RE‐NOVATE II Trial.

Methods	Study design: Randomised, double‐blind, double‐dummy, non‐inferiority, active‐controlled trial Country: 19 countries in Europe, North America, India, Australia, New Zealand and South Africa Setting: Multicentre (108 locations); hospital and home; March 2008 to May 2009 Intention‐to‐treat: Modified intention‐to‐treat: all participants who had surgery, received treatment and had evaluable venograms For the purposes of our meta‐analyses we used the reported ITT population of participants that underwent surgery
Participants	Number randomised: Total n = 2055 (dabigatran n = 1036; enoxaparin n = 1019) Exclusions post randomisation: Total n = 477 (dabigatran n = 243; enoxaparin n = 234: not treated: dabigatran 25 and enoxaparin 16. Dabigatran 9 and enoxaparin 11 did not have surgery, dabigatran 209 and enoxaparin 207 no or not evaluable venogram Losses to follow up: All participants accounted for Age mean years (SD): Dabigatran 62 (12); enoxaparin 62 (11) Sex F%: Dabigatran 53.6%; enoxaparin 50.0% Inclusion criteria: 18 years or older; scheduled to undergo a primary, unilateral, elective total hip replacement; > 40 kg body weight; gave written informed consent Exclusion criteria: History of bleeding diathesis; excessive risk of bleeding as judged by investigators; major surgery or trauma within three months of enrolment; recent unstable cardiovascular disease; any history of haemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm, atriovenous malformation or aneurysm; ongoing treatment for VTE; clinical relevant bleeding within six months of enrolment; gastric or duodenal ulcer within one year of enrolment; liver disease expected to have any potential impact on survival; active liver disease or liver disease decreasing survival; known severe renal insufficiency; elevated creatinine that contraindicates venography; Treatment with anticoagulants, clopidogrel, ticlopidine, abciximab, aspiring or NSAID within seven days prior to hip replacement or anticipated need of such medication; anticipated required use of intermittent pneumatic compression and electric stimulation of lower leg; active malignant disease or current cytostatic treatment; pre‐menopausal women who are pregnant or nursing, or are of child‐bearing potential and are not practising or do not plan to continue practising acceptable methods of birth control; allergy to radio opaque contrast media, heparins or dabigatran; contraindications to enoxaparin; participation in a clinical trial during the last 30 days; leg amputee; known alcohol or drug abuse which would interfere with study completion; previous participation in this study; history of thrombocytopaenia
Interventions	Treatment 1: 220 mg dabigatran etexilate (2 x 110 mg tablets), orally, once daily, initial dose of 110 mg on the day of surgery plus placebo injection identical to enoxaparin treatment Treatment 2: 40 mg enoxaparin, subcutaneous, once daily, initial dose evening before surgery plus placebo tablets identical to dabigatran treatment Duration: 28 ‐ 35 days
Outcomes	Primary: Composite of total VTE and all‐cause mortality (VTE includes both proximal and distal DVT, symptomatic DVT, PE) Secondary: Major VTE and VTE‐related death, proximal DVT, total DVT, symptomatic DVT, PE, all‐cause mortality, bleeding events, lab parameters and adverse events Bleeding definitions: Major bleeding ‐ fatal, clinically overt associated with loss of haemoglobin greater than or equal to 20 g/L or leading to transfusion of greater than or equal to 2 units of packed cells or whole blood; symptomatic retroperitoneal, intracranial, intraocular or intraspinal; requiring treatment cessation; leading to reoperation. Clinically relevant bleeding ‐ spontaneous skin haematoma greater than or equal to 25 cm2; wound haematoma greater than or equal to 100 cm2; spontaneous nose bleed lasting longer than 5 min; macroscopic haematuria spontaneous or lasting longer than 24 hours if associated with an intervention; spontaneous rectal bleeding (more than a spot on toilet paper); gingival bleeding lasting longer than 5 min; any other bleeding event considered clinically relevant by the investigator Minor bleeding ‐ any other bleeding events that were not classified as major or clinically relevant
Notes	Funding: Boehringer Ingelheim, Sweden Method of VTE evaluation/confirmation: DVT confirmed/detected by bilateral venography or compression ultrasound or autopsy; PE confirmed by pulmonary V‐Q scintigraphy, chest X‐ray, angiography, spiral CT or autopsy
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation by central computer‐generated system, stratified by centre, prepared in blocks of six
Allocation concealment (selection bias)	Low risk	Utilised central computer‐generated system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both treatment groups received one study drug and one placebo identical in appearance to the other active treatment
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Efficacy outcomes confirmed by blinded, central adjudication committee
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All participants were accounted for, with similar numbers in each treatment group, but no description was given for excluded participants that did not take study medication
Selective reporting (reporting bias)	Low risk	No protocol but all expected outcomes reported
Other bias	Unclear risk	Study sponsors were involved in the design and conduct of the trial. The data were collected and analysed by the sponsors of the study