Early addition of cerebrolysin to reperfusion therapy reduces haemorrhagic transformation after ischaemic stroke

A prospective, randomized, multicentre pilot study finds that early addition of cerebrolysin to reperfusion therapy is safe and significantly reduces the rate of haemorrhagic transformation (HT) after acute ischaemic stroke (AIS).

Cerebrolysin is a parenterally administered neuropeptide preparation that has shown neuroprotective effects in animal models of dementia and stroke. [J Neurosci Res 2010;88:3275-3281; Synapse 2016;70:378‐389; Neurosci Lett 2017;651:72-78] It was also found to be associated with accelerated recovery and reduced neuronal damage in some clinical trials involving AIS patients. [Neurol Sci 2018;39:629-640]

Although intravenous thrombolysis (IVT) within 4.5 hours of AIS substantially improves functional outcomes, associated reperfusion injury and HT are significant contributors to stroke-related morbidity and mortality that need to be managed through neuroprotective measures. [Engl J Med 2008;359:1317-1329] “The present study evaluated the effects of adding [neuroprotective] cerebrolysin to IVT vs IVT alone in AIS patients,” wrote the researchers.

CEREHETIS (Cerebrolysin as an Early Add-on to Reperfusion Therapy: Risk of Hemorrhagic Transformation after Ischaemic Stroke) was a prospective, randomized, open-label, active-control, multicentre, parallel-group phase IIIb pilot study, which compared concurrent cerebrolysin (30 mL/day over 14 days) with alteplase (0.9 mg/kg) (n=126) vs alteplase alone (n=215) in AIS patients. The primary endpoint was the rate of any and symptomatic HT on days 0–14. Secondary endpoints were drug safety and functional outcomes. [BMC Neurol 2023;doi:10.1186/s12883-023-03159-w]

HT mostly occurred within 24 hours of IVT. In the intention-to-treat (ITT) population, the rate of any HT was 15.9 percent in patients treated with cerebrolysin vs 23.3 percent in alteplase alone group (odds ratio [OR], 0.543; 95 percent confidence interval [CI], 0.281–1.050; p=0.078). The difference was even more pronounced in the per-protocol (PP) analysis, where the respective HT rates were 13.7 percent vs 22.9 percent (OR, 0.417; 95 percent CI, 0.200–0.871; p=0.032).

“Likewise, cerebrolysin treatment substantially decreased the rate of symptomatic HT [ITT population: 3.2 percent vs 9.3 percent; PP population: 2.6 percent vs 9.0 percent], with ORs of 0.248 [95 percent CI, 0.072–0.851; p=0.019] and 0.171 [95 percent CI, 0.040–0.726; p=0.022], respectively,” added the researchers.

Death occurred in 6.3 percent of patients who received cerebrolysin and 5.6 percent of patients in the control group (p=0.771). No serious adverse events (AEs) were attributed to cerebrolysin. Some mild-to-moderate AEs (eg, fever, nausea, vomiting) occurred in both groups within 48 hours after treatment initiation and lasted up to several hours without any consequences. The only AE that occurred significantly more often in the cerebrolysin group was agitation (3.2 percent vs 0.5 percent in the control group; p=0.045).

Day 14 functional outcomes as measured by the National Institutes of Health Stroke Scale (NIHSS) were significantly better in the overall cerebrolysin group (p=0.045), but not in patients with any HT (p=0.370). No statistically significant differences in functional outcomes were observed between groups on day 90, as measured by the modified Rankin scale.

“Our results demonstrate beneficial effects of cerebrolysin as an early add-on to IVT on any and symptomatic HT and early neurological recovery endpoints in AIS patients. However, this treatment approach did not affect long-term functional outcomes,” summarized the researchers.