5069Reversal of apixaban and rivaroxaban anticoagulation by andexanet alfa in ANNEXA-A&R as assessed by non-tissue factor (TF)-initiated thrombin generation independent of TF pathway inhibitor (TFPI)

Abstract

Background: Andexanet alfa is a modified factor Xa designed to bind and sequester factor Xa (FXa) inhibitors and thus reverse anticoagulation. Andexanet has been previously shown to reverse anticoagulation effects of FXa inhibitors, apixaban or rivaroxaban, in Phase 3 randomized studies (ANNEXA‐A&R) in older healthy volunteers. When administered as a bolus or a bolus plus a 2‐hour infusion in anticoagulated subjects, andexanet significantly reversed apixaban or rivaroxaban anti‐FXa activity, reduced unbound (pharmacologically active) concentrations of both FXa inhibitors, and restored TF‐initiated thrombin generation (TF‐TG) when compared with placebo. Purpose: Since andexanet, as a modified FXa, can also bind TFPI, this study compared the effect of andexanet‐TFPI interaction on restoration of TG via the TF (extrinsic) and non‐TF (intrinsic) pathways in the ANNEXA‐A&R. Methods: Retained plasma samples from ANNEXA‐A&R subjects who received andexanet bolus plus a 2‐hour infusion were analyzed using a validated non‐TFTG assay similar to the TF‐TG assay, using an aPTT reagent (Actin FS, Siemens) as an activator. Restoration of TG was assessed by endogenous thrombin potential (ETP) and other TG parameters. Results: Compared with placebo, andexanet significantly reduced both apixaban‐ and rivaroxaban‐induced inhibition of non‐TF‐TG assessed by each TG parameter (p<0.001 vs placebo). In apixaban‐treated subjects, andexanet (N=23), compared with placebo (N=8), fully restored normal ETP (in 100% vs 37.5% of subjects, p=0.0003). In rivaroxaban‐treated subjects, andexanet (N=26), compared with placebo (N=13), fully restored non‐TF‐TG (in 100% vs 15.4% of subjects, p<0.0001). Compared to TF‐TG, non‐TF‐TG had less of an increase in ETP above the pre‐anticoagulant baseline level. ETP returned to placebo level after ∼2 hours post infusion. Conclusions: The results support the overall conclusions that sequestration of the FXa inhibitor by andexanet is the major contributor in restoring TG during and immediately following andexanet administration. However, the andexanet‐TFPI interaction may contribute to the duration of the sustained reversal in the TF‐TG assay (extrinsic pathway that reveals the TFPI effect), while this effect is lacking in the non‐TF‐TG assay (intrinsic pathway). Importantly, andexanet fully restores TG to pre‐anticoagulant levels under both conditions, where TG is initiated with either the extrinsic or intrinsic pathway.