Hokusai‐VTE Study.

Methods	Study design: randomised, double‐blind, non‐inferiority study Duration of study: 12 months
Participants	Setting: multicentre Country: multinational No: 4921; edoxaban 2468, warfarin 2453 Age, mean (SD) years: edoxaban 55.7 (16.3) years, warfarin 55.9 (16.2) years Sex: edoxaban 2360 M/1758 F, warfarin 2356 M/1766 F Inclusion criteria: patients aged 18 or older who had objectively diagnosed, acute, symptomatic DVT involving the popliteal, femoral or iliac veins or acute, symptomatic PE (with or without DVT) Exclusion criteria: contraindications to heparin or warfarin, had received treatment for more than 48 hours with therapeutic doses of heparin, had received more than one dose of a VKA, had cancer for which long‐term treatment with LMWH was anticipated, had another indication for warfarin therapy, continued to receive treatment with aspirin at a dose of more than 100 mg daily or dual antiplatelet therapy, or had a creatinine clearance of less than 30 mL per minute
Interventions	Intervention 1: oral edoxaban 60 mg once daily or 30 mg once daily in patients with a creatinine clearance of 30 to 50 mL per minute or a body weight of 60 kg or less or in patients who were receiving concomitant treatment with potent P‐glycoprotein inhibitors Intervention 2: dose‐adjusted warfarin therapy to achieve an INR of 2.0 to 3.0 and edoxaban‐like placebo Follow‐up: days 5, 12, 30 and 60 after randomisation, monthly while on study drug or every 3 months after discontinuing the study drug and finally at 12 months
Outcomes	Primary: incidence of symptomatic recurrent VTE (DVT and fatal or non‐fatal PE), clinically relevant bleeding (major or clinically relevant non major) Secondary: none
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomisation was performed with the use of an interactive Web‐base system" Comment: insufficient information to permit judgement of high or low risk
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation was performed with the use of an interactive Web‐base system" Comment: study judged to be at a low risk of selection bias
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Edoxaban or warfarin was administered in a double‐blind fashion" Comment: study judged to be at a low risk of performance bias
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An independent committee, whose members were unaware of the study‐group assignments, adjudicated all suspected outcome and the results of baseline imaging tests and assessed the anatomical extent of thrombosis" Comment: study judged to be at a low risk of performance bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study's pre‐specified outcomes have been reported in the pre‐specified way
Other bias	Unclear risk	The study was funded by Daiichi‐Sankyo, the pharmaceutical company that developed edoxaban. It is possible that this may have influenced the timeframe of reported safety outcomes