Andexanet alfa

David Goldemund M.D.
Updated on 07/12/2023, published on 25/01/2022

In recent years, the anticoagulation therapy has been revolutionized by the introduction of direct oral anticoagulants (DOACs), such as factor Xa inhibitors. These agents pose unique challenges in managing acute bleeding episodes.  Andexanet alfa, a recombinant modified human Factor Xa molecule, was introduced as a targeted reversal agent for these anticoagulants. The chapter will explore the pharmacological properties, mechanism of action, and clinical application of andexanet alfa

Mechanism of action

  • until recently, prothrombin complex concentrates (PCCs) were used off-label to treat acute, life-threatening bleeding secondary to factor Xa (FXa) inhibitors
  • in 2018, the FDA approved andexanet alfa (ONDEXXYA, ANDEXXA) for the reversal of life-threatening bleeding in patients anticoagulated with FXa inhibitors (apixaban/rivaroxaban)  → more here
    • the drug is a modified recombinant inactive form of human FXa that specifically binds to and sequesters FXa inhibitor molecules, thereby rapidly reducing their activity
    • positive trials supporting its use include ANNEXA-A, ANNEXA-R, and ANNEXA-4  [Medscape 2016]
    • it is administered as an IV bolus over 15-30 minutes, followed by a 2-hour infusion
  • new guidelines now recommend the use of andexanet alfa as first-line therapy
  • ANNEXA-4 was a multicenter, prospective, open-label, single-arm trial evaluating patients experiencing major bleeding
  • the trial involved 352 participants
  • all patients received a bolus of andexanet alfa, followed by a 2-hour infusion to treat acute major bleeding after taking a factor Xa inhibitor in the previous 18 hours
    • ICH 64%, GIT bleeding 26%
    • rivaroxaban 36%, apixaban 55%, edoxaban 3%, enoxaparin 6% (those with doses > 1 mg/kg)
  • the study evaluated the decrease in anti-Xa activity and hemostatic efficacy 12 hours post-infusion
    • apixaban and rivaroxaban showed a 92% decrease in mean anti-Xa activity; enoxaparin showed a 75% decrease
    • hemostasis at 12 hours was rated as excellent or good in 82% of patients
  •  the 30-day mortality was 14%, with thrombotic events occurring in 10% of patients, and two patients had mild post-infusion reaction


Standard dose

  • ≥ 8 hours after DOAC administration
  • < 8h after administration of rivaroxaban ≤ 10 mg or apixaban ≤ 5 mg
  • administer IV bolus of 400mg at a rate of 30 mg/min (~ 13 min)
  • followed by an infusion at a rate of 4 mg/min for 120 min (total dose = 480 mg)

Higher dose

  • use if the dose or time of the last DOAC administration is uncertain or  if < 8h have passed since administration of > 10 mg rivaroxaban or > 5 mg apixaban
  • give an IV bolus of 800mg at a rate of 30 mg/min (approximately 13 min)
  • followed by an infusion at a rate of 8 mg/min for 120 min (total dose = 960 mg)
  • monitor actively for signs of thromboembolic complications during and after the infusion
  • consider the potential rebound phenomenon following the andexanet administration  Anti-Xa activity following andexanet administration
Andexanet dose regimens
Andexanet - standard and high dose criteria


  • andexanet alfa is a recombinant, inactive form of Factor Xa
  • it is used to reverse life-threatening bleeding in patients who are being treated with certain factor Xa inhibitors, such as apixaban and rivaroxaban
  • andexanet alfa acts by binding to and sequestering factor Xa inhibitors in the bloodstream. This action neutralizes their anticoagulant effects, thereby helping to control severe bleeding events
  • it is specifically used in emergencies to reverse life-threatening bleeding in patients treated with factor Xa inhibitors, especially when the bleeding is intracranial or gastrointestinal
  • yes, the efficacy of andexanet alfa has been demonstrated in clinical trials, notably the ANNEXA-4 trial, which evaluated its effectiveness and safety in stopping major bleeding events
  • some potential side effects include thromboembolic events, such as heart attack or stroke, and infusion-related reactions
  • it’s important to monitor patients closely during and after its administration
  • andexanet alfa is administered intravenously
  • the dosage depends on the specific factor Xa inhibitor, its dose, and the time since its last dose
  • andexanet alfa is primarily effective for reversing the effects of apixaban and rivaroxaban
  • its effectiveness with other factor Xa inhibitors, like edoxaban and enoxaparin, may vary
  • the safety of andexanet alfa in pregnant or breastfeeding women has not been established
  • its use should be considered only if the potential benefit justifies the potential risk to the fetus or infant

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Andexanet alfa