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

Introduction
Increasing 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.
Objective
To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban.
Materials and methods
In 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.
Results
Andexanet 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).
Conclusion
These 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.

研究背景：随着因子Xa（factor Xa）抑制剂的临床应用日益广泛，亟需有效的逆转制剂以应对相关出血风险。Andexanet alfa作为一种新型修饰重组人因子Xa，可快速逆转直接与间接FXa抑制剂的抗凝作用。
研究目的：评估andexanet在体外逆转依度沙班（edoxaban）介导的抗凝效果，并降低给予依度沙班的家兔模型中的出血量。
材料与方法：体外实验表征了andexanet与依度沙班的相互作用，以及其逆转依度沙班介导的抗FXa活性的能力。在手术诱导急性出血的家兔模型中，实验动物分为四组：依度沙班溶媒+andexanet溶媒对照组、依度沙班（1 mg/kg）+andexanet溶媒组、依度沙班+andexanet（75 mg，5分钟输注，于依度沙班给药后20分钟给予）组，以及伤前给予依度沙班溶媒+andexanet组。
实验结果：Andexanet与依度沙班的结合亲和力与FXa相近。体外实验中，andexanet可快速且呈剂量依赖性地逆转依度沙班对FXa活性及凝血药效学参数的影响。在依度沙班抗凝的家兔中，andexanet可使抗FXa活性降低82%（从548±87 ng/ml降至100±41 ng/ml；P<0.0001），血浆游离依度沙班平均浓度降低约80%（从100±10 ng/ml降至21±6 ng/ml；P<0.0001），与溶媒对照组相比出血量降低80%（经对照组校正后，2.6 g与12.9 g；P=0.003）。出血量的减少与抗FXa活性的降低呈正相关（r=0.6993，P<0.0001），同时与游离依度沙班浓度的降低亦呈正相关（r=0.5951，P=0.0035）。
研究结论：本研究数据证实，andexanet可快速逆转依度沙班的抗凝作用，提示其在急性出血及手术相关出血的临床管理中具有临床应用价值。出血量与抗FXa活性的相关性支持将抗FXa活性作为临床试验中评估抗凝逆转效果的生物标志物。