RE‐NOVATE Trial.

Methods	Study design: Randomised, double‐blind, active‐controlled trial Country: Multi‐country (16 countries) in Europe, Australia and South Africa Setting: Multicentre (115 centres); hospital and home; November 2006 to July 2006 Intention‐to‐treat: No, per‐protocol: excluding not treated, no surgery, and inadequate or no venogram For the purposes of our meta‐analyses we used the reported ITT population of participants that underwent surgery
Participants	Number randomised: Total n = 3493 (220 mg dabigatran n = 1157; 150 mg dabigatran n = 1174; enoxaparin n = 1162) Exclusions post randomisation: Total n = 322 (220 mg dabigatran n = 108; 150 mg dabigatran n = 102; enoxaparin n = 112), reason for all: did not complete study Losses to follow up: Not specified Age mean years (SD): 220 mg dabigatran 65 (10); 150 mg dabigatran 63 (11); enoxaparin 64 (11) Sex %F: 220 mg dabigatran 56%; 150 mg dabigatran 57%; enoxaparin 56% 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: Patients with an excessive risk of bleeding; active malignant disease or current cytostatic treatment; known severe renal insufficiency; liver disease expected to have any potential impact on survival, or elevated AST or ALT > 2 x upper limit of normal; recent unstable cardiovascular disease or history of myocardial infarction within the last three months; 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 or iodine, heparins (including heparin‐induced thrombocytopenia) or dabigatran; contraindications to enoxaparin; participation in a clinical trial during the last 30 days
Interventions	Treatment 1*: 150 mg dabigatran etexilate, orally, once daily, starting with half dose on day of surgery plus one placebo pill identical to other treatment and subcutaneous placebo injection Treatment 2*: 220 mg dabigatran etexilate, orally, once daily, starting with half dose on day of surgery plus one placebo pill identical to other treatment subcutaneous placebo injection Control: 40 mg enoxaparin, subcutaneous, once daily plus two placebo pills identical in appearance to active treatments Duration: 28 ‐ 35 days (average 33 days) *For the analyses within this review, the 150 mg and 220 mg treatment groups were combined as both dosages are considered normal therapeutic dosages.
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 Bleeding definitions: Major bleeding ‐ fatal, clinically overt associated with loss of haemoglobin greater than or equal to 20g/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: Steering committee and sponsor responsible for study design, data collection and analysis done by sponsor, independent data and safety committee monitored study, steering committee had overall responsibility for all aspects and final responsibility for decision to submit paper Method of VTE evaluation/confirmation: DVT detected and confirmed by bilateral venography; 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	All treatment groups received one study drug and one placebo identical in appearance to the other active treatment as well as a subcutaneous injection
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Efficacy outcomes initially assessed locally, then confirmed by blinded, central adjudication committee
Incomplete outcome data (attrition bias) All outcomes	Low risk	All exclusions were reported with reasons and by study group
Selective reporting (reporting bias)	Low risk	All outcomes reported on
Other bias	Low risk	No indication of other bias