Antithrombotic Agents for tPA‐Induced Cerebral Hemorrhage: A Systematic Review and Meta‐Analysis of Preclinical Studies

Abstract

Background tPA (tissue‐type plasminogen activator) remains the only approved drug for acute ischemic stroke, with a potentially serious adverse effect: hemorrhagic transformation. The effects of antithrombotic agents on tPA‐induced hemorrhagic transformation after ischemic stroke are not clearly defined. We performed a systematic review and meta‐analysis in preclinical studies aiming to evaluate the efficacy of antithrombotic agents on tPA‐induced hemorrhagic transformation after ischemic stroke. Methods and Results We conducted a systematic review and meta‐analysis of studies testing antithrombotic agents in animal models of tPA‐induced hemorrhagic transformation. The pooled effects were calculated using random‐effects models, and heterogeneity was explored through meta‐regression and subgroup analyses. Publication bias was assessed using trim and fill method and the Egger test. The efficacy of 18 distinct interventions was described in 22 publications. The pooled data showed a significant improvement in cerebral hemorrhage, infarct size, and neurobehavioral outcome in treated compared with control animals (standardized mean difference, 0.45 [95% CI, 0.11–0.78]; standardized mean difference, 1.18 [95% CI, 0.73–1.64]; and standardized mean difference, 0.91 [95% CI, 0.49–1.32], respectively). Subgroup analysis indicated that quality score, random allocation, control of temperature, anesthetic used, stroke model used, route of drug delivery, time of drug administration, and time of assessment were significant factors that influenced the effects of interventions. Conclusions Administration with antiplatelet agents revealed statistically significant improvement in all the outcomes. Anticoagulant agents showed significant effects in infarct size and neurobehavioral score, but fibrinolytic agents did not show any significant improvement in all the outcomes. The conclusions should be interpreted cautiously given the heterogeneity and publication bias identified in this analysis.