Cerebrolysin, Hemorrhagic Transformation, and Anticoagulation Timing after Reperfusion Therapy in Stroke: Secondary Analysis of the CEREHETIS Trial

Background The timing of anticoagulation resumption after ischemic stroke remains uncertain, especially in patients at high risk of hemorrhagic transformation (HT). Although Cerebrolysin reduces HT incidence, its impact on dynamic risk evolution and the safe therapeutic window is unknown. Methods This post-hoc survival analysis of the CEREHETIS trial (ISRCTN87656744) included 238 patients with middle cerebral artery infarction, stratified into low (HTI = 0) and high (HTI = 1–4) HT-risk groups. Temporal hazard dynamics over 14 days were modeled with the Gompertz distribution. Nonlinear hazard acceleration (NLHA) and the compounding effect—capturing self-amplifying instantaneous risk—were quantified to locate the inception point when hazard stabilization allows safe anticoagulation. A conservative NLHA threshold (5 % of peak = 0.23 % per day) defined this risk-equilibrium. Results In high-risk patients, Cerebrolysin significantly reduced hazards of symptomatic HT (HR = 0.245; 95 % CI 0.072–0.837; p = 0.020) and any HT (HR = 0.543; 95 % CI 0.297–0.991; p = 0.032). In controls, the compounding effect peaked on day 1 and persisted through day 3, whereas Cerebrolysin markedly attenuated this amplification and shortened the hazardous period. Inception points occurred on days 2–3 with Cerebrolysin versus days 4–5 in controls. In low-risk patients, both groups achieved constant hazard by day 2. Conclusion Cerebrolysin mitigates nonlinear hazard amplification, lowers HT risk, and advances the risk-equilibrium point by 1–2 days, enabling earlier and safer anticoagulation resumption and supporting a hazard-based, individualized approach to post-stroke management.