What can be given to reverse apixaban (Factor Xa inhibitor) effects in a patient requiring urgent surgery?

Reversal of Apixaban for Urgent Surgery

Andexanet alfa is the FDA-approved specific reversal agent for apixaban and should be administered immediately when urgent surgery is required in patients on apixaban, particularly for procedures with high bleeding risk. 1, 2

Primary Reversal Strategy: Andexanet Alfa

Indications for Reversal Before Surgery

• Urgent surgery with significant bleeding risk (e.g., neurosurgery, major abdominal, orthopedic, or vascular procedures) 1
• Emergency surgery where bleeding risk is considered significant 1
• Procedures requiring cardiopulmonary bypass 3
• Surgery that cannot be delayed 24-48 hours for drug clearance 2

Dosing Regimen

The dose depends on apixaban timing and amount 1, 4:

Low-dose regimen: 1, 4

• 400 mg IV bolus at 30 mg/min
• Followed by 480 mg continuous infusion at 4 mg/min for up to 120 minutes
• Use when: Last apixaban dose ≤5 mg OR last dose taken ≥8 hours prior

High-dose regimen: 1, 4

• 800 mg IV bolus at 30 mg/min
• Followed by 960 mg continuous infusion at 8 mg/min for up to 120 minutes
• Use when: Last apixaban dose >5 mg OR last dose taken <8 hours prior

Mechanism and Efficacy

• Andexanet alfa is a recombinant modified factor Xa decoy protein that binds apixaban with high affinity, sequestering it and restoring hemostasis 1, 4, 5
• Reduces anti-FXa activity by 92-93% within 2 minutes of bolus administration 1, 5, 6
• Effect is sustained during the 2-hour infusion but returns toward baseline approximately 2 hours after completion 4, 7
• In the ANNEXA-4 trial, normal hemostasis was achieved in 93% of patients requiring urgent surgery after idarucizumab (for dabigatran), establishing precedent for DOAC reversal efficacy 1

Critical Timing Considerations

• Do NOT delay andexanet administration for laboratory confirmation of apixaban levels in urgent surgical situations 4, 7
• Median time from andexanet to surgery should be within 2 hours to maximize reversal effect 1
• The anticoagulant effect of apixaban persists for at least 24 hours (two half-lives) after the last dose without reversal 2
• For prolonged surgical procedures, infusion modifications may be required (e.g., extending infusion at half-rate) 8

Alternative Reversal Options

When Andexanet Alfa is Unavailable

Four-factor prothrombin complex concentrate (4F-PCC): 1, 5

• Dose: 50 units/kg (maximum 5000 units) or 2000 units fixed dose 1, 5
• Less effective than andexanet and not specifically studied for apixaban reversal 7
• Contains factors II, VII, IX, and X 1

Activated PCC: 1, 2

• Dose: 50 units/kg once or 25-50 units/kg 1
• Not evaluated in clinical studies for apixaban reversal 2

Adjunctive Measures

• Activated charcoal 50g if apixaban ingestion occurred within 2-4 hours (unlikely in urgent surgical scenarios) 7, 2
• Hemodialysis is NOT effective for apixaban removal 2
• Protamine sulfate and vitamin K are NOT effective for apixaban reversal 2
• Tranexamic acid (15 mg/kg or 1g) may be considered as adjunctive hemostatic support 4

Laboratory Monitoring

Pre-Reversal Assessment

• Anti-factor Xa activity assay is the preferred test for quantifying apixaban levels 4, 5
• Threshold >50 ng/mL is clinically significant for bleeding risk 5
• PT, INR, and aPTT are NOT reliable for monitoring apixaban effect 1, 2

Post-Reversal Monitoring

• Standard anti-Xa assays are unreliable after andexanet administration due to drug dissociation during dilution 4
• Monitoring with PT, INR, aPTT, or anti-FXa activity is NOT useful or recommended when using reversal agents 1, 2
• Thromboelastography (TEG) may demonstrate normalization of R-time and ACT during surgery 8

Safety Considerations and Thrombotic Risk

Thrombotic Events

• Thrombotic events occur in approximately 10-18% of patients within 30 days after andexanet administration 1, 4, 7
• Prompt resumption of anticoagulation after hemostasis significantly reduces thrombotic risk 1, 4
• When anticoagulation was restarted within 30 days post-andexanet, no thrombotic events occurred in RE-VERSE AD study 1

Contraindications and Cautions

• Andexanet should NOT be used in surgery requiring anticoagulation (e.g., cardiopulmonary bypass requiring heparinization) as it can reverse unfractionated heparin 1
• However, successful use has been reported in aortic surgery with CPB when given pre-operatively 3
• Infusion reactions (mild/moderate) can occur but generally resolve without intervention 6

Practical Algorithm for Decision-Making

Step 1: Assess surgical urgency and bleeding risk 1

• High bleeding risk procedures: neurosurgery, major vascular, intra-abdominal, orthopedic
• Low bleeding risk: minor procedures, biopsies

Step 2: Determine if surgery can be delayed 1

• If surgery can wait 48-72 hours: hold apixaban and allow natural clearance (consider renal function: CrCl <30 mL/min requires 3 days; CrCl ≥30 mL/min requires 2 days) 1
• If surgery is truly urgent (cannot wait): proceed to reversal

Step 3: Administer andexanet alfa 1, 4, 5

• Select appropriate dose based on last apixaban dose and timing
• Do NOT delay for laboratory results
• Initiate surgery within 2 hours of andexanet bolus

Step 4: If andexanet unavailable 1, 5

• Administer 4F-PCC 50 units/kg (max 5000 units) or 2000 units fixed dose
• Recognize this is less effective than specific reversal

Step 5: Plan anticoagulation resumption 1, 4

• Resume anticoagulation 6-8 hours post-surgery for low thrombotic risk 1
• Resume anticoagulation 48-72 hours post-surgery for high bleeding risk procedures 1
• Consider bridging with prophylactic LMWH if anticoagulation must be delayed 1

Common Pitfalls to Avoid

• Do NOT wait for laboratory confirmation before administering andexanet in urgent situations 4, 7
• Do NOT use PT/INR/aPTT to guide reversal as these are unreliable for apixaban 1, 2
• Do NOT forget the transient nature of andexanet effect (only 2 hours post-infusion) 4, 7
• Do NOT delay anticoagulation resumption unnecessarily as this increases thrombotic risk 1, 4
• Do NOT use andexanet in procedures requiring intraoperative anticoagulation unless given pre-operatively 1