Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials

Natan M Bornstein, Alla Guekht, Johannes Vester, Wolf-Dieter Heiss, Eugene Gusev, Volker Hömberg, Volker W Rahlfs, Ovidiu Bajenaru, Bogdan O Popescu, Dafin Muresanu, Natan M Bornstein, Alla Guekht, Johannes Vester, Wolf-Dieter Heiss, Eugene Gusev, Volker Hömberg, Volker W Rahlfs, Ovidiu Bajenaru, Bogdan O Popescu, Dafin Muresanu

Abstract

This meta-analysis combines the results of nine ischemic stroke trials, assessing efficacy of Cerebrolysin on global neurological improvement during early post-stroke period. Cerebrolysin is a parenterally administered neuropeptide preparation approved for treatment of stroke. All included studies had a prospective, randomized, double-blind, placebo-controlled design. The patients were treated with 30-50 ml Cerebrolysin once daily for 10-21 days, with treatment initiation within 72 h after onset of ischemic stroke. For five studies, original analysis data were available for meta-analysis (individual patient data analysis); for four studies, aggregate data were used. The combination by meta-analytic procedures was pre-planned and the methods of synthesis were pre-defined under blinded conditions. Search deadline for the present meta-analysis was December 31, 2016. The nonparametric Mann-Whitney (MW) effect size for National Institutes of Health Stroke Scale (NIHSS) on day 30 (or 21), combining the results of nine randomized, controlled trials by means of the robust Wei-Lachin pooling procedure (maximin-efficient robust test), indicated superiority of Cerebrolysin as compared with placebo (MW 0.60, P < 0.0001, N = 1879). The combined number needed to treat for clinically relevant changes in early NIHSS was 7.7 (95% CI 5.2 to 15.0). The additional full-scale ordinal analysis of modified Rankin Scale at day 90 in moderate to severe patients resulted in MW 0.61 with statistical significance in favor of Cerebrolysin (95% CI 0.52 to 0.69, P = 0.0118, N = 314). Safety aspects were comparable to placebo. Our meta-analysis confirms previous evidence that Cerebrolysin has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke.

Keywords: Cerebrolysin; Early benefit; Meta-analysis; NIHSS; Recovery; Stroke.

Figures

Fig. 1
Fig. 1
Meta-analysis of NIHSS changes from baseline. Comparison of Cerebrolysin (30 ml/day) versus placebo at day 30 (or 21) in the ITT population; LOCF. Wei-Lachin pooling procedure (MERT), effect size: Mann-Whitney (MW)
Fig. 2
Fig. 2
Meta-analysis of mRS at day 90 in patients with baseline NIHSS > 12. Comparison of Cerebrolysin (30 ml/day) versus placebo in the ITT population; LOCF. Wei-Lachin pooling procedure (MERT), effect size: Mann-Whitney (MW)
Fig. 3
Fig. 3
Meta-analysis of mRS at day 90 in patients with baseline NIHSS > 12. Comparison of Cerebrolysin (30 ml/day) versus placebo in the ITT population; LOCF. Analysis of Covariance. “Classic” fixed effect and random effects analysis, effect size: mean difference
Fig. 4
Fig. 4
Deaths (all cause). Comparison of Cerebrolysin (30 ml/day) versus placebo in the safety population. “Classic” fixed effect and random effects analysis, effect size: odds ratio (OR)
Fig. 5
Fig. 5
Patients with at least one serious adverse event (TESAE). Comparison of Cerebrolysin (30 ml/day) versus placebo in the safety population. “Classic” fixed effect and random effects analysis, effect size: odds ratio (OR)
Fig. 6
Fig. 6
Patients with at least one adverse event (TEAE). Comparison of Cerebrolysin (30 ml/day) versus placebo in the safety population. “Classic” fixed effect and random effects analysis, effect size: odds ratio (OR)
Fig. 7
Fig. 7
Meta-analysis of early NIHSS changes in predominantly mild (a) and moderate-severe patients (b). Comparison of Cerebrolysin (30 ml/day) at day 30 (or 21); ITT; LOCF. Wei-Lachin pooling procedure (MERT), effect size: Mann-Whitney (MW)

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