Citicoline for treating people with acute ischemic stroke

Review question
What is the clinical benefit and harm of citicoline compared with placebo or other standard treatment for treating people with acute ischemic stroke?

Background
Acute ischemic stroke is defined as a sudden episode of disturbance of brain function caused by a blockage in the blood vessels of the brain. It is the leading cause of long-lasting disability and the second major cause of death. Citicoline is a substance that may prevent the death of brain cells located close to the area of brain damage.

Search date
Searching was completed on 29 January 2020

Study characteristics
We included randomized controlled trials, both published and unpublished. We did not apply any limitation by language, country, or study design. We included people (adults or children) with acute ischemic stroke irrespective of the underlying cause. Stroke was based on the clinical diagnosis confirmed with brain scans. We included trials that compared citicoline with placebo, usual care, or other usual treatment.

Key results
We identified 10 relevant trials that included 4281 participants; six trials were carried out in multiple centers and two were international. We considered most trials to be at high risk of bias and they included small numbers of participants. This raises the risk of over-estimating benefits and under-estimating harms. Trials tested citicoline given either by mouth or by injection. Citicoline did not seem to influence death or disability in daily activities, severe side-effects, functional recovery, or neurological recovery.

Quality of the evidence
Risks of bias, imprecision, and outcome reporting bias all make the quality of evidence low. None of the included trials reported data on quality of life. Researchers poorly reported harms caused by citicoline, so the profile of harms remains unclear.

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.

Read the full 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 strategy: 

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.

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