ARISTOTLE Study 2010.

Methods	Study design: double‐blind, double‐dummy RCT Study duration: 19 December to 2 April 2010 Median duration of study follow‐up: 1.8 years
Participants	Countries: Australia, China, Hong Kong, India, Japan, Malaysia, Philippines, Singapore, South Korea, Taiwan, Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Romania, Russia, South Africa, Spain, Sweden, Switzerland, Turkey, UK, Ukraine, Argentina, Brazil, Chile, Colombia, Mexico, Peru, Puerto Rico, Canada, USA Setting: multicentre Patients with non‐valvular AF; moderate kidney impairment (25≤ CrCl < 50 mL/min); aged ≥ 21 years, and at least one additional risk factors for stroke; age ≥ 75 years; previous stroke, TIA or systemic embolic event; symptomatic heart failure within previous 3 months or left ventricular ejection fraction of no more than 40%; DM; hypertension requiring pharmacologic treatment Number: treatment group (1502); control group (1515) Relevant health status: participants Mean age ± SD: 77.6 ± 7.1 years Sex (M/F): 1408/1609 Exclusion criteria: AF due to a reversible cause; moderate or severe mitral stenosis; conditions other than AF that required anticoagulation (e.g. a prosthetic heart valve); stroke within the previous 7 days; need for aspirin at a dose of > 165 mg/d or for both aspirin and clopidogrel; severe kidney insufficiency (SCr > 221 μmol/L or calculated CrCl < 25 mL/min)
Interventions	Treatment group Oral apixaban: either 2.5 mg or 5 mg twice/d, with dosage determined according to whether participants satisfied two or more of the following criteria: (i) age of at least 80 years; (ii) body weight of no more than 60 kg; or (iii) SCr ≥ 133 μmol/ L Control group Oral warfarin: dose‐adjusted (target INR 2.0 to 3.0)
Outcomes	All strokes and systemic embolic events All‐cause mortality Major bleeding Intracranial haemorrhage
Notes	Funding sources: Bristol‐Myers Squibb and Pfizer
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned to treatment groups according to the stratification by clinical site and prior VKA use, and the possibility that this method give the influence on the results was low
Allocation concealment (selection bias)	Low risk	Allocation was concealed because participants were assigned to each group using the Interactive Voice 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 on the basis of prespecified criteria by a clinical events committee whose members were unaware of study group assignments
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Primary efficacy outcome was analysed in ITT population. Primary safety outcome was analysed in modified ITT population including all randomised patients who received least one dose of the study drug and included all events from receipt of the study drug until 2 days after the last dose of the drug. It has unclear risk because 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 Bristol‐Myers Squibb and Pfizer