What is the mechanism of action and indications for use of andexanet alfa (a Factor Xa inhibitor antidote) in patients with life-threatening or uncontrolled bleeding on Factor Xa inhibitors such as rivaroxaban (Xarelto) and apixaban (Eliquis)?

Andexanet Alfa: Mechanism of Action and Clinical Indications

Mechanism of Action

Andexanet alfa is a recombinant modified human factor Xa decoy protein that competitively binds to factor Xa inhibitors with high affinity, sequestering them from endogenous factor Xa and thereby restoring normal hemostatic function. 1

The drug is catalytically inactive due to replacement of the active-site serine with alanine and deletion of the membrane-binding domain (Gla domain), which eliminates its ability to assemble the prothrombinase complex or exert procoagulant effects. 1 This structural modification allows andexanet to:

• Bind direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) with a 1:1 stoichiometric ratio 1
• Bind indirect factor Xa inhibitors (low-molecular-weight heparins, fondaparinux) that act through antithrombin 1
• Restore endogenous factor Xa activity by sequestering the inhibitors within the vascular space 1

The reversal effect is rapid (within 2-5 minutes of bolus administration) but transient, with a pharmacodynamic half-life of approximately 1 hour, necessitating administration as a bolus followed by continuous infusion. 1, 2

FDA-Approved Indications

Andexanet alfa is FDA-approved specifically for patients treated with rivaroxaban or apixaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. 3

Critical Limitation

The FDA label explicitly states that andexanet has not been shown to be effective for, and is not indicated for, bleeding related to any factor Xa inhibitors other than apixaban or rivaroxaban. 3 This approval was granted under accelerated approval based on reduction in anti-FXa activity in healthy volunteers, and continued approval is contingent upon demonstrating actual improvement in hemostasis in patients. 3

Specific Clinical Indications for Use

Life-Threatening Bleeding Scenarios

Andexanet should be administered for the following bleeding situations in patients on apixaban or rivaroxaban: 1, 4, 5

• Intracranial hemorrhage (most common indication, representing 69-80% of cases in clinical trials) 1
• Bleeding in closed spaces or critical organs: intraspinal, intraocular, pericardial, pulmonary, retroperitoneal, or intramuscular with compartment syndrome 4, 5
• Uncontrollable hemorrhage with hemodynamic instability or causing hemoglobin decrease ≥2 g/dL or requiring ≥2 units of RBCs 5
• Gastrointestinal bleeding that is severe and uncontrolled 1

Urgent Surgery Indication

Andexanet alfa should be administered immediately when urgent surgery with high bleeding risk is required in patients on apixaban or rivaroxaban, particularly for neurosurgery, major abdominal, orthopedic, or vascular procedures. 4 The American College of Cardiology recommends this approach when the anticoagulant cannot be cleared in time before the procedure. 4, 5

Dosing Regimens

Andexanet is administered as an intravenous bolus followed by a 2-hour continuous infusion, with dosing dependent on the specific factor Xa inhibitor, dose, and timing of last intake: 1

Low-Dose Regimen

• 400 mg IV bolus over 15 minutes followed by 480 mg infusion (4 mg/min) over 2 hours 1, 4
• Used for: Apixaban ≤5 mg or rivaroxaban ≤10 mg when last dose was ≥8 hours prior 1, 2

High-Dose Regimen

• 800 mg IV bolus over 30 minutes followed by 960 mg infusion (8 mg/min) over 2 hours 1, 4
• Used for: Apixaban >5 mg or rivaroxaban >10 mg when last dose was <7-8 hours prior, or for edoxaban (off-label) 1, 2

Clinical Efficacy Data

Anti-Factor Xa Activity Reduction

In the ANNEXA-4 study, andexanet reduced median anti-factor Xa activity by: 1

• 92-93% for apixaban from baseline 1
• 92% for rivaroxaban from baseline 1
• This reduction occurred within 2 minutes of bolus completion and was sustained during the 2-hour infusion 1, 2

Hemostatic Efficacy

• 80-82% of patients achieved excellent or good hemostasis at 12 hours after andexanet administration 1
• For intracranial hemorrhage specifically, 80% achieved effective hemostasis 1
• For gastrointestinal bleeding, 85% achieved effective hemostasis 1
• In the ANNEXA-I randomized trial for intracranial hemorrhage, andexanet demonstrated superior hemostatic efficacy compared to usual care (including prothrombin complex concentrates) 1

Off-Label Use for Edoxaban

While not FDA-approved, andexanet has been studied for edoxaban reversal with the high-dose regimen, showing a 68.9% median decrease in anti-factor Xa activity and 78.6% achieving excellent or good hemostasis. 2, 6 However, the American College of Cardiology notes this requires further confirmatory data. 2

Critical Safety Considerations

Thrombotic Risk

Thrombotic events occur in approximately 10-18% of patients within 30 days after andexanet administration, representing the most significant safety concern. 1, 4, 5 Key points include:

• In ANNEXA-4, thrombotic events occurred in 10% of patients, with none having resumed oral anticoagulation at the time of the event 1
• 16 thrombotic events occurred despite parenteral anticoagulant thromboprophylaxis 1
• In earlier analyses, 18% experienced thrombotic events during 30-day follow-up, with only 40% having restarted anticoagulation 7
• Four patients experienced thrombotic events within 3 days after andexanet treatment 7

Mitigation Strategy

Prompt resumption of anticoagulation after bleeding control is essential to reduce thrombotic risk. 2, 5 The American College of Cardiology recommends planning anticoagulation resumption with consideration of bridging with prophylactic low-molecular-weight heparin if anticoagulation must be delayed. 4

Transient Reversal Effect

The reversal effect is not sustained indefinitely—anti-factor Xa activity returns toward baseline approximately 2 hours after infusion completion, with a relative decrease from baseline of only 30-39% at 4 hours post-infusion. 1, 2, 5 This necessitates ongoing monitoring and potential repeat dosing in select cases.

Alternative Reversal Strategy

When andexanet alfa is unavailable, four-factor prothrombin complex concentrate (4F-PCC) should be administered at 50 units/kg IV (maximum 4,000-5,000 units) or 2,000 units fixed dose. 4, 2, 5 However, the American College of Cardiology acknowledges that 4F-PCC is less effective than andexanet alfa for factor Xa inhibitor reversal. 4

Laboratory Monitoring

• Anti-factor Xa activity assays are preferred for quantifying apixaban and rivaroxaban levels, with a threshold of >50 ng/mL considered clinically significant for bleeding risk 4, 5
• For edoxaban, the threshold is ≥40 ng/mL 1
• Do not use PT, INR, aPTT, or anti-FXa activity to monitor the effectiveness of reversal 5
• Laboratory testing should not delay andexanet administration in life-threatening bleeding situations 2
• Plasma levels of factor Xa inhibitors cannot be reliably measured with standard anti-Xa assays following andexanet administration due to dissociation during dilution 2

Common Pitfalls and Caveats

• Andexanet has not been studied in patients requiring urgent surgery without active bleeding and is not approved for this indication, though the American College of Cardiology recommends its use in this scenario 1, 4
• The drug carries a black box warning for thrombotic events, cardiac arrest, ischemia, and sudden death 8
• Minor infusion reactions and gastrointestinal upset are the most commonly reported adverse events 8
• The wholesale acquisition cost is substantial: $24,750 for standard dose and $49,500 for high-dose regimen 7