Pump the Brakes on Andexanet alfa

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Biologic effects of expensive DOAC reversal agent may not translate into improved clinical outcomes.

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 or injections needed. Despite these advantages, the risk of bleeding remains a concern.  These agents unfortunately do not have any specific reversal agents.  In May 2018, Andexanet alfa gained accelerated approval by the FDA for the reversal of these agents, but robust evidence in its support have been lacking.


In the ANNEXA-4 trial, 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 two-hour infusion.

  • Half Dose: Apixaban or rivaroxaban > seven hours prior to Andexanet alfa bolus = 400mg over 15 minutes and then a two hour infusion dose of 480mg
  • Full Dose: Enoxaparin, Edoxaban, or Rivaroxaban ≤ seven hours prior to Andexanet alfa bolus or unknown time = 800mg over 30 minutes followed by a two hour infusion dose of 960mg


This was a multicenter, prospective, open-label, single-group cohort study, assessing the biological efficacy and safety of andexanet in patients with acute major bleeding. Patients were enrolled at 63 centers in North America and Europe. Patients included adults ≥18 years of age with acute major bleeding receiving apixaban, rivaroxaban, or edoxaban at any dose or enoxaparin at a dose of at least 1mg/kg/day within the past 18 hours.


Acute major bleeding was defined as having one or more of the following features:

  • Potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise (i.e. severe hypotension, poor skin 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)

The co-primary outcomes were: Percent change in anti-factor Xa activity after Andexanet treatment and percentage of patients with excellent or good hemostatic control at 12 hours after completion of Andexanet alfa infusion. Safety outcomes included death, thrombotic events, and development of antibodies to andexanet or to native factor X and factor Xa.

A total of 352 patients were evaluated (227 patients, or 64%, had intracranial hemorrhage and 90 patients, or 26%, had gastrointestinal bleeding). The 134 patients on Apixaban and 100 patients on Rivaroxaban had a 92% reduction in their anti-factor Xa level.  At four, eight and 12 hours, patients on Apixaban had a median anti-factor Xa activity reduced from baseling by 32%, 34%, and 38% respectively, while patients on Rivaroxaban had a median anti-factor Xa activity reduction from baseline of 42%, 48%, and 62% respectively.  In terms of safety outcomes, death within 30 days occurred in 49 patients (14%) and thrombotic events occurred in 34 patients (10%).



There were several limitations of this study that bear mentioning.  First, the study was funded, designed and supervised by Portola Pharmaceuticals, the maker of Andexanet alfa.  Although, this does not refute the findings of this study, it should make readers skeptical.

Other limitations of this study included, it was a single arm trial with no comparator group, exclusion criteria removed the sickest patients, there were no patient-oriented outcomes and finally “hemostatic control” is a subjective outcome.

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. Finally, the cost of this agent is about $3k per 100mg vial, so at 900mg – 1800mg per bolus + infusion this is ≈27k – 55k per dose.

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% 30 day 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.


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


EDITOR-IN-CHIEF Dr. Rezaie is founder and editor of R.E.B.E.L EM.

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