Structural Heart Live Cases Supported by: Edwards Lifesciences Terumo Medical Corp

Disclosures Samin K. Sharma, MD, FACC Speaker’s Bureau – Boston Scientific Corp., Abbott Vascular Inc, ABIOMED, CSI Annapoorna S. Kini, MD, FACC Nothing to disclose Gilbert Tang, MD Physician proctor for Edwards Lifesciences George Dangas, MD

November 13, 2018- Structural Heart Live Case# 26: SP, 96 yo M Presentation: Severe dyspnea on exertion NYHA Class III x 4 months PMH: HTN, HLD, diabetes, AFib on anticoagulation & prostate cancer in remission Medications: Atorvastatin, Warfarin, Furosemide, Nebivolol, Saxagliptin, KCL Labs: Hgb 12.4, PLT 88K, K 3.6, Cr 0.9, INR 1.8 EKG (10/2/18): AF with RBBB TTE (10/21/18): EF 53%, mild MR, moderate TR, mild to moderate AR, moderate pulmonary hypertension, RV dysfunction, severe AS (PG/MG/AVA/PV= 29/16/0.65/2.7m/s), SVI 27ml/m2 Cath (9/11/18): Non-obstructive coronaries

Severe AS (PG/MG/AVA = 29/16/0.65) Severe Aortic Stenosis TTE Severe AS (PG/MG/AVA = 29/16/0.65) AV Peak velocity = 2.7 m/s Severe Aortic Stenosis

CTA: Aortic Annulus Aortic Annulus Max: 33.5 mm Min: 27.5 mm Mean: 30.5 mm Perimeter = 95.5 mm Area = 713.4 mm2 Annular angle = 55° Annulus: 27.5mmx33.5 mm Area: 713.4 mm2 Perimeter: 95.5 mm Annulus Angle: 55°

CTA: SOV, STJ, Coronary Ostia RCA: 17.7 mm RCC: 40.4 Sinus of Valsalva RCC = 40.4 mm LCC = 39.0 mm NCC = 37.6 mm STJ height (above annulus) = 30.0 mm STJ = 35.4 x 37.8 mm (mean 36.6 mm) LVOT = 25.7 x 34.2 mm (mean 30 mm) Ascending aorta = 35 x 36.7 mm (mean 35.9 mm) NCC: 37.6 LCC: 39.0 LM: 19.2 mm STJ 35.4 x 37.8 mm

Femoral Arterial Access 13x13mm 10.5 x12 mm 10x10 mm 10x12mm 11x11mm 11x12mm Longitudinal View Right Iliac/Femoral Longitudinal View Left Iliac/Femoral Access 3D

Great Vessel Anatomy for Cerebral Protection Device Consideration Innominate 13.5 mm Left common carotid 9 mm

Edwards Sapien-3 Patient Selection Patient CTA Findings Annulus: Max: 33.5 mm Min: 27.5 mm Mean: 30.5 mm Perimeter = 95.5 mm Area = 713.4 mm2 STJ= 35.4 x 37.8mm

Summary of Case Presentation: 96 year old male with NYHA Class III DOE TTE: EF 53%, mild to moderate AR, moderate pulmonary hypertension, RV dysfunction, low flow low gradient paradoxical severe AS (PG/MG/AVA/PV = 29/16/0.65/2.7m/s), SVI 27ml/mm2 STS risk mortality: 12% EuroScore risk: 13% Logistic Euroscore mortality: 37.1% Course: Patient was considered to have LF-LG paradoxical severe AS and was evaluated by Heart Team. Due to his multiple co-morbidities and frailty status, the patient was determined to be Extreme Risk for SAVR Plan: The patient is here for TAVR with a 29 mm (+2cc) SAPIEN-3 via transfemoral access (right percutaneous) with possible Sentinel cerebral protection.

Issues Related To The Case Balloon Expandable (BE) vs Self Expanding (SE) TAVR valve choice trials in severe AS

5/22/2019

PRAGMATIC Plus: VARC Outcomes in the Propensity-Matched Population at 30 Days 5/22/2019 MCV (n=204) ESV (n=204) % Life-threatening p=0.35 p=0.42 p=0.12 p=0.34 p=0.17 Chieffo et al., J AM Coll Cardiol 2013;61:830

PRAGMATIC Plus: VARC Outcomes in the Propensity-Matched Population at 1-Year 5/22/2019 MCV (n=204) ESV (n=204) p=0.14 p=0.27 p=0.20 % p=0.14 p=0.30 Chieffo et al., J AM Coll Cardiol 2013;61:830

5/22/2019

Balloon-Expandable THV Cohort Selection 5/22/2019 1005 unique TAVI patients from 2007-2013 in Ontario, Canada 723 unique patients Final Cohort = 714 Patients Self-Expanding THV n=397 patients Balloon-Expandable THV n=317 patients 282 excluded who had non-transfemoral or had two different types of TAVI devices 9 excluded who had TAVI procedure status Emergency or Salvage, or Cardiogenic shock, or Cardiac Arrest, or missing TAVI device type Wijeysundera et al., Am J Cardiol 2017;119:1094

Outcomes After Inverse Probability of Treatment Weighting 5/22/2019 Balloon-Expandable THV (n=317) Self-Expandable THV (n=397) Outcomes at 1-Year Outcomes at Last Follow-Up (Follow-up to March 31, 2015) % p=0.57 p=0.24 p=0.18 p=0.53 Wijeysundera et al., Am J Cardiol 2017;119:1094

Procedural Complications After Inverse Probability of Treatment Weighting 5/22/2019 Balloon-Expandable THV (n=317) Self-Expandable THV (n=397) p<0.05 p=0.02 p=0.13 p=0.01 p=0.45 p=0.002 p<0.0001 % (Mean±SD) Wijeysundera et al., Am J Cardiol 2017;119:1094

JAMA 2014;311:1503

CHOICE Trial Study Flow Abdel-Wahab et al., JAMA 2014;311:1503

CHOICE Trial: Primary Endpoint – Device Success Successful valve placement with vascular access, 1 valve in correct position & < mod AI

CHOICE Trial: Procedural Details Balloon-Expandable valve (n=121) Self-Expandable valve (n=117) p=0.001 % p=<0.001 p=0.78 p=0.35 p=0.38 p=0.03 p=0.77 p=0.33 Device Succ Echo Implant of Death Stroke Bleeding Vascular MACCE New PP primary endpt mod AI ≥2 valves compl Abdel-Wahab et al., JAMA 2014;311:1503

CHOICE Trial: Study Flowchart 241 Transfemoral TAVR patients enrolled and randomized Balloon-expandable valve (Edwards Sapien XT, n=121) Self-expandable valve (Medtronic CoreValve, n=120) Alive = 116 Dead = 5 LTFU = 0 Withdrawal = 0 Alive = 111 Dead = 6 LTUF = 1 Withdrawal = 2 30 Days Alive = 100 Dead = 21 LTFU = 0 Withdrawal = 0 Alive = 102 Dead = 15 LTUF = 0 Withdrawal = 3 1 Year 100% Clinical follow-up 97% Clinical follow-up Abdel-Wahab et al., J Am Coll Cardiol 2015;66:791

CHOICE Trial: Clinical Outcomes at 1 Year Balloon-Expandable Valve (n=121) Self-Expandable Valve (n=117) p=0.22 % p=0.37 p=0.85 p=0.19 p=1.00 p=0.36 p=0.54 p=0.12 Death Stroke HF repeat Bleeding Major vasc Valve New PPM MACCE hosp life threatening compl thrombosis Abdel-Wahab et al., J Am Coll Cardiol 2015;66:791

CHOICE Trial: 1-Year Outcome After TAVR with Balloon-Expandable vs Self-Expandable Valves Abdel-Wahab et al., J Am Coll Cardiol 2015;66:791

SOLVE-TAV A 2x2 Randomized Trial of Self-Expandable vs Balloon-Expandable Valves and General vs Local Anesthesia in Patients Undergoing Transcatheter Aortic Valve Implantation

Background I – Valve Strategy TAVR is developing as standard strategy for symptomatic patients with severe aortic stenosis at high to intermediate risk. TAVR device design led to relevant technical and clinical improvements (e.g. pacemaker rates, paravalvular leakage, vascular complications). There is limited evidence for direct valve comparisons (CHOICE, REPRISE III) in particular for latest generation valve designs.

Background II – Anesthesia Strategy In clinical routine TAVR is performed in ≈50% using general or local anesthesia with conscious sedation. Registry data suggest lower mortality lower morbidity shorter ICU and hospital stay shorter procedure times with local anesthesia. There is a lack of adequately powered randomized trials. Villablanca et al., Catheter Cardiovasc Interv. 2017;1

SOLVE-TAVI Program Thiele H, TCT 2018

Hypotheses Self-expanding CoreValve Evolut R is equivalent to balloon-expandable Sapien 3 (Edwards) valve Local anesthesia with conscious sedation is equivalent to general anesthesia in symptomatic aortic stenosis patients undergoing transfemoral TAVR Thiele H, TCT 2018

Study Flow Chart - Valve Strategy Thiele H, TCT 2018

Baseline Characteristics – Valve Strategy Evolut R (n=219) Sapien 3 Age (years); mean ±SD 81.7 ± 5.3 81.5 ± 5.7 Male sex; n/total (%) 105/219 (47.9) 109/219 (49.8) Risk scores STS score (%); mean ±SD 7.7 ± 7.2 7.6 ± 7.4 Log. EuroScore I (%), mean ±SD 18.4 ± 12.1 18.3 ± 13.1 EuroScore II (%), mean ±SD 6.1 ± 5.5 5.4 ± 4.9 Frailty; n/total (%) 93/216 (43.1) 80/217 (36.9) Peripheral arterial disease; n/total (%) 28/219 (12.8) 27/219 (12.3) Prior myocardial infarction; n/total (%) Prior PCI; n/total (%)  Prior CABG; n/total (%) Atrial fibrillation; n/total (%) Pacemaker/ICD; n/total (%) 19/219 (8.7) 84/219 (38.4) 26/219 (11.9) 103/219 (47.0) 24/218 (11.0) 22/219 (10.1) 79/219 (36.1) 18/219 (8.2) 93/219 (42.5) 23/219 (10.5) Prior stroke; n/total (%) 25/219 (11.4) 26/218 (11.9) Renal insufficiency; n/total (%) 177/216 (81.9) 184/214 (86.0) Pulmonary hypertension; n/total (%) 106/216 (49.1) 105/218 (48.2) COPD; n/total (%) 30/219 (13.7) 29/217 (13.4) Cardiovascular risk factors Diabetes; n/total (%) Arterial hypertension; n/total (%) HLP; n/total (%) Current smoking; n/total (%) 79/218 (36.2)  193/219 (88.1) 118/218 (54.1) 8/218 (3.7) 68/219 (31.1)  204/219 (93.2) 10/219 (4.6) Thiele H, TCT 2018

Treatment – Valve Strategy Characteristic Evolut R (n=219) Sapien 3 P Pre echo data AVA; cm2 AVA index; cm2/m2 Mean gradient; mmHg Peak gradient; mmHg TAPSE; mm LVEF >55%; n/total (%) LVEF 45-54%; n/total (%) LVEF 35-44%; n/total (%) LVEF <35%; n/total (%) 0.76 ± 0.19 0.41 ± 0.12 39.5 ± 14.4 63.9 ± 22.9 20.6 ± 4.6 114/203 (56.2) 56/203 (27.6) 21/203 (10.3) 12/203 (5.9) 0.77 ± 0.20 0.43 ± 0.12 64.2 ± 26.4 19.9 ± 5.7 114/201 (56.7) 52/201 (25.9) 16/201 (8.0) 19/201 (9.5) 0.60 0.39 0.52 0.37 0.49 Valve size 23 mm; n/total (%) 1/215 (0.5) 51/218 (23.4) 26 mm; n/total (%) 56/215 (26.2) 120/218 (55.1) 29 mm; n/total (%) 108/215 (50.2) 47/218 (21.6) 34 mm; n/total (%) 50/215 (23.3) Pre dilatation; n/total (%) 83/219 (37.9) 86/216 (39.8) 0.68 Post dilatation; n/total (%) 77/219 (35.2) 50/218 (22.9) 0.006 Recapturing; n/total (%) 55/204 (27.0) <0.001 Contrast agent, ml 119 ± 44 98 ± 33 Fluoroscopy time, min 14.2 ± 12.8 12.0 ± 6.1 0.02 Thiele H, TCT 2018

Primary Endpoint – Valve Strategy All-cause mortality, stroke, moderate or severe prosthetic valve regurgitation, permanent pacemaker implantation at 30 days Rate difference -1.14 90%CI -8.15 – 5.87 Pequivalence=0.02 Psuperiority=0.83 27.2% 26.1% % Thiele H, TCT 2018

Endpoints – Valve Strategy Individual Components Primary Endpoint Thiele H, TCT 2018

Secondary Endpoints – Valve Strategy Evolut R (n=219) Sapien 3 Rate difference Pequivalence Psuperiority Device time, min 63 ± 32 64 ± 43 0.80 Total procedural time, min 118 ± 48 117 ± 52 0.40 Cardiovascular mortality, n (%) 1/216 (0.5) 4/218 (1.8) 1.37 (-2.27 ─ 5.01) <0.001 0.37 Hospital stay, days 9 ± 7 0.97 VARC-2 criteria: Device success, n (%) 203/216 (94.0) 200/218 (91.7) -2.24 (-6.91 ─ 2.43) 0.002 0.46 Early safety, n (%) 24/217 (11.1) 33/219 (15.1) 4.01 (-1.57 ─ 9.59) 0.03 0.26 Clinical efficacy, n (%) 74/216 (34.3) 80/217 (36.9) 2.61 (-4.94 ─ 10.15) 0.05 0.61 Time-related safety, n (%) 41/217 (18.9) 58/219 (26.5) 7.59 (0.91-14.27) 0.27 0.07 Thiele H, TCT 2018

Study Flow Chart - Anesthesia Strategy Thiele H, TCT 2018

Treatment – Anesthesia Strategy Characteristic Local Anesthesia (n=218) General Anesthesia (n=220) P O2 saturation at start of anesthesia; % 92.7 ± 25.0 91.6 ± 27.3 0.08 Minimal O2 saturation during anesthesia; % 88.0 ± 27.4 93.3 ± 21.8 <0.001 O2 saturation at end of anesthesia; % 83.2 ± 36.7 81.9 ± 38.2 0.42 Conversion to general anesthesia Agitation; ; n/total (%) Emergency surgery; n/total (%) Respiratory insufficiency; n/total (%) Hemodynamic reasons; n/total (%) 13/218 (5.9) 3/13 (23.1) 5/13 (38.5) 2/13 (15.4) Transesophageal echocardiography; n/total (%) 8/210 (3.8) 73/217 (33.6) Anesthesia medication Remifentanyl; n/total (%) Propofol; n/total (%) Dexmedetomidine; n/total (%) Sufentanyl; n/total (%) Fentanyl; n/total (%) Piritramide; n/total (%) Other non-benzodiazepine drugs; n/total (%) 18/218 (8.3) 56/218 (25.7) 111/218 (50.9) 63/218 (28.9) 13/218 (6.0) 7/218 (3.2) 213/220 (96.8) 198/220 (90.0) 3/220 (1.4) 7/220 (3.2) 9/220 (4.1) 6/220 (2.7) 0.39 0.79 Thiele H, TCT 2018

Primary Endpoint – Anesthesia Strategy All-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, acute kidney injury at 30 days Rate difference -1.52 90%CI -8.47 – 5.42 Pequivalence=0.02 Psuperiority=0.74 27.0% 25.5% % Thiele H, TCT 2018

Endpoints– Anesthesia Strategy Individual components primary endpoint Thiele H, TCT 2018

Treatment – Anesthesia Strategy Characteristic Local Anesthesia (n=218) General Anesthesia (n=220) P O2 saturation at start of anesthesia; % 92.7 ± 25.0 91.6 ± 27.3 0.08 Minimal O2 saturation during anesthesia; % 88.0 ± 27.4 93.3 ± 21.8 <0.001 O2 saturation at end of anesthesia; % 83.2 ± 36.7 81.9 ± 38.2 0.42 Conversion to general anesthesia Agitation; ; n/total (%) Emergency surgery; n/total (%) Respiratory insufficiency; n/total (%) Hemodynamic reasons; n/total (%) 13/218 (5.9) 3/13 (23.1) 5/13 (38.5) 2/13 (15.4) Transesophageal echocardiography; n/total (%) 8/210 (3.8) 73/217 (33.6) Anesthesia medication Remifentanyl; n/total (%) Propofol; n/total (%) Dexmedetomidine; n/total (%) Sufentanyl; n/total (%) Fentanyl; n/total (%) Piritramide; n/total (%) Other non-benzodiazepine drugs; n/total (%) 18/218 (8.3) 56/218 (25.7) 111/218 (50.9) 63/218 (28.9) 13/218 (6.0) 7/218 (3.2) 213/220 (96.8) 198/220 (90.0) 3/220 (1.4) 7/220 (3.2) 9/220 (4.1) 6/220 (2.7) 0.39 0.79 Thiele H, TCT 2018

Situations Where You Favor One Valve Over Another? 5/22/2019 Situations Where You Favor One Valve Over Another? A Clinicians Perspective: Most of AV are suitable for either valve Evolut R Dense sub-annular calcium Intolerant to rapid pacing (↓↓EF) TAVR in SAVR (ViV) Ileo-femorals 5-6mm size Hypertrophied septum (HOCM) Subclavian approach Sapien 3 Ante-grade approaches Very large and very small annulus Horizontal Aorta >60 degrees Concerns about PPM Pt with extensive CAD or prior PCIs Low coronary heights/ small SOV

Lotus Valve System Radiopaque Marker Adaptive Seal Nitinol Frame Bovine Pericardium

REPRISE III: RCT Study Algorithm Heart Team assessment Case Review Committee confirmation Neurologist examination‡ DAPT ≥1m OR warfarin + ASA or clopidogrel ≥1m (if anticoagulation needed) Clinical & echocardiographic follow-up: discharge or 7d, 30d, 6m, annually 1-5 Randomized 2:1 (Lotus : CoreValve) N=912 Severe aortic stenosis; extreme or high operative risk Annulus ≥20 mm and ≤27 mm; transfemoral access Lotus Valve* (23, 25 & 27mm) CoreValve† (26, 29 & 31mm) ‡ Performed by a neurologist, neurology fellow, neurology physician assistant, or neurology nurse practitioner † CoreValve platform (includes CoreValve Classic and Evolut R) * Centres with no Lotus experience enrolled 2 roll-in patients before commencing enrollment of the evaluable cohort T Feldman EuroPCR 2017

REPRISE III: Primary Composite Safety Endpoint 1 Year − Intent-to-Treat Primary Composite Safety Endpoint* (%) 40 30.7% 10 30 20 CoreValve (305) Lotus Valve (607) P = 0.83 30.2% 30 90 180 270 365 *All-cause mortality, stroke, life-threatening/major bleed, stage 2/3 AKI, major vascular complications Feldman et al., JAMA 2017;319:27

REPRISE III: Kaplan-Meier Event Rate 1-Year – Intent-to-Treat All-Cause Mortality All-Cause Mortality/Disabling Stroke Feldman et al., JAMA 2017;319:27

REPRISE III: Additional VARC Events at 1 Year Intent-to-Treat CoreValve (N=305) Lotus (N=607) P Value Myocardial infarction, % 4.4 3.2 0.39 Life threatening bleeding, % 9.8 9.9 0.96 Major bleeding, % 8.4 8.3 0.97 New onset atrial fibrillation, % 4.7 6.6 0.25 Hospitalization*, % 13.8 11.2 0.27 Endocarditis, % 0.0 0.7 0.31 Valve thrombosis, % 1.5 0.03 Repeat procedure†, % 2.0 0.2 0.007 Feldman et al., JAMA 2017;319:27

REPRISE III: Paravalvular Leak at 1 Year Core Lab Assessment – Intent-to-Treat ≥ Moderate PVL Percent of Gradable Echocardiograms Lotus (N=442)† CoreValve (N=203)† Mod-Sev Paravalvular Leak* 39.9 11.3 36.9 10.8 1.0 81.7 5.9 10.4 0.2 1.8 All PVL Superiority Testing P <0.001 11.1% Patients with Moderate or Greater PVL (%) Moderate Mild Trace None 2.0% CoreValve (N=216) Lotus (N=451) Feldman et al., JAMA 2017;319:27

Take Home Message: Balloon Expandable (BE) vs Self Expanding (SE) TAVR Valve Choice in Severe AS Two RCTs and 2 registries of BE vs SE TAVR valves have showed similar outcomes in majority of severe AS pts with some pro and con of each valve in specific clinical and anatomic scenarios. Small vascular access will favor SE while presence of extensive CAD will favor BE device Future efforts need to focus on reducing the need of PPM, prosthetic regurgitation and leaflet deterioration after TAVR especially when this technology will be applied to younger and low risk pts. These are essential to really establish TAVR as the destination therapy in younger pts.

Question # 1 Correct answer: A Following are the RCTs or registry data comparing of SE vs BE TAVR except: A. NOTION B. CHOICE C. SOLVE-TAVI D. PRAGMATIC PLUS Correct answer: A

Correct answer: D Question # 2 Following are the true regarding the 30-day results of Choice trial comparing BE vs SE TAVR valve except: Stroke incidence is similar between 2 groups Mortality is higher in the SE group vs BE group PPM is higher in SE vs BE group Device success is similar between 2 groups Correct answer: D

Correct answer: C Question # 3 Following are the true regarding the 1-Year results of Choice trial comparing BE vs SE TAVR valve except: Stroke incidence is similar between 2 groups Mortality is similar between 2 group Vascular complication is higher in SE vs BE group Bleeding complication is similar between 2 groups Correct answer: C

Correct answer: A Question # 4 Following are the true regarding the results of Solve-TAVI trial comparing BE vs SE TAVR valve except: Stroke incidence is similar between 2 groups Mortality is similar between 2 groups PPM is similar between 2 groups Mod-severe AI is similar between 2 groups Correct answer: A

Correct answer: D Question # 5 Following are the true regarding the results of Solve-TAVI trial comparing LA vs GA during TAVR procedure except: Stroke incidence is similar between 2 groups Mortality is similar between 2 groups AKI is similar between 2 groups Catecholamine meds use is similar in GA vs LA group Correct answer: D