Flipping a Switch: Advances in DOAC Reversal in 2015

The direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban, are associated with reduced major bleeding, intracranial hemorrhage, and fatal bleeding compared with warfarin.¹  Nevertheless, reversal of these agents may be warranted in patients who have serious bleeding or who require an emergent procedure.

At this time last year, there was no standard of care for emergent DOAC reversal. Hospital committees grappled with low-quality evidence to define institutional protocols for reversal. Clinicians lacked guidance on how to manage patients. The best available options, prothrombin complex concentrate and activated prothrombin complex concentrate, were supported primarily by data from animal and healthy volunteer studies, and raised concerns about thrombotic risk. No data were available on the efficacy and safety of these agents in DOAC-treated patients with a clinical indication for emergent reversal.² 

2015 was a year of great forward momentum on the reversal front. In the RE-VERSE AD study, dabigatran-treated patients who have serious bleeding or who require an emergent procedure are treated with idarucizumab, a monoclonal antibody fragment that binds and neutralizes dabigatran. An interim analysis of the first 90 patients (51 with bleeding, 39 requiring a procedure) showed normalization of coagulation tests within minutes of infusion. Among patients requiring an emergent procedure, 92 percent were judged to have normal surgical hemostasis. Clinical outcomes, including cessation of bleeding, were more difficult to assess in the group with serious hemorrhage. Idarucizumab was well tolerated. Only one patient had a thrombotic event within 72 hours of administration.³  Based on the favorable results of RE-VERSE AD, idarucizumab was approved in the United States and Europe in autumn of 2015 and is now the standard of care for emergent dabigatran reversal in jurisdictions where it is available.

Not far behind idarucizumab in development is andexanet alfa, a modified recombinant factor Xa molecule that lacks catalytic and membrane-binding activity but retains the ability to bind and neutralize factor Xa inhibitors. In the recently published ANNEXA-A and ANNEXA-R trials, healthy volunteers taking apixaban and rivaroxaban, respectively, were randomized to receive andexanet or placebo. Rapid and profound reduction in anti-Xa activity was observed within minutes of bolus administration of andexanet. A continuous infusion following the bolus was necessary to sustain the reversal effect. Andexanet was well tolerated. Plasma samples from some subjects showed increased D-dimer and prothrombin 1+2 fragments.⁴  The clinical relevance of this observation is unknown. ANNEXA-4 (ClinicalTrials.gov Identifier: NCT02329327), an ongoing phase IIIb-IV study, will provide data on the efficacy and safety of andexanet in patients taking a factor Xa inhibitor who have serious bleeding.

Other DOAC-reversal agents are in earlier stages of development. Ciraparantag is a small, positively-charged molecule that binds to, and neutralizes factor Xa inhibitors through noncovalent interactions. It corrected coagulation tests in healthy edoxaban-treated volunteers within minutes of administration.⁵  Factor Xa^I16L, a zymogen-like variant of factor Xa, and ^superFVa, a variant of factor Va engineered to resist inactivation by activated protein C, both rapidly reversed the anticoagulant effect of rivaroxaban in vitro and in animal studies.^6,7 

A remarkable feature of DOAC reversal agents is the rapidity with which they normalize coagulation parameters. Hours are required for full reversal of the anticoagulant effect of warfarin by vitamin K or plasma. Correction is achieved more quickly with prothrombin complex concentrate, but 40 percent of patients have a persistently elevated INR (≥ 1.4) 30 minutes after infusion.⁸  In contrast, DOAC-reversal agents correct coagulation tests within minutes of administration, suggesting their potential to turn off anticoagulation almost instantly, like flipping a light switch.

Whether the effect of DOAC reversal agents on laboratory endpoints leads to improved clinical outcomes remains to be proven. Continued progress in the field of DOAC reversal in 2016 and beyond is expected to shed light on this and other crucial questions. Clinical observations from RE-VERSE AD and ANNEXA-4 will teach us more about the efficacy and safety of idarucizumab and andexanet alfa, respectively, in patients with DOAC-associated bleeding. Real world data on idarucizumab will be reported and recommendations for its use will be incorporated into clinical practice guidelines and institutional protocols.