Four-Factor Prothrombin Complex Concentrate (4-PCC) Effectively Reverses Edoxaban Induced Bleeding In a Rabbit Model Of Acute Injury

This study was designed to determine whether the four-factor Prothrombin Complex Concentrate (4-PCC) Beriplex^® P/N (Kcentra™) can effectively reverse bleeding following edoxaban administration in a rabbit kidney injury model.

The oral direct and selective factor Xa inhibitor edoxaban (Daiichi Sankyo) is currently available in Japan for the prophylaxis of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery and is undergoing investigation in phase III trials for the prevention of stroke in patients with atrial fibrillation and the treatment and secondary prevetion of VTE. The primary complication of any available anticoagulant therapy is the risk of bleeding. Rapid reversal of anticoagulation may be necessary in patients requiring emergency treatment due to uncontrolled bleeding. PCCs are frequently used to reverse the effect of vitamin K antagonists such as warfarin and have also been suggested to be potentially effective in reversing the effects of the new oral anticoagulants.

The present study was therefore designed to further investigate the ability of 4-PCC to reverse the anticoagulant action of edoxaban using an in vivo rabbit model of acute bleeding.

Animals were treated with a high intravenous bolus dose of edoxaban (1200 µg/kg) leading to increased and prolonged bleeding following standardized kidney injury compared to vehicle administration. Parallel monitoring of biomarkers of haemostasis showed that edoxaban treatment resulted in the prolongation of prothrombin time (PT), activated partial thromboplastin time, and whole blood clotting time (WBCT), and affected the thrombin generation parameters thrombin peak, endogenous thrombin potential (ETP), lagtime and time to peak. Subsequent administration of the 4-PCC (25-75 IU/kg) resulted in a dose-dependent reversal of edoxaban induced bleeding as indicated by reduced time to haemostasis and total blood loss. Both parameters achieved statistical significance compared to placebo at the 4-PCC dose of 50 IU/kg under fully blinded study conditions. The biomarkers correlating best with 4-PCC mediated edoxaban anticoagulation reversal included PT, WBCT and ETP.

In summary, 4-PCC treatment effectively decreased edoxaban induced hemorrhage in an animal model of acute bleeding at clinically relevant dose levels.