Hemorrhagic Transformation After Large Cerebral Infarction in Rats Pretreated With Dabigatran or Warfarin

Abstract

BACKGROUND AND PURPOSE: It is uncertain whether hemorrhagic transformation (HT) after large cerebral infarction is less frequent in dabigatran users than warfarin users. We compared the occurrence of HT after large cerebral infarction among rats pretreated with dabigatran, warfarin, or placebo.

METHODS: This was a triple-blind, randomized, and placebo-controlled experiment. After treatment with warfarin (0.2 mg/kg), dabigatran (20 mg/kg), or saline for 7 days, Wistar rats were subjected to transient middle cerebral artery occlusion. As the primary outcome, HT was determined by gradient-recalled echo imaging. For the secondary outcome, intracranial hemorrhage was assessed via gradient-recalled echo imaging in surviving rats and via autopsy for dead rats.

RESULTS: Of 62 rats, there were 33 deaths (53.2%, 17 technical reasons). Of the intention-to-treat population, 33 rats underwent brain imaging. HT was less frequent in the dabigatran group than the warfarin group (placebo 2/14 [14%], dabigatran 0/10 [0%], and warfarin 9/9 [100%]; dabigatran versus warfarin; P<0.001). In all 62 rats, compared with the placebo (2/14 [14.3%]), the incidence of intracranial hemorrhage was significantly higher in the warfarin group (19/29 [65.5%]; P=0.003), but not in the dabigatran group (6/19 [31.6%]; P=0.420). Mortality was significantly higher in the warfarin group than the dabigatran group (79.3% versus 47.4%; P=0.022), but not related to the hemorrhage frequency.

CONCLUSIONS: The risk of HT after a large cerebral infarction was significantly increased in rats pretreated with warfarin than those with dabigatran. However, the results here may not have an exact clinical translation.