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

Disclosures Samin K. Sharma, MD, FACC Speaker’s Bureau – Boston Scientific Corporation, Abbott Vascular Inc, ABIOMED, CSI, Trireme Inc Annapoorna S. Kini, MD, FACC Nothing to disclose George Dangas, MD, FACC Nothing to disclose regarding today’s presentation Allan Stewart, MD Nothing to disclose for today’s case Anelechi Anyanwu, MD

October 11th 2016 Structural Heart Live #14: DR, 81 yr. M Presentation: Worsening dyspnea on exertion NYHA class III PMH: Severe AS, HTN, HPL, CAD with multiple prior PCI’s, H/o bacterial meningitis in childhood with resultant cognitive impairment, Ex-smoker, Rheumatoid arthritis, Gout Medications: Aspirin, Atorvastatin, Furosemide, Amlodipine, Allopurinol, Methotrexate TTE (6/8/16): Severe valvular AS; PG/MG= 88/58mmHg, Doppler valve area = 0.66 cm2, Ao peak velocity = 4.7m/s, LVEF 63% EKG: Sinus bradycardia with narrow QRS, T inversion in V5-6 Cath (06/29/16): Non-obstructive CAD with patent stents, mild PAH.

October 11th 2016 Structural Heart Live Case #14 Contd…. CT Angiography: The bilateral lower extremity peripheral arterial accesses have minimal diameters 10.5mm STS risk mortality: 1.5% EuroScore II risk: 1.96% Logistic Euroscore mortality: 11.3% Course: Patient is determined to be intermediate risk for surgical AVR due to history of age and cognitive impairment. Plan Today: Patient is planned for Edwards Sapien-3 TAVR (23 mm) via percutaneous femoral access and conscious sedation. SLIDE TO BE EDITED BY JK

Transthoracic Echo Severe valvular aortic stenosis; peak gradient = 85 mmHg, mean gradient = 58 mmHg, Doppler valve area = 0.66 sq cm, Ao peak CW velocity = 4.7 m/sec, LVEF 63%

CTA: Aortic Annulus Annulus Max: 25.2 mm Min: 21.3 mm Mean: 23.0 mm Perimeter = 73.5 mm Area = 4.10 cm2 Annular angle = 38° Annulus diameter: 25.2x 21.3mm Annulus area: 410mm2 Annulus angle: 38°°

CTA: SOV and STJ Sinus of Valsalva Mean Diameter = 31.1 mm Sino-tubular junction height (above annulus) = 20.9 mm Ascending aorta = 33 mm 30.0 mm 32.1mm 31.1 mm RCA: 18.7 mm LM: 18.9 mm

CTA: Access – 3D

Access: Iliac and common femoral arteries Rt CIA: 11.4mm Lt CIA: 10.5mm Rt CFA: 9.7mm Lt CFA: 9.8mm Calcific Left CFA

Valve Sizing: Sapien 3 Our Patient 410 mm2 23.2 mm

SAPIEN Platforms in PARTNER Device Evolution

Summary of Case - 81 year old male - NYHA Class III - TTE: AS – mean gradient 58 mmHg STS mortality: 1.5% EuroScore II mortality: 1.96% Logistic Euroscore mortality: 11.3% Course: Patient is determined to be intermediate risk for surgical AVR due to age & cognitive impairment For 23 mm Edwards Sapien 3 valve via percutaneous femoral approach under conscious sedation.

Issues Related To The Case Increasing Benefit of TAVR in Intermediate Risk Group

Total and Annual Number of TAVR Candidates in the Individual Countries Total of TAVR Candidates in Different Countries Under Current Treatment Indications Annual Number of TAVR Candidates in Different Countries Under Current Treatment Indications Approx 3.4% of population beyond 75yrs have severe AS = 300,000 in USA Osnabrugge et al., J Am Coll Cardiol 2013;62:1002

K-M Curves of H-R Pts Treated with TAVR or SAVR with a STS Predictor Score of 7% or Less at 2 Yrs All-Cause Mortality Cardiovascular Mortality Reardon et al., JAMA Cardiol August 2016 Epub

Clinical Outcomes at 2 Yrs for H-R Patients Treated with TAVR or SAVR with STS PROM Score of <7% TAVR (n=202) SAVR (n=181) p=0.01 p=0.001 p=<0.001 p=0.01 p=<0.001 p=0.31 % p=0.01 Reardon et al., JAMA Cardiol August 2016 Epub

FRANCE-2 Registry: Late Outcomes of TAVR in High-Risk Patients for 3-Year Follow-Up (n=4201) (n=1731) (n=727) <20% (n=2341) 20%-30% (n=936) >30% (n=917) TF (n=3064) TA (n=735) SC (n=242) 0-1 (n=3072) 2-4 (n=529) Gilard et al. J Am Coll Cardiol 2016;68:1637

FRANCE-2 Registry: Multivariate Predictors Of 3-Year All-Cause Mortality Gilard et al. J Am Coll Cardiol 2016;68:1637

FRANCE-2 Registry: Cardiovascular Events Occurring at Different Time Periods After TAVR 0-1 Month (n=3999) 1-12 Months (n=3522) 1-2 Year (n=2966) 2-3 Year (n=2522) % Gilard et al. J Am Coll Cardiol 2016;68:1637

Echocardiographic Measurements for All Time Points FRANCE-2 Registry: Echocardiographic Evaluation of Valve Performance Before and After TAVR and During 3-Yr Follow-Up Echocardiographic Measurements for All Time Points Gilard et al. J Am Coll Cardiol 2016;68:1637

PARTNER 2A Trial: Study Design Randomized Patients n = 2032 Symptomatic Severe Aortic Stenosis ASSESSMENT by Heart Valve Team Operable (STS ≥ 4%) TF TAVR (n = 775) Surgical AVR VS. ASSESSMENT: Transfemoral Access Transapical (TA) / TransAortic (TAo) Transfemoral (TF) 1:1 Randomization (n = 482) 1:1 Randomization (n = 1550) TA/TAo TAVR (n = 236) Surgical AVR (n = 246) Yes No Primary Endpoint: All-Cause Mortality or Disabling Stroke at Two Years CR Smith, ACC 2016

PARTNER 2A Trial: Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke 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 Leon M et al. NEJM 2016;374:1609

PARTNER 2A Trial: Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke p (log rank) = 0.05 HR: 0.79 [95% CI: 0.62, 1.00] 16.8% 20.4% 3 6 9 12 15 18 21 24 10 20 30 40 50 15.9% 7.7% 12.3% 4.9% TF TAVR TF Surgery All-Cause Mortality or Disabling Stroke (%) Months from Procedure Leon M et al. NEJM 2016;374:1609

PARTNER 2A Trial: Clinical Endpoints (ITT) at 2 Years TAVR (n=1011) SAVR (n=1021) p=0.33 p=0.45 p=0.29 p=0.005 p=0.67 % p=0.83 p=0.02 Death/stroke Death All stroke Disabling Major vasc PPM AKI stroke compl Leon M et al. NEJM 2016;374:1609

PARTNER 2A Trial: Severity of PVR at 30 Days and All-Cause Mortality at 2 Years (VI) 14.1% 13.5% 34.0% 10 20 30 40 50 3 6 9 12 15 18 21 24 Overall Log-Rank p = 0.001 None/Trace Mild Moderate/Severe Mod/Sev (reference = None/Trace) p (Log-Rank) < 0.001 All-Cause Mortality (%) Months from Procedure Leon M et al. NEJM 2016;374:1609

Sapien-3 Observational Study: The PARTNER 2A and S3i Trial Lancet On-line

The PARTNER 2A and S3i Trials: Study Design Intermediate Risk Symptomatic Severe Aortic Stenosis Intermediate Risk ASSESSMENT by Heart Valve Team P2 S3i n = 1078 ASSESSMENT: Optimal Valve Delivery Access TA/TAo TAVR SAPIEN 3 Transapical / Transaortic (TA/TAo) TF TAVR Transfemoral (TF) P2A n = 2032 ASSESSMENT: Transfemoral Access Transapical / TransAortic (TA/TAo) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR SAPIEN XT Surgical AVR VS TA/Tao TAVR SAPIEN 3 Primary Endpoint: All-Cause Mortality, All Stroke, or Mod/Sev AR at One Year (Non-inferiority Propensity Score Analysis) Thourani , ACC 2016

Sapien-3 Trial: Unadjusted Time-to- Event Analysis – All-Cause Mortality and All Stroke (AT) 1077 1012 987 962 930 944 805 786 757 743 10 20 30 40 3 6 9 12 2.0% 8.0% 8.4% 16.6% All-Cause Mortality / Stroke Rate (%) SAPIEN 3 TAVR P2A Surgery Number at risk: S3 TAVR Months from Procedure Thourani et al. Lancet 2016;386:2218

Sapien 3 Observation Study: Outcomes at 1 Year Sapien 3 TAVR (n=1077) SAVR (n=944) % Death Stroke Disabling All-cause Rehosp New PPM stroke death Thourani et al. Lancet 2016;386:2218

CoreValve US Pivotal SURTAVI Trial: Design Severe AS Indication for AVR Separate randomization for AS+CAD Heart Team Discussion Europe: STS mortality risk score > 3% and < 8% US: STS mortality risk score > 4 and < 10% Yes Suitable for Randomization No Non-randomization Registries 1:1 Randomization N = 1400 N = 1760 AVR Control N = 220 TAVI VS AVR TAVI VS Medical Management Primary Endpoint: All cause Mortality and Stroke at 2 yrs N = 220 Endpoint: All-cause Mortality at 2 yrs Trial has completed enrollment and data will be presented in AHA 2017 35

Insights from the STS/ACC TVT Registry Relationship Between Procedure Volume and Outcome for Transcatheter Aortic Valve Replacement in U.S. Clinical Practice: Insights from the STS/ACC TVT Registry

There is a Range of TAVR Mortality in US Practice Risk Adjustment: Using variables from the previously developed TVT in-hospital mortality model. Edwards et al., JAMA, Epub March 9, 2016

TAVR Complications: Transfemoral Population In-Hospital Outcomes - Volume Mortality Vascular complications Bleeding Complications Unadjusted Adjusted Adjusted Adjusted Unadjusted Unadjusted P Value for Association Unadjusted = <0.0001 Adjusted = 0.1494 Unadjusted = <0.0001 Adjusted = <0.0001 JD Carroll, ACC 2016

The PARTNER 3 Trial: Study Design Symptomatic Severe Calcific Aortic Stenosis Age <65yrs Low Risk ASSESSMENT by Heart Team (STS < 3%, TF only) PARTNER 3 Registries 1:1 Randomization (n=1228) Alternative Access (n=100) (TA/TAo/Subclavian) TF - TAVR (SAPIEN 3) Surgery (Bioprosthetic Valve) CT Imaging Sub-Study (n=200) CT Imaging Sub-Study (n=200) Bicuspid Valves (n=100) Actigraphy/QoL Sub-Study (n=100) Actigraphy/QoL Sub-Study (n=100) ViV (AV and MV) (n=100) Primary Endpoint: Composite of all-cause mortality, all strokes, or re-hospitalization at 1 year post-procedure Follow-up: 30 days, 6 mos, 1 year and annually through 10 years

Medtronic TAVR in Low Risk Patients Trial Design & leaflet Sub-study Patient Population: Low Risk Cohort Determined by Heart Team to be low surgical risk Primary Endpoint: Safety: Death, all stroke, life-threatening bleed, major vascular complications or AKI at 30 days Efficacy: Death or major stroke at 2 yrs Sample Size: ~1200 Subjects Follow-up Evaluations: 30-days, 6-month , 18-month, and 1 through for 5 years Number of Sites: Up to 80 sites

Cumulative TAVR Procedures: TVT Registry 2012 to 2014 TAVR in USA Procedural Performance and Outcome of TAVR since FDA Approval 65% 35% 2016 Projections: ≈3000 TAVR per month in USA Holmes et al., J Am Coll Cardiol 2015

Estimated Global TAVR Procedure Growth SOURCE: Credit Suisse TAVI Comment –January 8, 2015. ASP assumption for 2024 and 2025 based on analyst model. Revenue split assumption in 2025 is 45% U.S., 35% EU, 10% Japan, 10% ROW In the next 10 years, TAVR growth will increase X4!

Take Home Message: Increasing Benefit of TAVR in Intermediate Risk RCT and carefully planned registries involving severe AS pts have shown the superiority of TAVR over SAVR including numerically lower neurological events. These observations have resulted in approval of Sapien TAVR in intermediate risk AS pts Long-term data of TAVR valve durability will be studied and essential in the low risk AS trials. Overall TAVR valve hemodynamics studies have shown valve gradient to be stable for 4-5 years of careful F/U. Ongoing studies utilizing 4D CTA will prospectively answer the question of TAVR vs SAVR valve durability.

Question # 1 Following is the true statement about benefit of TAVR vs SAVR in the PARTNER IIA trial: TAVR had significantly lower mortality than SAVR TAVR had lower CVA rates than SAVR TF TAVR had significantly lower mortality than SAVR TAVR had similar PPM rates than SAVR

Question # 2 FRANCE-2 long-term follow-up study has shown the following except: Majority of neurological events occurs early Majority of death on long-term occur from non-cardiac cause There is gradual deterioration of the TAVR valve on echo after 1 year Majority of PPM are implanted in first 30 days

Question # 3 Which of the following is the exclusion for the ongoing low risk trials of TAVR vs SAVR: A. Bicuspid aortic valve stenosis B. STS of <3 C. Femoral arteries size >6mm D. Age <65yrs

Correct answer: C Question # 1 Following is the true statement about benefit of TAVR vs SAVR in the PARTNER IIA trial: TAVR had significantly lower mortality than SAVR TAVR had lower CVA rates than SAVR TF TAVR had significantly lower mortality than SAVR TAVR had similar PPM rates than SAVR Correct answer: C

Correct answer: C Question # 2 FRANCE-2 long-term follow-up study has shown the following except: Majority of neurological events occurs early Majority of death on long-term occur from non-cardiac cause There is gradual deterioration of the TAVR valve on echo after 1 year Majority of PPM are implanted in first 30 days Correct answer: C

Correct answer: A Question # 3 Which of the following is the exclusion for the ongoing low risk trials of TAVR vs SAVR: A. Bicuspid aortic valve stenosis B. STS of <3 C. Femoral arteries size >6mm D. Age <65yrs Correct answer: A