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

Andexanet Alfa is the Specific Antidote for Apixaban

Andexanet alfa is the FDA-approved specific reversal agent for apixaban in cases of life-threatening or uncontrolled bleeding. 1 This recombinant modified factor Xa protein binds to apixaban with high affinity, rapidly neutralizing its anticoagulant effect.

Reversal Options for Apixaban

First-Line Therapy: Andexanet Alfa

• Mechanism: Recombinant modified human factor Xa protein that binds and sequesters factor Xa inhibitors 2
• FDA Indication: Specifically approved for reversal of apixaban or rivaroxaban 2
• Dosing regimen:
  • Low-dose regimen: 400 mg IV bolus at 30 mg/min followed by 4 mg/min infusion for 120 minutes 2
  • High-dose regimen: 800 mg IV bolus at 30 mg/min followed by 8 mg/min infusion for 120 minutes 2
• Efficacy: Reduces anti-FXa activity by >90% immediately, with 80% of patients achieving good or excellent hemostasis within 12 hours 3
• Onset: Within 2 minutes 2
• Duration: Effect maintained during the 2-hour infusion 3

Alternative Options When Andexanet Alfa is Unavailable

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

   • Non-specific hemostatic agent 2
   • Dosing: 25-50 units/kg based on severity 2
   • Onset: Within 10 minutes 2
   • Duration: 8 hours 2

2. Activated Prothrombin Complex Concentrate (aPCC)

   • May be used when specific reversal agents are unavailable 4
   • Clinical hemostasis achieved in approximately 69% of patients 4

3. Activated Charcoal

   • For known recent ingestion (within 2-4 hours) 2
   • Can reduce apixaban AUC by 50% when given 2 hours after ingestion 5

Indications for Reversal

Reversal of apixaban should be considered in the following scenarios 2:

1. Life-threatening bleeding:

   • Intracranial hemorrhage
   • Uncontrollable hemorrhage

2. Bleeding in a closed space or critical organ:

   • Intraspinal, intraocular, pericardial, pulmonary, retroperitoneal bleeding
   • Intramuscular bleeding with compartment syndrome

3. Persistent major bleeding despite local hemostatic measures

4. Need for urgent intervention with high bleeding risk

5. Emergency surgery in patients at high risk for procedural bleeding

Monitoring and Safety Considerations

• Thromboembolic risk: Andexanet alfa is associated with 10-18% risk of thromboembolic events within 30 days 3
• FDA warning: Treatment with andexanet alfa has been associated with serious adverse events including arterial and venous thromboembolic events, ischemic events, cardiac arrest, and sudden deaths 1
• Post-reversal monitoring: Monitor for thromboembolic events and initiate anticoagulation when medically appropriate 1
• Rebound anticoagulation: Consider monitoring for rebound anticoagulation after reversal agent administration 3

Resuming Anticoagulation

• Consider restarting anticoagulation 7-14 days after confirmed hemostasis 3
• The decision to restart should be based on the patient's thromboembolic risk and bleeding risk

Emerging Therapies

• Ciraparantag (PER977): A synthetic cationic small molecule that binds to apixaban and other anticoagulants 2
• Currently in clinical development but lags behind andexanet alfa 2

Important Caveats

• Andexanet alfa is approved under accelerated approval based on change from baseline in anti-FXa activity in healthy volunteers 1
• An improvement in hemostasis has not been definitively established in all clinical scenarios 1
• Vitamin K and fresh frozen plasma should not be used to reverse apixaban 6
• Laboratory testing to measure preoperative DOAC levels may be useful in emergent situations to determine whether reversal agents are needed 7

In summary, andexanet alfa is the specific reversal agent for apixaban-related bleeding emergencies, with 4F-PCC serving as an alternative when andexanet alfa is unavailable. The decision to reverse anticoagulation should be based on the severity and location of bleeding, balancing the risks of thromboembolism against the benefits of hemostasis.