Latest Data from Balloon Expendable Trials E. Murat Tuzcu, MD

Disclosures: No conflict of interest E. Murat Tuzcu, MD

First Randomized Trial in Intermediate Risk Patients SAPIEN XT was randomized to surgery S3i enrolled using the same exact protocol Pre-specified S3i comparison to surgery utilizing propensity score analysis PII A was a randomized trial of SAVR v Sapien XT in Intermediate Risk patients. The S3 valve became available after enrollment was complete but before the 2 year Primary Endpoint of PII A (as dictated by the FDA). PII S3i is a single arm study within P2A using the S3 valve in intermediate risk patients. Entry criteria for patients in the randomized trial and the registry were virtually identical. Outcomes of S3i were compared to the SAVR patients in PII A at 1 year using Propensity Scoring Methodology as agreed with the FDA

All-Cause Mortality or Disabling Stroke (%) PARTNER 2 Trial – 10 EP (ITT) All-Cause Mortality or Disabling Stroke 1 10 20 30 40 50 TAVR Surgery p (log rank) = 0.253 HR [95% CI] = 0.89 [0.73, 1.09] All-Cause Mortality or Disabling Stroke (%) 21.1% 16.4% 19.3% 8.0% 14.5% 6.1% 3 6 9 12 15 18 21 24 Months from Procedure Number at risk: Surgery 1021 838 812 783 770 747 735 717 695 TAVR 1011 918 901 870 842 825 811 801 774

All-Cause Mortality or Disabling Stroke (%) TF Primary Endpoint (AT) All-Cause Mortality or Disabling Stroke 1 p (log rank) = 0.04 HR: 0.78 [95% CI: 0.61, 0.99] 16.3% 20.0% 3 6 9 12 15 18 21 24 10 20 30 40 50 15.8% 7.5% 11.7% 4.5% TF TAVR TF Surgery All-Cause Mortality or Disabling Stroke (%) Months from Procedure Number at risk: TF Surgery 722 636 624 600 591 573 565 555 537 TF TAVR 762 717 708 685 663 652 644 634 612

Sapien T3 – P2A Propensity Matched Unadjusted Time-to-Event Analysis All-Cause Mortality (AT) 10 20 30 40 P2A Surgery SAPIEN 3 TAVR All-Cause Mortality (%) 13.0% 4.0% 7.4% 1.1% 3 6 9 12 Months from Procedure Number at risk: P2A Surgery 944 859 836 808 795 S3 TAVR 1077 1043 1017 991 963

Mortality, Stroke or AR ≥ Moderate Confirmed: SAPIEN 3 is Better Than Surgery for Intermediate-Risk Patients Propensity Sore Analysis merely confirmed that the large raw differences seen in KM Curves are indeed statistically significant Mortality, Stroke or AR ≥ Moderate The Propensity Scoring analysis merely confirmed the differences seen in the unadjusted data and showed that the S3 patients had improved outcomes compared to surgery in the Primary Outcome of mortality, stroke or AR> Mod

Health Status after TAVR P2A TAVR vs. SAVR MCID = 5 points 2 year D = 19 points KCCQ D = 11.4 P < 0.001 D = -0.4 P = NS D = 0.5 P = NS Significant interaction (P<0.001) between treatment effect and access site for the primary endpoint and multiple secondary endpoints ANCOVA analysis; adjusted for baseline MCID = minimum clinically important difference Cohen TCT 2016 8

Overall Clinical Status TF Cohort Cohen TCT 2016 9 *P-values from ordinal logistic regression

Alive, KCCQ-OS > 60, No KCCQ-OS decline Health Status after TAVR S3 –P2A TAVR vs. SAVR Alive, KCCQ-OS > 60, No KCCQ-OS decline Health status was evaluated in terms of categorical analyses as well so as to allow for a more global evaluation of a patient’s overall status after their valve replacement. Patients were defined as having a favorable outcome at 1 year if they were alive, had a KCCQ-overall summary score of greater than 60 (which generally correlates with New York Heart association class II symptoms) and if they did not have a significant decline (defined as greater than 10 points) in their KCCQ-overall summary score from baseline. Here again, S3-TAVR was found to be consistently superior to both surgical aVR as shown in the left panel as well as XT-TAVR as shown in the right panel. Baron TCT 2016

Cut Points for frailty components PARTNER 2 Trial – Frailty Cut Points for frailty components Variable Cutoff AUC p-value Katz 6 0.53 0.003 Gait Speed (m/sec) 0.63 0.52 0.04 Albumin 3.8 0.56 0.0006 Grip Strength (Female) 13 0.3 Grip Strength (Male) 26 0.54 0.01 Number of criteria met to be considered frail 2 0.0001 Green TCT 2016

2-Year Outcomes Stratified by Frailty Status – Death 13.9% 19.6% 15.9% 20.6% 10 20 30 40 50 TAVR (vs. SAVR) HR 0.92 [95% CI: 0.69, 1.23] p=0.3 Among Frail HR 0.41 [95% CI: 0.63, 1.2] p=0.4 Among Non-Frail 3 6 9 12 15 18 21 24 TAVR: Non-Frail TAVR: Frail SAVR: Non-Frail SAVR: Frail Overall Log-Rank p-value = 0.01 Months Death (%) Numbers at Risk TAVR: Non-Frail 526 496 488 470 461 452 447 444 433 TAVR: Frail 476 441 430 419 403 397 388 382 365 SAVR: Non-Frail 515 462 449 434 428 417 407 396 387 SAVR: Frail 482 392 377 371 357 353 345 331 Green TCT 2016

Valve Safety: Case Reviews of Hemodynamic ‘Outliers’ PARTNER 1 Trial Hemodynamic Trends over 5 Years Valve Safety: Case Reviews of Hemodynamic ‘Outliers’ VARC-2 ID’d ‘mild AS’ in 3-48% Similar rates in SAVR and TAVR Impractical for case review ↑ AV mean gradient ≥ 20 mmHg N=10 (0.45%) 6 deaths (3 CV), no reintervention Any mean gradient ≥ 40 mmHg N=11 (0.46%) 8 deaths (2 CV), 1 reintervention Any DVI ≤ 0.25 N=44 (1.8%) 22 deaths (5 CV), no reintervention Douglas TCT 2016

Does PVR Regress Paired comparison of PVR grade at 30 days and 1 year (1,213 patients) - 73% (24/33) of the patients with ≥ moderate PVR at 30 days showed a reduction in PVR severity at 1 year - 0.9% (11/1180) of the patients with < moderate PVR at 30 days had a worsening of PVR at 1 year Pibarot TCT 2016

Mitral Regurgitation: Baseline and Discharge As baseline, 3 percent of patients had severe, 18 percent had moderate and 51 percent had mild mitral regurgitation prior to TAVR implantation. In contrast, at discharge, 2 percent of patients had severe mitral regurgitation, representing a 33% relative reduction but an overall 1% absolute reduction in prevalence following TAVR implantation. In addition 14 percent of patents had moderate regurgitation, representing a 22% and 13.7% relative reduction these classifications. 40 percent had no mitral regurgitation, representing a 42 increase in this category. Petersen TCT 2016

Impact of Residual MR on Acute Heart Failure Readmission Severe Moderate 1 2 3 4 5 20 40 60 80 100 Mild None Years #/100 patients p-value < .0001 23 26 52 65 Plotted here is the association of severity of mitral valve regurgitation at discharge following TAVR and incidence of readmission for heart failure, adjusted by nested cohort methodology for the competing risk of death. Note that while the prevalence of severe mitral regurgitation is less and the prevalence of moderate mitral regurgitation is increased compared with baseline, the risk of readmission with severe mitral regurgitation is unchanged but the risk of moderate regurgitation is increased compared to regurgitation grade at baseline. Petersen TCT 2016

Edwards Transcatheter Valve Evolution Untreated Equine Tissue Untreated Equine Tissue Treated Bovine Tissue TFX Treated Bovine /CC Bovine/CC Skirt lower 1/3 Andersen Pig implant, 5/89 Cribier-Edwards™ FIM, 4/15/02 Edwards SAPIEN™ 8/07 Sapien XT™ 1/10 Sapien 3™ 2013 17 17 17