No Influence of Dabigatran Anticoagulation on Hemorrhagic Transformation in an Experimental Model of Ischemic Stroke

Abstract

BackgroundDabigatran 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.Methods44 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.ResultsAfter 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).ConclusionOur 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.

Management of Patients on Non–Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association

“…In experimental models of ischemic stroke, neither dabigatran pretreatment nor continued administration of dabigatran after stroke onset significantly increased the risk or volume of hemorrhagic transformation after middle cerebral artery occlusion. 95,96 Clinical data are anecdotal only. The phase III trials establishing the role of NOACs for stroke prevention in NVAF excluded patients within 7 to 30 days of stroke.…”

The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data

“…The same group reported similar results after treatment of experimental animals with dabigatran [ 13 ]. On the other hand, dabigatran did not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice [ 14 ] or risk of secondary hemorrhages after thrombolysis in various rodent models of ischemia and reperfusion [ 10 ] or collagenase-induced intracranial hemorrhage [ 11 ]. We and others reported that warfarin and dabigatran both induce glomerular hemorrhage in the kidney [ 4 , 15 ].…”

Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model

“…All rats were anesthetized with a mixture of nitrous oxide/oxygen/isoflurane (69%:30%:1%) during surgical preparation with an inhalation mask. Focal cerebral ischemia and ET was induced using the tMCAO model as described previously 11 , 32 , 33 . The rats’ body temperature was monitored and maintained at 37.0 ± 0.5 °C by a heating pad during the surgical procedure.…”