Elsevier

The Lancet

Volume 379, Issue 9811, 14–20 January 2012, Pages 123-129
The Lancet

Articles
Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial

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Summary

Background

Treatment of pulmonary embolism with low-molecular-weight heparin and vitamin K antagonists, such as warfarin, is not ideal. We aimed to assess non-inferiority of idrabiotaparinux, a reversible longlasting indirect inhibitor of activated factor X, to warfarin in patients with acute symptomatic pulmonary embolism.

Methods

In our randomised, double-blind, double-dummy, non-inferiority trial, we enrolled adults with objectively documented acute symptomatic pulmonary embolism attending 291 centres in 37 countries. We excluded patients who were pregnant, had active bleeding, kidney failure, or malignant hypertension, or were at high risk of death, bleeding, or adverse reactions to study drugs. We randomly allocated patients to receive 5–10 days' enoxaparin 1·0 mg/kg twice daily followed by subcutaneous idrabiotaparinux (starting dose 3·0 mg) or adjusted-dose warfarin (target international normalised ratio 2·0–3·0); regimens lasted 3 months or 6 months dependent on clinical presentation. Block randomisation was done with a central interactive computerised system, stratified by study centre and intended treatment duration. The primary efficacy outcome was recurrent venous thromboembolism at 99 days after randomisation. We estimated the odds ratio and 95% CI with a Mantel-Haenzsel χ2 analysis (non-inferiority margin 2·0) in the intention-to-treat population. The main safety outcome was clinically relevant bleeding (major or non-major) in all patients at day 99. This study is registered with ClinicalTrials.gov, number NCT00345618.

Findings

Between Aug 1, 2006, and Jan 31, 2010, we enrolled 3202 patients aged 18–96 years. 34 (2%) of 1599 patients randomly allocated to receive enoxaparin-idrabiotaparinux and 43 (3%) of 1603 patients randomly allocated to receive enoxaparin-warfarin had recurrent venous thromboembolism (odds ratio 0·79, 95% CI 0·50–1·25; pnon-inferiority=0·0001). 72 (5%) of 1599 patients in the enoxaparin-idrabiotaparinux group and 106 (7%) of 1603 patients in the enoxaparin-warfarin group had clinically relevant bleeding (0·67, 0·49–0·91; psuperiority=0·0098). We noted similar differences in outcomes in those patients treated to 6 months.

Interpretation

Idrabiotaparinux could provide an attractive alternative to warfarin for the long-term treatment of pulmonary embolism, and seems to be associated with reduced bleeding.

Funding

Sanofi-Aventis (Paris, France).

Introduction

Every year about one person in 1000 in developed countries is diagnosed with acute symptomatic pulmonary embolism, with associated risks of recurrence, death, and economic burden.1, 2 Effective, safe, and straightforward initial and continuing anticoagulant therapy is therefore essential.

Standard practice is initial treatment with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin, followed by a vitamin K antagonist such as warfarin.3 This treatment is very effective but is not ideal. Unfractionated heparin needs frequent dose monitoring and skilled dose adjustment. Low-molecular-weight heparins need daily or twice-daily injection, and there is a small but important risk of heparin-induced thrombocytopenia. Maintenance of effective and safe levels of anticoagulant effect can be hard to achieve with vitamin K antagonists, especially in routine practice, and the necessary effort imposes a burden on patients and their doctors.4

Idraparinux is a synthetic pentasaccharide with a specific inhibitory effect on factor Xa activity that is mediated through plasma antithrombin. This drug has a terminal half-life of about 66 days, enabling once-weekly subcutaneous injection.5 Use of such a regimen in patients with deep vein thrombosis had equivalent efficacy and safety as did standard therapy, but with improved quality of life.6, 7 Moreover, after 6 months of idraparinux, continued protection from recurrence was noted for several months after the last injection.8 However, idraparinux without initial low-molecular-weight heparin was less effective than was standard therapy in a parallel study6 of patients with pulmonary embolism.

The addition of a biotin moiety to idraparinux (ie, idrabiotaparinux) allows rapid reversal of the anticoagulant effect through infusion of avidin, but does not change its pharmacodynamic effects.9 Idrabiotaparinux and idraparinux have equivalent efficacy and safety outcomes in patients with deep vein thrombosis.10

In this study, we aimed to assess whether low-molecular-weight heparin (enoxaparin) followed by weekly subcutaneous idrabiotaparinux for 3–6 months was non-inferior in terms of incidence of recurrent venous thromboembolism and bleeding to standard anticoagulant therapy with enoxaparin and warfarin.

Section snippets

Study design and participants

In our randomised, double-blind, double-dummy, non-inferiority study, we enrolled consecutive patients with confirmed acute symptomatic pulmonary embolism attending 291 centres in 37 countries. Diagnostic eligibility criteria were an intraluminal filling defect in the subsegmental arteries or more proximal pulmonary arteries on spiral CT or conventional pulmonary angiography, a high-probability ventilation-perfusion lung scan, or an inconclusive CT, pulmonary angiogram, or lung scan together

Results

Between Aug 1, 2006, and Jan 31, 2010, we enrolled 3202 patients at 291 centres (figure 1). Demographic and clinical characteristics did not differ between treatment groups (table 1).

Table 2 shows data for treatment characteristics with enoxaparin, idrabiotaparinux, and warfarin for patients who received at least one dose of study drug. Duration of treatment with idrabiotaparinux or warfarin was much the same between groups (table 2). The intensity of treatment with vitamin K antagonists was

Discussion

Weekly subcutaneous idrabiotaparinux was non-inferior to warfarin in our study of anticoagulant treatment for acute symptomatic pulmonary embolism. All patients received 3 months of study treatment, 79% continued study therapy for 6 months, and both regimens included an initial course of low-molecular-weight heparin. Treatment with idrabiotaparinux was associated with less frequent bleeding than was treatment with warfarin. On the basis of these findings and reports from patients with deep vein

References (15)

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