Citicoline in the Treatment of Acute Ischemic Stroke: An International, Randomized, Multicentre, Placebo-Controlled Study (ICTUS Trial)

Study Questions:

What is the efficacy of citicoline for the treatment of acute ischemic stroke?


The investigators undertook a randomized, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralized minimization process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 hours after the onset of symptoms (1000 mg every 12 hours intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2 × 500 mg oral tablets given every 12 hours]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial hemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality.


A total of 2,298 patients were enrolled into the study from November 26, 2006, to October 27, 2011. Thirty-seven centers in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2,298 patients who gave informed consent and underwent randomization, 1,148 were assigned to citicoline and 1,150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2,078 patients. The final randomized analysis was based on data for 2,298 patients: 1,148 in citicoline group and 1,150 in placebo group. Global recovery was similar in both groups (odds ratio, 1.03; 95% confidence interval, 0.86-1.25; p = 0.364). No significant differences were reported in the safety variables or in the rate of adverse events.


The authors concluded that citicoline is not efficacious in the treatment of moderate-to-severe acute ischemic stroke.


This randomized study suggests that citicoline, a potential neurovascular protection and repair agent, while safe, is not efficacious in the treatment of moderate-to-severe acute ischemic stroke. As the trial was rigorously undertaken and was powered to detect an odds ratio of 1.26, it appears that either there is no treatment effect, or there is a decreased magnitude of the estimated treatment effect in previous meta-analyses. Routine clinical use of citicoline in acute ischemic stroke appears to be no longer justified.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Statins

Keywords: Odds Ratio, Stroke, Cytidine Diphosphate Choline, Portugal, Germany, Brain Ischemia, Intracranial Hemorrhages, Patient Selection, Spain, Cardiovascular Diseases, Medical Futility, National Institutes of Health (U.S.), Confidence Intervals, Informed Consent, Tissue Plasminogen Activator

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