What is the recommended approach for reversing the anticoagulant effects of Eliquis (apixaban)?

Reversal of Eliquis (Apixaban)

Andexanet alfa is the first-line specific reversal agent for life-threatening bleeding in patients taking Eliquis (apixaban), with dosing of either 400 mg IV bolus over 15 minutes followed by 480 mg infusion over 2 hours (low dose) or 800 mg IV bolus over 30 minutes followed by 960 mg infusion over 2 hours (high dose), depending on the timing and amount of the last apixaban dose. 1, 2, 3

When to Reverse Apixaban

Reversal should be initiated for:

• Life-threatening bleeding: Intracranial hemorrhage, symptomatic or expanding extradural hemorrhage, or uncontrollable hemorrhage 1, 3
• Bleeding in critical organs or closed spaces: Intraspinal, intraocular, pericardial, pulmonary, retroperitoneal, or intramuscular with compartment syndrome 1, 3
• Severe bleeding with hemodynamic instability or causing hemoglobin decrease ≥2 g/dL or requiring ≥2 units of RBCs 2
• Emergency surgery with high bleeding risk when apixaban cannot be cleared in time 4

Do not delay reversal for coagulation test results in life-threatening bleeding scenarios. 1

Primary Reversal Strategy: Andexanet Alfa

Mechanism and Efficacy

Andexanet alfa is a recombinant modified factor Xa protein that acts as a decoy, binding apixaban with high affinity and preventing it from inhibiting endogenous factor Xa. 1, 4 It rapidly reduces anti-factor Xa activity by 93-94% within 2-5 minutes of administration. 1, 5, 6

Dosing Regimen

Low dose: 400 mg IV bolus over 15 minutes, followed by 480 mg continuous infusion over 2 hours 2, 3

High dose: 800 mg IV bolus over 30 minutes, followed by 960 mg continuous infusion over 2 hours 2, 3

The choice between low and high dose depends on the timing of the last apixaban dose and the dose amount taken. 1 Lower doses are needed for apixaban compared to rivaroxaban because drug concentrations are lower with twice-daily dosing. 1

Clinical Evidence

In the ANNEXA-4 study, 80% of patients achieved excellent or good hemostatic efficacy at 12 hours after andexanet administration. 1, 7 The ANNEXA-I trial demonstrated that andexanet resulted in 67% excellent or good hemostatic efficacy versus 53.1% with usual care (P=0.003) in intracranial hemorrhage patients. 1

Alternative Reversal: 4-Factor Prothrombin Complex Concentrate (Kcentra)

When andexanet alfa is unavailable, administer 4-factor PCC (Kcentra) at 50 U/kg IV (maximum 4,000 units). 2 This is recommended by the American College of Cardiology as the alternative strategy. 2

The FDA label notes that prothrombin complex concentrate may be considered but has not been evaluated in clinical studies for apixaban reversal. 8

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 2, 3
• Do not use PT, INR, aPTT, or anti-FXa activity to monitor the effectiveness of PCCs when used for reversal 1
• Early assessment is recommended before reversal when feasible, but do not delay treatment in life-threatening scenarios 3

Critical Safety Considerations

Thrombotic Risk

Thrombotic events occur in approximately 10% of patients within 30 days of receiving andexanet alfa. 2, 4, 3 None of the patients who experienced thrombotic events in ANNEXA-4 had resumed anticoagulation. 1 This emphasizes the need for prompt resumption of anticoagulation after bleeding control. 4

Duration of Effect

The reversal effect of andexanet alfa is transient, with anti-factor Xa activity returning toward baseline approximately 2 hours after infusion completion. 4, 3 The pharmacodynamic effect of apixaban can be expected to persist for at least 24 hours after the last dose (approximately two drug half-lives). 8

Adjunctive Measures

• Activated oral charcoal reduces apixaban absorption if administered early after ingestion 8
• Tranexamic acid can be considered as adjunctive therapy to support hemostasis, though it does not directly reverse the anticoagulant effect 2
• Protamine sulfate and vitamin K are not expected to affect apixaban activity 8
• Hemodialysis does not substantially impact apixaban exposure 8

Common Pitfalls to Avoid

• Do not wait for laboratory confirmation before administering andexanet in life-threatening bleeding 1
• Do not fail to resume anticoagulation after bleeding control, as this significantly increases thrombotic risk 4
• Do not use andexanet in patients with prosthetic heart valves, as safety and efficacy have not been established 8
• Do not remove epidural/intrathecal catheters earlier than 24 hours after the last apixaban dose, and do not administer the next dose earlier than 5 hours after catheter removal 8