Physicians' Academy for Cardiovascular Education

Reversal agent for factor Xa inhibitors effective in patients with major bleeding on factor Xa inhibiting therapy

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

Literature - Connolly SJ, Crowther M, Eikelboom JW et al. - N Engl J Med. 2019. doi: 10.1056/NEJMoa1814051

Introduction and methods

Factor Xa inhibitors such as apixaban or rivaroxaban have a favorable benefit-risk profile for the treatment and prevention of thrombotic events. They are, however, associated with an increased risk of acute major bleeding, which can lead to substantial morbidity and mortality [1-5].

Andexanet alfa is a modified recombinant inactive form of human factor Xa that is specifically developed to bind and sequester factor Xa inhibitor molecules, to rapidly reduce anti-factor Xa activity [6,7]. In volunteers receiving apixaban or rivaroxaban, andexanet was shown to rapidly reduce both the unbound fraction of the plasma level of factor Xa inhibitor and anti-factor Xa activity [8]. The U.S. FDA approved andexanet in May 2018 for situations in which reversal of anticoagulation by apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding.

The Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study assessed the efficacy and safety of andexanet in patients with acute major bleeding while treated with a factor Xa inhibitor, in a multicenter, prospective, open-label single-group cohort study design. Patients were eligible if they had received within 18 hours prior to presentations with acute major bleeding one of the following: apixaban, rivaroxaban, or edoxaban at any dose or enoxaparin at a dose of at least 1 mg per kg body weight per day.

The two coprimary efficacy outcomes were percent change from baseline in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy 12 hours after the andexanet infusion. The efficacy analysis population included only patients who retrospectively met both of two criteria: baseline anti–factor Xa activity of at least 75 ng/mL (or ¬0.25 IU/mL for patients receiving enoxaparin) and confirmed major bleeding at presentation (n=254). All patients who had received andexanet were included in the safety analyses. All patients were followed for a minimum of 30 days or until death.

Main results


Administration of andexanet to patients presenting with acute major bleeding while on factor Xa inhibitor treatment yielded rapid reversal of factor Xa inhibition. 82% Of patients had excellent or good hemostatic efficacy at 12 hours.


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