Comparing Hemostatic Efficacy of Andexanet Alfa and 4-Factor Prothrombin Complex Concentrate in a Polytrauma Porcine Model Treated with Apixaban

Introduction: Andexanet alfa and 4-factor prothrombin complex concentrate (4F-PCC) are both first-line treatment options to reverse the effects of direct oral anticoagulants, such as the factor Xa (FXa) inhibitor, apixaban, in patients with trauma and massive bleeding. The purpose of this study was to directly compare the hemostatic efficacy of andexanet alfa with 4F-PCC in an apixaban anticoagulated porcine polytrauma model.

Methods: Male pigs (N=32) were administered 20 mg apixaban daily for 3 days and then trauma was simulated by inducing standard liver injuries and bilateral femur fractures. Animals were resuscitated with Ringer's solution and then received placebo, 4F-PCC (25 or 50 IU/kg), or andexanet alfa (1000 mg bolus followed by 1200 mg infusion over 2 hours); n=8 animals per group. Primary endpoints included survival and blood loss over 5 hours post trauma (or until death if earlier). Coagulation parameters, including thrombin generation, were also evaluated.

Results: Apixaban treatment resulted in clinically relevant plasma levels of the FXa inhibitor. Following polytrauma induction, treatment with both the 50 IU/kg 4F-PCC and andexanet alfa achieved 100% survival (in contrast to 0% in the control group and 37.5% in the 25 IU/kg 4F-PCC group). In addition, significant reductions in blood loss compared with the control group (3843 ± 406 mL) were achieved, with the largest effects observed for andexanet alfa (1123 ± 197 mL; p<0.001) followed by 50 IU/kg 4F-PCC (1855 ± 372 mL; p<0.001) and 25 IU/kg 4F-PCC (2865 ± 334 mL; p<0.01). The 50 IU/kg 4F-PCC dose was also significantly more effective at controlling bleeding than the 25 IU/kg dose at 60 mins post trauma (p<0.05). In line with the mode of action, administration of andexanet alfa led to significantly lower anti-FXa inhibitor levels (mean ± standard deviation [SD] 15.6 ± 6.2 ng/mL) compared with control or 4F-PCC treatment (p<0.0001), which remained significant until 180 mins post trauma. On the other hand, 4F-PCC treatment was able to dose-dependently overcome the apixaban-mediated reduction in coagulation factors II, IX, and X in contrast to andexanet alfa. Both treatments impacted thrombin generation, i.e. while andexanet alfa reduced lag time and peak thrombin generation, 4F-PCC dose-dependently improved peak height and endogenous thrombin potential over a more sustained period of time. Post-mortem histopathology revealed no thromboembolic complications in any treatment group.

Conclusions: This study demonstrated that both high-dose 4F-PCC and andexanet alfa are effective in achieving survival, hemostatic control, and reduction in bleeding following polytrauma in a porcine model of apixaban anticoagulation. Although hemostasis was achieved more rapidly with andexanet alfa, which directly reduced the levels of anti-FXa inhibitor levels, treatment with 4F-PCC showed sustained restoration of factors II, IX, and X levels, as well as thrombin generation after polytrauma.

Grottke:Abiomed, AstraZeneca, Alveron, Bayer Healthcare, Boehringer Ingelheim, CSL Behring, Ferring, Octapharma, Norgine, Novo Nordisk, Sanofi, Takeda, Werfen, the Federal Ministry of Education (BMBF) and the German research foundation (DFG): Consultancy, Other: Lecture fees, development of educational material, travel reimbursements , Research Funding. Herzog:CSL Behring: Current Employment.