Cerebrolysin for vascular dementia. — VialBase Research

Summary

Vascular dementia is the second most common cause of dementia globally and still lacks evidence-based treatments; Cerebrolysin, a porcine brain-derived preparation said to have neurotrophic and neuroprotective activity, is given as a series of daily intravenous infusions as a potential intervention in many parts of the world. This 2019 Cochrane review — the first update of a review published in 2013 — searched ALOIS, MEDLINE, Embase, PsycINFO, CINAHL, ISI Web of Knowledge, LILACS, the Cochrane Library, ClinicalTrials.gov, and the WHO ICTRP through May 2019, plus four Chinese databases from 2012 to May 2019, with no language restriction, and contacted pharmaceutical companies, trial authors, and experts for additional published or unpublished data. That exhaustive search added nothing: the same six randomised controlled trials with 597 participants that were eligible in 2013 remained the entire evidence base, and no new studies qualified. Participants had mild to moderate vascular dementia where severity was reported (four trials); doses, treatment durations, and follow-up varied widely (15 days to three years); five trials were conducted in China (three), Russia (one), and Romania (one); and where funding details were available, all studies were supported by the pharmaceutical industry (three studies). Pooling MMSE and ADAS-cog+ data from three studies (420 people) produced a beneficial effect on cognition of SMD 0.36 (95% CI 0.13 to 0.58) on very low-quality evidence. Global function response rates on CIBIC+ or CGI from two studies (379 participants) gave RR 2.69 (95% CI 1.82 to 3.98), also very low-quality evidence. Only one trial described mortality and reported no deaths; adverse event rates did not differ (RR 0.91, 95% CI 0.29 to 2.85, very low-quality evidence); no study reported quality of life or caregiver burden. Cochrane’s conclusion was carefully hedged: courses of intravenous Cerebrolysin improved cognition and general function with no suggestion of adverse effects, but these data are not definitive, analyses were limited by heterogeneity, included papers had high risk of bias, any benefit may be too small to be clinically meaningful, and Cerebrolysin continues to be used and promoted for vascular dementia on a weak supporting evidence base that requires adequately powered, methodologically robust trials.

Key Findings

• Six RCTs, 597 participants — unchanged since the 2013 review; despite an exhaustive multi-database, multi-language search including four Chinese databases, no new eligible studies had been published
• Cognition (pooled MMSE and ADAS-cog+, 3 studies, 420 people): SMD 0.36, 95% CI 0.13 to 0.58 — very low-quality evidence
• Global function response (CIBIC+ score < 3 or at least moderate CGI improvement, 2 studies, 379 participants): RR 2.69, 95% CI 1.82 to 3.98 — very low-quality evidence
• Adverse events: no difference between groups (2 studies, 379 people, RR 0.91, 95% CI 0.29 to 2.85, very low-quality evidence); one trial reported mortality and recorded no deaths; no study reported quality of life or caregiver burden
• All GRADE ratings were very low quality; analyses were limited by heterogeneity and high risk of bias in the included papers, and every study with disclosed funding was industry-supported
• Cochrane’s explicit conclusion: the data are not definitive, any effects may be too small to be clinically meaningful, and the evidence base supporting continued use and promotion of Cerebrolysin for vascular dementia is weak

Relevance to Cerebrolysin

This review is routinely cited by vendors as positive evidence for Cerebrolysin in cognition, and doing so requires stripping out everything Cochrane attached to the numbers. The point estimates are indeed favourable — an SMD of 0.36 on cognition and a near-tripled global-function response rate — but every single one carries a GRADE rating of very low quality, which is Cochrane’s way of saying the true effect is likely to be substantially different from the estimate. The reviewers state in their own conclusions that the data are not definitive, that heterogeneity and high risk of bias limited the analyses, and that if there are benefits the effects may be too small to be clinically meaningful. Two structural facts sharpen the picture: the entire evidence base is six small trials totalling 597 people, and not one new qualifying trial had appeared in the six years between the original review and this update, despite the compound remaining in commercial use. Where funding was disclosed, it was industry. The honest summary is that Cerebrolysin has suggestive but low-confidence cognitive data in vascular dementia, no adverse-event signal in this indication, and a manufacturer that has not funded the adequately powered trial that would settle the question.

Citation

Cui S, Chen N, Yang M, et al. Cerebrolysin for vascular dementia. The Cochrane database of systematic reviews. 2019;2019(11). doi:10.1002/14651858.CD008900.pub3.

See Also

• Parent compound: Cerebrolysin