Results from >2,300 Patients in The SOURCE TAVI Registry: Changes in Patient Populations with time. Dr Martyn Thomas on behalf of the SOURCE investigators. Clinical Director, Cardiovascular Services St Thomas’ Hospital Kings Health Partner’s London

Disclosure Statement of Financial Interest Grant/Research Support Consulting Fees/Honoraria Edwards Lifesciences Boston Scientific Cordis Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany

Background :THE SOURCE Registry describes the outcomes in the first group of TAVI patients treated with the Edwards SAPIEN Valve in Europe. COHORT 1:Nov 07 to Jan Centres with 1123 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 The SOURCE Registry has: 100% procedure data 30D Data: COH1 – 99.9% | COH2 – 98% 1Yr Data: COH1 – 98% | COH2 – Avail 2011 All consecutively enrolled Excluded: 2 Centres / 85 patients Unable to obtain Ethic Cte approval or administrative issues. 3 Data Extract – 17MAY2010, 30JUL Centres with 1038 patients COHORT 2: Feb 09 to Dec Centres with 1306 patients TOTAL: 38 Centres with 2344 patients = 2 Centres Elected not to participate. – – + =

Methods: Consecutive Patients 4 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.

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. 5

Site NamePtsSite NamePts Karlsruhe/Städisches Klinikum + Herzklinik – G Schymik, H Schroefel 204Frankfurt/Uniklinik – V Schächinger, M Doss50 Leipzig/Herzzentrum – T Walther, G Schuler162Zurich/KlinikimPark + Hirslanden – W Amann, F Bernet50 London/St Thomas’ + King’s – M Thomas, O Wendler149Lund/Universitetssjukhuset – G Olivecrona, P Johnsson42 Milan/Monzino – P Bigliogli, M Fusari113Jena/Uniklinik – K Hekmat, M Ferrari39 Hamburg/Uniklink – H Treede, O Franzen109Leiden/ – M Schalij, A de Weger37 Munich/DHZ – R Lange106A Coruna/ – N Vazquez, J Cuenca36 Paris/Bichat – D Himbert, P Nataf98Paris/HEGP – D Blanchard, JN Fabiani34 Mercogliano/Clinica Montevergine – P Rubino, G Sorrogpago 91Leuven/Gasthuisberg – C Dubois, P Herijgers32 Massy/Jacques Cartier – T Lefèvre, M Romano84Lübeck/Uniklinik – ED Kraatz, H Sier30 Essen/Uniklinik – H Eggebrecht, M Thielmann82Torino/ – I Sheiban, M Rinaldi30 Münster – H Baumgartner, H Reinecke80Padova/ – G Isabella, G Gerosa28 Madrid/S Carlos – C Macaya, E Rodriguez79Innsbruck/Uniklinik – L Mueller, T Bartel26 Milan/S Raff – I Michev, F Maisano79Cambridge/Papworth – C Densem, P Calvert22 Aarhus/Skejby – HR Andersen, KE Klaaborg71Utrecht/ – P Stella, J Kluin19 Rouen/CHU – H Eltchaninoff, JP Bessou66Barcelona/ – J Angel, A Igual,17 Bern/Inselspital – P Wenaweser, T Carrel60Tampere/ – P Kosonen, M Kohonen15 Bruxelles/St Luc – P Astarci, J Kefer59Vigo/ – A Inigues, G Pradas14 Athens/Onassis – K Spargias, G Stavridis55London/Brompton – M Mullen, N Moat13 San Sebastian/Gipuzkoa – J Goiti, M Larman53University of Hradec Kralove/ – J Stasek, J Vojacek10 TOTAL2344 The SOURCE Registry – Total Enrollment 6 Data Extract – 17MAY2010, 30JUL2010

The Logistic EuroSCORE overestimates but does categorise risk Don’t dismiss the value of EuroSCORE to categorise risk

Patient Groupings of Interest in the SOURCE Registry Hypothesis: Patient indication may have changed over the time course of the SOURCE registry. Log EuroSCORE >20 (“standard risk”) Log EuroSCORE <20 (usually patients with risk factors not captured by Log EuroSCORE – potentially “lower risk”……..but unclear) Other patients including “Valve in Valve” to treat degenerative aortic bioprosthesis. 8

Changes in patient groups with time (Numbers of patients per category) 9 Patient Number / Percentage Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value Log EuroSCORE >20695 / 66.9%734 / 56.2%<.0001 Log EuroSCORE < / 32.8%568 / 43.5%<.0001 Data Extract – 17MAY2010, 30JUL2010 Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value Mean Log EuroSCORE27.6 ± ± Category Cohort 1 (N=1038) Cohort 2 (N=1306) P-Value SAPIEN in prior aortic bioprosthesis 2 / 0.2%26 / 1.9%<.0001 (4 patients included in database outside Cohort 1 and Cohort 2 have been excluded) This was not anticipated!!

Has the different patient population resulted in a change in 30 day survival? 10 Data Extract – 17MAY2010, 30JUL2010 Cohort 1Cohort 2 30 day survival91.2%89.9%

30 Day Survival: “standard risk” Cohort 1 vs. Cohort 2 with ES>20 Patient Number / Percentage CategoryCohort 1 (N=1038)Cohort 2 (N=1306)P-Value Log EuroSCORE >20695 / 66.9%734 / 56.2%< Data Extract – 17MAY2010, 30JUL2010 Survival CategoryCohort 1 (N=1038)Cohort 2 (N=1306)All (N=2344)P-Value Log EuroSCORE >2090.1%88.2%89.1%0.2504

30 Day Survival: Cohort 1 vs. Cohort 2 with ES<20 Patient Number / Percentage CategoryCohort 1 (N=1038)Cohort 2 (N=1306)P-Value Log EuroSCORE <20340 / 32.8%568 / 43.5%< Data Extract – 17MAY2010, 30JUL2010 Survival CategoryCohort 1 (N=1038)Cohort 2 (N=1306)All (N=2344)P-Value Log EuroSCORE <2094.1%92.7%93.3%0.4272

Demographics and Risk Factors – Overall Group 20 Why TAVI for <20? 13 Data Extract – 17MAY2010, 30JUL2010 Risk Factor All Treatments < 20 (N=908) All Treatments >= 20 (N=1429) All Treatments p- value NYHA Class IV83 ( 9.14%)244 (17.07%)<.0001 Female523 (57.60%)815 (57.03%) Age >= 80 Years526 (57.93%)1016 (71.10%)<.0001 Smoking207 (22.80%)263 (18.40%) Coronary Artery Disease396 (43.61%)838 (58.64%)<.0001 Congestive Heart Failure218 (24.01%)499 (34.92%)<.0001 Myocardial Infarction99 (10.90%)262 (18.33%)<.0001 Carotid artery stenosis (over 50%)63 ( 6.94%)218 (15.26%)<.0001 Porcelain Aorta91 (10.02%)95 ( 6.65%) Mitral valve disease260 (28.63%)448 (31.35%) Cancer182 (20.04%)186 (13.02%)<.0001 Pulmonary disease206 (22.69%)389 (27.22%) Pulmonary disease: FEV1 less than ( 3.52%)29 ( 2.03%) Renal insufficiency / Failure195 (21.48%)476 (33.31%)<.0001 Post thoracic radiation therapy14 ( 1.54%)6 ( 0.42%) Peripheral vascular disease (non carotid)123 (13.55%)346 (24.21%)<.0001 PTCA / stent203 (22.36%)420 (29.39%) CABG108 (11.89%)392 (27.43%)<.0001 Carotid endarterectomy / Carotid stent20 ( 2.20%)70 ( 4.90%) Prior surgical aortic bioprosthesis in place? (VIV)6 ( 0.66%)20 ( 1.40%) “Frailty” not measured in the SOURCE database

Comparison of <20 patient demographics and risk factors in Cohort 1 and 2: Has the pattern of risk changed? 14 Data Extract – 17MAY2010, 30JUL2010 Comorbidity / Risk Factor Cohort 1 (N=340) Cohort 2 (N=568) P-Value by Cohort Female192 ( 56.47%)331 ( 58.27%) Coronary Artery Disease141 ( 41.47%)255 ( 44.89%) Congestive Heart Failure60 ( 17.65%)158 ( 27.82%) Carotid artery stenosis (over 50%)24 ( 7.06%)39 ( 6.87%) Porcelain Aorta38 ( 11.18%)53 ( 9.33%) Mitral valve disease68 ( 20.00%)192 ( 33.80%)<.0001 Pulmonary disease82 ( 24.12%)124 ( 21.83%) Renal insufficiency / Failure62 ( 18.24%)133 ( 23.42%) Peripheral vascular disease (non carotid)49 ( 14.41%)74 ( 13.03%) CABG43 ( 12.65%)65 ( 11.44%) “True risk” in Cohort 2 may have gone “up”.

1 Year Kaplan Meier Survival: when is Euroscore reflected in survival benefit? Cohort 1 – ES Data Extract – 17MAY2010, 30JUL2010 P= Cohort 1ES<20ES>20 1 year survival79.7%74.2%

“Valve in valve”: an indication for TAVI? In The SOURCE Registry trans-catheter 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 THE SOURCE Registry 17 Data Extract – 17MAY2010, 30JUL2010 Risk Factor Total Prior Surgical Bioprosthesis (N=28) Age Female12 (46.15%) EuroSCORE34.06 Peripheral vascular disease (non carotid)6 (23.08%) Coronary Artery Disease11 (42.31%) Congestive Heart Failure8 (30.77%) Myocardial Infarction6 (23.08%) Mitral valve disease12 (46.15%) PTCA / stent6 (23.08%) CABG7 (26.92%) VERY HIGH RISK GROUP OF PATIENTS 26/28 TA approach

Surgical redo AVR Patient Demographics Contemporary Surgical literature is limited Age56 Ejection Fraction57% Age63.5 Ejection fraction58% 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 Appears “low risk” patient population Age56 Ejection Fraction53% Reoperative surgery for degenerated aortic bioprostheses: predictors for emergency Surgery and reoperative mortality: Vogt et al Eur J Cardiothoarac Surg 2000

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

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

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 trans-catheter treatment appear so different it will be difficult to compare outcomes. Ideally a randomised trial would resolve this but patient numbers are now relatively small.

Changes in Patient Populations with time: CONCLUSIONS 1 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. However the true “risk” of Cohort 2 may well have gone up, reflected by increased patients with heart failure and mitral regurgitation. 30 day outcomes for Cohort 1 and 2 are the same. Urgent need for the development of “TAVI risk score” to include other factors ie. Frailty; as EuroSCORE may not be truly assessing “risk”. 22

Changes in Patient Populations with time: CONCLUSIONS 2 “Valve in valve” appears an emerging indication for TAVI. The “valve in valve” patients in SOURCE are very high risk. The contemporary data for redo surgical AVR as a comparator is limited but does suggest a completely different patient population. Comparison of these two treatment options will be difficult in the absence of randomised data.