Types of AVR Examples of replacement aortic valves: a) shows an aortic homograft, b) and c) show a xenograft, d) shows a ball and cage valve, e) shows a tilting-disk valve, f) shows a bi-leaflet valve

Elderly Patients Pts >80years, operative mortality as high as 30%. Percutaneous aortic balloon valvuloplasty is an alternative to valve replacement introduced in ‘80s. Inflating one or more large balloons across the aortic valve from a percutaneous route, a modest decrease in gradient and improvement in symptoms

Balloon Valvuloplasty Follow-up has demonstrated a high rate of re-stenosis (>60% at 6 months and nearly 100% at 2 years), with no decrease in mortality rate after procedure Therefore, now only has a role in critically ill elderly pts who are not candidates for surgery or as a “bridge” in critically ill pts before AV replacement

Building on 50 Years of Proven Valve Expertise

Helping to Solve a Grave Problem Aortic stenosis is life threatening and progresses rapidly Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1 “Surgical intervention [for severe AS] should be performed promptly once even…minor symptoms occur”1 Latent Period (Increasing Obstruction, Myocardial Overload) Survival, % 100 80 60 40 20 50 70 Age, y Onset Severe Symptoms Angina Syncope Average Survival, y Failure 2 4 6

Addressing a Serious Unmet Need At least 40% of patients with severe aortic stenosis (AS) do not have an AVR2-8 1999 2006 2009 2005 2010 Patients, % Aortic Valve Replacement (AVR) No AVR 46 57 40 39 26 48 31 54 43 60 61 74 52 69 20 80 100 Bouma Pellikka Charlson Varadarajan Jan Bach Freed

Edwards SAPIEN Transcatheter Heart Valve With the RetroFlex 3 Transfemoral System For inoperable patients with severe symptomatic native aortic valve stenosis

Patient-Focused Multidisciplinary Heart Team Approach Multidisciplinary in all aspects: Patient selection Procedure planning Patient treatment Post-operative care

The PARTNER Trial Protocol Not in Study Assessment Transfemoral Access Yes No Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) TF TAVR (n = 179) Standard Therapy (Control) vs 1:1 Randomization (n = 492) TA (n = 207) Primary Endpoint: All-Cause Mortality (1 yr) (Non-inferiority) (n = 244) AVR (n = 248) (n = 104) (n = 103) Cohort A (n = 699) Cohort B (n = 358) 2 Cohorts Individually Powered (N = 1,057) TA, transapical; TF, transfemoral. Operability Severe Symptomatic Native Aortic Valve Stenosis

A Seminal Date in Cardiovascular Medicine September 22, 2010 on NEJM.org

Absolute Reduction in Mortality Continues to Diverge at 2 Years HR [95% CI] = 0.57 [0.44, 0.75] P (log rank) < .0001 Edwards SAPIEN THV Standard Therapy 20 40 60 80 100 ∆ at 1 yr = 20.0% NNT = 5.0 pts 67.6% 50.7% All-Cause Mortality, % 43.3% 30.7% ∆ at 2 yr = 24.3% NNT = 4.1 pts Months Numbers at Risk Edwards SAPIEN THV 179 138 124 110 83 Standard Therapy 121 85 67 51

Edwards SAPIEN THV Delivered QOL Benefits 60 40 20 80 100 4 6 8 10 12 2 Standard Therapy Edwards SAPIEN THV ∆ = 13.9 P < .001 ∆ = 24.5 P < .001 KCCQ Score (Mean) MCID = 5 points Months Improvement in quality of life MCID, minimum clinically important difference.

Peri-procedural Hazards At 30 days, TAVR resulted in more frequent strokes, major vascular complications, and bleeding events than standard therapy All strokes, 7.3% vs 1.7%, P = .02 Major vascular complications, 16.8% vs 1.1%, P < .0001 Bleeding events, 16.2% vs 2.2%, P < .0001

Sobering Perspective 5-Year Survival Survival, % * 23 4 12 30 28 3 † * 23 4 12 30 28 3 5 10 15 20 25 35 Breast Cancer Lung Cancer Colorectal Prostate Ovarian Severe Inoperable AS * National Institutes of Health. National Cancer Institute. Surveillance Epidemiology and End Results. Cancer Stat Fact Sheets.http://seer.cancer.gov/statfacts/. Accessed November 16, 2010. † Using constant hazard ratio. Data on file, Edwards Lifesciences LLC. Analysis courtesy of Murat Tuczu.

Advancing the Science of TAVR

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

Background (1) Transcatheter aortic valve replacement (TAVR) is the recommended treatment for “inoperable” patients with severe aortic stenosis (AS), based upon 1-year results of The PARTNER Trial which demonstrated reduced mortality and improved quality of life. However, whether clinical benefit and valve performance are sustained beyond one year is unknown and longer term outcomes will importantly alter clinical practice decisions. 17

Objectives To evaluate the clinical outcomes of TAVR compared to standard therapy at 2 years in “inoperable” aortic stenosis patients. To assess valve hemodynamics and durability using echocardiography. To perform subgroup analyses to better define the impact of co-morbidities on outcomes. 18

Inclusion Criteria Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cm2 (EOA index < 0.5 cm2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s. NYHA functional class II or greater. Risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons must exceed 50%. Surgeons must agree and attest that before PARTNER these patients would not have received AVR treatment! 19

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 20

Study Flow - Inoperable Cohort Randomized Inoperable n = 179 Standard therapy n = 179 TAVR 85/85 patients 100% followed at 1 Yr 124/124 patients 100% followed at 1 Yr Note: The follow-up compliance is with regard to protocol defined windows. At 2 and 3 years the start of the window is 45 days before the nominal time point. The death counts agree with the counts in the death tables, where crossover patients are followed past crossover. The followed counts are greater than the at risk numbers in the Kaplan-Meier plots, because this flow diagram is based on windows. In contrast, the KM at risk numbers reflect the exact time points. 56/56 patients 100% followed at 2 Yr 99/102 patients* 97.1% followed at 2 Yr 5 withdrawals in the first year in Standard Rx arm *3 patients followed outside of protocol window in TAVR group No patients were lost to follow-up 21

Patient Characteristics (1) TAVR n = 179 Standard Rx p value Age – yr 83.1 ± 8.6 83.2 ± 8.3 0.95 Male sex (%) 45.8 46.9 0.92 STS Score 11.2 ± 5.8 12.1 ± 6.1 0.14 NYHA I or II (%) III or IV (%) 7.8 92.2 6.1 93.9 0.68 CAD (%) 67.6 74.3 0.20 Prior MI (%) 18.6 26.4 0.10 Prior CABG (%) 37.4 45.6 0.17 Prior PCI (%) 30.5 24.8 0.31 Prior BAV (%) 16.2 24.4 0.09 CVD (%) 27.4 27.5 1.00

Patient Characteristics (2) TAVR n = 179 Standard Rx n = 179 p value PVD (%) 30.3 25.1 0.29 COPD Any (%) O2 dependent (%) 41.3 21.2 52.5 25.7 0.04 0.38 Creatinine > 2 mg/dL (%) 5.6 9.6 0.23 Atrial fibrillation (%) 32.9 48.8 Perm. pacemaker (%) 22.9 19.5 0.49 Pulmonary HTN (%) 42.4 43.8 0.90 Frailty (%) 18.1 28.0 0.09 Porcelain aorta (%) 19.0 11.2 0.05 Chest wall radiation (%) 8.9 8.4 1.00 Chest wall deformity (%) 5.0 Liver disease (%) 3.4

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% Numbers at Risk TAVR 179 138 124 110 83 Standard Rx 121 85 62 42 Months

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

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

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 Cerebrovascular Events (%) Note: Percents are of patients in the trial (n/179). ≤ 30 Days 31 Days – 1 Year 1 Year – 2 Years All CVA p = 0.010 p = 0.387 p = 0.028 Ischemic Stroke p = 0.017 p = 0.155 p = 0.083 Hemorrhagic Stroke p = 0.316 p = 0.121 p = 0.415

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

Clinical Outcomes 1 Year and 2 Year (ITT) TAVR Standard Rx P value  2 Year n = 179 TAVR Standard Rx P value Myocardial infarction All, % (n) 0.8 (1) 0.7 (1) 0.906 1.6 (2) 2.5 (2) 0.694 Acute kidney injury Creatinine > 3 mg/dL, % (n) 1.1 (2) 2.8 (5) 0.449 Renal failure (CEC), % (n) 2.3 (4) 4.7 (7) 0.257 3.2 (5) 7.6 (9) 0.149 Bleeding – major, % (n) 24.2 (42) 14.9 (21) 0.038 28.9 (48) 20.1 (25) 0.093 Start with MI Check reTAVR Is this censored or ITT Cardiac re-intervention BAV, % (n) 1.1 (2) 82.3 (138) <.0001 2.8 (4) 85.3 (140) Re-TAVR, % (n) 1.7* (3) NA - AVR, % (n) 0 (0) 7.6 (10) 0.002 0.9 (1) 8.9 (11) 0.005 Endocarditis, % (n) 1.4 (2) 0.8 (1) 0.618 2.3 (3) 0.316 New pacemaker, % (n) 4.7 (8) 8.6 (14) 0.149 6.4 (10) 0.469 34

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 35

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). 38

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. 39

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. 40

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. 41

QUESTIONS?