What is the antidote for apixaban (factor Xa inhibitor) overdose or bleeding?

Antidote for Apixaban Overdose or Bleeding

Andexanet alfa is the FDA-approved specific antidote for apixaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. 1, 2

Mechanism of Action and Indications

• Andexanet alfa (brand name ANDEXXA) is a recombinant modified human factor Xa protein that binds and sequesters factor Xa inhibitors like apixaban 1
• It is specifically approved for reversal of apixaban or rivaroxaban in cases of:
  • Life-threatening bleeding
  • Uncontrolled bleeding
  • Critical organ bleeding
  • Persistent bleeding despite local hemostatic measures 1, 2

Dosing Regimen

The dosing of andexanet alfa depends on the dose of apixaban and time since last dose:

• Low-dose regimen: 400 mg IV bolus followed by 480 mg IV infusion over 2 hours 1
• High-dose regimen: 800 mg IV bolus followed by 960 mg IV infusion over 2 hours 1, 2

Administration should be started at a target rate of approximately 30 mg/min for the bolus, followed by the continuous infusion within two minutes of the bolus dose 2.

Efficacy and Onset of Action

• Andexanet alfa rapidly reduces anti-FXa activity by >90% within minutes of administration 1
• The reversal effect is maintained during the 2-hour infusion but may diminish afterward 1
• It's important to note that this indication was approved under accelerated approval based on change in anti-FXa activity in healthy volunteers, and an improvement in hemostasis has not been definitively established 2

Important Safety Considerations

Thromboembolic Risk

• WARNING: Treatment with andexanet alfa has been associated with serious adverse events including:

  • Arterial and venous thromboembolic events (10-18% of patients within 30 days)
  • Ischemic events including myocardial infarction and stroke
  • Cardiac arrest
  • Sudden deaths 1, 2

• Monitor patients for thromboembolic events and initiate anticoagulation when medically appropriate 2

Post-Reversal Management

• Monitor for rebound anticoagulation after andexanet alfa administration 1
• Consider restarting anticoagulation 7-14 days after confirmed hemostasis 1

Alternative Reversal Options

When andexanet alfa is unavailable, alternative options include:

1. Four-Factor Prothrombin Complex Concentrate (4F-PCC):

   • Can be considered for life-threatening bleeding 1, 3
   • Has onset of action within 10 minutes and duration of effect of 8 hours 1
   • Clinical hemostasis achieved in approximately 68.6% of patients in one study 3

2. Activated Prothrombin Complex Concentrates (aPCC):

   • May be an option for patients with major bleeding associated with apixaban 3
   • Thromboembolic events reported in 8.6% of patients in one study 3

3. Activated charcoal:

   • May be useful if administered within 2-6 hours of apixaban ingestion
   • Reduces mean apixaban AUC by 50% when given 2 hours after ingestion and 27% when given 6 hours after ingestion 4

Pitfalls and Caveats

• Andexanet alfa is not indicated for reversal of FXa inhibitors other than apixaban or rivaroxaban 2
• There is currently no data supporting the use of an additional dose of andexanet alfa if the initial dose is ineffective 2
• Vitamin K and fresh frozen plasma should NOT be used to reverse apixaban 5
• Concomitant medications that interact with apixaban can increase bleeding risk (seen in 60% of patients in one study) 3
• Unlike warfarin, routine laboratory monitoring of anticoagulant effect is not typically performed for apixaban, making assessment of reversal more challenging 6