Citicoline Provides No Benefit in Acute Ischemic Stroke

Daniel M. Keller, PhD

June 15, 2012

June 15, 2012 (Lisbon, Portugal) — Adding to a long line of negative study results for potential neuroprotective agents, the International Citicoline Trial on acUte Stroke (ICTUS) could not confirm any efficacy of this agent in the treatment of acute ischemic stroke.

Antoni Dávalos, MD, PhD, from the Hospital Universitari Germans Trias i Pujol in Badalona, Spain, presented the results of this randomized, placebo-controlled, double-blind, sequential clinical trial at the XXI European Stroke Conference (ESC).

Oral citicoline (cytidine-5'-diphosphocholine) had previously shown some positive results in single trials and in a meta-analysis for functional and neurologic recovery. It is an intermediate in the generation of phosphatidylcholine from choline in the body and is sold over the counter in many countries.

ICTUS investigated the effects of citicoline, 2000 mg/d, vs placebo on the recovery of patients with moderate to severe ischemic stroke at 3 months. After a stroke, citicoline, 1000 mg, was infused intravenously twice daily for 3 days, followed by oral citicoline to 6 weeks.

The study enrolled patients 18 years or older with an ischemic stroke referable to the territory of the middle cerebral artery who could receive the drug within 24 hours of symptom onset. They had a baseline National Institutes of Health Stroke Scale (NIHSS) score of 8 or greater, with at least 2 points from the motor sections and a prestroke modified Rankin Scale (mRS) score of 0 or 1. Tissue plasminogen activator (tPA) was allowed up to 4.5 hours from stroke onset.

The intention-to-treat populations assigned to citicoline (n = 1148) and to placebo (n = 1150) were well matched at baseline for age (mean, 73 years); sex (half male); NIHSS score (median, 15); time from onset to treatment (7 hours); and other demographic, treatment, and comorbidity characteristics.

In an intention-to-treat analysis, global recovery at 90 days, measured by combining favorable responses on 3 outcomes scales, did not differ between the citicoline and placebo groups (odds ratio [OR], 1.03; 95% confidence interval [CI], 0.86 - 1.25). No differences were found for the individual scales. Shift analyses of the mRS scores at 90 days also yielded very similar results for the 2 cohorts (OR, 1.02; 95% CI, 0.88 - 1.19).

Similar results were found when the data were analyzed by using only the patients who were treated per protocol: that is, there were no significant differences between groups on any of the measures.

A few subgroups appeared to benefit from citicoline: individuals not receiving tPA vs those who did (P = .041), those older than age 70 years vs those 70 years or younger (P = .001), and those with a baseline NIHSS score of 8 to 14 vs those with a higher score (P = .021).

Safety measures did not differ between the citicoline and placebo groups. The 90-day mortality rate was about 20% in each group (P = .31); symptomatic intracerebral hemorrhage (ICH), 6.0% and 7.9% (P = .25); any ICH, 22% (P = .98); and neurologic deterioration, 16.9% and 18.5%, respectively.

Dr. Dávalos concluded that the trial failed to confirm the efficacy of citicoline in moderate to severe ischemic stroke but that some subgroups may benefit. Citicoline had no effect on the hemorrhagic risk from tPA and was equivalent to placebo in safety and tolerability.

Interest Waning

Michael Hennerici, MD, professor and head of the Department of Neurology at the University of Heidelberg and at Mannheim Hospital in Mannheim, Germany, and chairman of the European Stoke Conference, commented to Medscape Medical News that he knows of some ongoing studies of neuroprotective agents, but interest has waned because many trials have failed to show benefits.

"These things are mainly pharmaceutical company driven," he said, including this study. "And the interest of your pharmaceutical companies has declined, of course... the results were always negative."

Dr. Hennerici said several mechanisms are at work in ischemia: genetic mechanisms, radical scavengers, peroxidase scavengers, receptor antagonists, and others.

"I'm convinced that as long as you just look for a neuroprotective agent, you are very unlikely to see a major effect," he said. "If you combine it with a revascularization methodology, it may be different. Or if you identify the high-risk patient and pretreat him with the drug... there may also be a bigger chance [of success]."

At this point, he said he puts more faith in investigations of hypothermia. In Europe, a large multicenter trial of hypothermia within 6 hours stroke onset is ongoing. "And this will be an interesting issue because we know that hypothermia is good for the brain," he said.

Dr. Dávalos has received financial compensation from Ferrer Grupo as chairman of the ICTUS steering committee. He has also received honoraria for consultancy, lectures, and advisory board meetings from ev3-Covidien, Lundbeck, and Ferrer Group. Dr. Hennerici was not involved in the study and has disclosed no relevant financial relationships.

XXI European Stroke Conference (ESC). Presented May 23, 2012.

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