Introduction: Dabigatran is effective in preventing stroke and reduces the risk of intracerebral hemorrhage when comparing with warfarin in patients with atrial fibrillation. However, it is uncertain whether hemorrhagic transformation (HT) after large cerebral infarction is also less frequent in dabigatran users than warfarin users.
Hypothesis: We hypothesized that intracerebral HT would occur less frequently following large cerebral infarction in rats pretreated with dabigatran than those with warfarin. We also compared the change of matrix metalloproteinases (MMPs), which play a key role in HT.
Methods: We performed randomized, double-blind experiments comparing warfarin and dabigatran in rats. After treatment with warfarin (0.2 mg/kg), dabigatran (20 mg/kg), or normal saline for 7 days, male wistar rats were subjected to permanent middle cerebral artery occlusion (MCAO) using a nylon thread. After 22 hours of MCAO, magnetic resonance imaging (MRI) was undergone (9.4T MR scanner, slice thickness = 0.5 mm). Operative procedures and assessment of MRI findings were performed by investigators who were blind to the group information. The presence of HT was assessed on gradient recalled-echo and infarction volume was measured on diffusion-weighted image. The MMP-2 and MMP-9 activities in brain tissues (obtained 24 hours after MCAO) were investigated using gelatin zymography.
Results and Conclusions: Of the 33 rats with MRI, HT was observed less frequently in the dabigatran group than the warfarin group (placebo 14% [2/14], dabigatran 0% [0/10], and warfarin 100% [9/9], p < 0.001 [dabigatran vs warfarin]). The volume of infarction was similar between the groups (placebo 432.45 ± 78.35 mm3, dabigatran 432.42 ± 60.27 mm3, and warfarin 446.55 ± 73.55 mm3). MMP-2 and MMP-9 activities were not different between the groups. In the placebo, dabigatran, and warfarin groups, mean international normalized ratio were 1.38 ± 0.13, 1.73 ± 0.20, and 4.72 ± 2.92, respectively; mean activated partial thromboplastin times were 30.20 ± 7.49, 31.14 ± 7.02, and 55.06 ± 24.05, respectively. The risk of HT after large cerebral infarction was remarkably reduced in rats pretreated with dabigatran. MMPs did not seem to play a major role in reduced risk of HT.