Table 2.

Non-vitamin K antagonist oral anticoagulants for acute and chronic coronary syndrome.

Study	Population	Intervention and Comparator(s)	Efficacy	Safety
NOACs vs comparator
Acute coronary syndrome
Oldgren et al. 2011 (REDEEM) [19]	$\bullet$ Patients with STEMI or NSTEMI	$\bullet$ Dabigatran 50, 75, 110, or 150 mg BID plus DAPT	Death	Bleeding – HR (95% CI)
RCT, Phase II		$\bullet$ Placebo plus DAPT	$\bullet$ 50 mg: 2.2%; 75 mg: 2.7%	$\bullet$ 50 mg: 3.5%; 1.77 (0.70, 4.50)
N = 1861			$\bullet$ 110 mg: 1.7%; 150 mg: 2.0%	$\bullet$ 75 mg: 4.3%; 2.17 (0.88, 5.31)
			$\bullet$ Placebo: 3.8%	$\bullet$ 110 mg: 7.9%; 3.92 (1.72, 8.95)
			Thrombotic events:	$\bullet$ 150 mg: 7.8%; 4.27 (1.86, 9.81)
			$\bullet$ 50 mg: 4.6%; 75 mg: 4.9%	$\bullet$ Placebo: 2.2%
			$\bullet$ 110 mg: 3.0%; 150 mg: 3.5%
			$\bullet$ Placebo: 3.8%
			D-dimer reduced in dabigatran dose groups (p = 0.001)
Alexander et al. 2009 (APPRAISE-1) [20]	$\bullet$ Patients with STEMI or NSTEMI	$\bullet$ Apixaban 2.5 mg BID, 10 mg OD, 10 mg BID, or 20 mg OD plus APT	Ischemic events	Total bleeding – HR (95% CI)
RCT, Phase II		$\bullet$ Placebo plus APT	$\bullet$ 2.5 mg BID: 7.6%; 0.73 (0.44, 1.19)	$\bullet$ 2.5 mg BID 1.6%; 1.78 (0.91, 3.48)
N = 1715			$\bullet$ 10 mg OD: 6.0%; 0.61 (0.35, 1.04)	$\bullet$ 10 mg OD: 1.9% 2.45 (1.31, 4.61)
				$\bullet$ 10 mg or 20 mg OD: excess total bleeding led to both arms discontinuation
				More bleeding when on DAPT
Alexander et al. 2011 (APPRAISE-2) [21]	$\bullet$ Patients with STEMI or NSTEMI	$\bullet$ Apixaban 5 mg BID plus APT	$\bullet$ CV death, MI, or ischemic stroke: 7.5% vs 7.9%; HR 0.95 (95% CI: 0.80, 1.11)	$\bullet$ Premature trial termination due to major bleeding
RCT		$\bullet$ Placebo plus APT	$\bullet$ Recurrent ischemic events: no reduction in rate	$\bullet$ Major bleeding: 1.3% vs 0.5%; HR 2.59 (95% CI: 1.50, 4.46)
N = 7392
Mega et al. 2009 (ATLAS ACS-TIMI 46) [24]	$\bullet$ Patients with ACS	$\bullet$ Rivaroxaban 5, 10, 15, or 20 mg per day (divided once or twice) plus APT	$\bullet$ Death, MI, stroke, or severe recurrent ischemia: 3.9% vs 5.5%; HR 0.69 (95% CI: 0.50, 0.96)	Significant bleeding – HR (95% CI)
RCT, Phase II				$\bullet$ 5 mg: 6.1%; 2.21 (1.25, 3.91)
N = 3491				$\bullet$ 10 mg: 10.9%; 3.35 (2.31, 4.87)
				$\bullet$ 15 mg: 12.7%; 3.60 (2.32, 5.58)
				$\bullet$ 20 mg: 15.3%; 5.06 (3.45, 7.42)
Mega et al. 2012 (ATLAS ACS 2-TIMI 51) [25]	$\bullet$ Patients with ACS	$\bullet$ Rivaroxaban 2.5, 5 mg BID	CV Death, MI, or stroke: 8.9% vs 10.7%; HR 0.84 (95% CI: 0.74, 0.96)	$\bullet$ Rivaroxaban increased the rates of major bleeding not related to CABG (2.2% vs 0.6%; HR 4.52 (95% CI: 2.27, 9.01)
RCT		$\bullet$ Placebo	$\bullet$ 2.5 mg: 9.1% vs 10.7%, p = 0.02
N = 15,526			$\bullet$ 5 mg: 8.8% vs 10.7%, p = 0.03
			2.5 mg only:
			$\bullet$ CV death: 2.7% vs 4.1%, p = 0.002
			$\bullet$ Death: 2.9% vs 4.5%, p = 0.002
Ohman et al. 2017 (GEMINI-ACS-I) [32]	$\bullet$ Patients with STEMI or NSTEMI	$\bullet$ Rivaroxaban 2.5 mg BID plus ${\mathrm{P2Y}}_{12}$	$\bullet$ CV death, MI, stroke, or definite stent thrombosis: 5.0% vs 5.0%; HR 1.06 (95% CI: 0.77, 1.46)	$\bullet$ Clinically significant non-CABG bleeding: 5.0% vs 5.0%; HR 1.09 (95% CI: 0.80, 1.50)
RCT		$\bullet$ Aspirin plus ${\mathrm{P2Y}}_{12}$
N = 3037
Chronic coronary syndrome
Eikelboom et al. 2017 (COMPASS) [39]	$\bullet$ Stable atherosclerotic vascular disease	$\bullet$ Rivaroxaban 2.5 mg BID plus aspirin	Rivaroxaban-plus-aspirin vs aspirin	Rivaroxaban-plus-aspirin vs aspirin
RCT		$\bullet$ Rivaroxaban 5 mg BID	$\bullet$ CV death, stroke, or MI: 4.1% vs 5.4%; HR 0.76 (95% CI: 0.66, 0.86)	$\bullet$ Major bleeding: 3.1% vs 1.9%; HR 1.70 (95% CI: 1.40, 2.05)
N = 27,395		$\bullet$ Aspirin	$\bullet$ Death: 3.4% vs 4.1%; HR 0.82 (95% CI: 0.71, 0.96)	$\bullet$ Fatal bleeding: no difference
			Rivaroxaban vs aspirin	Rivaroxaban vs aspirin
			$\bullet$ CV death, stroke, or MI: 4.9% vs 5.4%; HR 0.90 (95% CI: 0.79, 1.03)	$\bullet$ Major bleeding: 2.8% vs 1.9%; HR 1.51 (95% CI: 1.25, 1.84)
			$\bullet$ Death: 4.0% vs 4.1%; HR 0.97 (95% CI: 0.84, 1.12)	$\bullet$ Fatal bleeding: no difference
Zannad et al. 2018 (COMMANDER-HF) [43]	Chronic HF, LVEF $\le$40%, CAD, NSR, elevated concentrations of natriuretic peptides	$\bullet$ Rivaroxaban 2.5 mg BID	$\bullet$ Death from any cause, MI, or stroke: 25% vs 26.2% HR 0.94; (95% CI: 0.84, 1.05)	$\bullet$ Fatal bleeding or bleeding into a critical space with a potential for causing permanent disability: 0.7% vs 0.9%; HR 0.80 (95% CI: 0.43, 1.49)
RCT		$\bullet$ Placebo		$\bullet$ Rivaroxaban group: more bleeding requiring hospitalization and are at higher risk of major bleeding
N = 5022

Abbreviations: ACS, acute coronary syndrome; APT, antiplatelet therapy; BID, twice daily; CAD, coronary artery disease; CABG, coronary artery bypass grafting; CI, confidence interval; CV, cardiovascular; DAPT, dual antiplatelet therapy; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NOACs, non-vitamin K antagonist oral anticoagulants; NSR, normal sinus rhythm; NSTEMI, non-ST segment elevation myocardial infarction; OD, once daily; RCT, randomized controlled trial; STEMI, ST-segment elevation myocardial elevation.