Rivaroxaban Antidote for Life-Threatening Bleeding
Andexanet alfa is the specific FDA-approved antidote for rivaroxaban-associated life-threatening bleeding, administered as either a low-dose regimen (400 mg IV bolus followed by 480 mg infusion over 2 hours) or high-dose regimen (800 mg IV bolus followed by 960 mg infusion over 2 hours), depending on the timing and dose of the last rivaroxaban intake. 1, 2
Dosing Algorithm for Andexanet Alfa
Low-dose regimen (400 mg bolus + 480 mg infusion):
- Last rivaroxaban dose ≥8 hours prior 1
- Last rivaroxaban dose ≤10 mg taken <8 hours prior or timing unknown 1
High-dose regimen (800 mg bolus + 960 mg infusion):
- Last rivaroxaban dose >10 mg taken <8 hours prior or timing unknown 1
- Unknown dose of rivaroxaban taken <8 hours prior 1
The bolus is administered at 30 mg/min for high dose or over 15 minutes for low dose, followed by continuous infusion at 8 mg/min or 4 mg/min respectively for up to 120 minutes. 1, 2
Mechanism and Efficacy
Andexanet alfa is a modified recombinant factor Xa decoy protein that binds rivaroxaban with high affinity, preventing it from inhibiting endogenous factor Xa. 1, 3 In the ANNEXA-4 study, andexanet alfa reduced anti-factor Xa activity by 92-93% within minutes of administration, with 82% of patients achieving good or excellent hemostasis at 12 hours. 1, 2
Alternative Strategy: 4-Factor Prothrombin Complex Concentrate
When andexanet alfa is unavailable, administer 4-factor PCC at 50 U/kg IV (maximum 4,000 units). 1, 4 The 2024 World Society of Emergency Surgery guidelines recommend weight-based dosing: 1,500 units for patients <65 kg or 2,000 units for patients >65 kg. 1
Four-factor PCC increases prothrombin and factor X levels, inducing a compensatory pro-hemostatic effect through increased thrombin generation potential. 1 A 2019 study demonstrated that 4-factor PCC achieved clinical hemostasis in 72.4% of patients with rivaroxaban-associated major bleeding. 5
Adjunctive Measures
For recent ingestion (<2-4 hours):
- Administer activated charcoal to reduce absorption 1
- This is particularly effective if given within 3 hours of the last dose 1
Supportive measures:
- Discontinue rivaroxaban immediately 1
- Provide hemodynamic support and blood product transfusion as needed 1, 6
- Consider tranexamic acid as adjunctive therapy to support hemostasis 3, 4
Laboratory Assessment
Anti-factor Xa activity assays are preferred for quantifying rivaroxaban levels, with a threshold >50 ng/mL considered clinically significant for serious bleeding. 3, 7 Prothrombin time (PT) using rivaroxaban-sensitive reagents can provide qualitative assessment. 8
Do not use PT, INR, aPTT, or anti-FXa activity to monitor the effectiveness of PCCs when used for reversal. 1
Critical Safety Considerations
Thrombotic events occur in approximately 10% of patients within 30 days of receiving andexanet alfa. 3, 7, 9 The reversal effect is transient, with anti-factor Xa activity returning toward baseline approximately 2 hours after infusion completion. 3, 7
Rivaroxaban is not dialyzable due to high plasma protein binding (92-95%), except in specific circumstances. 1
Common Pitfalls to Avoid
- Do not use prophylactic hemostatic agents for emergency surgery even with high rivaroxaban concentrations present 8, 6
- Do not use fresh frozen plasma as it is ineffective for reversing direct factor Xa inhibitors 1
- Do not use platelet transfusion or desmopressin as there is no evidence supporting their use for DOAC-associated bleeding 1
- Andexanet alfa has not been studied in patients requiring urgent surgery and is not approved for this indication 1
Pediatric Considerations
For younger children with major bleeding on rivaroxaban, hold the medication and consider 3- or 4-factor PCC. 1 Andexanet alfa can be considered in older adolescents with major bleeding, though there are no pediatric studies. 1 Activated charcoal should be considered if the last dose was within 2 hours. 1