Is andexanet alfa (factor Xa inhibitor reversal agent) effective for reversing the anticoagulant effects of edoxaban (factor Xa inhibitor)?

Andexanet Alfa for Reversal of Edoxaban Anticoagulation

Andexanet alfa is effective for reversing the anticoagulant effects of edoxaban and may be considered as a reversal strategy in patients with acute major bleeding, though this use is currently off-label and requires further confirmatory data. 1

Mechanism of Action and Efficacy

• Andexanet alfa is a recombinant modified human factor Xa variant that acts as a decoy, binding to factor Xa inhibitors with similar affinity as native factor Xa, thereby restoring normal hemostatic function 2
• In phase 2 studies, andexanet alfa has been shown to rapidly and effectively reverse anticoagulation with edoxaban, decreasing anti-FXa activity by approximately 82% compared with placebo 3
• The stoichiometric ratios of andexanet alfa to total anticoagulant at maximum reversal of anti-FXa activity for edoxaban range from 1.41:1 to 2.58:1 3
• Initial evidence shows that andexanet alfa significantly decreases anti-Xa activity with good hemostatic efficacy in patients with acute major bleeding treated with edoxaban 1

Current Approval Status

• Andexanet alfa is currently approved by regulatory agencies for reversal of rivaroxaban and apixaban in patients with life-threatening or uncontrolled bleeding 3, 4
• Use for edoxaban reversal is currently off-label and requires further confirmatory data 1
• In Japan, andexanet alfa has been approved for patients with life-threatening or uncontrolled bleeding while on treatment with apixaban, rivaroxaban, or edoxaban tosilate hydrate 5

Dosing Considerations for Edoxaban

• For edoxaban reversal, the high-dose regimen is recommended: 800 mg bolus followed by a 960 mg infusion (8 mg/min) 1
• The effect is transient, with anti-FXa activity returning to pre-treatment levels approximately two hours after completion of infusion 2
• Sustained normalization of thrombin generation for approximately 2 hours and sustained decrease in unbound anticoagulant (maximum approximately 80%) for up to 4 hours following completion of andexanet alfa administration have been observed 3

Clinical Indications

• Andexanet alfa should be considered for edoxaban-treated patients with:
  • Life-threatening bleeding such as intracranial hemorrhage or uncontrollable hemorrhage 2
  • Bleeding in a closed space or critical organ (intraspinal, intraocular, pericardial, pulmonary, retroperitoneal) 1
  • Persistent major bleeding despite local hemostatic measures 1
  • Need for urgent intervention with high bleeding risk 2

Alternative Reversal Strategies for Edoxaban

• If andexanet alfa is unavailable or not approved for edoxaban in your region, prothrombin complex concentrates (PCCs) at 25-50 U/kg may be initiated 1
• An initial dose of 25 U/kg PCC is suggested, as this dose has been shown to provide effective hemostasis without increased rates of thromboembolic events 1
• Caution should be used with repeated PCC doses due to the possible thrombotic potential 1

Safety Considerations

• Andexanet alfa is generally well tolerated, with no serious adverse events or thrombotic events reported in phase 2 studies 3
• Prompt resumption of anticoagulation after bleeding control significantly reduces thrombotic risk 2
• Laboratory testing should not delay andexanet administration in life-threatening bleeding situations 2

Important Clinical Caveats

• Plasma levels of antifactor Xa agents following andexanet alfa administration cannot be reliably measured with standard anti-Xa assays due to dissociation of andexanet alfa from the anticoagulant during dilution 1
• Modified anti-Xa assays with reduced dilution are available in some coagulation laboratories 1
• Viscoelastic coagulation tests (ROTEM or ClotPro) may provide additional information about residual antifactor Xa activity 1
• Co-administration of tranexamic acid (15 mg/kg or 1 g) is indicated in trauma patients independent of the present DOAC and reversal strategy 1

While andexanet alfa shows promise for edoxaban reversal based on pharmacological principles and initial evidence, clinicians should be aware of its current off-label status for this specific indication in most regions and consider the availability of alternative reversal strategies when managing patients with life-threatening bleeding on edoxaban therapy.