Cerebrolysin for acute ischaemic stroke - PubMed (original) (raw)

Review

Cerebrolysin for acute ischaemic stroke

Liliya Eugenevna Ziganshina et al. Cochrane Database Syst Rev. 2023.

Abstract

Background: Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from porcine brain, which has potential neuroprotective properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. This is an update of a review first published in 2010 and last updated in 2020.

Objectives: To assess the benefits and harms of Cerebrolysin or Cerebrolysin-like agents for treating acute ischaemic stroke.

Search methods: We searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, and LILACS in May 2022 and a number of Russian databases in June 2022. We also searched reference lists, ongoing trials registers, and conference proceedings.

Selection criteria: Randomised controlled trials (RCTs) comparing Cerebrolysin or Cerebrolysin-like agents started within 48 hours of stroke onset and continued for any length of time, with placebo or no treatment in people with acute ischaemic stroke.

Data collection and analysis: Three review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, extracted data, and applied GRADE criteria to the evidence.

Main results: Seven RCTs (1773 participants) met the inclusion criteria of the review. In this update we added one RCT of Cerebrolysin-like agent Cortexin, which contributed 272 participants. We used the same approach for risk of bias assessment that was re-evaluated for the previous update: we added consideration of the public availability of study protocols and reported outcomes to the selective outcome reporting judgement, through identification, examination, and evaluation of study protocols. For the Cerebrolysin studies, we judged the risk of bias for selective outcome reporting to be unclear across all studies; for blinding of participants and personnel to be low in three studies and unclear in the remaining four; and for blinding of outcome assessors to be low in three studies and unclear in four studies. We judged the risk of bias for generation of allocation sequence to be low in one study and unclear in the remaining six studies; for allocation concealment to be low in one study and unclear in six studies; and for incomplete outcome data to be low in three studies and high in the remaining four studies. The manufacturer of Cerebrolysin supported three multicentre studies, either totally, or by providing Cerebrolysin and placebo, randomisation codes, research grants, or statisticians. We judged two studies to be at high risk of other bias and the remaining five studies to be at unclear risk of other bias. We judged the study of Cortexin to be at low risk of bias for incomplete outcome data and at unclear risk of bias for all other domains. All-cause death: Cerebrolysin or Cortexin probably result in little to no difference in all-cause death (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.65 to 1.41; 6 trials, 1689 participants; moderate-certainty evidence). None of the included studies reported on poor functional outcome, defined as death or dependence at the end of the follow-up period, early death (within two weeks of stroke onset), quality of life, or time to restoration of capacity for work. Only one study clearly reported on the cause of death: cerebral infarct (four in the Cerebrolysin and two in the placebo group), heart failure (two in the Cerebrolysin and one in the placebo group), pulmonary embolism (two in the placebo group), and pneumonia (one in the placebo group). Non-death attrition (secondary outcome): Cerebrolysin or similar peptide mixtures may result in little to no difference in non-death attrition, but the evidence is very uncertain, with a considerable level of heterogeneity (RR 0.72, 95% CI 0.38 to 1.39; 6 trials, 1689 participants; very low-certainty evidence). Serious adverse events (SAEs): Cerebrolysin probably results in little to no difference in the total number of people with SAEs (RR 1.16, 95% CI 0.81 to 1.66; 3 trials, 1335 participants; moderate-certainty evidence). This comprised fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38; 3 trials, 1335 participants; moderate-certainty evidence) and an increase in the total number of people with non-fatal SAEs (RR 2.39, 95% CI 1.10 to 5.23; 3 trials, 1335 participants; moderate-certainty evidence). In the subgroup of dosing schedule 30 mL for 10 days (cumulative dose 300 mL), the increase was more prominent (RR 2.87, 95% CI 1.24 to 6.69; 2 trials, 1189 participants). Total number of people with adverse events: Cerebrolysin or similar peptide mixtures may result in little to no difference in the total number of people with adverse events (RR 1.03, 95% CI 0.92 to 1.14; 4 trials, 1607 participants; low-certainty evidence).

Authors' conclusions: Moderate-certainty evidence indicates that Cerebrolysin or Cerebrolysin-like peptide mixtures derived from cattle brain probably have no beneficial effect on preventing all-cause death in acute ischaemic stroke. Moderate-certainty evidence suggests that Cerebrolysin probably has no beneficial effect on the total number of people with serious adverse events. Moderate-certainty evidence also indicates a potential increase in non-fatal serious adverse events with Cerebrolysin use.

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Conflict of interest statement

LEZ: is a Cochrane director (Cochrane Russia). She was not involved in the editorial process.

TRA: none known.

DN: none known.

KI: none known.

Figures

1

Study flow diagram

2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

1.1. Analysis

Comparison 1: Cerebrolysin or Cortexin versus placebo, Outcome 1: All‐cause death

1.2. Analysis

Comparison 1: Cerebrolysin or Cortexin versus placebo, Outcome 2: Non‐death attrition

1.3. Analysis

Comparison 1: Cerebrolysin or Cortexin versus placebo, Outcome 3: Total number of people with SAEs

1.4. Analysis

Comparison 1: Cerebrolysin or Cortexin versus placebo, Outcome 4: Total number of people with fatal SAEs

1.5. Analysis

Comparison 1: Cerebrolysin or Cortexin versus placebo, Outcome 5: Total number of people with non‐fatal SAEs

1.6. Analysis

Comparison 1: Cerebrolysin or Cortexin versus placebo, Outcome 6: Total number of people with adverse events

2.1. Analysis

Comparison 2: Sensitivity analyses: Cerebrolysin or Cortexin versus placebo, Outcome 1: All‐cause death. Sensitivity 1. Best‐case

2.2. Analysis

Comparison 2: Sensitivity analyses: Cerebrolysin or Cortexin versus placebo, Outcome 2: All‐cause death. Sensitivity 2. Worst‐case

2.3. Analysis

Comparison 2: Sensitivity analyses: Cerebrolysin or Cortexin versus placebo, Outcome 3: All‐cause death. Sensitivity 3. Complete case (missing data excluded)

2.4. Analysis

Comparison 2: Sensitivity analyses: Cerebrolysin or Cortexin versus placebo, Outcome 4: All‐cause death. Sensitivity 4. Risk of bias

Update of

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References

References to studies included in this review

Amiri Nikpour 2014 {published data only}

1. 1. Amiri-Nikpour MR, Nazarbaghi S, Ahmadi-Salmasi B, Mokari T, Tahamtan U, Rezaei Y. Cerebrolysin effects on neurological outcomes and cerebral blood flow in acute ischemic stroke. Neuropsychiatric Disease and Treatment 2014;10:2299-306. [DOI: 10.2147/NDT.S75304] - DOI - PMC - PubMed
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CASTA 2012 {published data only}

1. 1. Bornstein NM. CASTA - the background for the study and protocol design. International Journal of Stroke 2010;5 Suppl 2:50.
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CERE‐LYSE‐1 2012 {published data only}

1. 1. Lang W, Stadler CH, Poljakovic Z, Fleet D, Lyse Study Group. A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy combined treatment with alteplase (rt-PA) and cerebrolysin in acute ischaemic hemispheric stroke. International Journal of Stroke 2012;8(2):95-104. - PubMed
2. 1. NCT00840671. Combined treatment with alteplase (Rt-PA) and cerebrolysin® in acute ischemic hemispheric stroke (CERE-LYSE). clinicaltrials.gov/show/NCT00840671 (first received 10 February 2009).

Cortexin‐Shamalov 2014 {published data only}17707356https://www.elibrary.ru/item.asp?id=17707356

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Ladurner 2005 {published data only}

1. 1. Ladurner G, Gmeinbauer R, Moessler H. Cerebrolysin in acute ischaemic stroke: a randomized, placebo-controlled trial with a neuroprotective agent. Cerebrovascular Diseases 2001;11(4):75.
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Skvortsova 2004 {published data only}

1. 1. Skvortsova VI, Shamalov NA, Stakhovskaya LV, Gubsky LV, Tikhonova IV, Smichkov AS. Cerebrolysin in acute ischaemic stroke: results of randomised, double blind, placebo-controlled study. Cerebrovascular Diseases 2005;19 Suppl 2:76.
2. 1. Skvortsova VI, Stakhovskaia LV, Gubskii LV, Shamalov NA, Tikhonova IV, Smychkov AS. A randomized, double-blind, placebo-controlled study of Cerebrolysin safety and efficacy in the treatment of acute ischemic stroke. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova [Korsakov Journal of Neurology and Psychiatry] 2004;Suppl 11:51-5. - PubMed
3. 1. Skvortsova VI, Stakhovskaya LV, Gubsky LV, Shamalov NA, Tikhonova IV, Smychkov AS. Evaluation of safety and efficacy of cerebrolysin for treating acute ischaemic stroke [Issledovaniye bezopasnosti i effektivnosti tserebrolizina dlya lecheniya ostrogo ishemicheskogo insul’ta]. Рецепт [Prescription] 2007;5(55):94-8.

Xue 2016 {published data only}

1. 1. NCT02149875. Dl-3-n-butylphthalide and cerebrolysin treatment in acute ischemic stroke. clinicaltrials.gov/show/NCT02149875 (first received 29 May 2014).
2. 1. Xue LX, Zhang T, Zhao YW, Geng Z, Chen JJ, Chen H. Efficacy and safety comparison of DL-3-n-butylphthalide and cerebrolysin: effects on neurological and behavioral outcomes in acute ischemic stroke. Experimental and Therapeutic Medicine 2016;11(5):2015-20. - PMC - PubMed

References to studies excluded from this review

Belova 2018 {published data only}

1. 1. Belova LA, Mashin VV, Abramova VV, Slastyon EYu, Belov DV. Efficacy of cortexin in the acute period of hemispheric ischemic stroke [Эффективность кортексина в остром периоде полушарного ишемического инсульта]. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova [Korsakov Journal of Neurology and Psychiatry] 2018;7:30-4. [DOI: ] - PubMed

Bogolepova 2019 {published data only}

1. 1. Bogolepova AN. Possibilities of neurotrophic therapy in early recovery after stroke [Возможности нейротрофической терапии в раннем восстановлении после инсульта]. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova [Korsakov Journal of Neurology and Psychiatry] 2019;119(8):84-9. [DOI: ] - PubMed

CEREC‐Stroke {published data only}

1. 1. ISRCTN15233803. Evaluation of efficacy and safety of Cerebrolysin as add-on therapy in patients with acute stroke after failed recanalisation therapy. https://www.isrctn.com/ISRCTN15233803 (first received 25 May 2020). [DOI: ]
2. 1. Poljakovic Z, Supe S, Ljevak J, Starcevic K, Peric I, Blazevic N, et al. Efficacy and safety of Cerebrolysin after futile recanalisation therapy in patients with severe stroke. Clinical Neurology and Neurosurgery 2021;207:106767. [DOI: 10.1016/j.clineuro.2021.106767] [PMID: ] - DOI - PubMed

Gharagozli 2017 {published data only}

1. 1. Gharagozli K, Harandi AA, Houshmand S, Akbari N, Muresanu DF, Vester J, et al. Efficacy and safety of Cerebrolysin treatment in early recovery after acute ischemic stroke: a randomized, placebo-controlled, double-blinded, multicenter clinical trial. Journal of Medicine and Life 2017;10(3):153-60. - PMC - PubMed
2. 1. IRCT138803272042N1. The efficacy of cerebrolysin in the treatment of acute ischemic stroke. en.irct.ir/trial/1663 (first received 29 August 2009).

Kurenkova 2014 {published data only}

1. 1. Kurenkova NA, Filatova MS, Popov DV, Makarova LD, Makhankov OV. Efficiency of Cortexin in early rehabilitation of patients with ischemic stroke [Эффективность Кортексина при ранней реабилитации больных с ишемическим инсультом]. Russkii Meditsinskii Zhurnal [Russian Medical Journal] 2014 ;10:748. [RMJ: https://www.rmj.ru/articles/klinicheskaya_farmakologiya/Effektivnosty_Ko...]

NCT04904341 {published data only}

1. 1. NCT04904341. Efficacy of Cerebrolysin treatment as an add-on therapy to mechanical thrombectomy in acute ischemic stroke. https://classic.clinicaltrials.gov/ct2/show/NCT04904341 (first received 27 May 2021). [CLINICALTRIALS.GOV IDENTIFIER: NCT04904341]

Slyusar 2021 {published data only}

1. 1. Slyusar O, Maximov I, Babaskina L, Lobuteva L. Ineffective drugs: Cerebrolysin and piracetam. Research Journal of Pharmacy and Technology 2021;14:2643-8. [DOI: 10.52711/0974-360X.2021.00466] - DOI

References to ongoing studies

CEREHETIS {published data only}

1. 1. ISRCTN87656744. Cerebrolysin to prevent intracranial bleeding after intravenous thrombolysis (blood clot) in patients with ischemic stroke. https://www.isrctn.com/ISRCTN87656744 (first received 16 February 2021). [DOI: ]
2. 1. Kalinin M, Khasanova D. Cerebrolysin as an early add-on to reperfusion therapy: risk of hemorrhagic transformation after ischemic stroke (CEREHETIS). A prospective, randomized, active control, multicenter pilot study. European Stroke Journal 2021;6(1 Suppl):35. [DOI: 10.1177/23969873211034932] - DOI - PMC - PubMed

CERE‐REHA‐RU/01 {published data only}

1. 1. CERE-REHA-RU/01. Double-blind placebo-controlled multi-centre randomised parallel group clinical study of phase IV on effectiveness of adding cerebrolysin to standard rehabilitation complex interventions in patients with ischaemic stroke. grls.rosminzdrav.ru/CIPermissionMini.aspx?CIStatementGUID=70440249-c5c0-... (first received 19 January 2015).

GP20011‐P4‐32 {published data only}

1. 1. GP20011-P4-32. Multicenter, double-blind, placebo-controlled, randomized, in two parallel groups study of the efficacy of Cortexin®, 10 mg, manufactured by GEROPHARM LLC, Russia, in patients in the acute period of ischemic stroke [Многоцентровое двойное слепое плацебо контролируемое рандомизированное в двух параллельных группах исследование эффективности лекарственного препарата Кортексин®, 10 мг, производства ООО «ГЕРОФАРМ», Россия, у пациентов в остром периоде ишемического инсульта]. https://grls.rosminzdrav.ru/CIPermissionMini.aspx?CIStatementGUID=71c142... (first received 29 August 2019).

GP20011‐P4‐36 {published data only}

1. 1. GP20011-P4-36. Multicenter, double-blind, randomized, controlled, parallel study of the therapeutic equivalence of intramuscular and intravenous forms of administration of the drug Cortexin®, 10 mg, produced by GEROPHARM LLC, Russia, in relation to the degree of functional recovery in patients in the acute period of ischemic stroke [Многоцентровое двойное слепое рандомизированное контролируемое параллельное исследование терапевтической эквивалентности внутримышечной и внутривенной форм введения лекарственного препарата Кортексин®, 10 мг, производства ООО «ГЕРОФАРМ», Россия, в отношении степени функционального восстановления у пациентов в остром периоде ишемического инсульта]. https://grls.rosminzdrav.ru/CIPermissionMini.aspx?CIStatementGUID=5ee044... (first received 2 December 2021).

IRCT201406169014N36 {published and unpublished data}

1. 1. IRCT201406169014N36. The effect of cerebrolysin versus placebo on improvement of patients with acute ischemic stroke: a double blinded randomized clinical trial. en.irct.ir/trial/9475 (first received 23 March 2014).

ISRCTN54581790 (ESCAS) {published data only}

1. 1. ISRCTN54581790. Efficacy and safety of Cerebrolysin in the treatment of aphasia after acute ischemic stroke (ESCAS). https://www.isrctn.com/ISRCTN54581790 (first received 29 April 2020). [DOI: ]

ISRCTN88122184 (CODEC) {published data only}

1. 1. ISRCTN88122184. Can treatment with Cerebrolysin improve recovery after acute ischemic stroke? https://www.isrctn.com/ISRCTN88122184 (first received 29 April 2020). [DOI: ]

NCT05124353 {published data only}

1. 1. NCT05124353. Evaluation of the effect of early administration of neuroprotective drug (Cerebrolysin) on the outcome of patients with acute ischemic stroke undergoing endovascular therapy. https://clinicaltrials.gov/ct2/show/record/NCT05124353 (first received 17 November 2021).

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1. 1. Ziganshina LE, Abakumova T, Kuchaeva A. Cerebrolysin for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No: CD007026. [DOI: 10.1002/14651858.CD007026.pub2] - DOI - PubMed

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