Comparing Hemostatic Efficacy of Four-factor Prothrombin Complex Concentrate with Andexanet Alfa in an Apixaban-treated Polytrauma Male Porcine Model

Anesthesiology, vol. 145, pp. 387–400

Abstract

BACKGROUND: This study directly compared the hemostatic efficacy of two first-line treatments for reversing the effects of direct oral anticoagulants in patients with massive bleeding, andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC), in an apixaban anticoagulated male porcine polytrauma model. METHODS: Male pigs (N = 32) received 20 mg/day apixaban for 3 days. Trauma was simulated by inducing standard liver injuries and bilateral femur fractures. After resuscitation, the animals received control, 4F-PCC (25 or 50 U/kg), or andexanet alfa (1,000-mg bolus followed by 1,200-mg infusion over 2 h); n = 8 animals per group. Blood loss, survival, and coagulation parameters were evaluated. RESULTS: Both 50 U/kg 4F-PCC and andexanet alfa treatment achieved 100% survival. Blood loss was significantly reduced compared with the control group (mean ± SD 3,843 ± 406 ml), with the largest effects observed for andexanet alfa (1,123 ± 197 ml) followed by 50 U/kg 4F-PCC (1,855 ± 372 ml) and then 25 U/kg 4F-PCC. Consistent with the mechanism of action, andexanet alfa led to significantly lower apixaban anti-factor Xa activity (15.6 ± 6.2 ng/ml) compared with control or 4F-PCC treatment until 180 min after trauma. However, 4F-PCC treatment was able to dose-dependently overcome the trauma-induced reduction in coagulation factors II, VII, IX, and X in contrast to andexanet alfa. While andexanet alfa shortened lag time and increased peak thrombin generation, 4F-PCC dose-dependently improved peak height and endogenous thrombin potential. No thromboembolic complications were observed. CONCLUSIONS: In a male polytrauma porcine model of apixaban anticoagulation, both high-dose 4F-PCC and andexanet alfa were fully effective in achieving survival and hemostatic control. Andexanet alfa achieved hemostasis more rapidly, while 4F-PCC showed sustained restoration of factors II, VII, IX, and X levels, as well as thrombin generation.

Authors 5

1. Oliver Grottke corresponding Aachen Oliver Grottke Ph.D.: Department of Anesthesiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Oliver Grottke, M.D., Ph.D.: Department of Anesthesiology, RWTH Aachen University Hospital, Aachen, Germany

2. Till A. Braunschweig

   Pathologisches Institut · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Till Braunschweig, M.D.: Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany

3. Lars Heubner

   University Hospital Carl Gustav Carus · Technische Universität Dresden

   Affiliation as printed

   Lars Heubner, M.D.: Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany

4. Eva Herzog

   CSL (United States)

   Affiliation as printed

   Eva Herzog, Ph.D.: CSL Behring, King of Prussia, Pennsylvania

5. Farahnaz Rayatdoost Aachen Farahnaz Rayatdoost Ph.D.: Department of Anesthesiology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Farahnaz Rayatdoost, Ph.D.: Department of Anesthesiology, RWTH Aachen University Hospital, Aachen, Germany