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No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke.

Bohmann F, Mirceska A, Pfeilschifter J, Lindhoff-Last E, Steinmetz H, Foerch C, Pfeilschifter W - PLoS ONE (2012)

Bottom Line: We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Hospital, Goethe University, Frankfurt am Main, Germany.

ABSTRACT

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).

Conclusion: 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.

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Timeline diagram of the experimental procedures.
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pone-0040804-g001: Timeline diagram of the experimental procedures.

Mentions: First, we ascertained that our DE anticoagulation paradigm detailed in the following led to DE plasma concentrations that mirrored the therapeutic situation. In the first experiment, we randomized six mice per group to DE 37.5 mg/kg or saline to assess the influence of prior DE anticoagulation on HT volume and neurological deficit 24 h after the onset of 1 h tMCAO (Figure 1). Not finding significant differences in this model of moderate stroke, we randomized six mice per group in the second part of our study to DE 37.5 mg/kg, DE 75 mg/kg or saline prior to 3 h tMCAO. In order not to underestimate the risk of HT under DE anticoagulation, we doubled the DE dose in the second experiment to mimic the effect of supratherapeutic DE plasma concentrations that may occur in patients with reduced DE elimination, i.e. due to renal insufficiency. In the third part of our study, we randomized seven mice per group to either supratherapeutic DE anticoagulation (75 mg/kg) continued over an observation period of 72 h after 1 h tMCAO or saline. For this third part of our study, we chose an occlusion time of 1 h, because mice with an occlusion of 3 h had shown grave weight loss in the second part of our study as a sign of severe impairment, which might have led to inacceptably high rates of death and exclusion.


No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke.

Bohmann F, Mirceska A, Pfeilschifter J, Lindhoff-Last E, Steinmetz H, Foerch C, Pfeilschifter W - PLoS ONE (2012)

Timeline diagram of the experimental procedures.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404053&req=5

pone-0040804-g001: Timeline diagram of the experimental procedures.
Mentions: First, we ascertained that our DE anticoagulation paradigm detailed in the following led to DE plasma concentrations that mirrored the therapeutic situation. In the first experiment, we randomized six mice per group to DE 37.5 mg/kg or saline to assess the influence of prior DE anticoagulation on HT volume and neurological deficit 24 h after the onset of 1 h tMCAO (Figure 1). Not finding significant differences in this model of moderate stroke, we randomized six mice per group in the second part of our study to DE 37.5 mg/kg, DE 75 mg/kg or saline prior to 3 h tMCAO. In order not to underestimate the risk of HT under DE anticoagulation, we doubled the DE dose in the second experiment to mimic the effect of supratherapeutic DE plasma concentrations that may occur in patients with reduced DE elimination, i.e. due to renal insufficiency. In the third part of our study, we randomized seven mice per group to either supratherapeutic DE anticoagulation (75 mg/kg) continued over an observation period of 72 h after 1 h tMCAO or saline. For this third part of our study, we chose an occlusion time of 1 h, because mice with an occlusion of 3 h had shown grave weight loss in the second part of our study as a sign of severe impairment, which might have led to inacceptably high rates of death and exclusion.

Bottom Line: We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Hospital, Goethe University, Frankfurt am Main, Germany.

ABSTRACT

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).

Conclusion: 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.

Show MeSH
Related in: MedlinePlus