"If the results we have obtained are replicated in a large prospective trial, the neuroprotective drug, citicoline, may revolutionize the treatment of acute stroke," says the study's senior author Antoni Dávalos, M.D., Ph.D., chairman of the department of neurology at Hospital Universitari de Girona Doctor Josep Trueta in Girona, Spain.
Neuroprotectants are drugs that potentially could stop stroke damage and improve recovery. However, no neuroprotective drug has been effective. That may be because most studies had too few patients to show positive results, Dávalos says. This is the first systemic review to find positive results with a neuroprotective agent.
Dávalos and colleagues performed a meta-analysis of four prospective randomized clinical trials in which six weeks of citicoline treatment was compared to placebo in patients who had suffered an acute ischemic stroke. In a meta-analysis, results of clinical trials are pooled, allowing doctors to see trends that may not be apparent in smaller individual trials. The trials had used three oral doses of citicoline: 500, 1,000 or 2,000 milligrams (mg).
Patient recovery rates at three months were assessed using three standard scales: the Barthel Index, which measures ability to engage in everyday living activities; the Rankin scale, which measures global recovery, and the National Institutes of Health Stroke scale, which measures neurological functioning including a patient's visual capacity, speech and orientation.
Altogether, 583 patients received placebo and 789 were given citicoline. Patients' average age was 68; about half were male; and four-fifths were white. Average time-to-treatment from symptom onset was about 14.5 hours in both groups.
By three months, 25.2 percent of citicoline-treated patients had completely recovered, compared with 20.2 percent of placebo-treated patients. Compared to placebo, six weeks of oral citicoline treatment increased the odds of complete recovery by 33 percent. The dose showing the largest difference from placebo was 2,000 mg, with 27.9 percent of patients achieving recovery. The higher dose increased the odds of a favorable outcome by 38 percent compared to people treated with placebo.
Dávalos says there was an absolute risk reduction of 5 percent, meaning that for every 20 patients treated, one will achieve complete recovery.
"Even though 5 percent may seem like a small difference in recovery rate, the impact of this drug on stroke therapy may be great as its safety profile provides a favorable risk-to-benefit ratio," Dávalos says. "Our goal is to give patients back their independence and their ability to engage in daily living activities, and that's what we did."
Ischemic stroke occurs when a blood clot plugs an artery to the brain, cutting off the supply of oxygen and nutrients to nearby brain cells. As the cells die off, large amounts of chemicals that can poison surrounding cells are released.
Researchers found that citicoline packs a one-two punch against stroke, blocking this chain reaction, while also facilitating the repair of damaged brain cells.
Each year, about 600,000 Americans have a new or recurrent stroke, according to the American Heart Association. Ischemic strokes are the most common.
Almost all patients who suffer a stroke potentially could be treated with oral citicoline, Dávalos says. In contrast, the drug currently approved by the U.S. Food and Drug Administration to treat stroke is the clot buster tissue plasminogen activator (tPA). However, only about 2 percent of stroke patients receive tPA because it must be given within three hours of symptom onset. Citicoline can be given up to 24 hours after stroke onset and has no more side effects than placebo, Dávalos says.
The overall frequency of side effects was similar in the treated and placebo groups, though those who got citicoline were slightly more likely to suffer anxiety and leg swelling and those who got placebo were slightly more likely to be depressed or have incontinence.
There was no difference in death rates between the two groups. The trial was funded by Grupo Ferrer of Barcelona, which makes the drug, and Interneuron Pharmaceuticals of Lexington, Mass., which holds rights to the drug in the United States.
Co-authors are José Castillo, M.D., Ph.D.; José Álvarez-Sabín, M.D., Ph.D.; Julio J. Secades, M.D., Ph.D.; Joan Mercadal, B.S.; Sonia López, B.S.; Erik Cobo, M.D., Ph.D.; Steven Warach, M.D., Ph.D.; David Sherman, M.D.; Wayne M. Clark, M.D.; and Rafael Lozano, M.D.
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