Reversal agent for FXa inhibitors safely reverses FXa inhibitor-associated major bleeding

Interim Report on the ANNEXA-4 Study: Andexanet For Reversal of Anticoagulation in Factor Xa - Associated Acute Major Bleeding

News - Mar. 13, 2018

Introduction and methods

Factor Xa (FXa) inhibitors are effective, but can cause major bleedings resulting in hospitalization and fatality. There is no specific reversal agent available for FXa inhibitors. Andexanet was developed as a recombinant modified FXa protein designed to act as a decoy molecule for FXa inhibitors, effectively sequestering and neutralizing their anticoagulant effect. Andexanet has been demonstrated to reverse anti-FXa activity quickly and safely in healthy volunteers.

ANNEXA-4 is an on-going, prospective, open-label, single-arm study of andexanet in patients with acute major bleeding while taking an FXa inhibitor. Eligible patients have acute major bleeding, within 18 hours of their last FXa inhibitor dose. Enrolled patients are treated with either 400 or 800 mg andexanet bolus followed by a 4 or 8 mg/min infusion for 2 hours, based on FXa inhibitor received, dose and time since last dose. The primary efficacy endpoints are the change in anti-FXa activity with andexanet and the achievement of good or excellent hemostasis. Safety endpoints included the occurrence of thrombotic events and death at 30 days. In this interim analysis, 227 patients were enrolled in the safety population and 137 in the efficacy population.

Main results

  • At the end of infusion of andexanet, anti-FXa activity in rivaroxaban-treated patients (n=75) was decreased by 87% (95%CI: 82-89), in apixaban-treated patients (n=105) decreased by 91% (95%CI: 90-92) and in enoxaparin-treated patients by 73% (95%CI: 29-79).
  • The percentage of patients who achieved excellent or good hemostasis at 12 hours after andexanet infusion in 132 patients with major bleeding was 83% (95%CI: 0.75-0.89).
  • Thrombotic events occurred in 2.6% of patients within 3 days after andexanet and 11% within 30 days. Mortality rate was 12% by 30 days after andexanet.

Conclusion

In patients with acute major bleeding while taking an FXa inhibitor, andexanet rapidly reversed anti-FXa activity and resulted in a high rate of clinically effective hemostasis, with an acceptable rate of adverse events.

The study’s lead author, dr. Connolly, said in a press release: “This study is only focused on patients who are acutely bleeding, but there is also great interest in using a drug like andexanet for patients who come into a medical center on a Factor Xa inhibitor and require urgent surgery. We hope to study that patient population in the future.”

Disclosures

Our coverage of ACC.18 is based on the information provided during the congress.

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