Cerebrolysin and Risk of Hemorrhagic Transformation: A Pooled Analysis of Recent Studies

Dear Editor,We read with great interest the emerging clinical literature on the role of Cerebrolysin in acute ischemic stroke management, particularly in relation to hemorrhagic complications.Given the growing body of data from randomized controlled trials and observational cohorts, we performed a focused quantitative synthesis of studies published between 2021 and 2025 that evaluated the safety of Cerebrolysin with respect to intracranial bleeding events.Because Cerebrolysin is often used with reperfusion therapies that have a bleeding risk, it is important to balance the trade-off between its positive neuroprotective effects and the cost of increased hemorrhagic complications.Additionally, the neurotrophic and anti-inflammatory effects of Cerebrolysin 1 may help preserve the integrity of blood-brain barrier and reduce matrix-mediated vascular damage, offering a biological rationale for a potential reduction in hemorrhagic transformation (HT).A literature search of PubMed, Scopus, and Web of Science was conducted from their inceptions to June 2025, following PRISMA 2020 guidelines. 2 We included randomized controlled trials and observational cohort reports on hemorrhagic outcomes in acute ischemic stroke patients treated with Cerebrolysin.Nonhuman studies, reviews, case reports, abstracts, and studies that did not produce hemorrhagic outcome data were excluded.Quality assessment was performed using the ROB2 tool (https://methods.cochrane.org/bias/re- sources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials).The search strategy is presented in detail in Supplementary Table 1 (in the online-only Data Supplement).Our analyses identified four eligible studies conducted in Egypt, Russia, Croatia, and Poland that collectively enrolled 635 patients.3-6 The study designs included both randomized and observational cohorts, and comprised 274 patients who received Cerebrolysin and 361 patients who served as controls.The mean patient age ranged from 59.3 to 76.0 years in the Cerebrolysin arm and from 61.8 to 77.0 years in the control arm.The proportion of males varied between 41.3% and 60.9% in the intervention arm and 47.6% to 60.0% in the control arm.The study characteristics for the included trials and the risk of bias are presented in Supplementary Table 2 (in the online-only Data Supplement).Symptomatic intracranial hemorrhage (sICH) was the main safety endpoint, and was examined in all four included studies.3-6 The pooled odds ratio (OR) derived using a Hartung-Knapp REML random-effects model was 0.195 (95% confidence interval [CI]=0.031 to 1.214), which equated to a log OR of -1.638, suggesting that the risk of sICH was lower when taking Cerebrolysin, but with no statistically significant differences.The studies exhibited moderate heterogeneity (I 2 =57.5%).The leave-one-out analyses yielded ORs ranging from 0.162 to 0.330, with no single study substantially influencing the pooled estimate.Fig. 1 represents a more-detailed assessment of this outcome.The secondary outcome of any HT was assessed in three studies (n=535).3-5 The pooled OR was 0.341 (95% CI=0.065-1.788,log OR=-1.076),again indicating a trend toward lower Bassel Alrabadi