Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial.
Dabigatran etexilate is a direct thrombin inhibitor increasingly used for stroke prevention in patients with atrial fibrillation or for the treatment and the prevention of venous thromboembolism. Despite predictable pharmacokinetics and a very short half-life, bleeding remains an unavoidable complication of all anticoagulants including dabigatran. A large number of animal studies have tried to assess the efficacy of non-specific reversal strategies (e.g. 3-factor or 4-factor prothrombin complex concentrates [PCC], activated PCC or recombinant activated factor VII) in normalizing anticoagulation parameters and decreasing bleeding in the presence of dabigatran. Although some promising (but conflicting) results were obtained, the need for a specific antidote has been highlighted in some specific circumstances (e.g. emergent invasive or surgical procedures).
Idarucizumab is a humanized monoclonal antibody fragment that specifically inhibits dabigatran. In this article, Glund et al. describe the results of the second part of a phase 1 study (the rising-dose pharmacokinetic analysis was published recently; see Glund S et al. Thromb Haemost 2015;113:943-51), where the authors assessed the safety, efficacy and tolerability of increasing doses of idarucizumab on the reversal of dabigatran-induced anticoagulation in healthy male volunteers. Participants were enrolled into one of 4 dose groups (1 g, 2 g, 4 g as a 5-min intravenous infusion, or 5 g plus 2.5 g given as two 5-min infusions 1 hour apart), administered 2 hours after the final dabigatran dose (220 mg BID during 3 days, followed by a final dose on day 4).
Only minor side effects were reported after the administration of idarucizumab (e.g. infusion site erythema and hot flush (1 g, n=1), epistaxis (5 g plus 2.5 g, n=1). In healthy volunteers receiving dabigatran, idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner, with a complete and sustained effect over 72 h for doses of 2 g or higher.
Although these results suggest a promising perspective for the specific reversal of dabigatran’s effect, the results reported in healthy volunteers need to be confirmed in the prospective, randomized study (RE-VERSE AD, www.clinicaltrial.gov: NCT02104947) that is currently assessing the reversal effects of idarucizumab in patients treated with dabigatran experiencing either uncontrolled bleeding or requiring emergency invasive procedures.
– David Faraoni
