ARISTOTLE 2011.

Methods	Randomised, double‐blind, active controlled trial
Participants	18,201 people with documented AF or atrial flutter and at least 1 additional risk factor for stroke: at least 75 years old; previous stroke, TIA or systemic embolic event; symptomatic heart failure within previous 3 months or left ventricular ejection fraction of no more than 40%; diabetes mellitus; hypertension requiring pharmacologic treatment
Interventions	Apixaban (5 mg twice daily, or 2.5 mg twice daily in participants with at least 2 or more of the following criteria: age at least 80 years, body weight of no more than 60 kg, or serum creatinine level of 1.5 mg/dl or more; n = 9120) versus dose‐adjusted warfarin (target INR 2.0 to 3.0; n = 9081)
Outcomes	Primary efficacy outcome: composite of stroke or systemic embolic events Secondary efficacy outcomes: death from any cause, myocardial infarction Primary safety outcome: major bleeding (ISTH criteria) Secondary safety outcomes: composite of major bleeding and clinically relevant non‐major bleeding; any bleeding; other adverse events; liver function abnormalities
Notes	Study co‐sponsored by 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
Allocation concealment (selection bias)	Low risk	Participants were randomly assigned to treatment groups. Stratification by clinical site and prior VKA use
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 a clinical events committee whose members were not aware of study group assignments
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Efficacy and safety outcomes analysed in ITT population. Number of participants that discontinued during study and reasons are reported. Number of participants with missing data on vital status rather high (n = 380; 2.1%) and could have had an impact on the robustness of the mortality data from this study
Selective reporting (reporting bias)	Low risk	All predefined efficacy and safety outcomes reported for ITT population
Other bias	Low risk	_