Andexanet alfa

David Goldemund M.D.
Updated on 17/06/2024, published on 25/01/2022

the introduction of direct oral anticoagulants (DOACs) revolutionized anticoagulation therapy
however, FXa inhibitors, in particular, present a challenge in the management of acute bleeding episodes
until recently, prothrombin complex concentrates (PCC) have been used off-label to treat acute, life-threatening bleeding secondary to factor Xa (FXa) inhibitors
andexanet alfa (ONDEXXYA, ANDEXXA), a recombinant modified human factor Xa molecule, was developed as a targeted reversal agent for these anticoagulants
- andexanet was approved by the FDA in 2018 for the reversal of life-threatening bleeding in patients anticoagulated with FXa inhibitors → more here

Mechanism of action

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
guidelines now recommend the use of andexanet alfa as the 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

ANNEXA-I (2024) trial showed mixed effects of andexanet in patients with ICH who are taking factor Xa inhibitor anticoagulants
- andexanet resulted in better control of hematoma expansion than standard care (where PCC was used in 85%) but was associated with an increased risk of thrombotic events, including ischemic stroke
- hematoma expansion ≥12.5 mL – andexanet 11.1% (24/216) vs. standard care 16.8% (36/214)
- the anti-FXa activity was significantly reduced in patients with ICH treated with andexanet alfa
- thrombotic events occurred in 10.3% vs 5.6% (standard care), ischemic stroke occurred in 6.5% vs. 1.5% (standard care)
- there were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days (traditional 90-day mRS is not available)

≥ 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)

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

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