Table 1.

Summary of RCTs

STUDY	POPULATION	INTERVENTION OR COMPARATOR	OUTCOMES	COMMENTS
TT RCTs of patients who received a coronary stent
PIONEER-AF-PCI,² 2016 Open-label, randomized trial 26 countries (about 10% from North America) N = 2124	Nonvalvular AF and PCI with stent Mean age 70 y Elective PCI: 61.5% CHA₂ DS₂-VASc score: 0–1, 9.5%; 2–4, 54.7%; 5–7, 35.9% HAS-BLED score: ≤ 2, 29.8%; 3–4, 65.8%; ≥ 5, 4.5%	Group 1: 15 mg/d of rivaroxaban (10 mg/d if CrCl 30–50 mL/min) and P2Y₁₂ inhibitor for 12 mo Group 2: 2.5 mg of rivaroxaban twice daily and DAPT for 1, 6, or 12 mo; step down to rivaroxaban and ASA (75–100 mg/d) until 12 mo after stent Group 3: warfarin (INR 2.0–3.0) and DAPT for 1, 6, or 12 mo; step down to warfarin and ASA (75–100 mg/d) until 12 mo after stent P2Y₁₂ inhibitor: 94% clopidogrel Proportion of patients taking 10 mg/d of rivaroxaban not reported	Primary end point of clinically significant bleeding (composite of TIMI major and minor bleeding, and bleeding requiring medical attention): group 1, 16.8%; group 2, 18%; group 3, 26.7% P < .01 for groups 1 and 2 vs group 3; NNT = 11 and NNT = 12, respectively, at 1 y CV event (CV death, MI, or stroke): no difference	DAPT duration for groups 2 and 3 (non-randomized): 1 mo, 15.8%; 6 mo, 34.9%; 12 mo, 49.3% PPI use at baseline: 38% Not powered to assess CV outcomes Difference in major bleeding was not statistically significant between groups
ISAR-TRIPLE,⁸ 2015 Open-label, randomized trial Germany and Denmark N = 614	Indication for long-term OAC and need for PCI Mean age 73 y > 65% stable angina > 80% AF DES: 100% CHADS₂score: 0–1, 17%–21%; 2–3, 61%–64%; 4–5, 13%–20%; > 5, 1%–2% CHADS₂score ≥ 3: 6 wk (22.4%) vs 6 mo (14.5%)	TT (75 mg/d of clopidogrel, 75–200 mg/d of ASA, and warfarin [INR 2.0–3.0]) for 6 wk vs 6 mo	Primary end point(composite of death, MI, stent thrombosis, stroke, and TIMI major bleeding): no difference at 9 mo	No significant differences in secondary end points between groups, including TIMI major bleeding No net clinical benefit between 6 mo vs 6 wk of TT
WOEST,⁹ 2013 Open-label, randomized trial Netherlands N = 571	Indication for long-term OAC and need for PCI Mean age 70 y 69% AF Only 27% had ACS at baseline 65% DES, 30% BMS	Dual therapy (75 mg/d of clopidogrel and warfarin) for 12 mo vs TT (80–100 mg/d of ASA, 75 mg/d of clopidogrel, and warfarin) for 12 mo Target INR of 2.0–3.0 for both groups	Primary end point (any bleeding at 1 y): 19.4% vs 44.4%, HR = 0.36, P < .0001, NNT = 4 Secondary end point (composite of death, MI, stroke, target vessel revascularization, and stent thrombosis): 11.1% vs 17.6%, HR = 0.6, P = .025, NNT = 16, driven by reduction in death	Duration –BMS: 1 mo to 1 y –DES: at least 1 y No significant difference in TIMI major bleeding Underpowered for ischemic events PPI use at baseline: about one-third
TT trials with direct OACs for secondary ACS prevention^*
ATLAS ACS 2-TIMI 51,¹⁰ 2012 Randomized, double-blind phase 3 trial 44 countries (5.5% from North America) N = 15 526 Missing data for 15.5% patients who prematurely discontinued the study; vital status not obtained for 1117 (7.2%) at the end of the trial	Mean age 62 y STEMI: 50% NSTEMI: 25.6% Unstable angina: 24% 60% underwent revascularization	In addition to ASA plus clopidogrel or ticlopidine: Placebo vs 2.5 or 5 mg of rivaroxaban twice daily Mean of 13 mo	Primary end point (composite of CV death, MI, and stroke): placebo, 10.7%; 2.5-mg rivaroxaban, 9.1% (NNT = 63); 5-mg rivaroxaban, 8.8% (NNT = 53) Compared with placebo, 2.5 mg of rivaroxaban (but not 5 mg) decreased CV events (4.1% vs 2.7%) and overall mortality (4.5% vs 2.9%) (P < .05 for both) TIMI major bleeding not associated with CABG: placebo, 0.6%; 2.5-mg rivaroxaban, 1.8% (NNH = 84); 5-mg rivaroxaban, 2.4%(NNH = 56) Fatal bleeding: not statistically significant	In Canada, neither 2.5-mg nor 5-mg rivaroxaban tablets are commercially available, and 10-mg tablets are not scored
RE-DEEM,¹¹ 2011 Randomized, double-blind phase 2 trial 24 countries (5.4% from North America) N = 1861	Recent ACS STEMI: 60% NSTEMI: 40% PCI: 55% Mean age 61 y	In addition to ASA plus a P2Y₁₂ inhibitor: Placebo vs 50, 75, 110, and 150 mg of dabigatran twice daily	Primary end point (major [ISTH] or clinically relevant minor bleeding) at 6 mo: placebo, 2.2%; 50 mg, 3.5%; 75 mg, 4.3%; 110 mg, 7.9%; and 150 mg, 7.8%; P < .001 for linear trend Ischemic CV events: not statistically significant (underpowered to assess)	Addition of dabigatran to DAPT in post-MI patients was associated with a dose-dependent increase in major or clinically relevant minor bleeding 110-mg and 150-mg dabigatran groups associated with a 4-fold higher risk of bleeding than placebo
APPRAISE-2,¹² 2011 Randomized, double-blind trial After enrolling 7392 patients, terminated prematurely owing to increased bleeding risk without reduction in ischemic events	Recent ACS and ≥ 2 high-risk features STEMI: 40% NSTEMI: 42% Unstable angina: 18% PCI: 44% Median age 67 y	In addition to ASA plus a P2Y₁₂ inhibitor: 5 mg of apixaban twice daily (2.5 mg twice daily if CrCl < 40 mL/min) vs placebo Median 8 mo	Primary end point (CV death, MI, or stroke): apixaban, 7.5% vs placebo, 7.9% (P = .51) TIMI major bleeding: apixaban, 1.3% vs placebo, 0.5% (NNH = 125)	Addition of apixaban to DAPTafter ACS increased major bleeding risk without reducing ischemic events PPI use at baseline: 24%

ACS—acute coronary syndrome; AF—atrial fibrillation; APPRAISE-2—Apixaban for Prevention of Acute Ischemic Events 2; ASA—acetylsalicylic acid; ATLAS ACS#2–TIMI 51—Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome– Thrombolysis in Myocardial Infarction 51; BMS—bare-metal stent; CABG—coronary artery bypass graft; CHA₂DS₂-VASc—congestive heart failure, hypertension, age ≥ 75 y, diabetes mellitus, stroke or transient ischemic attack, vascular disease (previous MI, peripheral artery disease, or aortic plaque), age 65–74 y, sex category (ie, female); CHADS₂—congestive heart failure, hypertension, age ≥ 75 y, diabetes mellitus, and previous stroke or transient ischemic attack; CrCl—creatinine clearance; CV—cardiovascular; DAPT—dual antiplatelet therapy; DES—drug-eluting stent; HAS-BLED—hypertension with a systolic blood pressure > 160 mm Hg, abnormal renal or liver function, stroke (caused by a bleed), bleeding, labile INR, elderly (age > 65 y), drugs (ASA, NSAIDs) or alcohol (≥ 8 drinks/wk); HR—hazard ratio; INR—international normalized ratio; ISAR-TRIPLE—Intracoronary Stenting and Antithrombotic Regimen-testing of a 6-week versus a 6-month Clopidogrel Treatment Regimen in Patients with Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-eluting Stenting; ISTH—International Society on Thrombosis and Hemostasis; MI—myocardial infarction; NNH—number needed to harm; NNT—number needed to treat; NSAID—nonsteroidal anti-inflammatory drug; NSTEMI—non-ST-segment elevation MI; OAC—oral anticoagulant; PCI—percutaneous coronary intervention; PIONEER-AF-PCI—Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention; PPI—proton pump inhibitor; RCT—randomized controlled trial; RE-DEEM—Randomised Dabigatran Etexilate Dose Finding Study in Patients with Acute Coronary Syndromes Post Index Event with Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel; STEMI—ST-segment elevation MI; TIMI—Thrombolysis in Myocardial Infarction; TT—triple therapy; WOEST—What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting.
↵* Proportion of patients with AF not reported in the studies.