The discovery of dabigatran etexilate for the treatment of venous thrombosis

ABSTRACT

Introduction: Venous thromboembolism (VTE) can be life-threatening and requires anticoagulant treatment; for many years, vitamin K antagonists, e.g. warfarin, were the only oral anticoagulants available for long-term treatment. Although highly effective, they have many limitations including a slow onset, a multitude of drug–drug and drug–food interactions, and a narrow therapeutic range. These limitations spurred the search for non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran etexilate.

Areas covered: The authors illustrate the progression of preclinical and clinical studies leading to the development of dabigatran, the only approved NOAC to act by direct thrombin inhibition. They focus on molecule discovery, animal models of thrombosis, clinical trials and post-launch activities in VTE treatment.

Expert opinion: Dabigatran demonstrated comparable efficacy to the highly effective warfarin, and a more favourable safety profile in trials of VTE treatment. A favourable anticoagulant safety profile in addition to efficacy is essential for VTE treatment. Availability of the dabigatran-specific reversal agent, idarucizumab, provides a means of rapidly reversing the anticoagulant effect if required. Future investigations into the optimal duration of VTE treatment and an evaluation of the impact of idarucizumab, in real-world studies, could provide valuable information to help optimise treatment for selected patients.

KEYWORDS:

• Dabigatran etexilate
• deep vein thrombosis
• direct thrombin inhibitors
• non-vitamin K antagonist oral anticoagulants
• pharmacology
• prevention
• pulmonary embolism
• treatment
• venous thromboembolism

Article highlights

• Venous thromboembolism (VTE) is a life-threatening disease requiring long-term treatment with anticoagulants.

• For many years, vitamin K antagonists (VKAs) were the only oral anticoagulants available for extended VTE treatment. Although highly effective, they have many limitations including a slow onset, a multitude of drug and food interactions and a narrow therapeutic range, leading to the search for non-vitamin K antagonist oral anticoagulants (NOACs).

• X-ray crystallography and animal models of thrombosis were instrumental in the discovery and development of dabigatran etexilate, the only approved oral direct thrombin inhibitor for VTE treatment.

• In the large, Phase III RE-COVER^®, RE-COVER^® II, and RE-MEDY^™ trials of VTE treatment, dabigatran demonstrated comparable efficacy and a more favorable safety profile to warfarin, the highly effective and established VKA treatment.

• A favorable anticoagulant safety profile is crucial in the treatment of VTE, particularly in the long term since the risk of VTE recurrence is reduced over time but the risk of anticoagulant associated bleeding remains constant.

• In future, additional treatment options in the management of VTE could be achieved through a better understanding of the optimal duration of VTE treatment and the impact of the recently approved dabigatran-specific reversal agent, idarucizumab (for selected patients at risk of life-threatening bleeds or urgent surgery).

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Declaration of interest

M Feuring and J van Ryn are employees of Boehringer Ingelheim GmbH & Co. KG. Furthermore, these studies were funded by Boehringer Ingelheim Pharma GmbH & Co. KG. The authors have 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 assistance was utilized in the production of this manuscript and funded by Boehringer Ingelheim Pharma GmbH & Co. KG. Writing assistance was provided by Sarah Mohamad of PAREXEL, contracted by Boehringer Ingelheim for these services.