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

Conflict of Interest/Disclosure “Polypharmacy Anticoagulation: AF Meets PCI?” DSMB: Jannsen Pharmaceuticals (GEMINI Study) Research Grant: Merck (Steering Committee: TRACER and TRA2P) Astra Zeneca (Steering Committee: TWILIGHT Study)

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

Atrial Fibrillation Most common sustained cardiac arrhythmia Currently affects nearly 2.3 million Americans, or 1% of US population Prevalence expected to increase 2.5x 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 AF best managed with OAC among those needing antithrombotic therapy

Atrial Fibrillation ACTIVE-W: 6706 randomized patients; trial stopped ACTIVE-A: 7554 randomized patients; median follow-up of 3.6 years P = .01 8 Clopidogrel + ASA Vitamin K Antagonist Clopidogrel + ASA ASA 7 P = .0003 6 6 5 5 4 Outcome/Year (%) 4 P < .001 Outcome/Year (%) 3 P = .001 P = .53 3 P < .001 2 2 1 1 Vascular Event Stroke Major Bleeding Vascular Event Stroke Major Bleeding ACTIVE Investigators. Lancet. 2006;367:1903-1912 N Engl J Med. 2009;360:2066-2078

Leon MB et al. N Engl J Med 1998;339:129-1665-1671 STARS Successful BMS to 3.0-4.0mm Vessel N = 1,653 Aspirin 325 mg QD + Ticlid 250 mg BID Aspirin 325 mg QD + Warfarin INR 2-2.5 Aspirin 325 mg QD • 30-Day Clinical Events • Leon MB et al. N Engl J Med 1998;339:129-1665-1671

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% 5 10 15 20 25 30 Days Leon MB et al. N Engl J Med 1998;339:129-1665-1671

Lamberts M et al. Circulation 2012;126:1185-1193 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

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 26.3 HR 1.41* (1.10-1.81) 20% 19.4 20.1 14.2 10% 9.7 6.9 7.0 7.0 SAPT OAC DAPT OSAP TT SAPT OAC DAPT OSAP TT Bleeding Events Ischemic Events Lamberts M et al. Circulation 2012;126:1185-1193

Fiedler KA et al. J Am Coll Cardiol 2015:65:1619-1629 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

Fiedler KA et al. J Am Coll Cardiol 2015:65:1619-1629 ISAR-TRIPLE Ischemic Events BARC ≥2 2% 4% 6% 8% 10% 5% 10% 15% 20% 25% 6 Weeks (n=307) 6 Months (n=307) P=0.41 21.3 18.4 P=0.07 P=0.87 P=0.13 12.2 4.3 4.0 3.4 7.6 1.4 9 Months 6W to 9M 9 Months 6W to 9M Fiedler KA et al. J Am Coll Cardiol 2015:65:1619-1629

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

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 30 60 90 120 150 180 210 240 270 300 330 365 Days Dewilde et al. Lancet 2013:381:1107-1115

Dewilde et al. Lancet 2013:381:1107-1115 WOEST Death, MI, CVA, TVR, ST 20% 17.7% Triple Therapy 15% 10% Double Therapy 11.3% 5% HR 0.60 95% CI 0.38-0.94 P=0.025 30 60 90 120 150 180 210 240 270 300 330 365 Days Dewilde et al. Lancet 2013:381:1107-1115

Angiolillo et al. Circ Cardiovasc Intv 2016 Algorithm for AF-PCI Considerations Washout OAC INR ≤ 2.0 for radial INR ≤ 1.5 for femoral Withhold NOAC 24 hours (longer if SRI) Avoid polypharmacy anticoagulation (GPI) Low-dose ASA Lower INR target Shortened-course DAPT Lifelong OAC (± SAPT) Angiolillo et al. Circ Cardiovasc Intv 2016

Angiolillo et al. Circ Cardiovasc Intv 2016 Antithrombotic Management Recommended Algorithm Discontinuation of one antiplatelet agent should be considered 1-3 months after PCI, this may occur sooner (including immediately after PCI) or later (but not beyond 6 months) according to the ischemic/thrombotic and bleeding risk profiles of the patient. Angiolillo et al. Circ Cardiovasc Intv 2016

Angiolillo et al. Circ Cardiovasc Intv 2016 Algorithm for AF-PCI Considerations More frequent follow-up than AF alone or ACS alone or PCI alone Specific guidance for patient and PCP Choice, extent, duration of antithrombotic therapy may change for patient or guidelines Throughout post-PCI course need to reconsider antiplatelet risk-benefit Angiolillo et al. Circ Cardiovasc Intv 2016

Summary ~5% of ACS patients have pre-existing or soon-to- come AF Triple therapy is associated with a 40% increased risk of clinically significant bleeding Small RCT suggest Dual Therapy with OAC and SAPT (clopidogrel) at least as effective and safer For longer-term care, monotherapy vs “safer” dual Nanoparticle coated stent trial ongoing Many ongoing or planned RCT to better understand polypharmacy best practices and how NOACs and newer P2Y12 agents fit in

Ongoing Clinical Trials

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