Incorporating the intermediate risk in Transcatheter Aortic Valve Implantation (TAVI)

Incorporating the intermediate risk in Transcatheter Aortic Valve Implantation (TAVI) Larry S. Dean, MD, MSCAI Past President SCAI Professor of Medicine and Surgery University of Washington School of Medicine Seattle, WA USA

FINANCIAL OR OTHER RELATIONSHIP(S) DISCLOSURE: Grant/Research Support: Edwards Lifesciences

Lecture Outline Review the ACC/AHA Guidelines Case example of Complex TAVR Learnings from the TAVR trials Who is the appropriate intermediate patient for TAVR Conclusions

ACC/AHA Valvular Heart Disease Guidelines: Indications for AVR for AS Nishimura RA, et al 2014 Valvular Heart Disease Guideline JACC 2014

ACC/AHA Valvular Heart Disease Guidelines: Choice of Intervention Nishimura RA, et al 2014 Valvular Heart Disease Guideline JACC 2014

The PARTNER Trials

Device Evolution Untreated Equine Tissue Bovine Pericardial Tissue ThermaFix anti-calcification process Leaflets matched for both deflection and thickness Cobalt-Chromium Frame Bovine Pericardial Tissue ThermaFix anti-calcification process Leaflets matched for both deflection and thickness Cribier-Edwards THV Edwards SAPIEN THV 23mm, 26mm Edwards SAPIEN XT THV 23mm, 26mm, 29mm

lve Valve Sapien S3 Valve Home / Products / Transcatheter Heart Valves / Edwards SAPIEN 3 Edwards SAPIEN 3 Transcatheter Heart Valve Built upon the proven benefits of the SAPIEN valve family onic Frame design Enhanced frame geometry for ultra-low delivery profile High radial strength for circularity and optimal hemodynamics lts Low frame height Respects the cardiac anatomy Bovine pericardial tissue Leaflet shape optimized for hemodynamics and durability Carpentier-Edwards ThermaFix* process intended to reduce the risk of calcification Outer skirt Designed to minimize paravalvular leak Designed to minimize paravalvular leak while achieving an ultra-low delivery profile

Can the Indications for TAVI be Expanded to Intermediate Risk Patients with AS? To Help Understand my Answer We Need to Review Some of What We have Learned from PARTNER, CoreValve and Other Studies

PARTNER I Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened N = 699 High Risk Total = 1,057 patients 2 Parallel Trials: Individually Powered Inoperable N = 358 Yes ASSESSMENT: Transfemoral Access No ASSESSMENT: Transfemoral Access Transfemoral (TF) Transapical (TA) Yes No 1:1 Randomization 1:1 Randomization 1:1 Randomization Not In Study N = 244 N = 248 N = 104 N = 103 N = 179 N = 179 TF TAVR VS AVR TA TAVR VS AVR TF TAVR VS Standard Therapy Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)

Patient Characteristics: Inoperable Characteristic TAVR n = 179 Standard Rx n = 179 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 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 11

Death Incidence (%) Mortality Stratified by STS Score (ITT): PARTNER I Inoperable Standard Rx TAVR 100% STS <5 100% STS 5-14.9 100% STS 15 Cohort C 80% 80% 80% 60% 60% 60% 40% 40% 40% 20% 20% 20% 0% 0 6 12 18 24 0% 0 6 12 18 24 0% 0 6 12 18 24 Months Months Months Numbers at Risk 28 26 25 24 16 108 80 76 67 52 43 32 23 19 15 12 12 8 7 6 5 119 84 59 42 29 47 29 19 14 8

PARTNER I Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened N = 699 High Risk Total = 1,057 patients 2 Parallel Trials: Individually Powered Inoperable N = 358 Yes ASSESSMENT: Transfemoral Access No ASSESSMENT: Transfemoral Access Transfemoral (TF) Transapical (TA) Yes No 1:1 Randomization 1:1 Randomization 1:1 Randomization Not In Study N = 244 N = 248 N = 104 N = 103 N = 179 N = 179 TF TAVR VS AVR TA TAVR VS AVR TF TAVR VS Standard Therapy Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)

Patient Characteristics: High Risk Characteristic TAVR (N = 348) AVR (N = 351) p-value Age (yr) 83.6 ± 6.8 84.5 ± 6.4 0.07 Male sex - % 57.8 56.7 0.82 STS Score 11.8 ± 3.3 11.7 ± 3.5 0.61 Logistic EuroSCORE 29.3 ± 16.5 29.2 ± 15.6 0.93 NYHA II - % III or IV - % 94.3 94.0 0.79 CAD - % 74.9 76.9 0.59 Previous MI - % 26.8 30.0 0.40 Prior CV Intervention - % 72.1 71.6 0.93 Prior CABG - % 42.6 44.2 0.70 Prior PCI - % 34.0 32.5 0.68 Prior BAV - % 13.4 10.2 0.24 Cerebrovascular disease - % 5.7 6.0 29.3 27.4 0.60

All-Cause Mortality PARTNER I All-Cause Mortality (ITT): High Risk 70% 60% 50% TAVR AVR HR [95% CI] = 0.93 [0.74, 1.15] p (log rank) = 0.483 44.8% 40% 34.6% 44.2% 30% 26.8% 33.7% 20% 24.3% 10% 0% 0 6 12 18 24 30 36 No. at Risk Months post Randomization TAVR 348 298 261 239 222 187 149 AVR 351 252 236 223 202 174 142

Strokes Strokes (ITT): PARTNER I High Risk 70% 60% 50% TAVR AVR HR [95% CI] = 1.09 [0.62, 1.91] p (log rank) = 0.763 40% 30% 20% 10% 6.0% 3.2% 7.7% 4.9% 9.3% 8.2% 0% 0 6 12 18 24 30 36 Months Post Randomization No. at Risk TAVR 348 287 250 228 211 176 139 AVR 351 246 230 217 197 169 139

Mortality Impact of Total AR on Mortality (AT) TAVR Patients 70% 60% 50% None - Trace Mild Moderate - Severe 53.7% 60.8% 44.6% 40% 30% 38.2% 26.0% 32.5% 35.3% 20% 25.6% 10% 12.3% 0% 0 6 12 18 24 30 36 No. at Risk Months post Procedure None-Tr 131 121 114 102 93 80 63 Mild 171 146 125 117 110 94 62 Mod-Sev 34 24 21 18 15 12 9

Clinical Outcomes at 1, 2, and 3 Years (ITT) All Patients (N=699) 1 Year 2 Years 3 Years Outcome AVR (N = 351) TAVR (N = 348) p-value AVR (N = 351) TAVR (N = 348) p-value AVR (N = 351) TAVR (N = 348) p-value Major Vasc. Comp. no. (%) 13 (3.8) 42 (12.1) <0.001 13 (3.8) 43 (12.5) <0.001 13 (3.8) 43 (12.5) <0.001 Major Bleeding no. (%) 88 (26.7) 52 (15.7) <0.001 95 (29.5) 61 (19.3) 0.003 99 (31.5) 64 (20.8) 0.003 New PM no. (%) 16 (5.0) 21 (6.4) 0.44 19 (6.3) 24 (7.6) 0.54 20 (6.8) 25 (8.1) 0.56 Endocarditis no. (%) 3 (1.0) 2 (0.6) 0.63 3 (1.0) 4 (1.5) 0.62 6 (2.6) 4 (1.5) 0.37 SVD Requiring AVR 0 0 0 0 0 0 MI no. (%) 2 (0.6) 0 0.16 4 (1.5) 0 0.05 6 (2.7) 2 (1.1) 0.23 Acute Kidney Inj.* no. (%) 20 (6.5) 18 (5.4) 0.57 22 (7.3) 20 (6.2) 0.59 23 (7.9) 22 (7.2) 0.76 SVD = Structural Valve Deterioration * Renal replacement therapy

CoreValve

CoreValve Pivotal Trial Design 20

Baseline Demographics 21

Primary Endpoint: 1 Year All-cause Mortality ACC 2014 Surgical Transcatheter 19.1% 14.2% 4.5% P = 0.04 for superiority 3.3% 22

All Stroke 23

Other Endpoints 24

Outcomes in Lower Risk Patients n = 420 Lange R, et al. JACC 2012;59:280-7

Outcomes in Lower Risk Patients n = 420 Lange R, et al. JACC 2012;59:280-7

Conclusions The question at this point is not can we technically do TAVI in a lower risk population; obviously we can. The question is, should we do so based on the fairly limited non-randomized data that currently exist? I believe the answer at present is no, at least outside of well- designed trials. PARTNER II and SURTAVI are such a trials Dean LS. Cath Cardiovasc Intervt. 2012;79:141

The PARTNER II Trial Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT by Heart Valve Team n = 2000 Randomized Patients Operable (STS 4) Two Parallel Randomized Trials +6 Nested Registries Inoperable n = 560 Randomized Patients Yes ASSESSMENT: Transfemoral Access No ASSESSMENT: Transfemoral Access Transfemoral (TF) Transapical (TA) / TransAortic (TAo) Yes 1:1 Randomization 1:1 Randomization 1:1 Randomization 6 Nested Registries Sample Size TF TAVR SAPIEN XT VS Surgical AVR TAVR: TA / TAo SAPIEN XT Primary Endpoint: All-Cause Mortality + Disabling Stroke at Two Years (Non-inferiority) VS Surgical AVR TF TAVR SAPIEN XT VS TF TAVR SAPIEN Primary Endpoint: All-Cause Mortality + Disabling Stroke + Repeat Hospitalization at One Year (Non-inferiority) NR1 (Sm Vessel) 100 NR2 (Transapical) 100 NR3 (ViV) 100 NR4 (TAo) 100 NR5 (29 mm TF) 50 NR6 (29 mm TA) 50

Methods The SAPIEN 3 Trial Study Design Prospective, multicenter, non-randomized study Number of Patients 150 (TF [transfemoral] = 96, TAA [transapical / transaortic] = 54) 50 high-risk patients & 100 high-risk or intermediate-risk patients Patient Selection High-risk: STS score > 8 o 8 or L gistic EuroSCORE 15 Intermediate-risk: c STS s >4 o re < 4 to < 8 8 o or L gistic EuroSCORE 10 to < 15 Enrollment Period January 2013 to November 2013 Study Centers 16 sites in Europe and Canada Access Approach Transfemoral, transapical, or transaortic access, as determined by the Heart Team

Baseline Characteristics (2) Baseline Characteristics (%) TF PATIENTS (N = 96) TAA PATIENTS (N = 54) P-VALUE STS PROM Score 7.5 ± 4.26 7.3 ± 4.94 0.813 Logistic EuroSCORE (%) 19.8 ± 10.9 24.9 ± 14.0 0.022 Peripheral Vascular Disease 16.7 38.9 0.003 Previous Myocardial Infarction 11.5 27.8 0.014 Previous CABG 14.6 27.8 0.056 Atrial Fibrillation 22.9 35.8 0.125 Previous Aortic Valvuloplasty 10.4 3.7 0.213 Previous Pacemaker Implantation 13.5 16.7 0.635 Carotid Disease 25.0 25.9 1.000 Porcelain Aorta 1.0 1.9 1.000 Prior Stroke 7.3 7.4 1.000

Clinical Outcomes at 30 Days (1) Clinical Outcome TF (N = 96) EVENT RATE IN THE AT POPULATION # PATIENTS (KM %) TAA (N = 54) Overall (N = 150) All-Cause Mortality 2 (2.1%) 6 (11.1%) 8 (5.3%) Cardiac Mortality 2 (2.1%) 5 (9.3%) 7 (4.7%) All-Stroke* 1 (1.0%) 3 (5.6%) 4 (2.7%) Disabling Stroke 0 (0.0%) 0 (0.0%) 0 (0.0%) Major Vascular Complication 5 (5.2%) 4 (7.4%) 9 (6.0%) Major Bleeding 19 (19.8%) 11 (20.4%) 30 (20.0%) Life-Threatening Bleeding 2 (2.1%) 3 (5.6%) 5 (3.3%) Rehospitalization 0 (0.0%) 0 (0.0%) 0 (0.0%) Primary Endpoint TF (N = 95) EVENT RATE IN THE VI POPULATION # PATIENTS (KM %) TAA (N = 54) Overall (N = 149) All-Cause Mortality 1 (1.1%) 6 (11.1%) 7 (4.7%) VI, valve implant = all enrolled patients who received a SAPIEN 3 implant, and retain the valve upon leaving the cath lab * Severity of the one TF stroke unknown. Rehospitalization for for valve-related symptom or worsening of congestive heart failure.

Clinical Outcomes at 30 Days (2) EVENT RATE IN THE AT POPULATION # PATIENTS (KM %) Clinical Outcome TF (N = 96) TAA (N = 54) Overall (N = 150) Acute Kidney Injury (Stage II/III) 1 (1.0%) 3 (5.6%) 4 (2.7%) Myocardial Infarction 2 (2.1%) 0 (0.0%) 2 (1.3%) Reintervention* 1 (1.0%) 0 (0.0%) 1 (0.7%) Endocarditis 0 (0.0%) 0 (0.0%) 0 (0.0%) Valve Thrombosis 0 (0.0%) 0 (0.0%) 0 (0.0%) New-Onset Atrial Fibrillation 7 (7.3%) 11 (20.4%) 18 (12.0%) New Permanent Pacemaker Implanted 12 (12.5%) 8 (14.8%) 20 (13.3%) * Valve Malposition requiring a second valve on Day 0

SURTAVI: Study Design OUS STS mortality risk 4% and 10% US STS mortality risk 4% and 10% Meet I/E Criteria and eligible for SAVR and TAVI Heart Team Evaluation including assessment for significant CAD with determination of need for revascularization Randomization with 5 year follow up 2200 patients US and OUS STS 4-10% Recruitment Ongoing Presence of significant CAD with intended revascularization No intended revascularization TAVI + PCI SAVR + CABG TAVI SAVR 22

Transapical Valve in Valve

Transapical Valve in Valve

What are the Issues in Making this Technology Available to the Intermediate Risk Patient? Unknown durability of the valve The incidence of stroke The requirement for a permanent pacemaker which appears higher for some than others The vexing problem of post implant aortic regurgitation Lack of randomized data to inform the decision

Conclusions This is a disruptive technology The current devices are really first and at best second generation The future will bring better devices and delivery systems The final indications for the procedure are to be defined Intermediate risk has become, in some countries, accepted practice but this procedure is not without risk and some unknowns Studies to better define the outcomes, compared to surgery are ongoing