Transcatheter Aortic Valve Therapies Mark Russo Assistant Professor of Surgery Co-Director, Center for Aortic Diseases

SUMMARY POINTS This is NOT experimental therapy 45,000 implants worldwide In Germany, 20-25% of isolated AVRs are TAVI Indications Symptomatic, severe AS deemed inoperable Shown to be clinically effective in a well-selected patients RCT demonstrated an absolute 20% survival benefit 40%+ of OMM pts are dead at 6 months

ADVANCES IN THE RX OF STRUCTURAL HEART DISEASE 1951 - Cardiopulmonary Bypass 1977- Percutaneous Coronary Intervention 2011 - Transcatheter Valves

CHANGING TREATMENT PARADIGM Treatment options: Significant unmet need Delivery of care: “Heart team” concept Tools available: Catalyze other percutaneous technologies for treatment of structure heart disease

The Problem of Aortic Stenosis

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 1 Lester SJ, Heilbron B, Gin K, Dodek A, Jue J. The natural history and rate of progression of aortic stenosis. Chest. 1998;113:1109-1114. 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

THE BURDEN OF AORTIC STENOSIS In the US: AS: 1,500,000 Severe AS: 500,000 Severe, symptomatic AS: 250,000 AVRs performed annually: 85,000 >150,000 untreated AS patients

Addressing a Serious Unmet Need At least 43-74% of patients with severe aortic stenosis (AS) do not have an AVR 1999 2006 2009 2005 2010 Patients, % Aortic Valve Replacement (AVR) No AVR

Dismal Outcomes with Severe Inoperable AS 5-Year Survival Survival, % * * * * * † * 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.

Dismal Outcomes with Severe Inoperable AS The predicted survival of inoperable patients with severe AS who are treated with standard non-surgical therapy is lower than with certain metastatic cancers. 5-Year Survival Survival, % * * * * * † * 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.

Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1 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 Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1 1 Lester SJ, Heilbron B, Gin K, Dodek A, Jue J. The natural history and rate of progression of aortic stenosis. Chest. 1998;113:1109-1114.

TAVI for Who? What is the Data to Support Use?

INDICATIONS Severe Symptomatic AS Inoperable – determined by a surgeon Aortic Velocity > 40 m/sec Mean Gradient > 4 mmHg Valve Area < 1.0 cm2 Inoperable – determined by a surgeon Mortality > 15% Death or serious, irreversible morbidity > 50% STS score > 8-10

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

PARTNER COHORT B Source: NEJM, 2001

PARTNER COHORT B Mean Age: early 80s Mean STS Score: 11 Mean EuroScore: 12 NYSA III/IV - 90% s/p CABG - 40% COPD - 45% O2 - 20% PHTN - 40% Radiation - 10% Porcelain Aorta Source: NEJM, 2001

PARTNER TRIAL – COHORT B 20% Reduction in Mortality ∆ at 1 yr = 20.0% NNT = 5.0 pts 20 40 60 80 100 Edwards SAPIEN THV Standard Therapy All-Cause Mortality, % 50.7% HR [95% CI] = 0.51 [0.38, 0.68] P (log rank) < .0001 30.7% Months Numbers at Risk Edwards SAPIEN THV 179 138 124 103 60 Standard Therapy 121 85 56 24 Source: NEJM, 2001

PARTNER TRIAL – COHORT B 20% Reduction in Mortality ∆ at 1 yr = 20.0% NNT = 5.0 pts 20 40 60 80 100 Edwards SAPIEN THV Standard Therapy All-Cause Mortality, % 50.7% 20% absolute reduction in mortality at 1 year HR [95% CI] = 0.51 [0.38, 0.68] P (log rank) < .0001 30.7% Months Numbers at Risk Edwards SAPIEN THV 179 138 124 103 60 Standard Therapy 121 85 56 24 Source: NEJM, 2001

Paravalvular Leaks Over Time

PARTNER TRIAL – COHORT B Source: NEJM, 2001 NEJM, 2011

PARTNER TRIAL– COHORT B Quality of Life 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, minimum clinically important difference. MCID = 5 points Months Improvement in quality of life

CONCLUSIONS – PARTNER B Standard therapy (including BAV in 83.8% of pts) did not alter the dismal natural history of AS; all-cause and cardiovascular mortality at 1 year was 50.7% and 44.6% respectively Transfemoral balloon-expandable TAVI, despite limited operator experience and an early version of the system, was associated with acceptable 30-day survival (5% after randomization in the intention-to-treat population)

Inoperability Operative mortality > 15% Operative severe morbidity or death > 50% STS score > 8 Previous cardiac surgery – multiple, s/p CABG Home O2 PHTN Radiation Porcelain Aorta Frailty

Fried Frailty Index Fried Phenotype of Frailty Weight Loss (unintentional) > 10 lb in previous year Grip strength Lowest 20% by sex/BMI Exhaustion Self-report (CES-D depression scale) Walk time, 15 feet Lowest 20% by sex/height Low activity Males < 383 kcal/week Females < 270 kcal/week Frailty: ≥ 3 criteria Intermediate/prefrail: 1 or 2 criteria Fried LP, et al. J Gerontol A Biol Sci Med Sci. 2001;56:M146-M156. 25

Approaches

Approaches Transfemoral Illiac Conduit Transapical Subclavian Transaortic

TAVI - Transfemoral

TAVI - Transapical Anterior Thoracotomy

TAVI - Transapical Source: theheart.org

TAVI – LEFT SUBCLAVIAN APPROACH

TAVI-Transaortic