) Transseptal Experience (RECAST, I-REVIVE; 36 pts) FIRST-in-MANEdwards TOTAL = 3062 PTS OVERALL TOTAL 3726 PTS

At Risk: At Risk: TA: TF: Log-Rank p-value = Hazard Ratio = CI = POOLED* Monitored Edwards TAVI 2-Yr Mortality * REVIVE, REVIVAL, TRAVERCE and PARTNER EU 75% 58%

P = < P=0.008 P=0.008 P=0.04 P=0.02 P = ns TF (n=61) TA (n=69) Logistic EuroSCORE 25.7 ± 11.5 (Range: 6-65) 33.8 ± 14.7 (Range: 5-72) STS Score 11.3 ± 6.1 (Range: 4-32) 11.8 ± 6.8 (Range: 2-41) V. Schächinger; euroPCR 2009 PARTNER EU Trial Risk Profiles

POOLED* Monitored Edwards TAVI 30-Day Mortality (vs. SOURCE) SOURCE: Log-Rank p-value = Hazard Ratio = CI = POOLED: Log-Rank p-value = Hazard Ratio = CI = POOLED TA (n=281) POOLED TA (n=281) SOURCE TF (n=463) SOURCE TF (n=463) SOURCE TA (n=575) SOURCE TA (n=575) POOLED TF (n=222) POOLED TF (n=222) * REVIVE, REVIVAL, TRAVERCE and PARTNER EU 6.3% 10.3% 10.4% 16.4%

Clinical Trials 30d Mortality (%) 12% TAVI in Evolution Trans-apical Improved short-term outcomes! Courtesy of Dr. Martin Leon

12% Clinical Trials 30d Mortality (%) TAVI in 2010 Trans-apical Improved short-term outcomes! Courtesy of Dr. Martin Leon

65% TAVI in 2010 Trans-apical Clinical Trials 1-year survival (%) Improved one-year outcomes! Courtesy of Dr. Martin Leon

65% TAVI in 2010 Trans-apical 1-year survival (%) Clinical Trials Improved one-year outcomes! Courtesy of Dr. Martin Leon

POOLED* Monitored Edwards TAVI NYHA Class * REVIVE, REVIVAL, TRAVERCE and PARTNER EU

55% Vancouver TAVI Learning Experience Courtesy of John Webb 30 days – Trans-arterial

56% Courtesy of John Webb Vancouver TAVI Learning Experience 30 days – Trans-apical

4. Many TAVI complications have emerged and require further analysis and clarification  Paravalvular AR  Conduction disturbances  Vascular complications  Stroke  Coronary obstruction Lessons Learned… TAVI in 2010

Edwards TAVI Complications Multiple Data Sources (TA and TF) POOLED* (503 pts) SOURCE (1038 pts) VANCOUVER (250 pts) PARIS (75 pts) CA-Multictr (339 pts) Vascular (maj)** (%) AR >2+ (%) Stroke (%) New Pacemaker (%) Renal Failure (%) na2.6 Coronary Obstr (%) na00 *REVIVE, REVIVAL, TRAVERCE, PARTNER EU ** TF Only

Para-valvular Regurgitation

5. Long-term durability evaluations of TAVI bioprosthetic valves are still ongoing  Meticulous follow-up necessary including echocardiograms (core lab assessments)  Ultimate value of TAVI will require proof of “near surgical” valve durability Lessons Learned… TAVI in 2010

6. TAVI requires a major milieu adjustment to develop an optimal program  Hybrid cath lab - ORs  Intense clinical care continuum – screening, procedure, pot-procedure care, follow-up  Surgeons and interventionalists working closely together (Heart Valve Team)!!!  Strict training requirements Lessons Learned… TAVI in 2010

Transcatheter AVR Hybrid OR-Cath Lab Courtesy of Dr. Martin Leon

7. The PARTNER trial should provide valuable insights and will provide the evidence- based medicine justification for future expansion of TAVI! Lessons Learned… TAVI in 2010

Medical Management Control PRIMARY ENDPOINT All-cause mortality (1 yr) Non-inferiority 2 Trials Individually Powered (Cohorts A & B) PARTNER Trial Design Fully enrolled: continued access to both patient cohorts approved by FDA Symptomatic Severe Aortic Stenosis Assessment High Risk High Risk AVR Candidate YesNo Cohort A Cohort B Assessment Transfemoral Access Assessment Not in Study vs Trans Femoral Cohort A TF AVRControl vs TransApicalAVRControl vs TransFemoral 1:1 Randomization PRIMARY ENDPOINT All-cause mortality (1 yr) Superiority YesYesNo Cohort A TA 1:1 Randomization No N=491 N=203 N=694 N=358 Total = 1,052 pts

PARTNER Baseline Characteristics* Variable % Cohort A-TF (test control) Cohort A-TA (test control) Cohort B-TF (test control) Number of patients Age (years) Gender (male) Diabetes Hyperlipidemia Hypertension Smoking Prior MI *subset of all randomized patients in cohort A (TF+TA) and cohort B (incl. CA) Preliminary snapshotPreliminary snapshot Outcomes data blindedOutcomes data blinded

PARTNER High Risk Co-Morbidities (1)* Variable % Cohort A-TF (test control) Cohort A-TA (test control) Cohort B-TF (test control) Number of patients Periph Vasc Disease Hx CHF NYHA Class III/IV Prior CABG Prior PCI Prior BAV Severe COPD (O2 dep) *subset of all randomized patients in cohort A (TF+TA) and cohort B (incl. CA)

PARTNER High Risk Co-Morbidities (2)* Variable % Cohort A-TF (test control) Cohort A-TA (test control) Cohort B-TF (test control) Number of patients CNS Disease Recent Stroke/TIA Cirrhosis Porcelain aorta Chest radiation Chest wall deformity Frailty *subset of all randomized patients in cohort A (TF+TA) and cohort B (incl. CA)

Medical Management Control PRIMARY ENDPOINT All-cause mortality (1 yr) Non-inferiority 2 Trials Individually Powered (Cohorts A & B) PARTNER Trial Design Fully enrolled: continued access to both patient cohorts approved by FDA Symptomatic Severe Aortic Stenosis Assessment High Risk High Risk AVR Candidate YesNo Cohort A Cohort B Assessment Transfemoral Access Assessment Not in Study vs Trans Femoral Cohort A TF AVRControl vs TransApicalAVRControl vs TransFemoral 1:1 Randomization PRIMARY ENDPOINT All-cause mortality (1 yr) Superiority YesYesNo Cohort A TA 1:1 Randomization No N=491 N=203 N=694 N=358 Total = 1,052 pts First Presentation of PARTNER Data at TCT 2010!

8. The future is exciting – TAVI procedure device enhancements and expanded clinical indications! 8. The future is exciting – TAVI procedure device enhancements and expanded clinical indications!  New valve designs, lower profile systems, Lessons Learned… TAVI in 2010

New TAVI Technologies  Direct Flow  Sadra  AorTx  Jena Valve  HLT  ABPS PercValve  EndoTech  Ventor Embracer  Symetis

Next Clinical Targets Valve-in-valve for bio-prosthetic aortic and mitral valve failure Valve-in-valve for bio-prosthetic aortic and mitral valve failure Lower risk AS patients Lower risk AS patients Mixed AS and CAD patients Mixed AS and CAD patients Asymptomatic severe AS Asymptomatic severe AS Low flow - low gradient AS – impedance mismatch Low flow - low gradient AS – impedance mismatch Aortic regurgitation Aortic regurgitation TAVI in 2010

Transcatheter AVI Endless Possibilities! Trans-apicalAVR Courtesy of Dr. John Webb Trans-apicalMVR(valve-in-valve) Edwards-Sapien

In the next 5-10 years, many (? most) patients with severe AS requiring AVR will be treated using transcatheter lesser-invasive modalities! Martin Leon