Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model

PLoS One. 2018 Mar 28;13(3):e0195122. doi: 10.1371/journal.pone.0195122. eCollection 2018.

Abstract

Introduction: Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors.

Objective: To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban.

Materials and methods: In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury.

Results: Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035).

Conclusion: These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / pharmacology*
  • Antidotes / pharmacology*
  • Blood Coagulation / drug effects*
  • Disease Models, Animal
  • Factor Xa / pharmacology*
  • Factor Xa Inhibitors / pharmacology*
  • Hemorrhage / chemically induced
  • Hemorrhage / drug therapy*
  • Male
  • Pyridines / pharmacology*
  • Rabbits
  • Recombinant Proteins / pharmacology*
  • Thiazoles / pharmacology*

Substances

  • Anticoagulants
  • Antidotes
  • Factor Xa Inhibitors
  • PRT064445
  • Pyridines
  • Recombinant Proteins
  • Thiazoles
  • Factor Xa
  • edoxaban

Grants and funding

The study has been funded by Portola Pharmaceuticals. The study has been designed, performed, and analysed by all authors who were employees of Portola Pharmaceuticals and received salaries. Currently, all authors, besides PP and SJH, are employees of Portola. The authors have met the ICMJE criteria, participated in the development of the manuscript, agreed to the content, and approved its submission. No one other than the listed authors had control over the data, over how the data were analyzed or interpreted, or over the wording or conclusions used by the authors in the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.