Dr Martyn Thomas on behalf of the SOURCE investigators.

1. 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

2. Grant/Research Support Consulting Fees/Honoraria Edwards Lifesciences Boston Scientific Cordis 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. Affiliation/Financial Relationship Company

3. Background:THE SOURCE Registry describes the outcomes in the first group of TAVI patients treated with the Edwards SAPIEN Valve in Europe. COHORT 2: Feb 09 to Dec 09 40 Centres with 1306 patients TOTAL: 38 Centres with 2344 patients COHORT 1:Nov 07 to Jan 09 34 Centres with 1123 patients 32 Centres with 1038 patients • 2 Centres • Elected not to participate. • Excluded: 2 Centres / 85 patients • Unable to obtain Ethic Cte approval or administrative issues. – = + – = 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 3

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 Transfemoralsheaths and 26F Transapicalsheaths. 4

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. 5

6. The SOURCE Registry – Total Enrollment Data Extract – 17MAY2010, 30JUL2010 6

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

8. Patient Groupings of Interest in theSOURCE 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

9. Changes in patient groups with time(Numbers of patients per category) This was not anticipated!! (4 patients included in database outside Cohort 1 and Cohort 2 have been excluded) Data Extract – 17MAY2010, 30JUL2010 9

10. Has the different patient population resulted in a change in 30 day survival? Data Extract – 17MAY2010, 30JUL2010 10

11. 30 Day Survival: “standard risk”Cohort 1 vs. Cohort 2 with ES>20 Data Extract – 17MAY2010, 30JUL2010 11

12. 30 Day Survival: Cohort 1 vs. Cohort 2 with ES<20 Data Extract – 17MAY2010, 30JUL2010 12

13. Demographics and Risk Factors – Overall Group <20 & >20Why TAVI for <20? “Frailty” not measured in the SOURCE database Data Extract – 17MAY2010, 30JUL2010 13

14. Comparison of <20 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”. Data Extract – 17MAY2010, 30JUL2010 14

15. 1 Year Kaplan Meier Survival: when is Euroscore reflected in survival benefit?Cohort 1 – ES <20 vs. >20 P=0.0529 Data Extract – 17MAY2010, 30JUL2010 15

16. “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?

17. “Valve In Valve” Patient DemographicsTHE SOURCE Registry VERY HIGH RISK GROUP OF PATIENTS 26/28 TA approach Data Extract – 17MAY2010, 30JUL2010 17

18. Surgical redo AVRPatient DemographicsContemporary Surgical literature is limited Perioperative Risk of Redo Aortic Valve Replacement Ann ThoracCardiovascSurg 2009 Christiansen et al Operative risk of reoperative aortic valve replacement J ThoracCardiovascSurg 2005 Potter et al Reoperative surgery for degenerated aortic bioprostheses: predictors for emergency Surgery and reoperative mortality: Vogt et al Eur J CardiothoaracSurg 2000 Appears “low risk” patient population

19. 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 ThoracCardiovascSurg 2001 Jones et al

20. Risk factors for operative mortality of repeat heart surgery. 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

21. 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.

22. 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

23. 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.