Polypharmacy Anticoagulation AF Meets PCI David J Moliterno

Polypharmacy Anticoagulation: AF Meets PCI David J. Moliterno, MD Professor and Chairman Department of Internal Medicine The University of Kentucky Linda and Jack Gill Heart Institute

Disclosures “Polypharmacy Anticoagulation: AF Meets PCI” DSMB: Jannsen Pharmaceuticals (GEMINI Study) Research Grant: Merck (Steering Committee: TRACER and TRA 2 P) Astra Zeneca (Steering Committee: TWILIGHT Study)

Optimal Anticoagulation—does it exist? Bleeding Thrombosis intensity x duration

Intrinsic-Extrinsic-Cellular Intrinsic Pathway (Surface Contact) Extrinsic Pathway (Tissue Factor) VIIa XIa IXa Platelet surface Xa Thrombin (IIa) Fibrin-bound Thrombin

Antithrombotic Options Old New n Aspirin n Oral P 2 Y 12 n Thienopyridines n IV P 2 Y 12 n GP IIb/IIIa n PAR-1 n Heparin n Pentasaccharide n LMWH n Factor aptamers n Warfarin n Oral anti-Xa n DTI n Oral anti-IIa

Ischemia-Bleeding Trade-Off Trial MACE Bleeding (Drug) (D/M/C) (TIMI Major) CURRENT (clopidogrel HD) 0. 6% 0. 5% TRITON (prasugrel) 2. 2% 0. 6% PLATO (ticagrelor) 1. 9% 0. 7% TRACER (vorapaxar) 1. 7% 1. 1% DAPT (18 vs 30 mo) 1. 6% 0. 9% COMPASS (riva + ASA) 1. 3% 1. 2%

STARS Successful BMS to 3. 0 -4. 0 mm Vessel N = 1, 653 Aspirin 325 mg QD + Ticlid 250 mg BID Aspirin 325 mg QD + Warfarin INR 2 -2. 5 • 30 -Day Clinical Events • Leon MB et al. N Engl J Med 1998; 339: 129 -1665 -1671

STARS 30 -Day Death, MI, TVR, ST 5% RR 0. 15 -0. 20 P<0. 01 4% Aspirin 3. 6% 3% Aspirin + Warfarin 2. 7% 2% 1% Aspirin + Ticlopidine 0. 5% 0 0 5 10 15 20 Days Leon MB et al. N Engl J Med 1998; 339: 129 -1665 -1671 25 30

Atrial Fibrillation § Most common sustained cardiac arrhythmia § Currently affects nearly 2. 3 million Americans, or 1% of population § Prevalence expected to increase 2. 5 x by 2050 § Lifetime risk of developing AF: 1 in 4 for men and women ≥ 40 years of age § Among ACS-PCI patients, 5% have AF

Atrial Fibrillation • • • C 1 H A D S 2 Congestive Heart Failure = HTN (or treated HTN) = 1 Age ≥ 75 years = 1 Diabetes = 1 Prior Stroke or TIA = 2 Total Score 0 1 2 3 4 5 6 Annual Risk of Stroke (%) 1. 9 2. 8 4. 0 5. 9 8. 5 12. 5 18. 2 Gage BF et al. JAMA 2001; 285: 2864 -2870

Atrial Fibrillation ACTIVE-W: ACTIVE-A: 6706 randomized patients; trial stopped 7554 randomized patients; median follow-up of 3. 6 years 8 Clopidogrel + ASA 5 4 P =. 001 3 P =. 53 2 Outcome/Year (%) P =. 0003 5 4 P <. 001 2 0 0 Major Bleeding P <. 001 3 1 Stroke ASA 6 1 Vascular Event Clopidogrel + ASA 7 Vitamin K Antagonist 6 P =. 01 Vascular Event Stroke Major Bleeding ACTIVE Investigators. Lancet. 2006; 367: 1903 -1912 N Engl J Med. 2009; 360: 2066 -2078

Danish Registry § § Danish National Registry 2000 -2009 11, 480 subjects with AF and new MI or PCI Categorized as single, double, triple therapies Reviewed early and late (1 year) hospitalizations for bleeding and ischemic events Lamberts M et al. Circulation 2012; 126: 1185 -1193

Danish Registry Crude Incidence (100 person years) 50% *Adjusted Cox Model 40% 38. 0 HR 1. 15* (0. 95 -1. 40) 30% 26. 9 HR 1. 41* (1. 10 -1. 81) 20% 26. 3 19. 4 20. 1 14. 2 10% 6. 9 0 7. 0 9. 7 SAPT OAC DAPT OSAP Bleeding Events TT SAPT OAC DAPT OSAP Ischemic Events Lamberts M et al. Circulation 2012; 126: 1185 -1193 TT

ISAR-TRIPLE Patients receiving OAC undergoing DES N = 614 OAC + ASA 75 -200 mg daily Clopidogrel 300 -600 mg, then 75 mg daily 6 weeks Clopidogrel 300 -600 mg, then 75 mg daily 6 months • 9 -Month Death, MI, CVA, ST, TIMI Major Bleeding • Fiedler KA et al. J Am Coll Cardiol 2015: 65: 1619 -1629

ISAR-TRIPLE Ischemic Events 10% BARC ≥ 2 25% 6 Weeks (n=307) 8% 6 Months (n=307) P=0. 41 20% 21. 3 18. 4 6% 15% P=0. 07 P=0. 87 4% 4. 3 P=0. 13 4. 0 12. 2 10% 3. 4 2% 7. 6 5% 1. 4 0 0 9 Months 6 W to 9 M Fiedler KA et al. J Am Coll Cardiol 2015: 65: 1619 -1629

WOEST What is the Optimal antiplat. Elet and anticoagulant therapy in patients with oral anticoagulation and coronary Sten. Ting PCI OAC required ≥ 1 year: AF, mechanical valve N = 573 OAC + clopidogrel 75 mg daily OAC + clopidogrel 75 mg + ASA 81 mg daily • 1 -Year Any TIMI Bleeding • Dewilde et al. Lancet 2013: 381: 1107 -1115

WOEST Primary Outcome: Any TIMI Bleeding 50% Triple Therapy 40% 44. 4% 30% Double Therapy 19. 4% 20% 10% HR 0. 36 95% CI 0. 26 -0. 50 P<0. 0001 0 0 30 60 90 120 150 180 210 240 Days Dewilde et al. Lancet 2013: 381: 1107 -1115 270 300 330 365

WOEST Death, MI, CVA, TVR, ST 20% 17. 7% Triple Therapy 15% 10% 11. 3% Double Therapy 5% HR 0. 60 95% CI 0. 38 -0. 94 P=0. 025 0 0 30 60 90 120 150 180 210 240 Days Dewilde et al. Lancet 2013: 381: 1107 -1115 270 300 330 365

REDUAL PCI § § DES + atrial fibrillation; N= 2, 725 VKA+DAPT vs Dabigatran 110/150 mg+P 2 Y 12 Major bleeding or clinically relevant at 14 months MACE: death, MI, CVA, SE, unplanned revasc Cannon CP et al. N Engl J Med 2017; 377: 1513 -1524

REDUAL PCI Major or Clinically Relevant Bleeding 40% 32% 24% HR 0. 72 (0. 58 -0. 88) P<0. 001 HR 0. 52 (0. 42 -0. 63) P<0. 001 26. 9 25. 7 20. 2 16% 15. 4 8% 0 VKA + DAPT n=764 Dabigatran 150 + P 2 Y 12 n=763 VKA + DAPT n=981 Dabigatran 110 + P 2 Y 12 n=981 Cannon CP et al. N Engl J Med 2017; 377: 1513 -1524

REDUAL PCI MACE (Death, MI, CVA, SE, UR) 20% 16% HR 0. 89 (0. 67 -1. 19) P=0. 44 HR 1. 13 (0. 90 -1. 43) P=0. 30 15. 2 12% 12. 8 13. 4 11. 8 8% 4% 0 VKA + DAPT n=764 Dabigatran 150 + P 2 Y 12 n=763 VKA + DAPT n=981 Dabigatran 110 + P 2 Y 12 n=981 Cannon CP et al. N Engl J Med 2017; 377: 1513 -1524

Ongoing Studies GLOBAL LEADERS Vranckx P et al. Euro. Intervention 2016 TWILIGHT Baber U et al. Am Heart J 2016

Summary § ≥ 5% of ACS-PCI patients have or will soon develop AF § More potent or polypharmacy antithrombotics have reduced the incidence of ischemic events by 1 -2% but increased major bleeding events by 1% § Triple therapy (OAC + DAPT) is associated with ~40% increased risk of significant bleeding § WOEST and Re. DUAL suggest double therapy using OAC and SAPT (clopidogrel) at least as effective and safer than triple therapy with VKA § For longer-term care, monotherapy vs “safer” dual § European and North American Consensus documents provide assessment and management guidance