Edwards Sapien Transcatheter Valve System: OUS Data Jean Fajadet, MD, FESC President-elect of EAPCI (European Association of Percutaneous Cardiovascular Interventions) Clinique Pasteur, Toulouse, France

I do not have any potential conflict of interest Potential conflicts of interest Speaker’s name: Jean FAJADET I do not have any potential conflict of interest

The SOURCE Family of Registries Timeline 2009 2010 2011 SOURCE COHORT 1 Nov 07 SOURCE COHORT 2 PREVAIL SOURCE XT EU SOURCE XT Global 3 3

Excluded: 2 Centres / 85 patients Background:The SOURCE Registry describes the outcomes in a consecutive group of TAVI patients treated with the Edwards SAPIEN Valve in European centres. COHORT 1: 34 Centres with 1123 patients Excluded: 2 Centres / 85 patients Unable to obtain Ethic Cte approval or administrative issues. – = 32 Centres with 1038 patients + COHORT 2: 40 Centres with 1306 patients – 2 Centres Elected not to participate. = TOTAL: 38 Centres with 2344 patients The SOURCE Registry has: 100% procedure data 30D Data: COH1 – 99.9% | COH2 – 98% 1Yr Data: COH1 – 98% | COH2 – Avail 2011 All consecutively enrolled Data Extract – 17MAY2010, 30JUL2010 4

Methods: Consecutive Patients The current data is from centres who could provide data on 100% of their consecutively treated patients during this time. Centres that could not provide this were excluded. Transfemoral, Transapical, and [(trans-axillary & trans-aortic)=5] cases are included in this consecutive series. The SOURCE Registry used the 23mm and 26mm Edwards SAPIEN THV requiring 22/24F Transfemoral sheaths and 26F Transapical sheaths. 5

Methods This is a clinical registry. All events and values are site reported and there are no core labs. The SOURCE Registry Principal Investigators reviewed and adjudicated all clinical and adverse events reported into the Medidata Rave Database. 6

The SOURCE Registry – All Total Enrollment Site Name Pts Karlsruhe/Städisches Klinikum + Herzklinik – G Schymik, H Schroefel 204 Frankfurt/Uniklinik – V Schächinger, M Doss 50 Leipzig/Herzzentrum – T Walther, G Schuler 162 Zurich/KlinikimPark + Hirslanden – W Amann, F Bernet London/St Thomas’ + King’s – M Thomas, O Wendler 149 Lund/Universitetssjukhuset – G Olivecrona, P Johnsson 42 Milan/Monzino – P Bigliogli, M Fusari 113 Jena/Uniklinik – K Hekmat, M Ferrari 39 Hamburg/Uniklink – H Treede, O Franzen 109 Leiden/ – M Schalij, 37 Munich/DHZ – R Lange 106 A Coruna/ – waiting 36 Paris/Bichat – D Himbert, P Nataf 98 Paris/HEGP – D Blanchard, JN Fabiani 34 Mercogliano/Clinica Montevergine – P Rubino, G Sorrogpago 91 Leuven/Gasthuisberg – C Dubois, P Herijgers 32 Massy/Jacques Cartier – T Lefèvre, M Romano 84 Lübeck/Uniklinik – ED Kraatz, H Sier 30 Essen/Uniklinik – H Eggebrecht, M Thielmann 82 Torino/ – I Sheiban, M Rinaldi Münster – H Baumgartner, H Reinecke 80 Padova/ – G Isabella, G Gerosa 28 Madrid/S Carlos – C Macaya, E Rodriguez 79 Innsbruck/Uniklinik – L Mueller, T Bartel 26 Milan/S Raff – I Michev, F Maisano Cambridge/Papworth – C Densem, P Calvert 22 Aarhus/Skejby – HR Andersen, KE Klaaborg 71 Utrecht/ – P Stella, J Kluin 19 Rouen/CHU – H Eltchaninoff, JP Bessou 66 Barcelona/ – A Igual, 17 Bern/Inselspital – P Wenaweser, T Carrel 60 Tampere/ – P Kosonen, M Kohonen 15 Bruxelles/St Luc – P Astarci, J Kefer 59 Vigo/ – A Inigues 14 Athens/Onassis – K Spargias, G Stavridis 55 London/Brompton – M Mullen, N Moat 13 San Sebastian/Gipuzkoa – J Goiti, M Larman 53 University of Hradec Kralove/ – J Stasek, J Vojacek 10 TOTAL 2344 Centers listed in descending order of total enrollment N=130 patients – one patient identified in earlier presentations has been removed. Was a screening failure due to endocarditis and was not treated. Patient cohorts are reflective of intent-to-treat groups and not which approach was actually used. One London patient was crossed over to a transapical implantation but he remains in his intended transfemoral group for analysis. Data Extract – 17MAY2010, 30JUL2010 7

SOURCE COHORT 1 Baseline Demographics and Risk Factors TF (n=463) TA (n=575) P-Value Age (yrs) 81.7 80.7 0.022 Female 55.1% 55.8% NS Pulmonary Disease 24.6% 29.9% Renal Dysfunction 25.5% 32.5% 0.016 Logistic EuroSCORE 25.8 29.0 0.007 Peripheral Vascular Disease 10.6% 28.0% <0.001 Carotid Artery Stenosis (>50%) 7.1% 17.2% Incidence of CAD 47.5% 0.020 Porcelain Aorta 4.5% 11.3% 0.001 Prior CABG 17.5% 27.0% 0.003 Mitral valve disease 15.8% 32.0% Data Snapshot 5/03/2010 8 8

SOURCE: COHORT 1 1 Year Survival (All Approaches) TF KM 1Yr Mortality = 18.9% ALL KM 1 Yr Mortality = 23.9% TA KM 1Yr Mortality = 27.9% 30 Day Survival: TA 89.2% TF 93.7% ALL 91.2% ALL TA TF I Yr Survival 76.1% 72.1% 81.1% 9

Cohort 1: 1 YR (Events: Late) Freedom From: Stroke, PM, MI All Data as KM Curves Cohort 1: 1 YR (Events: Late) Freedom From: Stroke, PM, MI 10

Early Vascular Access Complications Relationship to 1 Year Mortality (NB 22/24F Device) Approach % Survival in Pts who did not have vascular access complications % Survival in Pts who did have vascular access complications P-Value TF 83.9% 72.2% 0.0121 TA 73.2% 47.4% 0.0188 11 11

Relationship between EuroSCORE and Survival 1 Year Mortality = 21.6% 1 Year Mortality = 26.5% 30 Day Survival: <20 93.5% 20-40 88.1% >40 85.7% I Year Mortality = 40.8% Strata Group Comparison Log-Rank Bonferroni adjusted P-value < 20 vs. 20-40 0.6142 20-40 vs. > 40 0.0125 < 20 vs. > 40 0.0012 >40 20-40 <20 I Yr Survival 59.2% 73.5% 78.4% 12

Relationship between EuroSCORE and Survival 1 Year Mortality = 16.5% 1 Year Mortality = 19.1% 1 Year Mortality = 27.5% 30 Day Survival: <20 94.7% 20-40 96.0% >40 83.3% Strata Group Comparison Log-Rank Bonferroni adjusted P-value < 20 vs. 20-40 1.0000 20-40 vs. > 40 0.0364 < 20 vs. > 40 0.2077 >40 20-40 <20 I Yr Survival 72.5% 83.5% 80.9% 13

Myocardial Infarction Causes of Death 30 Days to 1 Year ALL ALL 179 Cardiac 45 (25.1%) Heart Failure 28 (62.2%) Myocardial Infarction 6 (13.3%) Endocarditis 3 (6.7%) Other* 8 (17.8%) Non Cardiac 88 (49.2%) Pulmonary*** 21 (23.9%) Renal Failure 11 (12.5%) Cancer 10 (11.4%) Stroke 9 (10.2%) Gastrointestinal 5 (5.6%) Other** 32 (36.4%) Unknown 46 (25.7%) Sudden Death 18 (39.1%) Other 10 (21.7%) Other * = Arrhythmia, cardiac arrest Other** = Sepsis, vascular access related, major bleeding, infection, suicide, and multiple organ failure Pulmonary***= Respiratory Failure, Pulmonary Embolism and Pneumonia 14

Multivariate Analysis – 1YR Mortality (TA) Analysis of Maximum Likelihood Estimates Parameter P-Value Hazard Ratio 95% Hazard Ratio Confidence Limits Scaled Logistic EuroSCORE (%/10) <.0001 1.200 1.098 1.311 Renal insufficiency / Failure 0.0047 1.592 1.154 2.197 Carotid artery stenosis (over 50%) 0.0014 0.454 0.280 0.737 Liver disease 0.0005 3.154 1.646 6.043 Other 0.0345 1.489 1.029 2.153 Logistic EuroSCORE is most significant predictor for 1 year mortality in transapical patients 15 15

Multivariate Analysis – 1YR Mortality (TF) Analysis of Maximum Likelihood Estimates Parameter P-Value Hazard Ratio 95% Hazard Ratio Confidence Limits NYHA Class IV 0.0067 1.948 1.203 3.153 Renal insufficiency / Failure <.0001 2.382 1.553 3.656 Hyperlipidemia / Hypercholesterolemia 0.0293 0.602 0.382 0.950 Systemic Hypertension 0.0317 0.622 0.403 0.959 Smoking 0.0009 2.268 1.399 3.677 Mitral valvuloplasty 0.0040 8.237 1.956 34.690 Coagulopathy 0.0073 5.178 1.558 17.208 Logisitic EuroSCORE is not a predictor for 1 year mortality in patients treated with the transfemoral approach 16

Excluded: 2 Centres / 85 patients Background:The SOURCE Registry describes the outcomes in a consecutive group of TAVI patients treated with the Edwards SAPIEN Valve in European centres. COHORT 1: 34 Centres with 1123 patients Excluded: 2 Centres / 85 patients Unable to obtain Ethic Cte approval or administrative issues. – = 32 Centres with 1038 patients + COHORT 2: 40 Centres with 1306 patients – 2 Centres Elected not to participate. = TOTAL: 38 Centres with 2344 patients The SOURCE Registry has: 100% procedure data 30D Data: COH1 – 99.9% | COH2 – 98% 1Yr Data: COH1 – 98% | COH2 – Avail 2011 All consecutively enrolled Data Extract – 17MAY2010, 30JUL2010 17

Patient Number / Percentage Changes in patient groups and “risk” with time (Numbers of patients per category) Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value Mean Log EuroSCORE 27.6 ± 15.5 25.5 ± 21.9 0.0079 Patient Number / Percentage Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value Log EuroSCORE >20 695 / 66.9% 734 / 56.2% <.0001 Log EuroSCORE < 20 340 / 32.8% 568 / 43.5% Need correct number and percentage for Cohort 2 Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value SAPIEN in prior aortic bioprosthesis 2 / 0.2% 26 / 1.9% <.0001 This was not anticipated!! (4 patients included in database outside Cohort 1 and Cohort 2 have been excluded) Data Extract – 17MAY2010, 30JUL2010 18

Has the reduced EuroSCORE resulted in better 30 day survival? Cohort 1 Cohort 2 30 day survival 91.2% 89.9% Need survival table in chart Data Extract – 17MAY2010, 30JUL2010 19

30 Day Survival: “standard risk” Cohort 1 vs. Cohort 2 with ES>20 Patient Number / Percentage Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value Log EuroSCORE >20 695 / 66.9% 734 / 56.2% <.0001 Survival Category Cohort 1 (N=1038) Cohort 2 (N=1306) All (N=2344) P-Value Log EuroSCORE >20 90.1% 88.2% 89.1% 0.2504 Data Extract – 17MAY2010, 30JUL2010 20

30 Day Survival: “lower risk” Cohort 1 vs. Cohort 2 with ES<20 Patient Number / Percentage Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value Log EuroSCORE <20 340 / 32.8% 568 / 43.5% <.0001 Survival Category Cohort 1 (N=1038) Cohort 2 (N=1306) All (N=2344) P-Value Log EuroSCORE <20 94.1% 92.7% 93.3% 0.4272 Data Extract – 17MAY2010, 30JUL2010 21

Demographics and Risk Factors – Overall Group <20 & >20 Why TAVI for <20? All Treatments < 20 (N=908) All Treatments >= 20 (N=1429) All Treatments p- value NYHA Class IV 83 ( 9.14%) 244 (17.07%) <.0001 Female 523 (57.60%) 815 (57.03%) 0.6345 Age >= 80 Years 526 (57.93%) 1016 (71.10%) Smoking 207 (22.80%) 263 (18.40%) 0.0110 Coronary Artery Disease 396 (43.61%) 838 (58.64%) Congestive Heart Failure 218 (24.01%) 499 (34.92%) Myocardial Infarction 99 (10.90%) 262 (18.33%) Carotid artery stenosis (over 50%) 63 ( 6.94%) 218 (15.26%) Porcelain Aorta 91 (10.02%) 95 ( 6.65%) 0.0037 Mitral valve disease 260 (28.63%) 448 (31.35%) 0.1803 Cancer 182 (20.04%) 186 (13.02%) Pulmonary disease 206 (22.69%) 389 (27.22%) 0.0149 Pulmonary disease: FEV1 less than 1.0 32 ( 3.52%) 29 ( 2.03%) 0.0327 Renal insufficiency / Failure 195 (21.48%) 476 (33.31%) Post thoracic radiation therapy 14 ( 1.54%) 6 ( 0.42%) 0.0396 Peripheral vascular disease (non carotid) 123 (13.55%) 346 (24.21%) PTCA / stent 203 (22.36%) 420 (29.39%) 0.0002 CABG 108 (11.89%) 392 (27.43%) Carotid endarterectomy / Carotid stent 20 ( 2.20%) 70 ( 4.90%) 0.0009 Prior surgical aortic bioprosthesis in place? (VIV) 6 ( 0.66%) 20 ( 1.40%) 0.0166 “Frailty” not measured in the SOURCE database Data Extract – 17MAY2010, 30JUL2010 22

Comparison of <20 “lower risk” patient demographics and risk factors in Cohort 1 and 2: Has the pattern of risk changed? “True risk” in Cohort 2 may have gone “up”. Comorbidity / Risk Factor Cohort 1 (N=340) Cohort 2 (N=568) P-Value by Cohort Female 192 ( 56.47%) 331 ( 58.27%) 0.6273 Coronary Artery Disease 141 ( 41.47%) 255 ( 44.89%) 0.3333 Congestive Heart Failure 60 ( 17.65%) 158 ( 27.82%) 0.0005 Carotid artery stenosis (over 50%) 24 ( 7.06%) 39 ( 6.87%) 0.8937 Porcelain Aorta 38 ( 11.18%) 53 ( 9.33%) 0.4242 Mitral valve disease 68 ( 20.00%) 192 ( 33.80%) <.0001 Pulmonary disease 82 ( 24.12%) 124 ( 21.83%) 0.4613 Renal insufficiency / Failure 62 ( 18.24%) 133 ( 23.42%) 0.0669 Peripheral vascular disease (non carotid) 49 ( 14.41%) 74 ( 13.03%) 0.5497 CABG 43 ( 12.65%) 65 ( 11.44%) 0.5976 Data Extract – 17MAY2010, 30JUL2010 23

1 Year Kaplan Meier Survival: when is Euroscore reflected in survival benefit? Cohort 1 – ES <20 vs. >20 Cohort 1 ES<20 ES>20 1 year survival 79.7% 74.2% Need survival table P=0.0529 Data Extract – 17MAY2010, 30JUL2010 24

“Valve in valve”: an indication for TAVI? In The SOURCE Registry transcatheter valve therapy appears to be an emerging indication for the treatment of a failing surgical aortic bioprosthesis. Can we categorise these patients? Is there “gold standard” surgical data for redo surgery?

“Valve In Valve” Patient Demographics Risk Factor Total Prior Surgical Bioprosthesis (N=28) Age 78.73 + 6.99 Female 12 (46.15%) EuroSCORE 34.06 Peripheral vascular disease (non carotid) 6 (23.08%) Coronary Artery Disease 11 (42.31%) Congestive Heart Failure 8 (30.77%) Myocardial Infarction Mitral valve disease PTCA / stent CABG 7 (26.92%) VERY HIGH RISK GROUP OF PATIENTS Data Extract – 17MAY2010, 30JUL2010 26

The SOURCE Registry: “Valve in Valve” What valves have been treated The SOURCE Registry: “Valve in Valve” What valves have been treated? Where next? Previous bioprostheses include Carpentier Edwards, Hancock, Mitraflow and Mosaic (21-25mm valves). This patient population was not anticipated at the outset of the SOURCE registry. Careful data collection planned for this group in the SOURCE XT registry. Because the patient populations undergoing surgical redo AVR and transcatheter treatment appear so different it will be difficult to compare outcomes. A randomised trial may well be needed to compare these therapies.

Conclusions Outcomes at 1 year for COHORT 1 of The SOURCE Registry show an improvement compared to historical controls. Survival for the TF approach is now >80%. There has been a marked improvement in the TA outcomes with survival now similar to historical TF results. Lower risk TA (<20% euroscore) patients have the same 1 year outcome as TF. 28

Conclusions If the lower profile SAPIEN XT delivery systems result in lower vascular complications this should result in further improvement in 1 year survival. This will be tested in The SOURCE XT Registry. 29

Conclusions There has been a change in the patient population of TAVI patients between Cohort 1 and Cohort 2 of the SOURCE Registry. This is reflected by an increased number of patients with a Log EuroSCORE of <20 in Cohort 2. This change has NOT resulted in a reduced 30 day mortality but some features of Cohort 2 (heart failure and mitral regurgitation) suggest “higher risk”. Relationship between Log Euroscore and mortality possibly represented at 1year. Urgent need for the development of TAVI risk score to include other factors ie. frailty 30

Conclusions “Valve in valve” appears an emerging indication for TAVI. The “valve in valve” patients in SOURCE are very high risk. Comparison of redo surgery and “valve in valve” procedure will be difficult in the absence of randomised data.

Surgical redo AVR Patient Demographics Contemporary Surgical literature is lacking Age 56 Ejection Fraction 57% Age 63.5 Ejection fraction 58% Perioperative Risk of Redo Aortic Valve Replacement Ann Thorac Cardiovasc Surg 2009 Christiansen et al Operative risk of reoperative aortic valve replacement J Thorac Cardiovasc Surg 2005 Potter et al Age 56 Ejection Fraction 53% Reoperative surgery for degenerated aortic bioprostheses: predictors for emergency Surgery and reoperative mortality: Vogt et al Eur J Cardiothoarac Surg 2000 Appears “low risk” patient population

Risk factors for operative mortality of repeat heart surgery. Mean age 54.7yrs Factors associated with operative mortality - age - associated coronary bypass grafting - valve thrombosis or endocarditis - replacement of mechanical heart valve Repeat heart valve surgery: Risk factors for operative mortality. J Thorac Cardiovasc Surg 2001 Jones et al

Risk factors for operative mortality of repeat heart surgery. Predictive risk factors of re-operative AVR mortality Risk Factor Operative Mortality Gender Male Female 4.6% 13.3% Age at reop <60 60-70 >70 0% 8.5% 12.6% Ejection Fraction > 50% < 50% 6.5% 15.4% NYHA class I/II III IV 2.0% 4.2% 16.0% Re-operation for bioprosthetic aortic structural failure – risk assessment. Jamieson et al. Eur J Cardiothorac Surgery 2003