Introduction: Despite the safety of factor Xa inhibitors the management of life-threatening bleeding is challenging. Andexanet alfa is an antidote under investigation for reversal of factor Xa inhibitors.
Hypothesis: We investigated the hemostatic safety and efficacy of andexanet alfa in a large animal polytrauma model under apixaban anticoagulation.
Methods: Following ethical approval, oral apixaban (20 mg/day) was given to 21 male pigs on 3 consecutive days prior to the experiment. A standardized polytrauma by blunt liver injury and bilateral femur fractures was inflicted under anesthesia. Anticoagulated animals were randomized (n= 7 per group) to be administered an andexanet bolus (1000 mg), or a bolus (1000 mg) plus infusion of andexanet (1200 mg over 2 h), or a vehicle (control) 12 min after injury. Total blood loss (BL) and coagulation markers of activation were determined over 5 h or until death. Data were analyzed using two-way ANOVA and log rank tests (Mean ± SD).
Results: Before trauma infliction apixaban levels (192 ± 22 ng/mL) were comparable among study groups. The application of andexanet resulted in a significant reduction of BL (Bolus: 1264 ± 205 mL, Bolus + Infusion: 1202 ± 95 mL) and 100% survival. All control animals exsanguinated early (min-max survival time: 125-193 min) with the highest BL (3903 ± 501 mL, p<0.01 vs. andexanet treated groups). Anti-fXa levels of apixaban were close to zero after andexanet application and slowly increased over time whereas the anti-FXa levels remained lower following andexanet infusion (Figure 1a). Neutralization of apixaban was associated with a normalization of peak thrombin generation (Figure 1b), and with D-dimers expected in the normal range following trauma.
Conclusions: Both andexanet regimens effectively reversed apixaban anticoagulation without provoking a procoagulant state post-injury.