The SOURCE Family of Registries1 Year Results from Cohort 1 of the SOURCE Registry

The European Registry of Transcatheter Aortic Valve Implantation using the

Edwards SAPIEN Valve

Martyn Thomas, MD , Gerhard Schymik, MD, Thomas Walther, MD, Dominique Himbert, MD, Thierry Lefèvre, MD, Hendrik Treede, MD, Holger Eggebrecht, MD, Paolo Rubino, MD, Iassen Michev, MD, Rüdiger Lange, MD and Olaf Wendler, MD on behalf of the SOURCE investigators

Speaker’s name: Dr Martyn Thomas

I have the following potential conflicts of interest to report:

Research contractsConsulting for Edwards LifesciencesEmployment in industryStockholder of a healthcare companyOwner of a healthcare companyOther(s)

I do not have any potential conflict of interest

Potential Conflicts of Interest

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• Trans-catheter Aortic Valve Implantation (TAVI) is an alternative to open surgery in patients considered to be at high risk for the standard procedure.

• Cohort 1 of The SOURCE Registry describes the outcomes in a consecutive group of patients treated in 32 European centres during the first year of commercialisation of the Edwards SAPIEN Valve from Nov 07 to Jan 31st 09.

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Background

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SOURCE COHORT 1

SOURCE COHORT 2

PREVAIL

SOURCE XT EU

SOURCE XT Global

2009 2010 2011

Nov 07

The SOURCE Family of RegistriesTimeline

34 Centres Initially Participating in Commercial Launch1123 patients

Included:32 centres

1038 patients

The SOURCE Registry has 100% procedure data

98% 30 day dataAll consecutively enrolled

Excluded:2 Centres / 85 patients

• Unable to obtain Ethic Cte approval• Unable to secure administrative support• One missing patient due to admin. error

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99.9% 30 Day DataEuroPCR

2010

Methods: EuroPCR 09

We now present 1 year data that represents systematic

follow-up on 98% of implanted patients.

Site Name Pts Site Name Pts

Karlsruhe/Städisches Klinikum + Herzklinik –

G Schymik, H Schroefel

89 Rouen/CHU – H Eltchaninoff, JP Bessou 31

Leipzig/Herzzentrum - T Walther, G Schuler 87 Madrid/S Carlos – C Macaya, E Rodriguez 31

London/St Thomas’ + King’s -M Thomas, O Wendler 75 Bern/Inselspital- P Wenaweser, T Carrel 31

Paris/Bichat – D Himbert, P Nataf 56 Münster – H Baumgartner, H Reinecke 30

Massy/Jacques Cartier - T Lefèvre, M Romano 51 Jena/Uniklinik – K Hekmat, M Ferrari 26

Hamburg/Uniklink- H Treede, O Franzen 48 Lund/Universitetssjukhuset – G Olivecrona, P Johnsson 23

Essen/Uniklinik – H Eggebrecht, M Thielmann 47 Bruxelles/St Luc – P Astarci, J Kefer 21

Mercogliano/Clinica Montevergine-P Rubino, G Sorrogpago 47 San Sebastian/Gipuzkoa – J Goiti, M Larman 20

Milan/S Raff – I Michev, F Maisano 41 Leuven/Gasthuisberg – C Dubois, P Herijgers 17

Munich/DHZ – R Lange 41 Frankfurt/Uniklinik –V Schächinger, M Doss 15

Athens/Onassis – K Spargias, G Stavridis 36 London/Brompton – M Mullen, N Moat 12

Milan/Monzino – P Bigliogli, M Fusari 35 Innsbruck/Uniklinik – L Mueller, T Bartel 10

Paris/HEGP – D Blanchard, JN Fabiani 34 Lübeck/Uniklinik – ED Kraatz, H Sier 8

Aarhus/Skejby- HR Andersen, KE Klaaborg 34 Cambridge/Papworth – C Densem, P Calvert 8

Zurich/KlinikimPark+Hirslanden- W Amann, F Bernet 34

TOTAL 10386

The SOURCE Registry Enrollment

TF(n=463)

TA (n=575) P-Value

Age (yrs) 81.7 80.7 0.022

Female 55.1% 55.8% NSPulmonary Disease 24.6% 29.9% NS

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% <0.001

Incidence of CAD 47.5% 55.1% 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% <0.001

5/03/2010Data Snapshot7

Baseline Demographicsand Risk Factors

TF (n=463) TA (n=575) Total (n=1038)Death 6.3% 10.8% 8.8%

Stroke 2.6% 2.4% 2.5%

Renal Failure Requiring Dialysis

1.3% 7.0% 4.4%

Permanent Pacemaker

6.0% 7.7% 6.9%

5/03/10Data Snapshot8

Major Complications (≤ 30 Days)

To give Context of Early v Late Events

SOURCE: COHORT 11 Year Survival (All Approaches)

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All Data as KM CurvesCohort 1: 1 YR (Events: Late)

Freedom From: Stroke, PM, MI

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SOURCE vs Normal Elderly PopulationCause of Late Stroke (30 Days to 1 Year)

Type of Stroke (Total =19 patients) n/%

SOURCE HEMORRHAGIC (n=4/19) 4/21.1%

Mean (days to adverse event ) 176

Median (days to adverse event ) 167

NORMAL ELDERLY POPULATION* 13%

SOURCE NON-HEMORRHAGIC (n=13/19) 13/68.4%

Mean (days to adverse event ) 163

Median (days to adverse event )117

NORMAL ELDERLY POPULATION* 87%

SOURCE UNKNOWN (n=2) 2/10.5%

Mean (days to adverse event) 158

Median (days to adverse event ) 158

*Lloyd-Jones D, et al. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010 Feb 23;121(7):948-54. Erratum in: Circulation. 2010 Mar 30;121(12):e259.

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All Data as KM CurvesCohort 1: 1 YR (Events: Late)

Freedom From: Vascular Complication, Endocarditis, and Re-Operation

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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 didhave vascular access

complicationsP-Value

TF 83.9% 72.2% 0.0121TA 73.2% 47.4% 0.0188

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Causes of Death30 Days to 1 Year

ALL

ALL179

Cardiac45 (25.1%)

Heart Failure28 (62.2%)

Myocardial Infarction6 (13.3%)

Endocarditis3 (6.7%)

Other*8 (17.8%)

Non Cardiac88 (49.2%)

Pulmonary***21 (23.9%)

Renal Failure11 (12.5%)

Cancer10 (11.4%)

Stroke9 (10.2%)

Gastrointestinal5 (5.6%)

Other**32 (36.4%)

Unknown46 (25.7%)

Sudden Death18 (39.1%)

Unknown18 (39.1%)

Other10 (21.7%)

Other * = Arrhythmia, cardiac arrestOther** = Sepsis, vascular access related, major bleeding, infection, suicide, and multiple organ failurePulmonary***= Respiratory Failure, Pulmonary Embolism and Pneumonia

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Influence of EuroSCORE - Cohort 1 –EuroSCORE as predictor of 30 Day Mortality

Variable P-ValueHazard Ratio

95% Lower Confidence

Limit

95% Upper Confidence

LimitNumber of

Observations Used Deaths

Scaled Logistic EuroSCORE (%/10) <.0001 1.2122 1.1145 1.3186 574 167

Renal insufficiency / Failure 0.0005 1.7205 1.2671 2.3362 575 168

EuroSCORE >= 30 0.0008 1.6851 1.2433 2.2840 574 167

Liver disease 0.0046 2.5271 1.3315 4.7963 575 168

Other 0.0051 1.6872 1.1703 2.4323 575 168

None 0.0126 0.5365 0.3289 0.8749 575 168

Carotid artery stenosis (over 50%) 0.0158 0.5549 0.3439 0.8952 575 168

Coronary Artery Disease 0.0212 1.4456 1.0566 1.9779 575 168

EuroSCORE >= 20 0.0227 1.5292 1.0612 2.2036 574 167

Cardiomyopathy 0.0329 2.4306 1.0746 5.4974 575 168

PTCA / stent 0.0467 1.3871 1.0048 1.9148 575 168

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Univariate Analysis – 1YR Mortality (TA)

Variable P-ValueHazard Ratio

95% Lower Confidence

Limit

95% Upper Confidence

LimitNumber of

Observations Used Deaths

NYHA Class IV 0.0002 2.4224 1.5272 3.8422 453 93

Renal insufficiency / Failure 0.0005 2.0948 1.3842 3.1702 459 94

None 0.0012 0.4004 0.2304 0.6957 459 94

Hyperlipidemia / Hypercholesterolemia 0.0019 0.5065 0.3294 0.7788 459 94

Systemic Hypertension 0.0079 0.5774 0.3850 0.8658 459 94

Mitral valvuloplasty 0.0079 6.6950 1.6454 27.2410 459 94

Smoking 0.0098 1.8595 1.1616 2.9769 459 94

Scaled Logistic EuroSCORE (%/10) 0.0149 1.1764 1.0322 1.3407 458 94

Liver disease 0.0194 2.6851 1.1730 6.1464 459 94

Carotid artery stenosis (over 50%) 0.0390 0.1255 0.0175 0.9008 459 94

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Univariate Analysis – 1YR Mortality (TF)

Multivariate Analysis – 1YR Mortality (TA)

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*Logistic EuroSCORE is most significant predictor for 1 year mortality in transapical patients*

Analysis of Maximum Likelihood Estimates

Parameter P-ValueHazardRatio 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

Multivariate Analysis – 1YR Mortality (TF)

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*Logisitic EuroSCORE is not a predictor for 1 year mortality in patients treated with the transfemoral approach

Analysis of Maximum Likelihood Estimates

Parameter P-ValueHazardRatio 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

So what is the context for these results?

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30 Day Survival 1 Year Survival

SOURCE TA ES>20(Mean 36.1%)

87.4% 69.3%

SOURCE TF ES>20(Mean 33.5%)

93.1% 81%

The data/outcomes of all historical monitored EW THV clinical studies were pooled to provide a comparator to The SOURCE Registry

“Monitored EW THV clinical trials” means 100% source data monitored, Core lab read and CEC adjudicated studies.

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Historical Comparison –TAVI Studies Included

Study No. of Sites

TA n=

TF n=

Dates of Study Principal Investigators

REVIVE 9 _ 106 Jan 2006 - Dec 2007 H Eltchaninoff

REVIVAL 4 55 40 Dec 2005 - Feb 2008 W O’Neill, M Leon, C Smith

TRAVERCE 3 172 _ Feb 2007 – Apr 2008 T Walther, F Mohr, G Wimmer-Greinecker, E Wollner

PARTNER EU 9 69 61 Apr 2007- Jan 2008 T Lefèvre, G Wimmer-Greinecker

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Is there a relationship between the logistic

EuroSCORE and 1 year outcomes?

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Relationship between EuroSCORE and Survival

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Relationship between EuroSCORE and Survival

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TF and TAOutcomes in “lower risk” patients

SOURCE-TA SOURCE-TFI Yr Survival 78.4% 80.9%

Are we learning in terms of the who should and who should

not have TAVI?

A glimpse into COHORT 2 of the SOURCE Registry

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SOURCE COHORT 1

SOURCE COHORT 2

PREVAIL

SOURCE XT EU

SOURCE XT Global

2009 2010 2011

Nov 07

The SOURCE RegistryTimeline

Feb 09 Dec 09

N = 1301 (482 TF/819TA) from 38 centers

ALLCOHORT 1(n=1038)

ALLCOHORT 2(n=1301) P-Value

Age (yrs) 81.2 81.0 NS

Female 576/55.5% 767/59.0% 0.05Pulmonary Disease 286/27.6% 309/23.8% 0.03

Renal Dysfunction 305/29.4% 365/28.1% NS

Logistic EuroSCORE 1035/27.6 1297/25.4 0.006

Peripheral Vascular Disease 210/20.2% 255/19.6% NS

Carotid Artery Stenosis (>50%) 132/12.7% 150/11.5% NS

Incidence of CAD 537/51.7% 694/53.3% NS

Porcelain Aorta 86/8.3% 101/7.8% NS

Prior CABG 236/22.7% 262/20.1% NS

Mitral valve disease 257/24.8% 450/34.6% <0.0001

5/03/2010Data Snapshot32

Baseline Demographics and Risk Factors:All Cohort 1 vs. All Cohort 2

• 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.

• Univariant and multivariant analysis of the COHORT 1 dataset should allow work to start on the development of a TAVI risk score.

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Conclusions

• COHORT 1 outcomes provide a benchmark against which future TAVI cohorts may be measured.

• The lower risk profile of COHORT 2 patients may lead to further improvement in 1 year outcomes.

• 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.

Conclusions

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