Elsevier

The Lancet

Volume 370, Issue 9591, 15–21 September 2007, Pages 949-956
The Lancet

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

https://doi.org/10.1016/S0140-6736(07)61445-7Get rights and content

Summary

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.

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.

Section snippets

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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