Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors

Trial Reference

Connolly SJ, Crowther M, Eikelboom JW, et al.; ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Feb 7 [Epub ahead of print].

Abstract | Full Text

 

Expert Comment

Prof. Krzysztof J. Filipiak, Medical University of Warsaw

 

Andexanet alfa is an inactive form of human factor Xa developed for reversal of factor Xa inhibitors. To be more precise, andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa). FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective hemostasis.  The drug reverses effect of all anticoagulants that act through FXa directly or indirectly (by binding antithrombin III). The drug is not effective against factor IIa inhibitor  – dabigatran (Pradaxa®).

In ANNEXA-4 trial, 352 patients with acute major bleeding within 18 hours after administration of a factor Xa inhibitor were evaluated. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti–factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti–factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). Patients of mean age of 77 years, most with substantial cardiovascular disease and predominantly intracranial [64%] or gastrointestinal bleeding [26%] were on either apixaban (Eliquis®) or rivaroxaban (Xarelto®).

The median anti–factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter and from 211.8 ng per milliliter to 14.2 ng per milliliter respectivelly after the andexanet bolus (92% reduction). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti–factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.

The most important limitation of this trial is that it did not include a randomized comparison with a control group. At the time of study initiation, it was determined that a randomized, controlled trial would have logistic and ethical challenges, given the perceived risks of placebo assignment in this highly vulnerable population. However, continued use of unapproved agents, despite a lack of rigorous clinical data, has changed the equipoise for a trial. Thus, under the guidance of the FDA and as a condition of accelerated approval in the United States in May 2018, the sponsor is conducting a randomized trial (ClinicalTrials.gov number, NCT03661528) that is expected to begin later this year.

Conclusion

In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. Not only dabigatran (idarucizumab), but also more popular nowadays xabans – rivaroxabn and apixaban – have efficient antidote drug.

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