PB0516 - Andexanet alfa versus 4-F prothrombin complex concentrate in an apixaban anticoagulated porcine polytrauma model

Background: First-line treatment options for reversal of direct oral anticoagulants in patients with trauma and massive bleeding include andexanet alfa (ADA) and four-factor prothrombin complex concentrate (4-PCC). This study investigated the effectiveness of ADA vs. 4F-PCC to restore hemostasis and control bleeding in a preclinical porcine polytrauma model under apixaban anticoagulation.

Aims: Effectiveness investigation of ADA versus 4F-PCC in an apixaban anticoagulated porcine polytrauma model.

Methods: After ethical approval, 32 male pigs (n=8/group) were orally fed apixaban (20 mg daily/3 days). Standardized blunt liver injuries and bilateral femur fractures were induced. The animals received placebo (control), 4F-PCC (25 and 50 IU/kg) or ADA (1000mg bolus + 1200mg infusion for 2h). Total blood loss (BL) after injury was primary endpoint. A panel of coagulation parameters, including thrombin generation, were monitored for 300 minutes after trauma or until death.

Results: Mean anti-FXa levels before trauma induction were 218±16 ng/mL and were significantly higher in control and 4F-PCC groups compared to ADA after reversal throughout.
BL 10 minutes after polytrauma was comparable between groups (732±229 mL). Control (3,843±406 mL) and PCC25 (2,865±334 mL) had the highest total BL post-injury, with 100% and 37.5% mortality, respectively. Although BL was significantly less both in the PCC50 (1,855±372 mL) and ADA (1,123±197 mL) groups, ADA showed the highest reduction in BL due to a faster onset of reversal at 60 min post-inury (Fig 1). While 4F-PCC recovered peak height (PK) and endogenous thrombin potential (ETP) dose-dependently and over a sustained period of time, ADA significantly shortened lag time and restored PK (Fig 2). Post-mortem histopathology revealed no thromboembolic complications in any treatment group.

Conclusion(s): This study shows that high-dose 4-F PCC and ADA are effective for emergency reversal of apixaban following polytrauma. TG indicates the temporary effect of ADA, whereas 4-F PCC showed a sustained restoration of TG after trauma.