Low Dose Rivaroxaban Versus Aspirin, in Addition to P2Y12 Inhibition, in Acute Coronary Syndromes (GEMINI-ACS-1)

Low Dose Rivaroxaban Versus Aspirin, in Addition to P2Y12 Inhibition, in Acute Coronary Syndromes (GEMINI-ACS-1) Caitlin C. Akerman, PharmD PGY2 Cardiology Resident WakeMed Health & Hospitals Raleigh, NC

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Dr. Caitlin C. Akerman (presenter) Dr. Akerman is the current PGY2 Cardiology Resident at WakeMed Health & Hospitals in Raleigh, North Carolina. She received her Bachelor of Science in Chemistry at Appalachian State University in 2012 and her Doctor of Pharmacy from the UNC Eshelman School of Pharmacy in 2016. She completed her PGY1 Pharmacy Practice Residency at WakeMed Health & Hospitals.

Dr. John Lindsley (mentor) Dr. Lindsley is a Clinical Pharmacy Specialist in the Cardiac Care Unit and the Program Director for the PGY-2 Cardiology Residency at the Johns Hopkins Hospital. He graduated from Rutgers University College of Pharmacy and completed a PGY-1 Residency at UC Health and a PGY-2 Residency in Cardiology at The Ohio State University Medical Center.

Disclosure Statement I have no financial relationships with commercial interests that pertain to the content presented in this program.

Background 2016 ACC/AHA guidelines recommend at least 12 months of dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) patients Despite the use of DAPT, morbidity and mortality rates remain elevated in post-acs patients Trial P2Y12 Inhibitor Primary Outcome Event* CURE Clopidogrel + ASA 9.3% TRITON-TIMI 38 Prasugrel + ASA 9.9% PLATO Ticagrelor + ASA 9.8% *Composite cardiovascular mortality, non-fatal MI, or non-fatal stroke J Am Coll Cardiol 2016;68(10):1082-1115. N Engl J Med 2001;345:494-502. N Engl J Med 2007;357:2001-2015. N Engl J Med 2009;361:1045-1057.

Potential Benefit of Oral Anticoagulant Am Heart J 2016;174;120-128.

Triple Therapy Post-ACS ATLAS ACS- TIMI 46 Dose titrated rivaroxaban (5, 10, 15, 20 mg daily) vs placebo in post-acs patients receiving DAPT Dose-dependent increases in bleeding but not efficacy ATLAS ACS-2- TIMI 51 Low dose rivaroxaban (2.5 mg BID or 5 mg BID) vs placebo in post-acs patients receiving DAPT Reduced primary composite of death from CV causes, MI, or stroke (p=0.008, NNT 56) Increased risk of bleeding with rivaroxaban (p<0.001, NNH 67) Lancet 2009;374:29-38. N Engl J Med 2012;366:9-19.

Triple Therapy Post-ACS APPRAISE-2 Apixaban 5 mg BID vs placebo post-acs in patients receiving DAPT High risk patient population Study ended early due to increased bleeding risk without additional clinical benefit RE-DEEM Dose-titrated dabigatran (50 mg, 75 mg, 110 mg, 150 mg BID) vs placebo in DAPT patients Dose-dependent increased rates of bleeding Numerically lower rate of CV death, non-fatal MI, or stroke in 110 and 150 mg BID groups N Engl J Med 2011;365:699-708. Eur Heart J 2011;32(22):2781-89.

Removing Aspirin from Triple Therapy WOEST Warfarin + DAPT vs warfarin + clopidogrel alone Rates of bleeding significantly higher in the triple therapy group Composite of death, MI, stroke, stent thrombosis, and revascularization lower in double therapy group PIONEER AF-PCI Rivaroxaban 15 mg + P2Y12 inhibitor vs rivaroxaban 2.5 mg BID + DAPT vs warfarin + DAPT Increased rate of bleeding in the triple therapy warfarin group No difference in composite CV mortality, MI, or stroke Lancet 2013;381:1107-15. N Engl J Med 2016;375:2423-2434.

Potential Benefit of Rivaroxaban vs Aspirin In vivo rat models found that thrombin generation with ticagrelor + rivaroxaban was: Comparable to triple therapy More effective than DAPT In vitro models of platelet inhibition saw synergy with ticagrelor + rivaroxaban Anti-inflammatory effects in the left ventricle Theorized reduction in GI bleeding events Am Heart J 2016;174;120-128. J Cardiovasc Pharmacol Ther 2015;20:554-562. Int J Cardiol 2016;220:602-7.

GEMINI-ACS-1: Objective To determine if adding low dose rivaroxaban to clopidogrel or ticagrelor would have acceptable bleeding rates compared with DAPT (P2Y12 inhibitor plus aspirin) Lancet 2017;389:1799-808.

Methods Design Phase 2, multicenter, double-blind, RCT 1:1 randomization to either rivaroxaban or aspirin (ASA) Provider could choose P2Y12 inhibitor Treatment Rivaroxaban 2.5 mg PO BID + P2Y12 inhibitor + placebo vs ASA 100 mg PO daily + P2Y12 inhibitor + placebo Lancet 2017;389:1799-808.

Study Population Inclusion > 18 years old Unstable angina, NSTEMI, STEMI Diabetes or previous MI in patients <55 years Exclusion Active bleeding, h/o ICH, or significant GI bleed in the previous 12 months Omeprazole in clopidogrel group CrCl < 20 ml/min Indication for full dose anticoagulation Lancet 2017;389:1799-808.

Outcomes Primary endpoint: non-cabg TIMI clinically significant bleeding Exploratory efficacy analysis: Composite cardiovascular (CV) death, myocardial infarction (MI), stroke, or definite stent thrombosis Individual components of above composite All cause mortality Lancet 2017;389:1799-808.

Lancet 2017;389:1799-808. Demographic Baseline Demographics Aspirin (n=1518) Rivaroxaban (n=1519) Total (n=3037) Age, years (IQR) 63 (57-69) 62 (57-69) 62 (57-69) Clopidogrel, n (%) Ticagrelor, n (%) 666 (44%) 852 (56%) 667 (44%) 852 (56%) 1333 (44%) 1704 (56%) Time from admission to randomization, days (IQR) 5.1 (3.0-7.3) 5.1 (3.1-7.2) 5.1 (3.1-7.2) STEMI, n (%) NSTEMI, n (%) Unstable angina, n (%) 741 (49%) 612 (40%) 165 (11%) 743 (49%) 611 (40%) 165 (11%) 1484 (49%) 1223 (40%) 330 (11%) Cardiac catheterization, n (%) 1430 (87%) 1425 (87%) 2855 (87%) Stent placed, n (%) DES BMS Concomitant medications, n (%) Beta blockers ACEi/ARB Statins 1286 (85%) 870 (68%) 423 (33%) 984 (65%) 960 (63%) 1065 (70%) 1295 (85%) 859 (66%) 438 (34%) 970 (64%) 947 (62%) 1038 (68%) 2581 (85%) 1729 (67%) 861 (33%) 1954 (64%) 1907 (63%) 2103 (69%) Diabetes, n (%) 460 (30%) 446 (29%) 906 (30%)

Primary Endpoint Lancet 2017;389:1799-808.

Other Bleeding Endpoints Bleeding Category Aspirin (n=1518) Rivaroxaban (n=1519) HR (95% CI) p value TIMI fatal bleeding 0 2 (<1%) NA NA Intracranial hemorrhage 0 1 (<1%) NA NA TIMI major bleeding 8 (1%) 10 (1%) 1.25 (0.49-3.17) 0.6341 TIMI non-cabg major bleeding 8 (1%) 10 (1%) 1.25 (0.49-3.17) 0.6341 TIMI minor bleeding 4 (<1%) 9 (1%) 2.25 (0.69-7.29) 0.1664 TIMI bleeding requiring medical attention 62 (4%) 62 (4%) 1.01 (0.71-1.44) 0.9581 TIMI insignificant bleeding 25 (2%) 21 (1%) 0.84 (0.47-1.50) 0.5504 GUSTO life threatening, severe, moderate, or mild bleeding 96 (6%) 99 (7%) 1.04 (0.79-1.38) 0.7869 ISTH major bleeding 17 (1%) 31 (2%) 1.83 (1.01-3.31) 0.0420 BARC 3a and higher bleeding 13 (1%) 22 (1%) 1.70 (0.85-3.37) 0.1263 Lancet 2017;389:1799-808.

Efficacy Analysis Lancet 2017;389:1799-808.

Additional Analyses No significant interaction noted between any subgroups Non-significant but numerically higher incidence of bleeding and ischemic events in first 30 days with rivaroxaban Lancet 2017;389:1799-808.

Conclusions Similar risk of TIMI non-cabg clinically significant bleeding with rivaroxaban vs aspirin No difference in ischemic events or mortality with rivaroxaban vs aspirin Further studies needed to explore efficacy of rivaroxaban compared to aspirin Lancet 2017;389:1799-808.

Critique Strengths Study design (randomized, placebo-controlled, international, multicenter) Standard-of-care comparator Majority of patients received PCI Limitations Lack of racial diversity Prasugrel not studied Most patients had normal renal function Not powered to detect difference in ischemic events Excluded patients requiring full dose anticoagulation

Practice Implications Currently do not anticipate change in practice Phase II study Possible increase in ischemic and bleeding events with rivaroxaban at 30 days 2.5 mg dosage not available in US Increased cost of rivaroxaban Future studies comparing oral anticoagulants + P2Y12 inhibitor to DAPT warranted Am Heart J 2016;174;120-128. Lancet 2017;389:1799-808.

Acknowledgements John Lindsley, PharmD, BCPS-AQ Cardiology J. Erin (Allender) Ledford, PharmD, BCPS-AQ Cardiology, BCCCP Janna Beavers, PharmD, BCPS