ANNEXA-4: Andexanet Alfa and Factor Xa Inhibitors

Background: Over the past few years we have seen a surge in the use of oral Factor Xa inhibitors (apixaban, rivaroxaban etc) for anticoagulation.  The reason for this is the ease of use, standard dosing with no levels to check and no injections needed. Despite these advantages, the risk of bleeding remains a concern.  These agents unfortunately do not have any specific reversal agents.  In May of 2018, Andexanet alfa gained accelerated approval by the FDA for the reversal of these agents, but robust evidence in its support have been lacking.

What They Did:

• Andexanet Alfa, a Novel Antidote to the anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4)
• Patients with acute major bleeding within 18 hours after administration of a factor Xa inhibitor were given a bolus of andexanet alpha followed by a 2-hour infusion.
  • Apixaban or rivaroxaban >7hrs prior to Andexanet Alfa bolus = 400mg over at minutes and then a 2hr infusion dose of 480mg
  • Enoxaparin, Edoxaban, or Rivaroxaban ≤7hrs prior to Andexanet Alfa bolus or unknown time = 800mg over 30 minutes followed by 2hr infusion dose of 960mg
• Multicenter, prospective, open-label, single-group cohort study, assessing the biological efficacy and safety of andexanet in patients with acute major bleeding
• Patients enrolled at 63 centers in North America and Europe
• Acute Major Bleeding = bleeding having one or more of the following features:
  • Potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise (i.e. severe hypotension, poor kin perfusion, confusion, or low cardiac output that could not otherwise be explained)
  • Bleeding associated with a decrease in hemoglobin level of at least 2g/dL (or a Hb ≤8g/dL if no baseline hemoglobin)
  • Bleeding in a critical area or organ (i.e. retroperitoneal, intra-articular, pericardial, epidural, or intracranial bleeding, or intramuscular bleeding with compartment syndrome)

Outcomes:

• Primary:
  • Percent change in anti-factor Xa activity after andexanet treatment
  • Percentage of patients with excellent or good hemostatic control at 12 hours after completion of andexanet alpha infusion
• Safety:
  • Death
  • Thrombotic events
  • Development of antibodies to andexanet or to native factor X and factor Xa

Inclusion:

• Adults ≥18 years
• Acute major bleeding
• Received apixaban, rivaroxaban, or edoxaban at any dose or enoxaparin at a dose of at least 1mg/kg/day 18 hours within the past 18 hours

Exclusion:

• Planned surgery within 12 hours after andexanet treatment (Exception = minimally invasive operations or procedures)
• ICH with a GCS <7 or estimated hematoma volume >60cc
• Expected survival of < 1month
• Occurrence of a thrombotic event within 2 weeks before enrollment
• Use of vitamin K antagonist, dabigatran, prothrombin complex concentrate, recombinant factor VIIa, whole blood, or plasma in the previous 7 days

Results:

• 352 patients evaluated
  • 227 patients (64%) with ICH
  • 90 patients (26%) with GIB
• Patients on Apixaban (134 patients):
  • Median anti-factor Xa activity decreased from 149.7 ng/mL at baseline to 11.1 ng/mL after andexanet bolus (92% reduction; 95% CI 91 – 93)
  • At 4, 8, and 12hrs after andexanet infusion, median anti-factor Xa activity reduced from baseline by 32%, 34%, and 38% respectively
• Patients on Rivaroxaban (100 patients):
  • Median anti-factor Xa activity decreased from 211.8 ng/mL to 14.2 ng/mL after andexanet bolus (92% reduction; 95% CI 88 – 94)
  • At 4, 8, and 12hrs after andexanet infusion, median anti-factor Xa activity reduced from baseline by 42%, 48%, and 62% respectively
• Patients on Enoxaparin (16 patients):
  • Median anti-factor Xa activity decreased from 0.48IU/mL at baseline to 0.15IU/mL after andexanet bolus (75% reduction; 95% CI 66 – 79)
• Hemostatic Efficacy Outcomes (254 patients):
  • 204 (82%) “excellent” or “good” hemostatic efficacy at 12 hours (95% CI 77 – 87)
    • GIB – 85% (95% CI 76 – 94)
    • ICH – 80% (95% CI 74 – 86)
  • Safety Outcomes:
    • Death within 30 days occurred in 49 patients (14%)
    • Thrombotic events occurred in 34 patients (10%)

Strengths:

• An independent data and safety monitoring committee reviewed study data for safety
• An endpoint adjudication committee assessed whether patients met criteria for major bleeding and adjudicated hemostatic efficacy, thrombotic events, and cause of death

Limitations:

• Study funded, designed, and supervised by Portola Pharmaceuticals the maker of Andexanet alpha. Although, this does not refute the findings of this study, it should make readers skeptical.
• Patients not randomized
• No comparator group
• Exclusion criteria, removed the sickest patients
• Convenience sample of patients
• No patient-oriented outcomes
• Exclusion criteria are likely to be difficult for clinicians to assess real time leading to protocol violation
• Dose adjustment for time from ingestion likely to lead to protocol violation as this info difficult to assess
• Primary outcome of hemostatic control is subjective
• Assessors unblinded to treatment

Discussion:

• The majority of patient received rivaroxaban and apixaban (≈90%) in this study
• The most common sites of bleeding were intracranial (≈65%) and gastrointestinal (≈25%) of patients
• The most common indication for anticoagulation in 280 patients (80%) was atrial fibrillation
• An extension of this study is to be continued in Germany and also expected to enroll patients in Japan this year. The reason for this is to gain experience with patients receiving edoxaban and Japanese patients.
• The key line in this paper: “Overall, there was no significant relationship between hemostatic efficacy and a reduction in anti-factor Xa activity during andexanet treatment.”
• Theoretically, factor Xa inhibition reversal to increase the rapidity of hemostatic control should improve clinical outcomes, however this cannot be stated as fact based on the results of this trial.
• In this trial, reduction of anti-factor Xa activity did not predict clinical response in the overall population, however in individual cases there may be a role for andexanet alfa, but this should be considered hypothesis generating for further research.
• The cost of this agent is about $3k per 100mg vial, so at 900mg – 1800mg per bolus + infusion this is ≈27k – 55k per dose

Author Conclusion:“In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria.” 

Clinical Take Home Point: Andexanet alfa may work, based on mechanism of action alone, however it is impossible to tell based on this study if the reduction in factor Xa levels correlates to patient-oriented outcomes. At a cost of $27k – $55k per dose, a 14% 30day mortality, and 10% thrombotic rate in a study excluding the sickest patients and no comparison arm, it is impossible to say if the andexanet alfa is causing this or just the disease process itself.

At this time, I cannot recommend using andexanet alfa until further evidence shows both safety and efficacy in patient-oriented outcomes. 

References:

1. Connolly SJ et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM 2019. PMID: 30730782 

For More Thoughts on This Topic Checkout:

• First10EM: Andexanet Alfa – More Garbage Science in the New England Journal of Medicine
• EM Lit of Note: Disutility, thy Name is ANEXXA-4
• The SGEM: Nothing Compares to You…Because There was no Comparison Group

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)