Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan

J Atheroscler Thromb. 2024 Mar 1;31(3):201-213. doi: 10.5551/jat.64223. Epub 2023 Aug 26.

Abstract

Aims: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan.

Methods: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment.

Results: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events.

Conclusion: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

Keywords: Anticoagulation; Antidote; Asian; Bleeding; Intracranial hemorrhage.

MeSH terms

  • Anticoagulants / adverse effects
  • Antithrombin III / therapeutic use
  • Factor Xa / pharmacology
  • Factor Xa / therapeutic use
  • Factor Xa Inhibitors / adverse effects
  • Fibrinolytic Agents
  • Hemorrhage / chemically induced
  • Hemorrhage / drug therapy
  • Hemorrhage / prevention & control
  • Hemostatics* / therapeutic use
  • Humans
  • Japan
  • Prospective Studies
  • Pyridines*
  • Recombinant Proteins / adverse effects
  • Rivaroxaban / adverse effects
  • Thiazoles*
  • Thrombosis* / drug therapy

Substances

  • Factor Xa Inhibitors
  • edoxaban
  • Rivaroxaban
  • PRT064445
  • Factor Xa
  • Antithrombin III
  • Hemostatics
  • Fibrinolytic Agents
  • Recombinant Proteins
  • Anticoagulants
  • Pyridines
  • Thiazoles