What is the recommended reversal regimen for a patient on apixaban who has life‑threatening bleeding or requires urgent surgery, including dosing of andexanet alfa (and alternative 4‑factor prothrombin complex concentrate)?

Reversing Apixaban Anticoagulation

For life-threatening bleeding or urgent surgery in patients on apixaban, administer andexanet alfa as the first-line specific reversal agent, with dosing based on the timing and dose of the last apixaban intake: low-dose regimen (400 mg IV bolus over 15 minutes followed by 480 mg infusion over 2 hours) for apixaban ≤5 mg or last dose ≥8 hours prior, or high-dose regimen (800 mg IV bolus over 30 minutes followed by 960 mg infusion over 2 hours) for apixaban >5 mg or last dose <8 hours prior. 1, 2, 3

Primary Reversal Strategy: Andexanet Alfa

Indications for Use

• Life-threatening bleeding including intracranial hemorrhage, uncontrollable hemorrhage, bleeding into closed spaces or critical organs (intraspinal, intraocular, pericardial, retroperitoneal), or persistent major bleeding despite local hemostatic measures 1, 2
• Urgent surgery with high bleeding risk, particularly neurosurgery, major abdominal, orthopedic, or vascular procedures 4
• Do not delay administration for laboratory confirmation in life-threatening situations—administer immediately if the patient is presumed to be on apixaban 1, 2

Mechanism and Efficacy

• Andexanet alfa is a recombinant modified factor Xa decoy protein that competitively binds apixaban with high affinity (1:1 stoichiometric ratio), sequestering it from endogenous factor Xa and restoring hemostasis 3
• Reduces anti-factor Xa activity by 92-94% within 2 minutes of bolus completion 1, 3, 5
• Achieves excellent or good hemostasis in 80-82% of patients at 12 hours, with 80% efficacy specifically in intracranial hemorrhage 1, 3
• Normal hemostasis achieved in 93% of patients requiring urgent surgery in the ANNEXA-4 trial 1, 4

Dosing Algorithm

Step 1: Determine the appropriate dose regimen based on:

• Last apixaban dose amount (≤5 mg vs >5 mg)
• Time since last dose (<8 hours vs ≥8 hours)

Step 2: Administer the appropriate regimen:

Low-Dose Regimen (for apixaban ≤5 mg OR last dose ≥8 hours prior):

• 400 mg IV bolus over 15 minutes
• Followed immediately by 480 mg continuous infusion over 2 hours (4 mg/min) 1, 2, 3

High-Dose Regimen (for apixaban >5 mg OR last dose <8 hours prior):

• 800 mg IV bolus over 30 minutes
• Followed immediately by 960 mg continuous infusion over 2 hours (8 mg/min) 1, 2, 3

Important Caveats

• The reversal effect is transient—anti-factor Xa activity returns toward baseline approximately 2 hours after completion of infusion 2, 6
• For prolonged surgical procedures, consider extending the infusion at half the standard rate to maintain reversal throughout the operation 7
• Storage requires refrigeration 1

Alternative Reversal: Four-Factor Prothrombin Complex Concentrate (4F-PCC)

When andexanet alfa is unavailable, use 4F-PCC as a second-line alternative, though it is significantly less effective 1, 2, 3

Dosing

• 50 units/kg IV (maximum 4,000-5,000 units) OR
• 2,000 units fixed dose 1, 3

Critical Limitations

• 4F-PCC only normalizes thrombin generation at very low apixaban concentrations (<75 ng/mL), making it unreliable for most clinical scenarios where therapeutic levels are present 8
• Works through a compensatory mechanism by increasing prothrombin and factor X levels rather than directly binding the anticoagulant 1
• Not FDA-approved for factor Xa inhibitor reversal 8

Laboratory Monitoring

Pre-Reversal Assessment

• Anti-factor Xa activity assay is the preferred test to quantify apixaban levels 3, 4
• Threshold of >50 ng/mL is clinically significant for bleeding risk 3, 4
• Prothrombin time (PT) will be prolonged but is less specific 9
• However, do not delay andexanet administration waiting for laboratory results in life-threatening bleeding 2, 4

Post-Reversal Monitoring

• Anti-factor Xa levels cannot be reliably measured after andexanet administration due to dissociation during dilution 2
• PT and thromboelastography (TEG) parameters normalize after successful reversal 9

Critical Safety Considerations

Thrombotic Risk

• Thrombotic events occur in 10-18% of patients within 30 days after andexanet administration—this is the most significant safety concern 1, 3
• Most thrombotic events occur in patients who did not resume anticoagulation 1
• Promptly resume anticoagulation after bleeding control to reduce thrombotic risk 2, 3, 4
• Consider bridging with prophylactic low-molecular-weight heparin if oral anticoagulation must be delayed 4

Other Safety Issues

• Mild to moderate infusion reactions may occur but generally resolve without intervention 5
• No significant hemodynamic changes or respiratory compromise reported in clinical trials 5

Adjunctive Measures

• Tranexamic acid (15 mg/kg or 1 g IV) should be co-administered in trauma patients independent of reversal strategy 2
• Activated charcoal may be used for known recent ingestion of apixaban 2
• Discontinue apixaban immediately 1
• Provide supportive care including blood product transfusion as needed 1

Common Pitfalls to Avoid

1. Do not use 4F-PCC as first-line when andexanet is available—it is substantially less effective at therapeutic apixaban levels 8
2. Do not delay reversal for laboratory confirmation in life-threatening bleeding 2, 4
3. Do not forget to resume anticoagulation after hemostasis—failure to do so dramatically increases thrombotic risk 1, 2
4. Do not use recombinant factor VIIa as a first-line reversal agent 1
5. Do not rely on fresh frozen plasma for reversal—it is ineffective for direct oral anticoagulants 1