Structural Heart Live Cases Supported by: Medtronic inc Bard Inc 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 George Dangas, MD, FACC Nothing to disclose for today’s presentation Gilbert Tang, MD Physician proctor for Medtronic Inc

March 14th 2017 Structural Heart Live #16: CS, 88 yr. F Presentation: Worsening dyspnea on exertion NYHA class III PMH: Hypertension, Hyperlipidemia, HFpEF, DM, AF on Coumadin, PPM, CABG, Colorectal Carcinoma, PUD, Anemia, Hypothyroidism and OSA Medications: Aspirin, Warfarin, Torsemide, Atorvastatin, Telmisartan, Omeprazole, Levothyroxine TTE (1/31/17): Severe AS; PG/MG= 68/42mmHg, Doppler valve area = 0.64 cm2, Ao peak velocity = 4.13 m/s, LVEF 62% EKG (03/13/17): Paced (Previous AV node ablation and PPM) Cath (1/30/17): III V CAD, patent LIMA and SVG to D2, RPDA, RPL1 and RI. Moderate PHTn

March 14th 2017 Structural Heart Live #16 Contd…. CT Angiography: The bilateral lower extremity peripheral arterial accesses have minimal diameters 6.5 mm STS risk mortality: 13.86 % EuroScore II risk: 24.62% Logistic Euroscore mortality: 49.15% Course: Patient is determined to be extreme risk for surgical AVR due to age and co-morbidities. Plan Today: Patient is planned for Medtronic Evolut-R TAVR (29 mm) via percutaneous femoral access and GA. SLIDE TO BE EDITED BY JK

Transthoracic Echo Severe aortic stenosis; peak gradient = 68 mmHg, mean gradient = 42 mmHg, Doppler valve area = 0.64 sq cm, Ao peak CW velocity = 4.13m/sec, LVEF 62%

CTA: Aortic Annulus Annulus Min: 21 mm Max: 26 mm Mean: 23.5 mm Perimeter = 75.4 mm Area = 442 mm2 Annular angle = 51° Annulus diameter: 21 x 26mm Annulus perimeter:75.4mm Annulus angle: 51°°

CTA: SOV, STJ, Coronary Ostia Sinus of Valsalva Mean Diameter = 32.7 mm Sino-tubular junction height (above annulus) = 22.0 mm Ascending aorta = 33 mm 31.5 mm 33.7mm 32.9 mm RCA: 15mm LM: 16 mm

CTA: Access – 3D

Access: Iliac and common femoral arteries Rt CIA: 7.9 mm Lt CIA: 8.6 mm Rt CFA: 6.9mm Lt CFA: 6.5mm

EVOLUT R 29 MM Patient Selection Matrix Criteria CoreValve Evolut R TAV Valve Size Selection Size 23 mm 26 mm 29 mm 34 mm Annulus Diameter 18 – 20 mm 20 – 23 mm 23 – 26 mm 26 - 30 mm Annulus Perimeter (π x Diam) 56.5 – 62.8 mm 62.8 – 72.3 mm 72.3 – 81.7 mm 81.7 – 94.2 mm Sinus of Valsalva Diameter (Mean) ≥ 25 mm ≥ 27 mm ≥ 29 mm ≥ 31 mm Sinus of Valsalva Height (Mean) ≥ 15 mm ≥ 16 mm Our patient 23.5 75.4 32.7 22.0

Summary of Case - 88 year old male - NYHA Class III - TTE: AS – mean gradient 42 mmHg - STS mortality: 13.86 % - EuroScore II mortality: 24.62 % - Logistic Euroscore mortality: 49.15 % - Patient is determined to be extreme risk for surgical AVR due to age and co-morbidities - For 29 mm Medtronic Evolut-R CoreValve via percutaneous femoral approach under GA

Issues Related To The Case Oral anticoagulation and adverse impact of AFib Post-TAVR

TAVR Valve Degeneration: Progression and Predictors

Clinical Outcomes (Stroke/TIA) at F/u Impact of Anticoagulation & Reduced Leaflet Motion % % (n=0/13) (n=10/35) (n=1/115) (n=3/17) Makkar et al., N Engl J Med 2015;373:2015

Mechanisms of Embolic Complications During and After TAVR: Acute Risk Highest and Likely Embolic Stortecky and Windecker, Circulation 2012; 126:2921

Warfarin and Antiplatelet Therapy Versus Warfarin Alone for Treating Patients With Atrial Fibrillation Undergoing Transcatheter Aortic Valve Replacement JACC Card. Intervention 2016; 9: 1706

Study Flowchart Seeger et al., J Am Coll Cardiol Intv 2017;10:66 Stop VKA 7days/non-VKA 2 days prior to TAVR Continuous aspirin 100 mg/d or loading dose 500 mg Transfemoral TAVR (n=617) Atrial fibrillation/ new-onset AF (n=272) Antiplatelet therapy for 4 weeks Restart oral anticoag 48 hrs post TAVR VKA (n=131) Apixaban (n=141) 30 days follow-up 12 months follow-up Sinus rhythm (n=345) Antiplatelet therapy Pre-procedure 48 hours 30 days 12 months Seeger et al., J Am Coll Cardiol Intv 2017;10:66

30-Day Clinical Outcomes Atrial Fibrillation (n=272) Sinus Rhythm (n=345) Atrial Fibrillation (n=272) P Value Early safety endpoint (%) 33 59 <0.01 Secondary outcome measure (%) 14 27 0.02 All-cause mortality (%) 8 7 0.84 Disabling and non-disabling stroke (%) 10 0.82 Intracerebral bleeding (%) 1 0.26 Acute kidney injury stages 2 and 3 (%) 5 0.01 Life-threatening bleeding (%) 3 12 Major vascular complications (%) 13 15 0.32 Valve dysfunction requiring a repeat procedure (%) - Endocarditis (%) Seeger et al., J Am Coll Cardiol Intv 2017;10:66

Late Follow-up at 12 Months Atrial Fibrillation (n=131) Sinus Rhythm (n=154) Atrial Fibrillation (n=131) P Value Secondary outcomes measure (All-cause mortality and All-stroke) (%) 14 27 0.02 MACE (%) 18 31 All-cause mortality (%) 12 25 0.01 Disabling and non-disabling stroke (%) 2 0.87 Major bleeding (%) 1 0.35 Myocardial infarction (%) 0.19 Rehospitalization (%) 22 0.28 Seeger et al., J Am Coll Cardiol Intv 2017;10:66

Landmark Analysis of Mortality Seeger et al., J Am Coll Cardiol Intv 2017;10:66

Patients with Atrial Fibrillation: 30 Day Clinical Outcome Apixaban (n=141) Vitamin K Antagonist (n=131) P Value Early safety endpoint (%) 19 40 <0.01 All-cause mortality (%) 2 5 0.22 Disabling and non-disabling stroke (%) 3 7 0.17 Intracerebral bleeding (%) 1 0.34 Acute kidney injury stages 2 and 3 (%) 11 Life-threatening bleeding (%) Major vascular complications (%) 10 0.09 Valve dysfunction requiring a repeat procedure (%) - Endocarditis (%) Seeger et al., J Am Coll Cardiol Intv 2017;10:66

Patients with Atrial Fibrillation: 12-Month Follow-Up Apixaban (n=81) Vitamin K Antagonist (n=50) P Value MACE (%) 22 9 0.34 All-cause mortality (%) 19 6 0.18 Disabling and non-disabling stroke (%) 1 0.73 Rehospitalization (%) 14 8 0.87 Secondary outcome measure (All-cause mortality and All stroke) (%) 20 7 0.23 Seeger et al., J Am Coll Cardiol Intv 2017;10:66

Outcomes in Patients with AF: Apixaban vs VKA Short-Term Follow-Up until 30 Days Post-Procedure Landmark Analysis of All Stroke Apixaban (n141) Vit K antagonist (n131) Apixaban (n141) Vit K antagonist (n131) 0 50 100 150 200 250 300 350 Event-free survival from stroke, % Hazard ratio 1.04 (95% CI 0.06-16.6) Log-rank p=0.98 p=0.42 p=0.60 % p=0.52 All-cause Disabling/ Secondary outcome mortality nondisabling stroke measure Seeger et al., J Am Coll Cardiol Intv 2017;10:66

The ARTE trial (Aspirin Versus Aspirin + ClopidogRel Following Transcatheter Aortic Valve Implantation) ~300 patients undergoing TAVR Receive drugs 24 hrs in advance* Aspirin (atleast 6 months) Aspirin (atleast 6 mths) + clopidogrel (atleast 3 months) 12 Months F/U The ACCOAST will test preloading with a reduced dose of prasugrel  Death, MI, ischemic stroke/Transient ischemic attack (TIA) or life threatening/major bleeding * For trans-apical start clopidogrel within 24 hrs after TAVR Rhodes-Cabau J. clinicaltrials.gov/show/NCT01559298‎

Ongoing TAVI Pharmacology Trial

- 2017: The ENVISAGE Trial - Successful TAVR n=2200 Patients With an Indication to Chronic Oral Anticoagulation RANDOMIZE 1:1 1-5 Days after the procedure Background Tx: Single Antiplatelet Therapy as per treating MD discretion (Stratification Variable) Warfarin (target INR 2-3) n = 1100 Edoxaban 60mg n= 1100 Minimum duration of randomized therapy 12 months CLINICAL FOLLOW-UP: 1, 6, 12 Months Primary Safety Endpoint: Major Bleeding Primary Endpoint - NACE [Composite of Death, MI, Stroke, TIA, systemic thromboembolism or VARC-2 Life-threatening (LT) or Major bleeding] Ancillary Imaging Study MRI substudy 4D CT substudy Cost-Effectiveness Neurocognitive function, frailty & QoL substudy Secondary Endpoints All-cause Death, MI, Stroke or TIA, VARC-2 Life-threatening (LT) bleeding and Major bleeding

Take Home Message: Oral Anti-coagulation and Impact of AFib post-TAVR Pts undergoing TAVR who had or develops Afib have worse prognosis compared to pts with sinus rhythm. This higher MACE in Afib TAVR pts is the result of higher mortality (not stroke) at F/u Comparative efficacy of VKA vs NOACs in Afib pts post TAVR has shown NOACs to be better at short term but VKA pts have trend towards better outcomes at one year. This question is being investigated in a planned RCT of VKA vs NOAC in pts with Afib post TAVR

Correct answer: C Question # 1 Following are the true statement regarding outcomes of Afib vs NSR in TAVR pts except: Stroke incidence is similar between 2 groups Mortality is higher in the Afib group vs NSR Mortality is similar between 2 groups Vascular complications and bleeding is numerically higher in the Afib gp vs NSR gp Correct answer: C

Correct answer: C Question # 2 Following are the true statements regarding outcomes of Afib pts on NOAC vs VKA except: NOAC pts has better short term outcomes vs VKA NOAC pts have lower bleeding vs VKA NOAC pts have lower MACE rates at 1 year vs VKA pts RCT are ongoing to assess the efficacy of NOAC vs VKA Correct answer: C

Correct answer: A Question # 3 Following are the RCT of antithrombotic post TAVR except: A. SENTINEL B. ATLANTIS C. GALILEO D. ENVISAGE Correct answer: A