Comparison of the effect of edoxaban, a direct factor Xa inhibitor, with a direct thrombin inhibitor, melagatran, and heparin on intracerebral hemorrhage induced by collagenase in rats.
BACKGROUND
Intracerebral hemorrhage (ICH) is a major clinical concern with anticoagulation therapy. The effect of a new oral direct FXa inhibitor, edoxaban, was determined in a rat model of ICH and compared with a direct thrombin inhibitor, melagatran, and heparin.


METHODS
To induce ICH, 0.1 U collagenase type VII was injected into the striatum of male Wistar rats under anesthesia with thiopental or halothane. Immediately after ICH induction, edoxaban, melagatran, or heparin were infused intravenously. Five hours after ICH induction, the brain was removed and ICH size was measured. To estimate the margin of safety, antithrombotic effects were evaluated in a rat venous thrombosis model.


RESULTS
Edoxaban at 6mg/kg/h significantly increased ICH volume (1.8-fold) and prolonged prothrombin time (PT) 2.8-fold compared to the vehicle group. No deaths were observed with edoxaban. Melagatran at 1mg/kg/h increased ICH volume at 1mg/kg/h (2.8-fold) with 6.1-fold PT prolongation. At 3mg/kg/h, all rats died due to severe ICH (3.9-fold). Heparin at both 100 and 500U/kg/h significantly increased ICH. At 500U/kg/h, 5 out of 8 rats died. The doses required for 50% inhibition of thrombosis of edoxaban, melagatran, and heparin were 0.045mg/kg/h, 0.14mg/kg/h, and 55U/kg/h, respectively. The safety margins between antithrombotic and ICH exacerbation effects of these anticoagulants were 133, 7.1, and 1.8, respectively.


CONCLUSIONS
The safety margin of edoxaban was wider than that of melagatran or heparin. These results suggest that edoxaban may be preferable from the perspective of ICH exacerbation risk.
Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Japan.
Yasufumi
Y
Shirasaki
Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Japan. Electronic address: morishima.yoshiyuki.t4@daiichisankyo.co.jp.
Yoshiyuki
Y
Morishima
R&D Planning Department, R&D Division, Daiichi Sankyo Co., Ltd., Japan.
Toshiro
T
Shibano
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000991:Antithrombins / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D002543:Cerebral Hemorrhage / Q000097:blood / Q000188:drug therapy*; D017364:Collagenases; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*
D000925:Anticoagulants; D000991:Antithrombins; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C109573:melagatran; D006493:Heparin; D017364:Collagenases; C552171:edoxaban
Anticoagulant; Edoxaban; Factor Xa inhibitor; Heparin; Intracerebral hemorrhage; Thrombin inhibitor