Letter to the Editor

Kumar et al report their experience (n 1⁄4 7) and present a thoughtful set of recommendations for managing lifethreatening, dabigatran-associated hemorrhage. Randomized trials have shown the overall frequency of bleeding complications with dabigatran and warfarin to be similar, although intracranial bleeding events are lower with dabigatran. Furthermore, all anticoagulants have the potential to cause bleeding, and the benefit-to-risk profile of each agent needs to be considered when making treatment decisions. The authors state that ‘‘there is no quick method to assess plasma dabigatran activity or a specific antidote for its reversal.’’ As members of the study leadership for the Reversal of Active Dabigatran (RE-VERSE AD) study, we would like to make several comments. First, the thrombin clotting time (TCT) and activated partial thromboplastin time (aPTT) provide qualitative measures of the anticoagulant activity of dabigatran, whereas the dilute thrombin time and chromogenic ecarin assay with dabigatran calibrators can be used for quantitative assessment of dabigatran concentrations in plasma. These tests, together with information about the timing of the last dose and current renal function, can be helpful to determine the expected duration of anticoagulation in dabigatran-treated patients who require urgent surgery or interventions. Completely normal aPTT or TCT provides reassurance that very little anticoagulant activity attributable to dabigatran is in effect. Likewise, in dabigatran-treated patients who present with serious bleeding, the potential contribution of dabigatran to the bleeding can be assessed by considering coagulation assay values, renal status, and time since last dose. Second, the authors point out that there is no specific antidote for dabigatran. However, idarucizumab, a monoclonal antibody fragment against dabigatran, has been developed and shown to completely reverse dabigatran effects in healthy volunteers, and a study evaluating its utility for reversal of the anticoagulant effects of dabigatran in patients with serious bleeding or in those requiring urgent surgery is currently underway (clinicaltrials.gov NCT02104947). Idarucizumab almost instantaneously shortens the clotting times in animals and healthy human volunteers treated with dabigatran. We believe that the availability of an effective antidote will enhance the safety profile of dabigatran, as its use expands into new indications besides stroke prevention in nonvalvular atrial fibrillation, such as treatment of venous thromboembolism. Third, until idarucizumab is available for clinical use, it is important to point out that repletion strategies, such as recombinant factor VIIa and prothrombin complex concentrate (PCC), which are suggested by Kumar and colleagues, as well as fresh frozen plasma, have not been definitively shown to be of benefit in managing dabigatran-associated bleeding. Nonetheless, because PCC reduces dabigatran-induced bleeding in various animal models, it can be considered in patients with life-threatening hemorrhage. Finally, we wish to point out that despite logistical challenges, hemodialysis is an effective method for reducing plasma concentrations of dabigatran. Until the results of the RE-VERSE AD study are known, our best guidance for the evaluation and management of