What is the recommended reversal agent for Xarelto (rivaroxaban)?

Reversal Agent for Xarelto (Rivaroxaban)

Andexanet alfa is the recommended specific reversal agent for Xarelto (rivaroxaban) in patients with life-threatening or uncontrolled bleeding. 1

Mechanism of Action and Efficacy

Andexanet alfa (Andexxa) is a modified recombinant human factor Xa protein that acts as a decoy molecule:

• Binds directly to rivaroxaban with high affinity
• Sequesters the drug away from endogenous factor Xa
• Rapidly reverses anticoagulant effects within minutes 1, 2

In clinical studies, andexanet alfa demonstrated:

• Reduction of anti-factor Xa activity by >90% in patients taking rivaroxaban 1
• Rapid reversal of anticoagulant effects within minutes of administration 2
• Sustained reversal during continuous infusion 2

Dosing Protocol

Dosing depends on the timing of last rivaroxaban dose:

• If last dose was >7 hours before reversal or unknown: 800 mg IV bolus followed by 960 mg infusion (8 mg/min for 120 minutes)
• If last dose was <7 hours before reversal: 400 mg IV bolus followed by 480 mg infusion (4 mg/min for 120 minutes) 1

Clinical Indications

Andexanet alfa should be used in the following scenarios:

• Life-threatening bleeding (e.g., intracranial hemorrhage)
• Bleeding into critical organs or closed spaces
• Persistent major bleeding despite local hemostatic measures
• High risk of recurrent bleeding due to delayed clearance or overdose
• Need for urgent surgery with high bleeding risk 1

Important Considerations and Risks

1. Thrombotic risk: Thrombotic events occur in approximately 10% of patients within 30 days of treatment 1

   • Monitor for signs of thrombosis
   • Resume anticoagulation as soon as medically appropriate 2

2. Laboratory monitoring:

   • Anti-factor Xa activity can be measured to confirm reversal
   • Standard coagulation tests (PT, INR, aPTT) are not reliable for monitoring rivaroxaban or its reversal 3

3. Availability and alternatives:

   • If andexanet alfa is unavailable, prothrombin complex concentrates (PCCs) may be considered
   • However, PCCs do not truly reverse anti-Xa activity and have inconsistent results 1, 4
   • PCCs carry increased risk of thrombotic events 4

Alternative Reversal Strategies

When andexanet alfa is not available:

1. Prothrombin Complex Concentrates (PCCs):

   • Less effective than andexanet alfa for rivaroxaban reversal
   • Dosing: Start with 25 U/kg, may increase to 50 U/kg in life-threatening bleeding 4
   • Limited evidence of efficacy; studies show inconsistent reversal of anti-Xa activity 1

2. Supportive measures:

   • Discontinue rivaroxaban
   • Local hemostatic measures
   • Blood product support as needed
   • Consider activated charcoal if ingestion within 2 hours

3. Other investigational agents:

   • Ciraparantag (PER977): A synthetic molecule that binds to rivaroxaban, but clinical development is less advanced than andexanet alfa 1

Resumption of Anticoagulation

• Anticoagulation should be resumed as soon as medically appropriate after bleeding is controlled
• Premature discontinuation of anticoagulation increases thrombotic risk 3
• The timing should balance bleeding and thrombotic risks
• When restarting is safe, consider prophylactic doses initially before resuming therapeutic anticoagulation 4

Andexanet alfa represents a significant advancement in the management of rivaroxaban-associated bleeding, offering targeted reversal with rapid onset of action compared to non-specific hemostatic agents.