Specific Antidotes for Direct Oral Anticoagulant Reversal

Abstract

D irect oral anticoagulants (DOAC) are recommended as the preferred option for the treatment and prevention of thromboembolic events because of a favorable benefit-risk profile when compared with vitamin K antagonists. Nevertheless, the fear of bleeding owing to the lack of a specific antidote has been a major concern. Idarucizumab was marketed in 2018 for the reversal of the thrombin inhibitor dabigatran. Recently, after the publication of the ANNEXA-4 study, andexanet alfa, the antidote for factor Xa (FXa) inhibitors, was approved. 1 The results of this study question whether these antidotes fulfill an unmet need and improve DOAC-treated patient outcomes. Major bleeding occurs annually in 1% to 3% of DOAC-treated patients and results in high mortality. The short half-life of DOACs compared with warfarin obviates the use of an antidote in most cases. However, anticoagulant reversal is unquestionably required in specific situations including urgent invasive procedures, overdose, or life-threatening traumatic or spontaneous bleeding. Because rapid vitamin K antagonist reversal reduces mortality of patients facing major bleeding and minimizes hematoma expansion after intracerebral hemorrhage, immediate reversal of DOAC should similarly improve outcomes. 2 This is based on the assumption that by reversing the anticoagulant effects, the antidote restores hemostasis, stops hemorrhage, and therefore reduces mortality. Ideally, the perfect antidote should induce immediate, complete, and sustained reversal of the anticoagulant activity correlated with clinical improvement, with no side effects, especially throm-boembolic, should be user friendly, and should be available at an acceptable price. Idarucizumab (Praxbind, Boehringer Ingelheim) is a humanized monoclonal an-tibody fragment with structural analogies with thrombin that specifically binds dabigatran with high affinity, forming complexes cleared by the kidneys. The Food and Drug Administration approved idarucizumab for dabigatran reversal in life-threatening or uncontrolled bleeding, or emergency procedures. Indeed, the single-arm REVERSE AD study (Reversal Effects of Idarucizumab on Active Dabigatran) demonstrated that intravenous infusion of 5 g idarucizumab provided immediate, effective (100% median maximum percentage reversal), and sustained reversal of anticoagulant activity in 503 dabigatran-treated patients who had uncontrolled bleeding or faced emergency surgery. 3 Andexanet alfa (Andexxa, Portola) is a genetically modified FXa that acts as a decoy to bind FXa inhibitors, including apixaban, rivaroxaban, and edoxaban, but also low-molecular-weight heparins. It has no active site and is therefore catalytically inactive. It has no membrane-binding Gla-domain, so it is unable to assemble into the prothrombinase complex. The Food and Drug Administration granted accelerated approval for patients treated with apixaban or rivaroxaban, when reversal is needed because of life-threatening or uncontrolled bleeding, beginning in May 2018 after the intermediate analysis of the ANNEXA-4 study (The Andexanet