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

  • 352 Patients were included, of whom 36% received rivaroxaban, 55% received apixaban, 3% received edoxaban and 6% received enoxaparin.
  • The primary site of bleeding was intracranial in 64% of patients and gastrointestinal in 26%.
  • In the efficacy population, anti-factor Xa activity was reduced by 92% (95%CI: 91-93) at the end of bolus administration in the 134 patients receiving apixaban, and by 92% (95%CI: 88-94) in the 100 patients on rivaroxaban. Patients on enoxaparin showed 75% (95%CI: 66-79) reduction of anti-factor Xa activity.
  • 4, 8 and 12 hours after andexanet infusion, the median value for anti-factor Xa activity was reduced from baseline by 32%, 34% and 38% respectively in those treated with apixaban, and by 42%, 48% and 62% in those on rivaroxaban.
  • 82% of 249 patients who could be evaluated for hemostatic efficacy were adjudicated as having excellent or good hemostatic efficacy at 12 hours (95%CI: 77-7). 171 had excellent hemostatic efficacy.
  • 85% Of patients admitted with gastrointestinal bleeding had excellent or good hemostatic efficacy, and 80% of those with intracranial bleeding.
  • 10% of patients (34) had a thrombotic event during follow-up, 11 of whom within 5 days after andexanet therapy. 11 had an event between 6 and 14 days, and 12 between 15 and 30 days. 49 patients died within 30 days after enrollment, 35 of whom due to CV causes.


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.


1. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-510.

2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365: 883-91.

3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-92.

4. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.

5. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377: 1319-30.

6. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-51.

7. Ghadimi K, Dombrowski KE, Levy JH, Welsby IJ. Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation. Expert Rev Hematol 2016; 9: 115-22.

8. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373: 2413-24.

Find this article online at NEJM

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free