Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent

The results of early trials evaluating the tolerability, efficacy,and safety of specific antidotes for the DOACs are promising (Table 2), but none of these agents are as yet approved for clinical use. Until they are approved, clinicians attempting to reverse the anticoagulant effects of DOACs will be limited to the use of general hemostatic agents, such as(activated) PCCs or rFVIIa,3-12 and to hemodialysis or hemofiltration for removal of DOACs that are not highly protein-bound.The overall goal of using reversal agents is to prevent morbidity and mortality.23 Even without specific antidotes, the randomized trials have demonstrated that DOACs compared with standard therapies are associated with similar or lower rates of major bleeding and lower rates of intracranial bleeding,2,24 with similar or lower mortality rates after bleeding.25,26 In order to be approved for clinical use, future trials with specific antidotes will need to demonstrate their efficacy in clinical studies involving patients treated with DOACs. At this stage however, it is unclear whether regulatory agencies will require evidence of control of bleeding or whether demonstration of reversal of anticoagulant effects of DOACs will be sufficient for their approval. Demonstration of hemostatic efficacy will be challenging because bleeding of sufficient severity to require reversal of DOACs is uncommon, the half-life of DOACs are short, creating a limited window to administer the antidote, and the appropriate outcome measure for such studies is uncertain.However, because the overall goal of reversal agents is to prevent morbidity and mortality rather than to normalize prolonged coagulation tests, demonstration of hemostatic efficacy will be essential to establish that specific antidotes for DOACs can also make a clinically important difference.