Ever since the release of direct-acting oral anticoagulants, emergency physicians have been tasked with managing their associated complications. The introduction and initial popularity of dabigatran caught us lacking, with no useful options for managing hemorrhage. A specific antidote was not available, nor was a factor replacement strategy clearly efficacious. This situation has been improved with the availability of idarucizumab, the monoclonal antibody for reversal of dabigatran.1 We hope this antidote will produce clinically meaningful hemostasis following administration, but unfortunately, the best data available come to us from a single-arm trial.

ANNEXA-4 Results

Now, in a similar fashion, the full cohort results from the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) study have been released to great fanfare at the 2019 International Stroke Conference, with simultaneous publication in The New England Journal of Medicine.² This, like the Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran (RE VERSE-AD), details the efficacy of andexanet alfa as a reversal agent for the factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban, and enoxaparin). Rather than a monoclonal antibody like idarucizumab, andexanet alfa is a modified, recombinant human factor Xa molecule. The mechanism of reversal then is a greater affinity for the various factor Xa inhibitors than human native factor Xa. Displacing factor Xa inhibitors from native factor Xa contributes to normalization of the coagulation cascade, allowing for subsequent clot formation.

Another important difference is in the practical use of andexanet. Idarucizumab practically irreversibly binds dabigatran and leads to excretion of the idarucizumab-dabigatran complex without prominent rebound phenomena. Andexanet, in contrast, has a much shorter half-life and is administered as a bolus and a two-hour continuous infusion. In ANNEXA-4, monitoring of anti–factor Xa activity demonstrated profound improvement immediately following completion of the bolus. While this improvement was sustained through the end of the two-hour infusion protocol, by four hours after initiation of the bolus, anti–factor Xa activity had rebounded dramatically.

These characteristics complicate evaluation of ANNEXA-4 and its true clinical utility. The underlying hypothesis driving clinical efficacy relates to the restoration of factor Xa activity during the infusion, thus leading to new clot formation and stabilization. This leads to the core leap of faith required with andexanet: The clot will theoretically remain stable and provide clinically meaningful hemostasis following cessation of andexanet, even when anti–factor Xa levels rise above therapeutic thresholds. This also suggests important considerations for follow-up care, as any urgent surgical procedures performed after cessation of the andexanet infusion will not benefit from any hemostatic activity.

It is not all bad news from the andexanet camp in ANNEXA-4. Of the 254 patients evaluated for efficacy, 204 (82 percent) were judged to have “good” or “excellent” hemostatic efficacy. Unfortunately, these hemostatic surrogates are not clearly tied to patient-oriented outcomes. For example, approximately two-thirds of the bleeding sites included were intracranial hemorrhage. At this site, “good” or “excellent” hemostasis required an increase in maximum thickness of ≤35 percent at a 12-hour follow-up assessment. The logical follow-up questions are, is this good—or excellent—enough, and how much of this hemostasis can be attributed to andexanet?