Abstract WP79: Appropriate Timing of Fluoxetine and Statin Administration Reduces the Risk of Secondary Hemorrhagic Infarct After Ischemic Stroke

Abstract

Introduction: Ongoing clinical trials are testing the effect of fluoxetine delivered 2-15 days from the onset of an acute ischemic stroke where a majority of patients are taking statins. We hypothesized that earlier drug delivery would result in smaller infarcts. Methods: Endothelin-1-induced strokes were initiated in 10-12 month old Sprague-Dawley rats, targeting the forelimb motor cortex. Combined medications of 5 mg/kg fluoxetine and 1 mg/kg simvastatin were orally administered either beginning 6-12 hours or 20-26 hours after stroke induction and continued daily for 90 days. Infarct volumes were assessed at post-stroke day 91 using Nissl stained coronal brain sections. An unpaired T-test with Welch’s correction for unequal variances was used for statistical comparison of the infarct volumes. Results: Control animals typically had 5-13 mm3 infarct volumes. Animals that received fluoxetine and simvastatin beginning 20-26 hours after stroke induction showed a strong trend of reduced infarct volume (3 ± 0.3447 mm3 SEM, P=0.0563). Earlier drug delivery (6-12 hours after stroke) resulted in significantly larger infarct volumes (15.4 ± 4.260 mm3 SEM, P=0.0157) when the drug groups were directly compared (Fig.1). Examination of the infarct volumes showed that earlier drug delivery induced secondary hemorrhagic infarcts, while later delivery did not (P=0.0427; Fisher’s exact test). Conclusions: There appears to be substantial danger of developing hemorrhagic infarct if the combination of fluoxetine and statin is given within 6-12 hours of stroke induction (RR= 4.36, 95% CI = 0.64-29.5). For that reason, it is crucial to monitor stroke patients for statins and fluoxetine, and withhold the statin for at least 20 hours after stroke onset. Delivery of both drugs after 20-26 hours of stroke onset resulted in significantly reduced infarcts.