From Pages to Practice

By James Yeh, MD, MPH

Published March 27, 2019


The estimated prevalence of atrial fibrillation is 1%–2% in the general population. Many patients with atrial fibrillation and indications for anticoagulation are treated with oral factor Xa inhibitors (e.g., apixaban, rivaroxaban, and edoxaban) to reduce the risk of cerebral or systemic embolism. These anticoagulants are as effective as warfarin for treating thromboembolism and reducing the risk of thromboembolic complications. They are also associated with lower risk of major bleeding, intracranial bleeding, and all-cause mortality.

Factor Xa inhibitors have relatively short half-lives. Therefore, when patients on factor Xa inhibitors experience minor or non-life-threatening bleeding, treatment discontinuation may be sufficient. However, when patients on factor Xa inhibitors have major bleeding or intracranial hemorrhage that increases risk of hematoma expansion and neurological deterioration, rapid anticoagulation reversal may be necessary. Andexanet — a recombinant modified human factor Xa decoy protein that reverses the inhibition of factor Xa — is approved by the FDA for the reversal of rivaroxaban and apixaban when anticoagulation reversal is necessary due to life-threatening or uncontrolled bleeding.

In 2016, NEJM published the early results of a multicenter, open-label, single-group study (ANNEXA-4) of andexanet in patients with acute major bleeding while taking a factor Xa inhibitor. Now the full study results have been published and demonstrate that, consistent with the earlier report, andexanet is an effective antidote to factor Xa inhibitors. Andexanet reduced anti-factor Xa activities with effective hemostasis in those with acute major bleeding associated with factor Xa inhibitor use.

The following NEJM Journal Watch summary explains the study.


Andexanet for Major Hemorrhage in Patients on Factor Xa Inhibitors

An uncontrolled study shows rapid efficacy in reducing elevated anti-FXa inhibitor levels.

The anticoagulant activity of oral direct factor Xa (FXa) inhibitors and low-molecular-weight heparins such as enoxaparin can be reversed by andexanet, a modified, recombinant inactive form of FXa. Andexanet was recently approved by the FDA for this indication in patients on apixaban or rivaroxaban experiencing major bleeding.

To examine the efficacy and safety of andexanet, investigators conducted an industry-sponsored, multicenter, prospective, open-label cohort study in 352 patients with major bleeding while taking an FXa inhibitor. For patients exposed to apixaban, or to rivaroxaban more than 7 hours previously, the bolus dose of andexanet was 400 mg, followed by a 2-hour continuous infusion of 480 mg; for patients exposed to enoxaparin or edoxaban, or to rivaroxaban within 7 hours, the bolus was 800 mg and the infusion dose 960 mg.

The following results were reported:

  • Patients' mean age was 77 years, bleeding was intracranial in 64% and gastrointestinal in 26%, and most were exposed to apixaban (55%) and rivaroxaban (36%).

  • After the andexanet bolus, anti-FXa activity declined from 150 to 11 ng/mL in those on apixaban, from 212 to 14 ng/mL in those on rivaroxaban, and from 0.48 IU/mL to 0.15 IU/mL in the 16 patients on enoxaparin.

  • Hemostatic efficacy 12 hours after the infusion was rated as excellent or good in 82%.

  • Thrombotic events occurred in 10% during the 30 days after the infusion.

  • No patients developed antibodies to FXa or neutralizing antibodies to andexanet.

Comment: In this uncontrolled study, andexanet rapidly decreased elevated levels of anti-FXa inhibitor and improved hemostatic efficacy. Although cessation of bleeding was not directly measured, the decrease in anti-FXa activity predicted the change in extent of intracranial hemorrhage. Although few enoxaparin-treated patients were included in this study, the preliminary data suggest that andexanet could be beneficial for major bleeding related to this commonly used anticoagulant.

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James Yeh, MD MPH, Physician at NEJM Group
James Yeh, MD MPH is an internist and assistant in medicine at the Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. His clinical and academic interests are in evidence-based medicine, medical education, continuing medical education, cardiopulmonary diseases, cardiovascular risk reduction, critical illness, care transition, polypharmacy, and health communication. He was a NEJM editorial fellow in 2015-2016.