Raj R. Makkar, MD On behalf of The PARTNER Trial Investigators Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in “Inoperable” Patients With Severe Aortic Stenosis: The PARTNER Trial Raj R. Makkar, MD On behalf of The PARTNER Trial Investigators TCT 2011 | San Francisco, CA | November 10, 2011

Disclosures Raj R. Makkar is a principal site investigator for The PARTNER Trial (US) for Edwards Lifesciences and is national principal investigator for the St Jude TAVR study. He has received consulting fees, grant support and lecture fees from Medtronic, equity from Entourage Medical Technologies and grant support from St Jude Medical.

Transcatheter Aortic Valve Replacement (TAVR) is the standard of care for inoperable patients with severe aortic stenosis (AS), demonstrating 1-year outcomes of the PARTNER Trial, offering reduced mortality and improved quality of life. Published October 2010 4

Key End-Points for 2 Year Analysis All cause mortality Cardiac mortality Rehospitalization Stroke NYHA functional class Days alive and out of hospital Echo-derived valve areas, transvalvular gradients, paravalvular aortic regurgitation Mortality outcomes stratified by STS score 8

All Cause Mortality (ITT) Crossover Patients Followed HR [95% CI] = 0.57 [0.44, 0.75] p (log rank) < 0.0001 Standard Rx TAVR ∆ at 2 yr = 24.3% NNT = 4.1 pts 67.6% 43.3% ∆ at 1 yr = 20.0% NNT = 5.0 pts 50.7% All Cause Mortality (%) 30.7% Point-in-time at 2 yrs: p < 0.0001 Months Numbers at Risk TAVR 179 138 124 110 83 Standard Rx 121 85 67 51

All Cause Mortality (ITT) Landmark Analysis Standard Rx TAVR Mortality 0-1 yr Mortality 1-2yr HR [95% CI] = 0.57 [0.44, 0.75] p (log rank) < 0.0001 HR [95% CI] = 0.58 [0.37, 0.92] p (log rank) = 0.0194 50.7% All Cause Mortality (%) 35.1% 30.7% 18.2% Months Numbers at Risk TAVR 179 138 124 110 83 Standard Rx 121 85 62 42

Cardiovascular Mortality (ITT) Crossover Patients Censored Standard Rx HR [95% CI] = 0.44 [0.32, 0.60] p (log rank) < 0.0001 TAVR ∆ at 2 yr = 31.4% NNT = 3.2 pts 62.4% 31.0% ∆ at 1 yr = 24.1% NNT = 4.1 pts 44.6% Cardiovascular Mortality (%) 20.5% Point-in-time at 2 yrs: p < 0.0001 Months Numbers at Risk TAVR 179 138 124 110 83 Standard Rx 121 85 62 42

Repeat Hospitalization (ITT) Standard Rx HR [95% CI] = 0.41 [0.30, 0.58] p (log rank) < 0.0001 TAVR ∆ at 2 yr = 37.5% NNT = 2.7 pts 72.5% 35.0% ∆ at 1 yr = 26.9% NNT = 3.7 pts 53.9% Repeat Hospitalization (%) 27.0% Point-in-time at 2 yrs: p < 0.0001 Months Numbers at Risk TAVR 179 115 100 89 64 Standard Rx 86 49 30 17

Hospitalization Through 2 Years TAVR Standard Tx p value Repeat Hospitalizations (No.) 78 151 <.0001 Repeat Hospitalizations (%) 35.0% 72.5% Days Alive Out of Hospital Median [IQR] 699 [201-720] 355 [116-712] .0003 This endpoint captures the total hospital days from the index procedure or randomization to one year post-procedure or randomization. An analysis of DAOH allows for an assessment of two important objectives of the device therapy- improvement in mortality and quality of life.

NYHA Class Over Time Survivors p = 0.61 p < 0.0001 p < 0.0001 16.9% 23.7% 57.5% 60.8% Percent 92.2% 93.9% Treatment Visit Baseline 1 Year 2 Year

All Stroke (ITT) HR [95% CI] = 2.79 [1.25, 6.22] p (log rank) = 0.009 Standard Rx HR [95% CI] = 2.79 [1.25, 6.22] p (log rank) = 0.009 TAVR Incidence (%) ∆ at 1 yr = 5.7% ∆ at 2 yr = 8.3% 5.5% 13.8% 11.2% 5.5% Point-in-time at 2 yrs: p = 0.0137 Months Numbers at Risk TAVR 179 128 116 105 79 Standard Rx 118 84 62 42

All Strokes (# pts) Events ≤ 30 Days 31 Days – 2 Years All stroke Ischemic Stroke p = 0.017 p = 0.437 Hemorrhagic Stroke p = 0.316 p = 0.160

Days post randomization Stroke - Hemorrhagic ITT arm Age Days post randomization Description Trauma Medication Procedure related* Device related* TAVR 91 9 Right sided hemorrhage No Coumadin on admission Yes 84 53 Traumatic subarachnoid Fall Coumadin 85 54 Intraparenchy-mal and subdural Not stated 124 Intracranial 88 155 Subdural hematoma DAPT Standard therapy (BAV) 243 "Massive cerebral hemorrhage" n/a *CEC adjudicated

Mortality or Stroke (ITT) Standard Rx HR [95% CI] = 0.64 [0.49, 0.84] p (log rank) = 0.0009 TAVR ∆ at 2 yr = 21.9% NNT = 4.6 pts 68.0% 46.1% ∆ at 1 yr = 16.1% NNT = 6.2 pts 51.3% All Cause Mortality or Stroke (%) 35.2% Months Numbers at Risk TAVR 179 128 116 105 79 Standard Rx 118 84 62 42

Mean Gradient & Valve Area EOA Mean Gradient Mean Gradient (mm Hg) AVA (cm²) N = 158 N = 162 N = 137 N = 143 N = 84 N = 89 N = 65 N = 9 Error bars = ± 1 Std Dev 30

Mortality Stratified by Paravalvular Leak (ITT) Starting at Discharge Moderate or Severe None to Mild p (log rank) = 0.891 Death Incidence (%) 41.2% 40.5% 35.3% 27.2% Determination of first PV Leak starts with the discharge echo Months Numbers at Risk None to Mild 147 118 107 95 72 Moderate or Severe 17 12 11 10 8

Mortality Stratified by STS Score (ITT) Standard Rx TAVR p value (log rank) = 0.676 p value (log rank) = 0.012 Death Incidence (%) Months Numbers at Risk Months 12 8 7 6 5 119 84 59 42 29 47 19 14 28 26 25 24 16 108 80 76 67 52 43 32 23 19 15

Conclusions (1) At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery… TAVR remained superior to standard therapy with incremental benefit from 1 to 2 years, markedly reducing the rates of… All cause mortality Cardiovascular mortality Repeat hospitalization TAVR improved NYHA functional status and decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001). 34

Conclusions (2) At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery… There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients. After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR patients. A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is in patients without extreme clinical co-morbidities. 35

Conclusions (3) At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery… TAVR hemodynamics by echo showed durable improvements in AVA and mean gradients up to 3 years after implantation. Moderate or severe paravalvular AR in the TAVR patients did not influence 2-year survival and there was a trend towards reduced paravalvular AR between 1 and 2 years. 36

Clinical Implications Two year data continues to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates. The ultimate value of TAVR in “inoperable” patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR and render the intervention futile. 37

Thank You to the Dedicated Study Teams at All PARTNER Investigational Sites 38

BACKUP SLIDES

All Cause Mortality (ITT) HR [95% CI] = 0.57 [0.44, 0.75] p (log rank) < 0.0001 Standard Rx TAVR ∆ at 1 yr = 20.0% NNT = 5.0 pts ∆ at 2 yr = 24.7% NNT = 4.0 pts 68.0% 43.3% 50.7% All Cause Mortality (%) 30.7% Months Numbers at Risk TAVR 179 138 124 110 83 47 14 Standard Rx 121 85 62 42 19 5

All Cause Mortality (ITT) Cumulative Hazard Standard Rx TAVR 1.14 0.57 Cumulative Hazard 0.71 0.37 Months

Cardiovascular Mortality (ITT) Landmark Analysis Standard Rx TAVR Cardiovascular Mortality 0-1 yr Cardiovascular Mortality 1-2 yr HR [95% CI] = 0.44 [0.32, 0.60] p (log rank) < 0.0001 HR [95% CI] = 0.48 [0.29, 0.81] p (log rank) = 0.0043 Cardiovascular Mortality (%) 44.6% 32.1% 20.5% 13.2% Months Numbers at Risk TAVR 179 138 124 110 83 Standard Rx 121 85 62 42

All Cause Mortality (ITT) Entire Cohort vs STS Score <5 Standard Rx TAVR Entire Cohort STS <5 Death Incidence (%) Months Months Numbers at Risk 179 138 124 110 83 47 14 121 85 62 42 19 5 28 26 25 24 16 11 2 12 8 7 6 5 3

Mortality Stratified by STS Score (ITT) Standard Rx TAVR STS <5 STS 5-14.9 STS ≥15 Death Incidence (%) Months Months Months Numbers at Risk 28 26 25 24 16 12 8 7 6 5 108 80 76 67 52 119 84 59 42 29 43 32 23 19 15 47 29 14 8

Mortality Stratified by STS Score (ITT) STS <15 vs STS ≥15 (out to 36 months) Standard Rx TAVR STS <15 STS ≥15 Death Incidence (%) Months Months Numbers at Risk 136 106 101 91 68 35 8 131 92 66 48 34 14 4 43 32 23 19 15 12 6 47 29 14 8 5 1

Proportional Hazards Analysis of Predictors of Death Predictor Variable Non-missing observations Log hazard ratio P value Hazard ratio Lower confidence limit Upper confidence limit Body Mass Index (lbs/in²) 179 -0.0489 0.0061 0.952 0.920 0.986 STS Risk Score 0.0424 0.0125 1.043 1.009 1.079 CV Conditions: Stroke or TIA within last 6-12 months 1.1563 0.0128 3.178 1.279 7.901 CV Conditions: Arrhythmia 0.4236 0.0447 1.527 1.010 2.310 CV Conditions: Peripheral vascular disease 178 0.4050 0.0586 1.499 0.985 2.281 High Risk – Oxygen dependent COPD 0.3709 0.1232 1.449 0.904 2.322 Mean Gradient -- Baseline 170 -0.0108 0.1713 0.989 0.974 1.005 CV Surgery: CABG -0.2927 0.2006 0.746 0.477 1.168 Non-CV Conditions: Liver disease 0.5803 0.2087 1.787 0.723 4.415 CV Surgery: PCI -0.3039 0.2207 0.738 0.454 1.200 NYHA Class 0.2010 0.2377 1.223 0.876 1.707 Moderate or Severe Mitral Regurgitation -- Baseline 171 -0.3166 0.2530 0.729 0.423 1.254 CV Surgery: Pacemaker implant 0.2759 0.2670 1.318 0.810 2.145 CV Surgery: Carotid endarterectomy / Carotid stent -0.4219 0.2831 0.656 0.303 1.417 CHAD Stroke Risk Score (ignoring fibrillation) 0.1156 0.3578 1.123 0.877 1.436 CV Surgery: Prior aortic valvuloplasty -0.2697 0.4040 0.764 0.405 1.439 High Risk – Porcelain Aorta -0.2248 0.4138 0.799 0.466 1.369 Aortic Valve Area -- Baseline 166 -0.4680 0.4334 0.626 0.194 2.020 High Risk – Radiation -0.2441 0.5347 0.783 0.362 1.693 High Risk – Pulmonary Hypertension 118 0.1332 0.6035 1.142 0.691 1.889 Aortic Valve Baseline: AV Annulus Diameter (cm) 150 -0.2411 0.6354 0.786 0.290 2.129 CV Surgery: Peripheral bypass graft -0.4089 0.6843 0.664 0.093 4.770 Other vascular stent of PTA (arterial) 0.2369 0.6873 1.267 0.400 4.017 Logistic EuroSCORE 0.0022 0.7072 1.002 0.991 1.014 CV Conditions: Coronary artery Disease -0.0826 0.7074 0.921 0.598 Ejection Fraction -- Baseline 172 -0.0030 0.7102 0.997 0.981 1.013 CV Conditions: Previous Q wave or non-Q wave MI 177 -0.0935 0.7281 0.911 0.538 1.543 CV Risk Factors: Diabetes Mellitus 0.0758 0.7307 0.701 1.660 Age at Screening (years) 0.0033 0.7851 1.003 0.980 1.027 Patient has Coronary Artery Stenosis> 50%? 0.0530 0.7990 1.054 1.586 CV Risk Factors: Pulmonary Hypertension -0.0429 0.8383 0.958 0.635 1.446 Atrial Fibrillation -- per ecg corelab 156 0.0479 0.8606 1.049 0.615 1.791 High Risk – Renal Failure 116 -0.0737 0.8872 0.929 0.336 2.570 Gender 0.0229 0.9124 1.023 0.681 1.538 Baseline Creatinine 0.0198 0.9328 1.020 0.644 1.616 CV Conditions: Cerebrovascular disease 175 0.0075 0.9740 1.008 0.642 1.582

95% Upper Confidence Limit 95% Lower Confidence Limit Proportional Hazard Analysis of Predictors of Death Multivariable Analysis Label Parameter Estimate p Hazard Ratio 95% Upper Confidence Limit 95% Lower Confidence Limit Body Mass Index (lbs/in²) -0.05032 0.0050 0.951 0.985 0.918 Stroke or TIA within last 6-12 months 1.09824 0.0194 2.999 7.530 1.194 High Risk - Oxygen dependent COPD 0.52611 0.0310 1.692 2.730 1.049

All Cause Mortality vs BAV TAVR Standard Rx: BAV Standard Rx: No BAV Death Incidence (%) Months Numbers at Risk TAVR 179 138 124 110 83 47 14 Standard Rx: BAV 142 105 74 54 37 18 5 Standard RX: No BAV 39 13 10 7 2 1

All Stroke Plus TIA (ITT) Standard Rx HR [95% CI] = 3.1 [1.41, 6.83] p (log rank) = 0.003 Point-in-Time at 2 Yrs: p = 0.0029 TAVR Incidence (%) ∆ at 1 yr = 6.4% NNT = 15.6 pts ∆ at 2 yr = 10.7% NNT = 9.3 pts 5.5% 16.2% 11.9% 5.5% Months Numbers at Risk TAVR 179 127 115 103 76 Standard Rx 118 84 62 42

Mortality Stratified by Stroke (ITT) TAVR (stroke) TAVR (no stroke) Standard Rx (stroke) Standard Rx (no stroke) Death Incidence (%) Months Numbers at Risk TAVR (stroke) 25 16 14 10 7 Standard Rx (stroke) 8 4 1 TAVR (no stroke) 154 122 110 100 76 Standard Rx (no stroke) 171 117 84 62 42

Paravalvular Regurgitation: TAVR Slight Changes Over Time None/Trace Moderate Mild Severe

Cardiovascular Mortality Stratified by First PV Leak (ITT) Starting at Discharge Moderate or Severe Determination of first PV Leak starts with the discharge echo None to Mild p (log rank) = 0.381 ∆ at 1 yr = 14.4% NNT = 6.9 pts Death Incidence (%) ∆ at 2 yr = 9.7% NNT = 10.3 pts 36.7% 27.0% 30.3% 15.9% Months Numbers at Risk None to Mild 147 118 107 95 72 Moderate or Severe 17 12 11 10 8

Echocardiography Baseline TAVR n = 179 Standard Rx n = 179 p value Aortic valve area (cm2) 0.6 ± 0.2 0.7 ± 0.2 0.6077 Mean AV gradient (mm Hg) 44.2 ± 14.9 43.0 ± 15.1 0.4608 Mean LVEF (%) 53.7 ± 13.1 51.3 ± 14.2 0.1135 1 Year Aortic valve area (cm2) 1.6 ± 0.5 0.7 ± 0.3 <0.0001 Mean AV gradient (mm Hg) 10.9 ± 5.5 44.4 ± 15.7 Mean LVEF (%) 57.3 ± 9.9 57.1 ± 10.2 0.8924 2 Year Aortic valve area (cm2) 1.6 ± 0.5 0.7 ± 0.2 <0.0001 Mean AV gradient (mm Hg) 10.6 ± 4.4 41.9 ± 20.7 Mean LVEF (%) 57.3 ± 8.2 56.3 ± 11.1 0.6387

Cross-Over Patients n = 20 Mean Std Dev. Min Max Days from ITT to cross-over 699.5 166.5 462.0 979.0 Days from cross-over start to cross-over 73.9 72.6 248.0 Days from 1 year visit to 334.2 164.8 117.0 595.0 Cross-Over approved: May 28, 2010

Patients Status Did Not Cross-Over Frequency Percent Died after cross-over process started* 12 7.55 Died before cross-over process started 116 72.96 No cross-over – still alive 23 14.47 Withdrew after cross-over process started 3 1.89 Withdrew before cross-over process started 5 3.14 - 121 pts who could not have crossed over - 116 died before - 5 withdrew (same as from 1 year) - 38 who could have crossed over who didn’t (out of 58 pts). Of those, 23 never crossed over. *Days from cross-over start to death N Mean Std Dev Minimum Maximum 12 200.3 120.5 30.0 388.0 121 patients could not cross over (116 died, 5 withdrawn) 38/58 (65%) who could have crossed over did not of which 23 (39.6%) are alive

Patient Status After Cross-Over Frequency Percent Alive – no implant due to access issues 2 10 Alive after implant 16 80 Died after implant Mean follow-up as of analysis date = 197 days