Current Strategies for the Management of Bleeding Associated with Direct Oral Anticoagulants and a Review of Investigational Reversal Agents

Abstract

Background: The management of life-threatening bleeding in patients who are receiving direct oral anticoagulants (DOACs) is a serious medical concern.

Objective: This review provides a concise, balanced overview of the current and future approaches for reversing the anticoagulation effects of DOACs, particularly factor Xa (FXa) inhibitors.

Discussion: The anticoagulant activity of the direct thrombin inhibitor dabigatran can be reversed by idarucizumab, but until recently, options for the management of major bleeding in patients who were receiving FXa inhibitors were limited to nonspecific strategies, including supplementation of clotting factors with prothrombin complex concentrates (PCCs) or activated PCCs for attenuating anticoagulation effects. They appear as a treatment option in many hospital guidelines despite the lack of approval by the U.S. Food and Drug Administration and the lack of rigorous medical evidence supporting their use in this setting. The development of specific reversal agents may provide improved strategies for the management of bleeding. Andexanet alfa is a modified FXa molecule approved in the United States to reverse the anticoagulant effects of FXa inhibitors (rivaroxaban and apixaban) in patients with life-threatening or uncontrolled bleeding. Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects.

Conclusion: The current guidelines for management of DOAC-associated bleeding are being updated to reflect that the reversal agent for rivaroxaban and apixaban is now available. For other FXa inhibitors, in the absence of a reversal agent, nonspecific strategies that include PCCs are recommended. The population of patients anticoagulated with DOACs is growing, and we hope that specific reversal agents will improve the approach to management of major bleeding in this population.

Keywords: DOAC; FXa; bleeding; reversal of anticoagulation.