ArticlesDabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial
Introduction
Deep-vein thrombosis diagnosed by contrast venography occurs in up to 20% of patients who have undergone hip replacement surgery, despite routine treatment for 5–11 days with low-molecular-weight heparin, warfarin, or pentasaccharide.1 The risk of deep-vein thrombosis can be further reduced by continuing treatment with these agents for 1 month after surgery.1, 2, 3, 4, 5 However, most patients do not continue anticoagulant prophylaxis after discharge from hospital,6, 7 and because the duration of hospital stays is falling (mean 3–4 days), only a few patients receive even the minimum 10 days of treatment recommended by the guidelines.1 By contrast, the use of once-daily oral aspirin after hospital discharge has increased markedly, despite very limited efficacy, presumably because of the convenience of its administration.6 New oral treatments that do not share the narrow therapeutic index of warfarin8 and do not need frequent laboratory monitoring and dose adjustment are clearly needed.
There is evidence to suggest that new, orally bioavailable anticoagulants can be used for prevention and treatment of thrombotic disorders.9, 10 Dabigatran etexilate is an oral, direct thrombin inhibitor under investigation for prevention and treatment of venous and arterial thromboembolic disorders. It is the prodrug of the active compound dabigatran, which binds directly to thrombin with a high affinity and specificity.11, 12 Data from a dose-ranging study suggest that the optimum total daily dose for effective and safe prevention of venous thromboembolism in total hip or knee replacement surgery is between 100 mg and 300 mg.13
RE-NOVATE—a randomised, double-blind, non-inferiority study—was designed to compare the efficacy and safety of two doses of dabigatran etexilate (220 mg or 150 mg) with the low-molecular-weight heparin enoxaparin, given for 1 month, to reduce the risk of venous thromboembolism after hip replacement surgery.
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Patients
Patients aged 18 years or older, weighing at least 40 kg, who were scheduled for primary elective unilateral total hip replacement were eligible for enrolment. Exclusion criteria included: any bleeding diathesis; history of acute intracranial disease or haemorrhagic stroke; major surgery, trauma, uncontrolled hypertension, or myocardial infarction in the past 3 months; gastrointestinal or urogenital bleeding, or ulcer disease in the past 6 months; severe liver disease; alanine or aspartate
Results
Of 3613 patients enrolled between December, 2004, and April, 2006, 3494 were randomised. Of the randomised patients, 2651 (76%) were included in the primary efficacy analysis (figure). Demographic and surgical characteristics of the three groups were much the same (table 1). Dabigatran etexilate was initiated a mean of 3·4 h after surgery. Overall, median treatment duration was 33 days, with 87% of patients receiving treatment for 28–35 days.
Table 2 shows the number of patients in each group
Discussion
Our results show that oral dabigatran etexilate, 220 mg or 150 mg once daily, given for a median of 33 days, was non-inferior to enoxaparin for reducing the risk of total venous thromboembolism and all-cause mortality after total hip replacement surgery. There was no significant difference in the rates of major venous thromboembolism and thrombosis-related death with either dose of dabigatran etexilate versus enoxaparin. Furthermore, the frequency of bleeding was low and comparable between the
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