Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model

Abstract

IntroductionIncreasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors.ObjectiveTo evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban.Materials and methodsIn vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury.ResultsAndexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035).ConclusionThese data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum

“…Andexanet alfa has been shown to reverse edoxaban in a rabbit bleeding model and in healthy volunteers . Only 10 edoxaban‐treated patients were enrolled in ANNEXA‐4, though there is a plan to enroll more in an extension of the study in Germany and Japan .…”

Role of direct oral anticoagulants in patients with kidney disease

“…Its clearance is predominantly renal (80% as dabigatran or active metabolites) ( Table 1). [37][38][39][40] In contrast, there are currently 4 approved factor Xa antagonist DOACs: rivaroxaban, apixaban, edoxaban, and betrixaban. These drugs all bind reversibly to the factor Xa active site and dampen downstream thrombin and fibrin generation.…”

Andexanet Alfa: First Global Approval

“…The modifications mean that andexanet alfa is unable to cleave and activate prothrombin and cannot assemble into the prothrombinase complex [2, 7–9]. Andexanet alfa binds to apixaban, betrixaban, edoxaban and rivaroxaban with high affinity (0.53–1.53 nmol/L), similar to that seen with endogenous factor Xa [24, 25]. Consequently, andexanet alfa sequesters factor Xa inhibitors, leading to reversing the anticoagulant effects of factor Xa inhibitors and restoring the activity of endogenous factor Xa [2, 7, 8].…”

“…In vitro, andexanet alfa dose-dependently reversed the anti-factor Xa activity of apixaban, betrixaban, edoxaban, rivaroxaban, enoxaparin and fondaparinux in human and rat plasma [24, 25]. In addition, andexanet alfa was shown to bind to tissue factor pathway inhibitor, an endogenous inhibitor of factor Xa, and transiently increased the level of prothrombin fragments 1 and 2, thrombin-antithrombin complex and D-dimer; this interaction can modulate tissue-factor initiated thrombin generation [9, 26].…”

“…In preclinical studies, andexanet alfa rapidly reversed the anticoagulant effects of factor Xa inhibitors (as measured by reduction in anti-factor Xa activity and unbound plasma concentrations of factor Xa inhibitors), thereby decreasing total blood loss in various animal models [24, 25, 27–31]. For instance, in a porcine model of polytrauma (a blunt liver injury and bilateral femur fractures) under apixaban anticoagulation, andexanet alfa significantly ( p  < 0.01) reduced total blood loss compared with vehicle when andexanet alfa was administered as a bolus (1264 vs. 3903 mL) or a bolus plus 2 h infusion (1202 vs. 3903 mL); survival was 100% in the andexanet alfa group.…”