Is andexanet safe for coagulation reversal of Direct Oral Anticoagulants (DOACs) given the high risk of bleeding?

Safety of Andexanet Alfa for DOAC Reversal

Andexanet alfa is safe and effective for reversal of factor Xa inhibitors in life-threatening bleeding situations, but carries a significant thrombotic risk of approximately 10.7% within 30 days of administration, with most events occurring in patients not restarted on anticoagulation. 1, 2

Efficacy and Mechanism of Action

• 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 1
• It rapidly reverses anticoagulation with factor Xa inhibitors, decreasing anti-FXa activity by >90% for apixaban and rivaroxaban within minutes of administration 1, 3
• Andexanet alfa has demonstrated excellent or good hemostatic efficacy in approximately 78.5% of patients with major bleeding on DOACs 4
• The reversal effect is transient, with anti-FXa activity returning to pre-treatment levels approximately two hours after completion of infusion 1, 2

Safety Concerns

Thrombotic Risk

• The ANNEXA-4 study reported thrombotic events in 45/419 (10.7%) patients within 30 days of andexanet alfa administration 2
• Median time to first thrombotic event was 10 days, with 17 patients (38% of events) experiencing thrombosis within the first three days of treatment 2
• Thrombotic events included cerebrovascular accidents (42%), deep venous thrombosis (24%), myocardial infarction (20%), pulmonary embolism (11%), and transient ischemic attack (2%) 2
• The thrombotic risk appears higher with andexanet alfa compared to other reversal strategies in meta-analyses 4

Mitigating Thrombotic Risk

• Prompt resumption of anticoagulation after bleeding control significantly reduces thrombotic risk 1
• Of 266 patients who received prophylactic anticoagulation within 30 days after andexanet treatment, only 14 (5.3%) experienced thrombotic events 2
• In contrast, among 153 patients who did not receive prophylactic anticoagulation, 31 (20.3%) had thrombotic events 2
• No thrombotic events were reported when anticoagulation was resumed within 30 days of andexanet therapy 1

Other Safety Considerations

• Andexanet alfa can cause unresponsiveness to unfractionated heparin, leading to non-prolongation of activated clotting times and serious thrombotic events 2
• It should not be used for reversal of direct FXa inhibitors prior to heparinization 2
• Infusion-related reactions are rare (0.5% in ANNEXA-4) and generally mild to moderate 2

Appropriate Clinical Use

Indications for Use

• Life-threatening bleeding (intracranial hemorrhage, uncontrollable hemorrhage) 1
• 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 that cannot be delayed 1
• Emergency surgery in patients at high risk for procedural bleeding 1

Contraindications/When Not to Use

• Elective surgery 1
• Gastrointestinal bleeds that respond to supportive measures 1
• High drug levels without associated bleeding 1
• Surgery that can be delayed to allow for drug clearance 1
• Prior to procedures requiring heparinization (e.g., cardiopulmonary bypass) 1, 2

Dosing Considerations

• Lower doses are needed for apixaban than rivaroxaban due to lower drug concentrations with twice-daily dosing 1
• Standard dosing includes:
  • Low dose (400 mg IV bolus followed by 4 mg/min infusion for 120 minutes) for apixaban ≤5 mg or rivaroxaban ≤10 mg, or when last dose was ≥8 hours prior 1
  • High dose (800 mg IV bolus followed by 8 mg/min infusion for 120 minutes) for apixaban >5 mg or rivaroxaban >10 mg, or when last dose was <8 hours prior 1
• For edoxaban, high-dose andexanet alfa is recommended, though this is off-label 1, 5

Practical Considerations

• Laboratory testing should not delay andexanet administration in life-threatening bleeding situations 1
• Andexanet requires refrigeration and reconstitution, which may delay administration if not stored in the emergency department 1
• If andexanet alfa is unavailable, prothrombin complex concentrates (PCCs) or activated PCCs can be considered as alternative hemostatic agents 1
• Activated charcoal may be used for known recent ingestion (within 2-4 hours) of factor Xa inhibitors 1

Conclusion

While andexanet alfa effectively reverses factor Xa inhibitor activity and achieves hemostasis in most patients with life-threatening bleeding, the significant thrombotic risk must be carefully considered. Prompt resumption of anticoagulation once hemostasis is achieved is critical to mitigate this risk. The decision to use andexanet alfa should be based on the severity and location of bleeding, with clear indications for its use in life-threatening situations.