ENGAGE AF‐TIMI 48 Study 2013.

Methods	Study design: double‐blind, double‐dummy RCT Study duration: 19 November 2008 to 22 November 2010 Median duration of study follow‐up: 2.8 years
Participants	Countries: USA, Canada, Argentina, Brazil, Chile, Colombia, Mexico, Peru, Guatemala, Belgium, Finland, France, Germany, Greece, Israel, Italy, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, Turkey, UK, Denmark, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Poland, Romania, Russia, Serbia and Montenegro, Slovakia, Ukraine, Australia, China, India, Korea, New Zealand, Philippines, South Africa, Taiwan, Thailand, Japan Relevant health status: participants aged ≥ 21 years with non‐valvular AF, moderate kidney impairment (30≤ CrCl <50 mL/min); a score of 2 or higher on the CHADS2 risk assessment Setting: multicentre Number: treatment group (1379); control group (1361) Median age (IQR): 79 years (75 to 83) Sex(M/F): 1260/1480 Exclusion criteria: AF due to a reversible disorder; an estimated CrCl < 30 mL/min; a high risk of bleeding; use of dual antiplatelet therapy; moderate‐to severe mitral stenosis; other indications for anticoagulation therapy; acute coronary syndromes, coronary revascularization, or stroke within 30 days before randomisation; an inability to adhere to study procedures
Interventions	Treatment group Oral edoxaban: 30 mg/d Control group Oral warfarin: dose‐adjusted (target INR 2.0 to 3.0)
Outcomes	All strokes and systemic embolic events MI All‐cause mortality Major bleeding Minor bleeding GI bleeding Intracranial haemorrhage
Notes	Funding source: Daiichi Sankyo Pharma Development
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned to treatment groups with the use of a central, 24‐horur, interactive, computerized response system
Allocation concealment (selection bias)	Low risk	Allocation was concealed because participants were assigned to each group using a central, 24‐horur, interactive, computerized response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, double‐dummy design
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Efficacy and safety outcomes were adjudicated by an independent clinical end‐point committee whose members were not aware of study group assignments
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Primary efficacy outcome was reported in both ITT and modified ITT population. Primary safety outcome was analysed in modified ITT population. The number of participants that discontinued during study was reported, but the reason was unclear
Selective reporting (reporting bias)	Low risk	All predefined efficacy and safety outcomes were reported
Other bias	High risk	The study was funded by Daiichi Sankyo Pharma Development