No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke.
BACKGROUND
Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor. Clinical trials point towards a favourable risk-to-benefit profile of DE compared to warfarin. In this study, we evaluated whether hemorrhagic transformation (HT) occurs after experimental stroke under DE treatment as we have shown for warfarin.


METHODS
44 male C57BL/6 mice were pretreated orally with 37.5 mg/kg DE, 75 mg/kg DE or saline and diluted thrombin time (dTT) and DE plasma concentrations were monitored. Ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h or 3 h. We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO.


RESULTS
After 1 h tMCAO, HT blood volume did not differ significantly between mice pretreated with DE 37.5 mg/kg and controls (1.5±0.5 µl vs. 1.8±0.5 µl, p>0.05). After 3 h tMCAO, DE-anticoagulated mice did also not show an increase in HT, neither at the dose of 37.5 mg/kg equivalent to anticoagulant treatment in the therapeutic range (1.3±0.9 µl vs. control 2.3±0.5 µl, p>0.05) nor at 75 mg/kg, clearly representing supratherapeutic anticoagulation (1.8±0.8 µl, p>0.05). Furthermore, no significant increase in HT under continued anticoagulation with DE 75 mg/kg could be found at 72 h after tMCAO for 1 h (1.7±0.9 µl vs. control 1.6±0.4 µl, p>0.05).


CONCLUSIONS
Our experimental data suggest that DE does not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice. From a translational viewpoint, this indicates that a continuation of DE anticoagulation in case of an ischemic stroke might be safe, but clearly, clinical data on this question are warranted.
Department of Neurology, University Hospital, Goethe University, Frankfurt am Main, Germany.
Ferdinand
F
Bohmann
Ana
A
Mirceska
Josef
J
Pfeilschifter
Edelgard
E
Lindhoff-Last
Helmuth
H
Steinmetz
Christian
C
Foerch
Waltraud
W
Pfeilschifter
D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000097:blood* / Q000188:drug therapy / Q000209:etiology*; D000069604:Dabigatran; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D020521:Stroke / Q000097:blood* / Q000150:complications* / Q000209:etiology; D016896:Treatment Outcome; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D000991:Antithrombins; D001562:Benzimidazoles; D011725:Pyridines; D015091:beta-Alanine; D000069604:Dabigatran