title: Comparison of antithrombotic and hemorrhagic effects of edoxaban, a novel factor Xa inhibitor, with unfractionated heparin, dalteparin, lepirudin and warfarin in rats.
abstract: BACKGROUND
  Edoxaban is a novel, potent and orally active direct Factor Xa (FXa) inhibitor under development for prophylaxis and treatment of thromboembolic diseases. Properties of dose response and margin of safety of anticoagulants are the key factors for a positive risk/benefit of novel oral anticoagulants.
  
  
  OBJECTIVE
  To compare the dose response of antithrombotic effect and margin of safety between antithrombotic and hemorrhagic effects of edoxaban with conventional anticoagulants, unfractionated heparin (UFH), dalteparin (low molecular weight heparin), lepirudin, and warfarin in rat models of thrombosis and hemorrhage.
  
  
  METHODS
  Rats were treated with edoxaban, UFH, dalteparin, and lepirudin by continuous intravenous (iv) infusion, or with oral warfarin for 4 days before inducing thrombosis or bleeding. Thrombosis was induced by inserting a platinum wire into the inferior vena cava for 60 minutes. Tail template bleeding time was measured after making an incision on the tail.
  
  
  RESULTS
  In rats, iv infusion of edoxaban inhibited venous thrombosis in a dose-dependent manner. The other anticoagulants also exerted dose-dependent antithrombotic effects. The slopes of the dose-response curves of edoxaban were significantly shallower than the slopes of UFH, dalteparin, and warfarin. At supratherapeutic doses, edoxaban prolonged bleeding time in a rat tail bleeding model. To determine bleeding risk, the margins between antithrombotic and bleeding-time prolongation were compared. The margins of safety of edoxaban were wider than those of UFH, dalteparin, lepirudin, and warfarin.
  
  
  CONCLUSIONS
  These results suggest that edoxaban may be more easily controlled and has the potential for a more positive risk/benefit ratio compared to conventional anticoagulants.
authors.affiliation: Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd. Electronic address: morishima.yoshiyuki.t4@daiichisankyo.co.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Honda
authors.forename: Chikako
authors.initials: C
authors.lastname: Kamisato
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shibano
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D013923:Thromboembolism / Q000188:drug therapy; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006629:Hirudins; D011725:Pyridines; D011994:Recombinant Proteins; D013844:Thiazoles; D014859:Warfarin; D006493:Heparin; C552171:edoxaban; C083544:lepirudin
keywords: APTT; Anticoagulant; Antithrombotic effect; BT2; Bleeding; CI; Dose response; ED(50); Edoxaban; FXa; INR; LMWH; Margin of safety; PT; SEM; UFH; VTE; activated partial thromboplastin time; confidence interval; dose required for 50% inhibition of thrombus formation; dose required to double bleeding time; factor Xa; international normalization ratio; intravenous; iv; low molecular weight heparin; oral administration; po; prothrombin time; standard error of mean; unfractionated heparin; venous thromboembolism