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Meta-Analysis
. 2020 Aug 29;8(8):CD013066.
doi: 10.1002/14651858.CD013066.pub2.

Citicoline for treating people with acute ischemic stroke

Arturo J Martí-Carvajal  1   2 , Claudia Valli  3 , Cristina Elena Martí-Amarista  4 , Ivan Solà  5 , Joan Martí-Fàbregas  6 , Xavier Bonfill Cosp  7
Affiliations
Meta-Analysis

Citicoline for treating people with acute ischemic stroke

Arturo J Martí-Carvajal et al. Cochrane Database Syst Rev. .

Abstract

Background: Stroke is one of the leading causes of long-lasting disability and mortality and its global burden has increased in the past two decades. Several therapies have been proposed for the recovery from, and treatment of, ischemic stroke. One of them is citicoline. This review assessed the benefits and harms of citicoline for treating patients with acute ischemic stroke.

Objectives: To assess the clinical benefits and harms of citicoline compared with placebo or any other control for treating people with acute ischemic stroke.

Search methods: We searched in the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS until 29 January 2020. We searched the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. Additionally, we also reviewed reference lists of the retrieved publications and review articles, and searched the websites of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).

Selection criteria: We included randomized controlled trials (RCTs) in any setting including participants with acute ischemic stroke. Trials were eligible for inclusion if they compared citicoline versus placebo or no intervention.

Data collection and analysis: We selected RCTs, assessed the risk of bias in seven domains, and extracted data by duplicate. Our primary outcomes of interest were all-cause mortality and the degree of disability or dependence in daily activities at 90 days. We estimated risk ratios (RRs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We conducted our analyses using the fixed-effect and random-effects model meta-analyses. We assessed the overall quality of evidence for six pre-specified outcomes using the GRADE approach.

Main results: We identified 10 RCTs including 4281 participants. In all these trials, citicoline was given either orally, intravenously, or a combination of both compared with placebo or standard care therapy. Citicoline doses ranged between 500 mg and 2000 mg per day. We assessed all the included trials as having high risk of bias. Drug companies sponsored six trials. A pooled analysis of eight trials indicates there may be little or no difference in all-cause mortality comparing citicoline with placebo (17.3% versus 18.5%; RR 0.94, 95% CI 0.83 to 1.07; I² = 0%; low-quality evidence due to risk of bias). Four trials found no difference in the proportion of patients with disability or dependence in daily activities according to the Rankin scale comparing citicoline with placebo (21.72% versus 19.23%; RR 1.11, 95% CI 0.97 to 1.26; I² = 1%; low-quality evidence due to risk of bias). Meta-analysis of three trials indicates there may be little or no difference in serious cardiovascular adverse events comparing citicoline with placebo (8.83% versus 7.77%; RR 1.04, 95% CI 0.84 to 1.29; I² = 0%; low-quality evidence due to risk of bias). Overall, either serious or non-serious adverse events - central nervous system, gastrointestinal, musculoskeletal, etc. - were poorly reported and harms may have been underestimated. Four trials assessing functional recovery with the Barthel Index at a cut-off point of 95 points or more did not find differences comparing citicoline with placebo (32.78% versus 30.70%; RR 1.03, 95% CI 0.94 to 1.13; I² = 24%; low-quality evidence due to risk of bias). There were no differences in neurological function (National Institutes of Health Stroke Scale at a cut-off point of ≤ 1 points) comparing citicoline with placebo according to five trials (24.31% versus 22.44%; RR 1.08, 95% CI 0.96 to 1.21; I² = 27%, low-quality evidence due to risk of bias). A pre-planned Trial Sequential Analysis suggested that no more trials may be needed for the primary outcomes but no trial provided information on quality of life.

Authors' conclusions: This review assessed the clinical benefits and harms of citicoline compared with placebo or any other standard treatment for people with acute ischemic stroke. The findings of the review suggest there may be little to no difference between citicoline and its controls regarding all-cause mortality, disability or dependence in daily activities, severe adverse events, functional recovery and the assessment of the neurological function, based on low-certainty evidence. None of the included trials assessed quality of life and the safety profile of citicoline remains unknown. The available evidence is of low quality due to either limitations in the design or execution of the trials.

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Conflict of interest statement

Arturo Martí‐Carvajal: none known. Claudia Valli: none known. Cristina Martí‐Amarista: none known. Ivan Solà: none known. Joan Martí‐Fàbregas: none known. Xavier Bonfill Cosp: none known.

Figures

1
1
‐Study flow diagram.
2
2
Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
4
4
Trial Sequential Analysis for citicoline versus placebo or no intervention on all‐cause mortality. The diversity‐adjusted required information size (DARIS) was calculated based on an expected relative risk reduction (RRR) of 14% from proportion event in control (Pc) group of 18.5% with an alpha of 5% and beta of 20%. Cumulative Z‐curve (blue line) reached futility area after seven trials, which means that no more trials are needed.
5
5
Trial Sequential Analysis for citicoline versus placebo or no intervention on degree of disability or dependence in daily activities according to the modified Rankin scale. The diversity‐adjusted required information size (DARIS) was calculated based on an expected relative risk reduction (RRR) of 19% from proportion event in control (Pc) group of 19.95% with an alpha of 5% and beta of 20%. Cumulative Z‐curve (blue line) reached futility area after four trials, which means that no more trials are needed.
1.1
1.1. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 1: All‐cause mortality
1.2
1.2. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 2: All‐cause mortality: subgroup analysis
1.3
1.3. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 3: All‐cause mortality: subgroup analysis
1.4
1.4. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 4: All‐cause mortality: sensitivity analysis: impact of missing outcome data
1.5
1.5. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 5: All‐cause mortality: sensitivity analysis: best‐case scenario
1.6
1.6. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 6: All‐cause mortality: sensitivity analysis: worst‐case scenario
1.7
1.7. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 7: All‐cause mortality: sensitivity analysis: the Gamble‐Hollis analysis
1.8
1.8. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 8: Patients with moderate or lower degree of disability or dependence (according to < 3 scores in the modified Rankin scale)
1.9
1.9. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 9: Patients with moderate or lower degree of disability or dependence (according to < 3 scores in the modified Rankin scale): subgroup analysis
1.10
1.10. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 10: Patients with moderate or lower degree of disability or dependence (according to < 3 scores in the modified Rankin scale): sensitivity analysis: impact of missing outcome data
1.11
1.11. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 11: Patients with moderate or lower degree of disability or dependence (according to < 3 scores in the modified Rankin scale): sensitivity analysis: best‐case scenario
1.12
1.12. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 12: Patients with moderate or lower degree of disability or dependence (according to < 3 scores in the modified Rankin scale): sensitivity analysis: worst‐case scenario
1.13
1.13. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 13: Patients with moderate or lower degree of disability or dependence (according to < 3 scores in the modified Rankin scale): sensitivity analysis: the Gamble‐Hollis analysis
1.14
1.14. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 14: Severe adverse events
1.15
1.15. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 15: Non‐severe adverse events
1.16
1.16. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 16: Functional recovery: assessed with the Barthel Index
1.17
1.17. Analysis
Comparison 1: Citicoline versus placebo or not intervention, Outcome 17: Patients with minor impairment (according to ≤ 1 scores in the National Institutes of Health Stroke Scale)
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Update of

  • doi: 10.1002/14651858.CD013066

References

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