Reversal Agent for Apixaban
Andexanet alfa is the first-line specific reversal agent for apixaban, administered as either a low-dose regimen (400 mg IV bolus over 15 minutes followed by 480 mg infusion over 2 hours) or high-dose regimen (800 mg IV bolus over 30 minutes followed by 960 mg infusion over 2 hours), depending on the timing and dose of the last apixaban intake. 1
Primary Reversal: Andexanet Alfa
Andexanet alfa is FDA-approved and recommended by the American College of Cardiology as the preferred reversal agent for life-threatening or uncontrolled bleeding in apixaban-treated patients. 1, 2
Mechanism and Efficacy
Andexanet alfa is a recombinant modified factor Xa protein that acts as a decoy molecule, binding apixaban with high affinity and preventing it from inhibiting endogenous factor Xa. 1
The agent reduces anti-factor Xa activity by 93-94% within 2-5 minutes of administration, providing rapid and sustained reversal throughout the infusion period. 3, 1, 4
In the ANNEXA-4 study, 80% of patients achieved excellent or good hemostatic efficacy at 12 hours after andexanet administration. 3, 1
Dosing Strategy
Low-dose regimen: 400 mg IV bolus over 15 minutes followed by 480 mg infusion over 2 hours. 1
High-dose regimen: 800 mg IV bolus over 30 minutes followed by 960 mg infusion over 2 hours. 1
The choice between low and high dose depends on the timing of the last apixaban dose and the amount taken, with lower doses generally needed for apixaban compared to rivaroxaban due to twice-daily dosing resulting in lower drug concentrations. 1
Clinical Indications for Reversal
Reversal with andexanet alfa should be initiated for the following scenarios:
Life-threatening bleeding, including intracranial hemorrhage, symptomatic or expanding extradural hemorrhage, or uncontrollable hemorrhage. 1
Bleeding in critical organs or closed spaces, including intraspinal, intraocular, pericardial, pulmonary, retroperitoneal, or intramuscular bleeding with compartment syndrome. 1
Severe bleeding with hemodynamic instability or causing hemoglobin decrease ≥2 g/dL or requiring ≥2 units of RBCs. 1
Emergency surgery with high bleeding risk when apixaban cannot be cleared in time. 1
Alternative Reversal: 4-Factor Prothrombin Complex Concentrate
When andexanet alfa is unavailable, administer 4-factor PCC (Kcentra) at 50 U/kg IV (maximum 4,000 units) as the alternative strategy. 1
The FDA label for apixaban notes that prothrombin complex concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor VIIa may be considered, though these have not been evaluated in clinical studies. 2
Do not use PT, INR, aPTT, or anti-FXa activity to monitor the effectiveness of PCCs when used for reversal. 1
Critical Safety Considerations
The reversal effect of andexanet alfa is transient, with anti-factor Xa activity returning toward baseline approximately 2 hours after infusion completion. 1, 5
Thrombotic events occur in approximately 10% of patients within 30 days of receiving andexanet alfa, with most events occurring in patients whose baseline anticoagulation had not been restarted. 3, 1
Prompt resumption of anticoagulation after bleeding control is essential to reduce thrombotic risk, though timing should be individualized based on bleeding severity and control. 1, 5
Laboratory Assessment
Anti-factor Xa activity assays are preferred for quantifying apixaban levels, with a threshold of >50 ng/mL considered clinically significant for serious bleeding. 1
The pharmacodynamic effect of apixaban can be expected to persist for at least 24 hours after the last dose (approximately two drug half-lives). 2
Adjunctive Measures
Tranexamic acid can be considered as adjunctive therapy to support hemostasis, though it does not directly reverse the anticoagulant effect. 1
Activated oral charcoal reduces absorption of apixaban and can lower plasma concentration if administered early. 2
Hemodialysis does not have a substantial impact on apixaban exposure and is not recommended for reversal. 2
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. 2