Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial

Background After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. Methods In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28–35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7·7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. Findings Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6·7%) of 897 individuals in the enoxaparin group versus 53 (6·0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference −0·7%, 95% CI −2·9 to 1·6%) and 75 (8·6%) of 874 people in the 150 mg group (1·9%, −0·6 to 4·4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0·44 for 220 mg, p=0·60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. Interpretation Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile. After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28–35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7·7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6·7%) of 897 individuals in the enoxaparin group versus 53 (6·0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference −0·7%, 95% CI −2·9 to 1·6%) and 75 (8·6%) of 874 people in the 150 mg group (1·9%, −0·6 to 4·4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0·44 for 220 mg, p=0·60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile. Trials of venous thromboembolism preventionIn today's Lancet, Bengt Eriksson and colleagues report the RE-NOVATE trial on prevention of venous thromboembolism after total hip replacement.1 This trial is in many important methodological respects exemplary: it is an international multicentre study, with robust randomisation, double-dummy blinding, central outcome-adjudication with imaging, and prespecified statistical analyses, and was reported according to CONSORT criteria. The modified intention-to-treat efficacy analysis, in view of the high compliance with the protocol, is unlikely to be different from an as-treated or per-protocol analysis, usually deemed to be more conservative for non-inferiority designs. Full-Text PDF Department of ErrorEriksson BI, Dahl OE, Rosencher N, et al, for the RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949–56—In this Article (Sept 15), the tenth sentence of the third paragraph in the Results section should read “Major bleeding events started before the first oral dose in 57% of patients in the 220 mg group, 47% of those in the 150 mg group, and 44% of those who received enoxaparin.” Full-Text PDF