What is the recommended reversal agent for edoxaban (factor Xa inhibitor)?

Reversal Agent for Edoxaban

Andexanet alfa is the recommended reversal agent for edoxaban in patients with life-threatening or uncontrolled bleeding, with prothrombin complex concentrate (PCC) as an alternative when andexanet alfa is unavailable. 1, 2

First-Line Reversal Agent: Andexanet Alfa

Andexanet alfa is a recombinant modified factor Xa protein that acts as a decoy by binding to factor Xa inhibitors with high affinity. It lacks catalytic activity and cannot participate in coagulation, which allows it to rapidly reduce anti-factor Xa activity.

Efficacy for Edoxaban Reversal:

• Reduces anti-factor Xa activity by approximately 82% within minutes of administration in edoxaban-treated patients 3
• Clinical evidence shows excellent or good hemostasis achieved in 78.6% of patients with acute major bleeding on edoxaban within 12 hours of andexanet alfa administration 2
• Sustained normalization of thrombin generation for approximately 2 hours 3

Dosing Regimen:

• High-dose regimen (for last dose <7 hours or unknown timing):

  • 800 mg IV bolus over 15-30 minutes
  • Followed by 960 mg IV infusion over 2 hours 1

• Low-dose regimen (for last dose >7 hours before reversal):

  • 400 mg IV bolus
  • Followed by 480 mg IV infusion over 2 hours 1

Important Considerations:

• Thrombotic events occurred in 10-18% of patients within 30 days of administration 1
• This risk is thought to be related to temporary inhibition of tissue factor pathway inhibitor (TFPI) 1
• Monitor for rebound anticoagulation after reversal agent administration 1

Alternative Reversal Agent: Prothrombin Complex Concentrate (PCC)

When andexanet alfa is unavailable, 4-factor PCC can be used as an alternative reversal agent.

Dosing:

• Standard dose: 50 U/kg 1
• Alternatively, dose based on INR:
  • INR 2 to <4: 25 units/kg
  • INR 4-6: 35 units/kg
  • INR >6: 50 units/kg 1

Emerging Reversal Agent: Ciraparantag (PER977)

Ciraparantag is a synthetic molecule that binds to edoxaban and other anticoagulants:

• Early studies show it reversed edoxaban-induced prolongation of whole blood clotting time within 10 minutes of infusion 4
• Still under investigation and not yet FDA-approved 4

Post-Reversal Management

1. Monitor for rebound anticoagulation after reversal agent administration
2. Consider restarting anticoagulation 7-14 days after confirmed hemostasis 1
3. Supportive measures:
   • Local hemostatic measures
   • Fluid resuscitation
   • Blood product support as needed
   • Tranexamic acid (1 g IV, repeated every 6 hours if needed) 1

Clinical Pitfalls and Caveats

• Off-label use: While andexanet alfa is FDA-approved for rivaroxaban and apixaban, its use for edoxaban is off-label but supported by clinical evidence 2, 5
• Thrombotic risk: Be vigilant about the increased risk of thromboembolic events following andexanet alfa treatment 6
• Cost and availability: Andexanet alfa may not be available in all healthcare settings, making PCC an important alternative
• Timing matters: The efficacy of reversal agents diminishes with time from the last dose of edoxaban, so prompt administration is crucial
• Stoichiometric considerations: The ratio of andexanet alfa to edoxaban needed for effective reversal (1.41:1 to 2.58:1) is higher than for other factor Xa inhibitors 3

In emergency situations requiring urgent surgery, as demonstrated in a case report, andexanet alfa has been used successfully for edoxaban reversal without adverse effects, though this requires careful multidisciplinary management 5.