University of Pennsylvania Success in “High-Risk / Inoperable” Patients is Enough for Submission to the FDA Howard C. Herrmann, MD University of Pennsylvania Philadelphia Disclosures Research Funding: Edwards Lifesciences Inc Discussion will include unapproved and off-label devices, procedures, and indications

FDA Requirements (www.fda.gov) Class III medical device (poses significant risk of illness or injury) Requires pre-market application (PMA) for approval Most stringent type of device marketing application The PMA must demonstrate: “sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s)”

PARTNER Trial 2.0: One Valve, Two delivery systems, TF & TA Eligibility Met For High Risk Symptomatic, Critical Calcific Aortic Stenosis Surgical (Cohort A); N=690 Medical Mgmt (Cohort B); N=350 Operable Assessment Yes No Femoral Access Evaluation Y/N Femoral Access Evaluation Y/N No Yes No Out of study Yes 1:1 Randomization 1:1 Randomization 1:1 Randomization Medical Mgmt Control AVR Control AVR Control Transfemoral TF vs Transapical TA vs Transfemoral TF vs Sub-group analyses: TA vs. control TF vs. control TF and TA vs. control (combined)

Questions That May Arise at Advisory Panel Will success in high-risk / inoperable patients be enough for submission to the FDA? Will safety and efficacy endpoints be met? Is high-risk and “inoperable” adequately defined in the trial? Is the goal worthwhile for patients? Are there concerns about indication creep to younger patients/low risk if approved? How will cost and reimbursement concerns enter into this equation? Will physicians accept this new therapy for patients if results are similar to surgery?

Smith CR, www.tctmd.org

Smith CR, www.tctmd.org

Smith CR, www.tctmd.org

Smith CR, www.tctmd.org

Smith CR, www.tctmd.org

362 patients with severe aortic stenosis not eligible for TAVI Results: 362 patients with severe aortic stenosis not eligible for TAVI 274 (75.7%) Medical /BAV arm 88 (24.3%) Surgical arm Ben Dor et al, CRT website, manuscript submitted

Baseline characteristics and clinical profile and operative risk Medical/BAV arm N=274 Surgical AVR N=88 P Age (years) 81.4±9.1 79.9±8.7 0.16 Female (%) 154(56.2) 40 (45.4) 0.11 STS score (%) 12.8±7.0 8.5±5.1 <0.001 Standard Euroscore 13.3±3.4 10.5±3.0 Logistic Euroscore 42.4±22.8 24.4±18.1 NYHA Class IV % 138(50.4) 18(20.4) Diabetes (%) 93(33.9) 32(36.3) 0.76 Hypertension (%) 222(81.1) 75(85.2) 0.37 CAD (%) 182(66.4) 56(63.6) 0.71 COPD (%) 86 (31.3) 16(18.1) 0.01 Renal failure (%) 118 (43.1) 26(29.5) 0.02 Prior CVA/TIA (%) 44 (16.0) 6(6.8) Arrhythmia (%) 109(39.7) 20(22.7) 0.003 PVD (%) 25(28.4) 0.38 Prior CABG (%) 96(35.0) 27(30.6) 0.45 Ben Dor et al, CRT website, manuscript submitted

Death (%) 102(37.2%) 19(21.5%) 0.001 Medical /BAV arm N=274 Surgical AVR N=88 P Death (%) 102(37.2%) 19(21.5%) 0.001 Duration of follow up (days) 377.5 [164-632.5] 386 [169-640.75] 0.01 Ben Dor et al, CRT website, manuscript submitted

1-year mortality 20-25% REVIVE and REVIVAL Pooled N=196 80.3% [74.0, 86.5] 73.8% [66.6, 81] 62.2% [48.6, 75.8] 95% confidence limits 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 6 12 18 24 Months past Procedure Freedom from Death Total at risk (n) 108 66 13 8 161 88.8% [83.9, 93.7] REVIVE and REVIVAL Pooled N=196 SOURCE COHORT I N=463 1-year mortality 20-25%

Questions That May Arise at Advisory Panel Will safety and efficacy endpoints be met? I believe that they will be in both arms of Partner Is high-risk and “inoperable” adequately defined in the trial? Yes. Study well conducted with conference calls, strict STS criteria Is the goal worthwhile for patients? Yes. Large # of untreated, surgery refusals Are there concerns about indication creep to younger patients/low risk if approved? Absolutely. Will be a challenge for physicians and hospitals How will cost and reimbursement concerns enter into this equation? I anticipate some limits on use to approved indications, rationing, probably by physicians Will physicians accept this new therapy for patients if results are similar to surgery? Patients will drive the choice Will success in high-risk / inoperable patients be enough for submission to the FDA? …Yes.