Idarucizumab for Dabigatran-Related Gastrointestinal Bleeds

Abstract

The introduction of direct oral anticoagulants (DOACs), including the oral direct thrombin inhibitor dabigatran etexilate, ushered in a new era for chronic thrombotic disease management. Despite evidence of DOAC safety, there are valid concerns regarding an anticoagulant effect in the setting of uncontrolled bleeding. Unlike the coagulation defect induced by vitamin K antagonists, which is correctable with vitamin K and coagulation factor replacement, there were no agents to reverse DOAC anticoagulant effect until recently. Idarucizumab is a monoclonal antibody fragment that binds to dabigatran with high affinity, and andexanet alfa is a form of deactivated factor Xa that acts as a decoy to bind factor Xa inhibitor molecules.1,2 These reversal agents rapidly correct the coagulopathy induced by the respective DOACs and should improve clinical outcomes. In the multicenter, open-label, single-cohort REVERSE-AD study (Reversal Effects of Idarucizumab on Active Dabigatran), idarucizumab corrected laboratory indices of anticoagulation and reduced the level of active drug in dabigatran-treated individuals with uncontrolled bleeding or the need for urgent surgery.3 Gastrointestinal bleeding accounted for 46% (137/301) of bleeding events in REVERSE-AD, the characteristics and outcomes of which are reported by van der Wall et al4 in this issue of Circulation. Gastrointestinal bleeding represents about 40% of major oral anticoagulant (OAC)–related bleeds.5,6 In contemporary trials of OACs for stroke prevention in atrial fibrillation, the annual risk of major gastrointestinal bleeding is ≈1% to 2%.7–10 Although the morbidity and mortality of acute gastrointestinal bleeding is lower than intracranial hemorrhage, it frequently necessitates hospitalization and procedures (eg, endoscopy, embolization) and is associated with significant healthcare costs.11,12 Over the next 50 years, the number of patients with atrial fibrillation (the most common indication for OACs) is expected to increase 2.5-fold, making atrial fibrillation and its complications a growing major health problem.13 REVERSE-AD included 137 dabigatran-treated patients with gastrointestinal bleeds judged by treating clinicians as uncontrollable and which were subsequently classified as minor (16%), major (60%), or life-threatening (22%). Idarucizumab (given as two 2.5-g intravenous boluses) rapidly reversed the anticoagulant effect of dabigatran in 98% of patients, an effect that persisted for up to 24 hours in most patients (59%). Given the methodological limitations of an open-label singlecohort study design, the contribution of idarucizumab to promoting and maintaining hemostasis remains uncertain. In the absence of a control group, it is unclear whether idarucizumab (in addition to supportive measures) leads to improved clinical outcomes. Furthermore, there are inherent clinical and methodological challenges in determining the timing of gastrointestinal bleed cessation, in particular, by treating clinicians, as was done in this study. © 2019 American Heart Association, Inc.