Cerebrolysin for acute ischaemic stroke. — VialBase Research

Summary

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from porcine brain with claimed neuroprotective properties, widely used for acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. This 2023 Cochrane review — an update of a review first published in 2010 and last updated in 2020 — assessed the benefits and harms of Cerebrolysin or Cerebrolysin-like agents in acute ischaemic stroke, searching the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, Web of Science, LILACS, and a number of Russian databases. Seven randomised controlled trials totalling 1773 participants met inclusion criteria, including one newly added trial of the Cerebrolysin-like agent Cortexin contributing 272 participants. The risk-of-bias picture was poor: selective outcome reporting was unclear across all Cerebrolysin studies; allocation sequence generation and allocation concealment were low risk in only one study and unclear in the remaining six; incomplete outcome data was high risk in four of seven; the manufacturer supported three multicentre studies either totally or by providing drug, placebo, randomisation codes, research grants, or statisticians; and two studies were judged at high risk of other bias. On outcomes, moderate-certainty evidence indicates Cerebrolysin or Cortexin probably result in little to no difference in all-cause death (RR 0.96, 95% CI 0.65 to 1.41; 6 trials, 1689 participants). None of the included studies reported poor functional outcome (death or dependence at end of follow-up), early death within two weeks of onset, quality of life, or time to restoration of capacity for work. Moderate-certainty evidence indicates little to no difference in the total number of people with serious adverse events (RR 1.16, 95% CI 0.81 to 1.66) and in fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38), but an increase in people with non-fatal serious adverse events (RR 2.39, 95% CI 1.10 to 5.23; 3 trials, 1335 participants), more prominent in the 30 mL for 10 days dosing subgroup (RR 2.87, 95% CI 1.24 to 6.69; 2 trials, 1189 participants). Cochrane’s stated conclusions are that Cerebrolysin or Cerebrolysin-like peptide mixtures probably have no beneficial effect on preventing all-cause death, probably no beneficial effect on the total number of people with serious adverse events, and are associated with a potential increase in non-fatal serious adverse events.

Key Findings

• Seven RCTs, 1773 participants, including one trial of the Cerebrolysin-like agent Cortexin (272 participants) added in this update
• All-cause death: RR 0.96 (95% CI 0.65 to 1.41), 6 trials, 1689 participants, moderate-certainty evidence — probably little to no difference
• Non-fatal serious adverse events increased: RR 2.39 (95% CI 1.10 to 5.23), 3 trials, 1335 participants, moderate-certainty evidence; in the 30 mL for 10 days (cumulative 300 mL) subgroup the increase was more prominent at RR 2.87 (95% CI 1.24 to 6.69), 2 trials, 1189 participants
• Total people with SAEs: RR 1.16 (95% CI 0.81 to 1.66) and fatal SAEs RR 0.90 (95% CI 0.59 to 1.38), both moderate certainty; total people with adverse events RR 1.03 (95% CI 0.92 to 1.14), low certainty; non-death attrition RR 0.72 (95% CI 0.38 to 1.39), very low certainty with considerable heterogeneity
• No included study reported poor functional outcome (death or dependence at end of follow-up), early death within two weeks, quality of life, or time to restoration of capacity for work — the outcomes that matter most to stroke patients were simply not measured
• Substantial manufacturer involvement: three multicentre studies were supported by the manufacturer totally or through drug, placebo, randomisation codes, grants, or statisticians; two studies were at high risk of other bias

Relevance to Cerebrolysin

This is the top of the evidence pyramid for Cerebrolysin in acute ischaemic stroke and its verdict is unfavourable, so it must be reported as Cochrane wrote it rather than balanced away with lower-grade positive reviews. Three points carry the weight. First, there is no mortality benefit — moderate-certainty evidence of essentially no difference in all-cause death. Second, and more striking, not one of the seven included trials reported the outcome that actually defines stroke recovery: death or dependence at end of follow-up. A drug marketed for neuroprotection in stroke has an evidence base that never measured whether patients ended up functionally independent. Third, there is a safety signal pointing the wrong way — a moderate-certainty doubling of non-fatal serious adverse events, rising further at the 30 mL for 10 days schedule, which is the dosing many protocols use. Layered on top is a bias profile that would disqualify most drug programmes: manufacturer funding or material support in three multicentre trials, unclear selective-outcome-reporting risk across the board, and high risk of incomplete outcome data in four of seven trials. When a Cerebrolysin stroke claim is made, this review is the correct citation, and its conclusions should not be softened.

Citation

Ziganshina LE, Abakumova T, Nurkhametova D, et al. Cerebrolysin for acute ischaemic stroke. The Cochrane database of systematic reviews. 2023;10(10):CD007026. doi:10.1002/14651858.CD007026.pub7.

See Also

• Parent compound: Cerebrolysin