Pharmacological reversal of the direct oral anticoagulants—A comprehensive review of the literature

ESSENTIALS: There remains clinical concern regarding the optimal management of direct oral (DOAC) anticoagulant effect for emergencies such as bleeding or urgent surgery/procedures. Idarucizumab is the preferred agent for urgent reversal of dabigatran for severe bleeding or urgent surgeries/procedures. There are currently no commercially available specific reversal agents for direct Xa inhibitors. Evidence for prothrombin complex concentrate (PCC), activated PCC (aPCC), and recombinant VIIa (rVIIa) is limited primarily to animal bleeding models and studies in human volunteer subjects. PCC, aPCC, or rVIIa may contribute to hemostasis for severe bleeding or urgent surgery/procedures in patients receiving factor Xa inhibitors, or dabigatran if idarucizumab is unavailable but benefits and harms are uncertain. The direct oral anticoagulants (DOACs) are used for stroke prevention in atrial fibrillation (SPAF) and the prevention and treatment of venous thromboembolic disease (VTE). Although DOAC‐associated bleeding events are less frequent as compared to vitamin K antagonists, there is significant concern surrounding physicians’ ability to evaluate and manage DOAC‐associated bleeding when it does occur. Idarucizumab is a specific reversal agent for dabigatran and is the agent of choice for dabigatran reversal in the setting of major bleeding or urgent surgery/procedures. There are no commercially available specific reversal agents for the direct Xa inhibitors. Although they have not been rigorously studied in DOAC‐treated patients requiring urgent anticoagulant reversal, limited evidence from in vitro studies, animal bleeding models, human volunteer studies (in vivo and in vitro) and case series suggest that coagulation factor replacement with prothrombin complex concentrate (PCC) and activated PCC (FEIBA) may contribute to hemostasis. However, the safety and efficacy of these agents and the optimal dosing strategies remain uncertain.