Postmarketing Report: Did We Reduce the Complication Rates in the Postmarketing Phase? Jodi J. Akin, MS VP Global Clinical Affairs, Transcatheter Heart Valve Therapy Edwards Lifesciences, LLC

Contemporary Post Approval Assessment Paradigms in TAVR Outcomes and Appropriateness Sponsor Investigator Societies Government PAS have multiple stakeholders with multiple interests and objectives. The Primary objective of a PAS is to assess generalizable outcomes and appropriateness of therapy over time

Contemporary Post Approval Assessment Paradigms in TAVR Outcomes and Appropriateness Sponsor Investigator Societies Government -assess learning curve -observe for safety and effectiveness signals not captured in a clinical trial -detect opportunities for device and procedure improvements -assess healthcare economics -expand indications for therapy where appropriate Speaking on behalf of the sponsor perspectives, particularly in the landscape of medical devices additional and important aims are -assess learning curve -observe for safety and effectiveness signals not captured in a clinical trial -detect opportunities for device and procedure improvements -expand indications for therapy where appropriate

Approval and Post Approval Surveillance SAPIEN Platforms Edwards’ Global Post Approval Activities ‘07 ‘08 ‘09 ‘10 ‘11 ‘12 ‘13 ‘14 CE Mark CE Mark Edwards SAPIEN® XT THV Cobalt-Chromium Frame Bovine Pericardial Tissue Semi-closed leaflets Reduced crimped profile Sizes 23, 26 and 29mm Transfemoral, transapical and transaortic > 5000 patients in post approval surveillance Edwards SAPIEN® THV Stainless Steel Frame Bovine Pericardial Tissue 23 and 26mm Transfemoral, Transapical I would like to take you through the First in class experience with Edwards SAPIEN platform in TAVR which began in 2007 and so now reflects more than 5 years of experience in PAS for this therapy The CE Mark was conferred for essentially high risk and inoperable patients defined as a predecited risk of greater the 15T or Euroscore of 20 And including both transfemoral and transapical access. A registry- know as the SOURCE Registry commenced in the first 32 consecutive commercial sites and more than 1000 patients were enrolled consecutively. This was the largest post approval study and generated tremendous interest and therefore a second cohort was added to evaluate the secnd year of experience in the same centers for learning curve and indication assessments. The second generation platform, SAPIEN XT received CE Mark in 2010, followed by a second registry SOURCE XT. This indication included now expanded size and access options. More than 2700 patients were enrolled over a one year period. The SOURCE Registry The SOURCE XT Registry 4

Post Approval Surveillance SOURCE Registry SOURCE XT Post Approval Study Patients 2307 2706 Enrollment November 2007 – December 2009 July 2010 – October 2011 Centers 37 94 Countries 14 17 Access Routes Transfemoral Transapical Transfemoral, Transapical, Transaortic and Subclavian Valve SAPIEN 23mm, 26mm SAPIEN XT 23mm, 26mm, 29mm Adverse Event Adjudication Principal Investigators Independent Clinical Endpoint Committee, VARC Guidelines Monitored Min Yes Follow-up 30 Days, 1 Year and 2 Years Annually to 5 Years Here you see some information about the 2 registries side by side. Of interest, these studies were not mandated as post approval requirements but rather for the the objectives previously stated

All Edwards SAPIEN® THV Studies Transfemoral (30 Day) REVIVE TF (n=106) PARTNER EU* TF (n=61) SOURCE Co 1 TF (n=463)^^ Co 2 TF (n=457)^^ Mean EuroSCORE (%) 28.9 ± 13.2 25.7 ± 11.5 25.8 ± 14.4 22.0 ± 13.7 Implant Success 88% 96.4% 95.2% NA Freedom from Death 86.7% 91.8% 93.7% 91.2% Freedom from Stroke 97.0% 96.7% 97.4% Vascular Complications (Access-Related) 15.5%** 27.9.0% 9.3% + 8.2%+ Renal Failure /Dialysis NR 1.6% 1.3% 2.4% Freedom from Reoperation 99.0% 98.4% 99.1% 97.1% Freedom from PPM 98.2% 93.9% 92.6% Data Extract Nov 30 2009 Feb 1 2010 Apr 28 2011 The question was asked, have outcomes improved in the post approval era. Here you can see the answer is yes when marching down the timeline from the preapproval studies REVIVE and PARTNER EU (which was the precursor to PARTNER IDE). At 30 days... * Lefevre, T et al. One year follow-up of the multi-centre European PARTNER transcatheter heart valve study. Eur Hrt J: 2011 32; 148-157. ** Pooled REVIVE/REVIVAL (TF and TA pooled) ^ Rodes-Cabau et al., Transcatheter Aortic Valve Implantation for the Treatment of Severe Symptomatic Aortic Stenosis in Patients at Very High or Prohibitive Surgical Risk: Acute and Late Outcomes of the Multicenter Canadian Experience. JACC: 2010 Mar 16; 55 (11). ^^ Wendler O. Presented at EuroPCR May 2011. + Major Vascular Complications Monitored Pooled Studies TF: PARTNER EU, REVIVAL, REVIVE, CANADA, and SOURCE

All Edwards SAPIEN® THV Studies Transfemoral (1 Year) REVIVE TF (n=106) PARTNER EU* TF (n=61) SOURCE Co 1^ TF (n=463) Co 2^^ TF (n=457) Freedom from Death 72.5% 78.7% 81.0% 79.2% KM Mortality % 27.5% 21.3% 19.0% 20.8% Freedom from Stroke 97.8% 93% 96.3% 95.6% Freedom from PPM NR 98.2% 92.4% 91.0% Data Extract Nov 30 2009 Feb 1 2010 Apr 28 2011 * Lefevre, T et al. One year follow-up of the multi-centre European PARTNER transcatheter heart valve study. Eur Hrt J: 2011 32; 148-157. ** Pooled REVIVE/REVIVAL (TF and TA pooled) ^ Rodes-Cabau et al., Transcatheter Aortic Valve Implantation for the Treatment of Severe Symptomatic Aortic Stenosis in Patients at Very High or Prohibitive Surgical Risk: Acute and Late Outcomes of the Multicenter Canadian Experience. JACC: 2010 Mar 16; 55 (11). ^^ Wendler O. Presented at EuroPCR May 2011. + Freedom from Renal Failure Monitored Pooled Studies TF: PARTNER EU, REVIVAL, REVIVE, CANADA,

Harmonization of Clinical Trial Endpoints Standardization of ascertainment and analysis of endpoints Reasonable comparisons of iterations Meta analyses as guidance documents VARC VARC II Data analysis point of view Lessons learned from revascularization era MACCE Effective comparison, but for eventuality of OPC

SOURCE XT Registry Rigor, Oversight, Transparency Executive Committee Martyn Thomas, Olaf Wendler, Alec Vahanian, Thierry Lefevre, Stephan Windecker, Helmut Baumgartner, Gerhardt Schymick, Stefan Sack, Marie Claude Morice, Philip Urban, Marc Casselman, Thomas Walther, Gerhard Wimmer-Greinecker, Axel Unbehahn Disciplines Societies Regions Clinical Event Committee 15 Members Cardiology (7) Cardiac Surgery (4) Neurology (3) 7300 events, nearly 17% captured by CEC trigger VARC II 7 endpoints Death, Stroke, Vascular, Bleeding, Renal, Pacemaker, Valve performance Monitoring 100% CEC Events Source documents in 13 languages

30-day outcomes in an international post approval clinical study with a second generation balloon expandable transcatheter heart valve using multiple access techniques Alec Vahanian, MD Hopital Bichat Paris France on behalf of the SOURCE XT Investigators

SOURCE XT Clinical Outcomes at 30 Days Intensified adjudication (VARC II), decrease in major event rates * VARC definitions /CEC Adjudicated

Baseline Characteristics Results (n = 2706) Age (years, mean± SD) 81.3 ± 6.6 Female - % (n) 57.7 (1561) Logistic EuroScore (mean±SD) 20.5 ± 12.6 STS Score (mean±SD) 8.5 ± 7.0 Previous Stroke / TIA - %(n) 8.4 (226) / 4.6 (123) COPD - %(n) 20.1 (544) Renal Insufficiency - %(n) 28.0 (758) Peripheral Vascular Disease - %(n) 21.2 (572) Frail Condition (mean±SD) 5.2 ± 1.4

Contemporary Post Approval Assessment Paradigms in TAVR Outcomes and Appropriateness Sponsor Investigator Societies Government There have also been investigator initiated studies

Pan Canadian Post Approval Study In particular- Led by Josep Rodes and John Webb in Canada- and all canadian retrospective analysis was conducted, demonstrating similar results as previously described

Contemporary Post Approval Assessment Paradigms in TAVR Outcomes and Appropriateness Sponsor Investigator Societies Government Also in these 5 years since first commercial approvals, in an unprecedented fashion, societies teamed up with government entities to establish independent registries and we have now seen multiple European country registries presented and published

National TAVR Registries The two largest series are from France and Germany, with the German Registry now being the largest in the world and inclusive not only of TAVR but all Aortic Valve interventions

SAPIEN TAVR Surveillance Across Types 30 Day Mortality Edward SAPIEN (TF) VANCOUVER (114) b Showing results spnsor, investigator and scociety/national registries, we see fairly similar outcomes BELGIUM (99) g CANADIAN (168) h FRENCH 10-11 (853) i PARTNER EU (61) c SOURCE (920) d FRENCH 95 ( ) e UK (172) f bWebb TCT 2008; cLefevre et al EurHeartJ 2011;32:148-57; dThomas et al Euro PCR 2011; eEltchaninoff Eur Heart J 2010; Sept 15, 2010 epub; fLudman EuroPCR 2010; gBelgium; hRodes-Cabau et al. JACC 2010;55:In Press; iGilard M EuroPCR 2011

Large Series Weighted Meta-Analysis: 16 Studies, 3519 Patients

Approval and Post Approval Surveillance SAPIEN Platforms Edwards’ Global Post Approval Activities ‘07 ‘08 ‘09 ‘10 ‘11 ‘12 ‘13 CE Mark FDA Approval Edwards SAPIEN® THV Stainless Steel Frame Bovine Pericardial Tissue 23 and 26mm Transfemoral, Transapical Inoperable TF only High Risk Transfemoral Transapical Moving to the US experience, FDA approval came in late 2011 for the inoperrable patient and 2012 for the high risk for surgery population. In parallel to the approval and drawing from the global experience including VARC initiatives, national registries in Europe, remibursment objectives and sponsor commitment a new paradigm for post approval studies was introduced STS/ACC TVT Registry Commences The SOURCE Registry 19

New outcomes registry of TAVR STS/ACC TVT Registry New outcomes registry of TAVR >400 data elements Web based data entry Standardized data elements- VARC definitions 30 day risk adjusted clinical outcomes Linked to CMS claims data for long term outcomes Will be harmonized with STS database for surgical AVR The TVT Registry is ambitious with more than 400 data elements, linkage to CMS claims data base and embedded with opportunities to address specific sponsor post approval requirements from FDA

Steering Committee STS Members ACC Members Registry Operations Center Fred Edwards Fred Grover Michael Mack Dave Shahian ACC Members Ralph Brindis John Carroll David Holmes Murat Tuzcu Registry Operations Center NCDR Ex Officio Members FDA - Danica Marinac-Dabic CMS - Jyme Schafer NHLBI - Frank Evans Chair TVT R&P Subcommittee - John Rumsfeld DCRI – Eric Peterson, Matt Brennan Data Analytics Center DCRI The leadership is stellar and representative of all possible stakeholders whose commitment has been exemplary. This committee meets by telecon weekly and is already making preparations for a first publication this year. Staff Cynthia Shewan, Hilary Kirk Joan Michaels, Kathleen Hewitt, Barb Christensen

Current Status February 2013 178 enrolled sites 3,116 patient records Nested registries for PAS II for Edwards SAPIEN Valve in progress

Opportunities, Challenges and Requirements of Surveillance The Good TAVR unprecedented in level of oversight since global commercialization Genuine collaboration of stakeholders Trend of improvement in outcomes through observation The Challenge Overlapping initiatives are expensive and burdensome The Future Harmonization Technological advancements data, patient follow-up Balancing of pre and post market evidence for rapid innovation Economies of scale International cooperation

Patient and Clinician Choices Conclusion Surveillance Safety Appropriateness Iteration Patient and Clinician Choices Surveillance of TAVR is expansive No unanticipated safety signals to date National and International Registry Initiatives are being realized and may replace pave the way for a new paradigm in pre and post approval requirements