Physicians' Academy for Cardiovascular Education

Antidote reverses FXa inhibitor anticoagulation after acute major bleeding

Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors

Literature - Milling TJ Jr, Middeldorp S, Xu L, et al. - Circulation. 2023 Feb 20. doi: 10.1161/CIRCULATIONAHA.121.057844

Introduction and methods


In patients with nonvalvular AF and venous thromboembolism, treatment with factor Xa (FXa) inhibitors reduces thrombotic events, but this comes at the cost of an increased bleeding risk. Andexanet alfa, a modified recombinant inactive FXa, was specifically designed to reverse the anticoagulation induced by FXa inhibitors [1]. Andexanet alfa was given conditional approval for the reversal of anticoagulation in life-threatening or uncontrolled bleeding by the US Food and Drug Administration (in 2018) and European Medicines Agency (in 2019); in Japan, full market approval was obtained (in 2022).

Previously, results from 2 analyses (in 67 and 352 patients, respectively) of the ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) study were published [2,3]. The current analysis comprised the final cohort (n=479).

Aim of the study

The study aim was to assess the safety and efficacy of andexanet alfa and the relationship among anti-FXa activity level, mortality, and hemostatic efficacy in patients with FXa inhibitor–related major bleeding.


The ANNEXA-4 study was an international, prospective, open-label, phase 3b/4, single-group cohort study in which 479 patients presenting with acute major bleeding within 18 hours of receiving an FXa inhibitor (apixaban, rivaroxaban, edoxaban, or enoxaparin) were treated with andexanet alfa (administered as a 15–30-minute bolus and subsequently a 2-hour infusion).

Anti-FXa activity and the unbound fraction of the FXa inhibitor in plasma before andexanet alfa treatment were measured in blood samples at the end of the bolus administration, at the end of the infusion, and at 4, 8, and 12 hours after infusion. Patients with intracranial hemorrhage (ICH) underwent follow-up imaging. An independent adjudication committee assessed whether patients met major bleeding criteria and adjudicated hemostatic efficacy, thrombotic events, and cause of death.


The 2 co-primary endpoints were percent change from baseline in anti-FXa activity during andexanet alfa treatment and percentage of patients with good or excellent hemostatic efficacy (based on prespecified criteria, such as hematoma volume expansion for ICH) at 12 hours after andexanet alfa infusion. Primary safety endpoints were death, thrombotic events, and development of antibodies to andexanet alfa or to native FX and FXa between baseline and day 30. A secondary endpoint was the endogenous thrombin potential at baseline and across the follow-up period.

Main results

Anti-FXa activity

Hemostatic efficacy


Thrombin generation

Relationship among anti-FXa activity, hemostatic efficacy, and mortality


In the final ANNEXA-4 study cohort of 479 patients with FXa inhibitor–related acute major bleeding, andexanet alfa reduced anti-FXa activity up to 94% and was associated with good or excellent hemostatic efficacy in 80% of patients.


Show references

Find this article online at Circulation.

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