ONE-YEAR OUTCOMES OLAF WENDLER, MD PHD FRCS ON BEHALF OF THE SOURCE 3 INVESTIGATORS

Potential Conflicts of Interest Speaker's name: Olaf Wendler I have the following potential conflicts of interest to report: Consultant to Edwards Lifesciences

Design and Execution Patients 1946 Enrollment July 2014 – Oct 2015 Centres 80 Countries 10 Access Routes TF, TA, TAo, SC, TC THV SAPIEN 3™ 23mm, 26mm, 29mm Clinical Endpoint Adjudication Independent CEC, VARC 2 Definitions Follow-up 30 Days, Annually to 5 Years

Study Administration Principal Investigators Olaf Wendler, MD King’s College Hospital, London, UK Alec Vahanian, MD Hôpital Bichat, Paris, France Clinical Events Committee Chairman: Philip Urban, MD Hôpital de La Tour, Meyrin, Switzerland Echo Sub-study Core Laboratory José Luis Zamorano, MD University Hospital Ramon y Cajal, Madrid, Spain Steering Committee Helmut Baumgartner, MD University Clinics, Muenster, Germany Nicolas Dumonteil, MD Clinique Pasteur, Toulouse, France Franz-Josef Neumann, MD University Heart Center, Bad Krozingen, Germany Gerhard Schymik, MD Municipal Hospital, Karlsruhe, Germany Giuseppe Tarantini, MD Policlinico Universitario, Padova, Italy Hendrik Treede, MD University Clinics, Halle, Germany

Top 30 Enrolling Centers SITE PATIENTS Municipal Hospital, Karlsruhe, Germany 133 King’s Health Partners, London, UK 107 Kerckhoff Clinic, Bad Nauheim, Germany 99 German Heart Center, Munich, Germany 92 Heart Center, Bad Segeberg, Germany 66 University Clinics (UKE), Hamburg, Germany 61 Institut Jacques Cartier, Massy, France 60 University Hospital, Angers, France 52 University Hospital, Kiel, Germany Aarhus University Hospital, Skejby, Denmark 49 Asklepios Clinic, Hamburg, Germany 48 Charles Nicolle Hospital, Rouen, France University Hospital La Timone, Marseille, France 40 Institut Mutualiste Montsouris, Paris, France University Hospital, Strasbourg, France 38 SITE PATIENTS University Hospital La Cavalle Blanche – Brest, France 37 Centre Cardiologique du Nord Saint-Denis, France 36 University Clinics, Ulm, Germany 35 University Hospital, Clermont-Ferrand, France 34 University Hospital Laennec, Nantes, France University Hospital, Bern, Switzerland 33 University Clinics, Muenster, Germany Herzzentrum Brandenburg, Bernau, Germany Helios Clinics, Siegburg, Germany 32 University Hospital, Lille, France 30 University Medical Center, Utrecht, The Netherlands Hôpital Bichat, Paris, France 29 DHZ Bad Oeynhausen, Germany Hospital Clinics, Augsburg, Germany 28 University Hospital Rangueil, Toulouse, France 27

Baseline Characteristics Total N=1946 TF N=1694 Non-TF N=251 p-value Age (years ±SD) 81.6 ±6.7 81.7 ±6.7 80.8 ±6.4 0.025 Female (%) 48 49.2 39.7 0.006 BMI (mean ±SD) 27.0 ±5.0 27.0 ±5.1 26.82 ±4.6 0.75 Chronic Lung Disease (%) 11.9 11 17.9 0.003 Renal Insufficiency (%) 27.5 26.9 31.7 0.11 Log EuroSCORE (med) 14.42 13.96 17.83 <0.001 <10 (%) 29.0 30.6 18.5 >30 (%) 15.8 14.5 24.6 (Wendler et al. Circulation 2017)

Cardiovascular Characteristics Total N=1946 TF N=1694 Non-TF N=251 p-value LVEF <30% (%) 6.0 6.3 4.2 0.28 Congestive Heart Failure (%) 36.3 34.8 46.8 <0.001 Prior CABG (%) 11.4 9.4 24.6 Prior PCI (%) 33.8 32.7 41.7 0.005 Porcelain Aorta (%) 4.8 3.5 13.5 Prior Stroke (%) 8.4 7.8 12.7 0.014 Carotid Artery Disease (%) 15.4 13.9 25.4 Peripheral Vascular Disease (%) 15.2 11.9 37.3

Procedural Information Total N=1946 TF Approach (%) 87.1 Percutaneous/Closure Device (%) 93.0 Conscious Sedation (%) 53.0 No Pre-BAV (%) 50.5 Correct Placement at Intended Site (%) 98.8 Post-Dilation (%) 10.7 Procedure Time (min) 72.8 Fluoroscopy Time (min) 13.9 Contrast Volume (ml) 120.9

Survival – Approach (AT Population) 100 88.2% 90 87.4% 80 81.5% 70 60 TF All Non-TF 50 3 6 9 12 Months from Procedure Survival (%) Number at Risk: All TF Non-TF 1946 1903 1866 1853 1824 1804 1779 1754 1736 1722 1691 1649 1436 1694 1661 1628 1617 1594 1579 1561 1541 1528 1517 1489 1455 1262 252 242 238 236 230 225 218 213 208 205 202 194 174

Survival – Baseline EuroSCORE (AT Population) 100 89.7% 90 87.4% 80 80.4% 70 60 All <10 >30 50 3 6 9 12 Months from Procedure Survival (%) Number at Risk: All 1946 1903 1866 1853 1824 1804 1779 1754 1736 1722 1691 1649 1436 Log ES<10 518 509 500 497 490 486 479 472 469 465 459 446 380 Log ES>30 282 266 260 259 253 246 240 236 235 231 227 223 205

1-Year Clinical Outcomes (CEC adjudicated) Total N=1946 TF N=1694 Non-TF N=251 Mortality (%) 12.6 11.8 18.5 Cardiovascular Mortality (%) 8.0 7.5 11.3 All Stroke (%) 3.1 2.7 5.6 Disabling Stroke (%) 1.4 1.1 3.6 New Onset AF (%) 7.9 7.1 13.3 New Permanent Pacemaker (%) 13.2 13.6 10.4 Endocarditis (%) 1.3 1.2 Clinical Valve Thrombosis (%) 0.4 0.3 0.8 Rehospitalisation* (%) 8.1 8.7 *Rehospitalisations for valve related symptoms or worsening congestive heart failure.

NYHA Classification Total§ TF§ Non-TF§ 100 Class IV Class III Class II Class I 90 80 70 60 50 40 30 20 10 % of Population Baseline 30-Days One-Year Baseline 30-Days One-Year Baseline §p-value <0.001: Baseline vs. 30-Days and 1-Year 30-Days One-Year

Haemodynamics 50 2 44.1±16 1.6±0.5 1.7±1.4 Mean Ao Gradient (mmHg) 40 1,6 30 1,2 EOA (cm2) 20 0,8 0.7±0.2 10 12.3±5.1 0,4 11.8±5.1 Mean Ao Gradient EOA Mean AVG Baseline 30-Days One-Year *AT Population; All Values are CEC adjudicated

Paravalvular Regurgitation Total§ TF§ Non-TF¶ Severe Paired Analyses p-values between discharge and one-year are § p-value<0.001 and ¶p-value=0.19

Causes of Mortality (n=245/1946, 12.6%) Cardiovascular (n=152, 62%) 30 Days % (n) Vascular Injury 18.8 (6) Heart Failure 9.4 (3) Cardiogenic Shock Cardiac Tamponade 6.3 (2) Fatal Bleeding 31 Days-1 Year 25.0 (30) Sudden Cardiac Death 11.7 (14) Endocarditis 10.0 (12) Stroke 7.5 (9) Multi-System Organ Failure 3.3 (4) Non-Cardiovascular (n= 93, 38%) 30 Days % (n) Sepsis 33.3 (4) Pulmonary Malignancy 16.7 (2) Multi-system Organ Failure 8.3 (1) 31 Days-1 Year 29.6 (24) 23.5 (19) 12.3 (10) Cachexia 11.1 (9) Multi-System Organ Failure 6.2 (5) *VARC 2 definition

Univariate Predictors 1-Year Mortality Variable HR* p-value Tricuspid Regurgitation Mod-Severe 2.19 <0.001 NYHA IV 2.37 0.109 Renal Insufficiency 2.04 Atrial Fibrillation 1.77 Log EuroSCORE 1.02 Mean Aortic Valve Gradient 0.98 Body Mass Index 0.97 0.021 Procedure Time (Skin-Skin) 1.00 0.150 Transfemoral Access 0.61 0.003 Acute Kidney Injury (≤7d) 3.13 Major Vascular Complications (≤30d) 2.59 ICU Length of Stay 1.07 Days from Implant to Discharge 1.04 Baseline Peri-Procedural *HR: Hazard Ratio; All variables with p-value < 0.2 were included in the multivariable analyses

Multivariable Predictors 1-Year Mortality HR [CI]* p-value Baseline Baseline NYHA IV 2.53 [1.25, 5.12] 0.010 Renal Insufficiency 1.30 [1.06, 1.59] Body Mass Index 0.98 [0.96, 1.00] 0.027 Peri-Procedural Procedure Time (Skin-Skin) 1.01 [1.00, 1.01] <0.001 Acute Kidney Injury (≤7d) 1.93 [1.32, 2.83] ICU Length of Stay (d) 1.05 [1.04, 1.06] *HR: Hazard Ratio; All variables with p-value < 0.2 were included in the multivariable analyses;

SOURCE Registries (n=6953) 1-Year Mortality 40 SOURCE (2007-2009) SOURCE XT (2010-2011) SOURCE 3 (2014-2015) All-Cause Mortality (%) 30 23.8% 20 19.4% 10 12.6% 3 6 Time in Months 9 12 Number at Risk: SOURCE SOURCE XT SOURCE 3 2319 2688 1946 1941 2406 1853 1848 2294 1779 1794 2227 1721 1724 2135 1455

SAPIEN 3 Global Experience 1-Year Mortality 40 PII S3HR SOURCE 3 30 All-Cause Mortality (%) 20 14.8% 10 12.6% 3 6 Time in Months 9 12 Number at Risk: PII S3HR 671 SOURCE 3 1946 635 1853 601 1779 578 1721 557 1455

Conclusions The low peri-procedural complication rate at 30 days reported in SOURCE 3 has resulted in excellent survival at 1-year. After 1-year more than 90% of patients are in NYHA I/II. No severe PVL has been observed and the rate of moderate PVL is low (2.6%). NYHA IV and renal insufficiency are the strongest baseline characteristics to predict 1-year mortality in the multivariable analysis. These European results from the largest reported registry with SAPIEN 3 are consistent with 1-year outcomes observed in North American trials.

Implications The clinical outcomes of SOURCE 3 highlight the improvements of TAVI treatment in general and the SAPIEN 3 THV in particular. The similarities of 30-day and 1-year outcomes of the global experience may indicate that the present balloon- expandable technology has become less dependent of operator variability. SOURCE 3 provides further evidence on TAVI, however, longer follow-up is vital before TAVI is rolled out to low risk patients.

Fast Track Publication Accepted for Fast Track Publication