Dabigatran for the treatment of venous thromboembolism

Abstract

Venous thromboembolism (VTE) is a major cause of morbidity and mortality, and individuals with a first VTE are at risk of recurrent VTE. VTE treatment is divided into three phases: a first short phase of acute (traditionally parenteral) anticoagulation, followed by a second maintenance phase with an oral anticoagulant, which may be continued into a third extended maintenance phase in patients considered to be at increased risk of recurrent VTE. Vitamin K antagonists are effective oral anticoagulants but have well-known limitations; non-vitamin K oral anticoagulants including dabigatran etexilate (DE) were therefore developed. DE was approved for VTE treatment on the basis of an extensive clinical trial program that evaluated DE during both the maintenance phase and the extended maintenance phase of VTE treatment. This article provides a comprehensive overview of DE in VTE treatment, from its preclinical characteristics and pharmacokinetic properties to its efficacy and safety in major clinical trials.

Keywords:

• anticoagulant
• dabigatran
• deep vein thrombosis
• pulmonary embolism
• venous thromboembolism

Financial & competing interests disclosure

S Schellong has received speaker fees from Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Sanofi and Leo. He has received consultancy fees from Bayer HealthCare, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline and Sanofi. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing support was provided by Lauren Godwin, PhD, of PAREXEL, who was contracted by Boehringer Ingelheim for this service.

Key issues

• Individuals with venous thromboembolism (VTE) are at risk of death, recurrent VTE and serious complications such as post-thrombotic syndrome or chronic thromboembolic pulmonary hypertension.

• Treatment of VTE is divided into three phases:

• 1. An acute phase of intense (traditionally parenteral) anticoagulation lasting for at least 5 days.

• 2. Maintenance therapy with an oral anticoagulant (traditionally a vitamin K antagonist such as warfarin), lasting between 3 and 6 months.

• 3. Extended maintenance therapy with an oral anticoagulant in patients deemed to be at increased risk of VTE recurrence.

• The well-known limitations of vitamin K antagonists prompted the development of non-vitamin K oral anticoagulants that do not require regular monitoring and dose adjustment, including the direct thrombin inhibitor dabigatran etexilate (DE).

• The safety and efficacy of DE in the treatment of VTE were assessed in four randomized, controlled, Phase III trials: RE-COVER and RE-COVER II, which compared DE with warfarin during the maintenance phase of VTE treatment, and RE-MEDY and RE-SONATE, which compared DE with warfarin and placebo in extended maintenance therapy.

• In both the maintenance phase and the extended maintenance phase, DE had non-inferior efficacy compared with warfarin and was associated with reduced risks of any bleeding and of major bleeding events (MBEs)/clinically relevant non-major bleeding events (CRBEs). In the pooled analysis of RE-COVER and RE-COVER II, using data from the start of oral-only treatment, there was a statistically significant reduction in MBEs, MBEs/CRBEs and any bleeding events in patients receiving DE compared with those receiving warfarin.

• In the extended maintenance phase, the primary end point of recurrent or fatal VTE or unexplained death occurred in fewer patients receiving DE than placebo (a reduction of 92%), but with more bleeding events. In the active-control study, recurrent or fatal VTE events were more frequent with DE, but with fewer bleeding events than warfarin.

• Selection of a patient for DE treatment should be guided by a careful evaluation of the benefit/risk balance, and by the European Summary of Product Characteristics for DE in VTE treatment.

Notes