Citicoline for treating people with acute ischemic stroke (Review)

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 showed that citicoline may not increase the proportion of patients with a moderate or lower degree of disability or dependence compared with placebo, according to the Rankin Scale (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 suggested that citicoline results in no difference in functional recovery, according to the Barthel Index, compared 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). Citicoline may not increase the proportion of patients with a minor impairment (according to ≤ 1 scores in the National Institutes of Health Stroke Scale) (5 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). None of the included trials reported data on quality of life. A pre‐planned Trial Sequential Analysis suggested that no more trials may be needed for the primary outcomes. 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, functional recovery, neurological function and severe adverse events, 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.post-print982 K