EXTEND Study.

Methods	Study design: Randomised, double‐blind, parallel‐group study Country: Multi‐country (16 countries) Setting: Multicentre; hospital and home; September 2005 to February 2006 Intention‐to‐treat: No analysis performed as study stopped prematurely For the purposes of our meta‐analyses we used the per‐protocol population as reported by the authors
Participants	Number randomised: Total n = 1158; 641 completed at time of termination (ximelagatran n = 580; enoxaparin n = 578) Exclusions post randomisation: Total n = 150 (ximelagatran n = 70; enoxaparin n = 80) Not treated: 23 melagatran, 16 enoxaparin; Premature stop: 47 melagatran, 64 enoxaparin Losses to follow up: Study terminated early Age median years (range): Hip replacement: ximelagatran 64.7 (24 ‐ 89); enoxaparin 63.9 (21 ‐ 89); Fracture surgery: ximelagatran 73.1 (44 ‐ 91); enoxaparin 70.7 (26 ‐ 94) Sex M/F: Hip replacement: ximelagatran 229/250; enoxaparin 211/268; Fracture surgery: Ximelagatran 17/60; enoxaparin 23/50 Inclusion criteria: 18 years or older; undergoing primary elective unilateral total hip replacement or surgery for hip fracture Exclusion criteria: "same as in the previously reported phase III studies in orthopaedic surgery on ximelagatran"
Interventions	Treatment 1: 3 mg ximelagatran subcutaneously 4 ‐ 8 hours after surgery and twice daily for up to 2 days post‐op, followed by 24 mg oral ximelagatran twice daily Treatment 2: 40 mg enoxaparin subcutaneous once daily starting the night before surgery or post‐operatively Duration: 32 ‐ 38 days after surgery; Randomised within 5 days before surgery
Outcomes	Primary: Efficacy outcomes: composite of proximal DVT, any clinically suspected and objectively confirmed DVT and/or PE, VTE‐related death or death where VTE could not be ruled out. Safety outcomes: major bleeding events, transfusions of whole blood and packed red blood cells, injection site haematomas > 2 cm, clinically verified and adjudicated myocardial infarction, evidence of hepatic injury Secondary: No distinction between primary and secondary Bleeding definitions: Major bleeding ‐ transfusions of whole blood and packed red blood cells, injection site haematomas > 2 cm, clinically verified and adjudicated myocardial infarction, evidence of hepatic injury
Notes	Funding: AstraZeneca, Sweden; employees of AstraZeneca contributed to study design, interpretation of results and decision to submit paper Method of VTE evaluation/confirmation: bilateral compression ultrasound (CUS) of the legs at the end of treatment period
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Interactive web‐based randomisation system; stratified by type of surgery
Allocation concealment (selection bias)	Low risk	Used web‐based randomisation system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcomes adjudicated by a blinded, independent committee
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	ITT numbers do not add up; insufficient information given
Selective reporting (reporting bias)	Unclear risk	No details of the VTE events were provided
Other bias	High risk	Terminated early due to safety issues, AstraZeneca supported trial ‐ had influence on study design, interpretation of results and decision to submit paper