Table 5.

Major RCTs for DOACs as a treatment option in AF.

	ARISTOTLE [70]	AVERROES [74]	ROCKET-AF [72]	RELY-AF [73]	ENGAGE AF-TIMI 48 [71]
Study design	Randomized, double bind	Randomized, double bind, double dummy	Randomized, double bind, double dummy	Randomized, open label	Randomized, double bind, double dummy
Statistical objective	Non inferiority	Superiority	Non inferiority	Non inferiority	Non inferiority
Follow-up period	40 months	1.1 years	40 months	24 months	24 months
Primary efficacy	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism	Composite of stroke and systemic embolism
Principal safety	Major bleeding	Major bleeding	Major bleeding	Major bleeding	Major and non-major clinically relevant bleeding
Warfarin arm	Dose-adjusted warfarin	ASA	Dose-adjusted warfarin	Dose-adjusted warfarin	Dose-adjusted warfarin
DOAC arm	Apixaban 5 mg BID, 2.5 mg if creatinine $>$1.5 mg/dL	Apixaban 5 mg BID, 2.5 mg if creatinine $>$1.5 mg/dL	Rivaroxaban 20 mg QD, 15 mg QD with CrCl 30–40 mL/min	Dabigatran 1150 or 110 mg BID	Edoxaban 60 mg or 30 mg QD
Inclusion	AF, flutter, stroke or 2 of: LVEF 40%, age $>$75, DM, HTN	AF, LVEF 35%, age $>$75, DM, HTN, previous stroke, PAD	AF, stroke or 2 of: LVEF 35%, age $>$75, DM, HTN	AF, stroke or 2 of: LVEF 35%, age $>$75, DM, HTN	AF, LVEF 35%, age $>$75, DM, HTN, previous stroke, CHADS $>$2
Exclusion	Intracranial bleed, stroke within 7 days, valvular heart disease, renal insufficiency, ASA and clopidogrel use	Serious bleed, stroke within 10 days, valvular heart disease, renal insufficiency, drug abuse	TIA within 3 days, stroke within 14 days, valvular heart disease, high bleeding risk, liver disease, kidney disease, aspirin use	Severe heart disease, stroke within 14 days, high bleeding risk, elevated creatinine, liver disease	Creatine clearance 30 mL/min, high bleeding risk, use of aspirin or clopidogrel, valvular heart disease, stroke within 30 days
Type of bleeding reported	Major bleeding, intracranial and GI	Major bleeding, intracranial and GI	Extracerebral, intracranial and major bleeding	GI, intracranial and major bleeding	Major bleeding
${\mathrm{CHADS}}_2$score	2.1	2.1	3.48	2.1	2.8

DOACs, direct oral anticoagulants; AF, atrial fibrillation; ASA, acetylsalicylic acid; BID, bis in die; QD, quaque die; CrCl, creatinine clearance; LVEF, left ventricular ejection fraction; DM, diabetes mellitus; HTN, hypertension; PAD, peripheral artery disease; TIA, transient ischemic attack; GI, gastrointestinal; RCT, randomized controlled trial.