Previous studies have indicated an association between elevated levels of total homocysteine and stroke and heart disease, according to background information in the article. Folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12) reduce plasma homocysteine levels. The effectiveness of homocysteine-lowering therapy to reduce the risk of stroke has not been confirmed by randomized trials.
James F. Toole, M.D., of Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues conducted a double-blind randomized controlled trial from September 1996 to May 2003 to determine whether high doses of folic acid, vitamin B6, and vitamin B12, reduce the risk of an additional stroke over a 2-year period, compared with low doses of these vitamins. The study included 3,680 adults who had experienced a nondisabling stroke. It was conducted at 56 university-affiliated hospitals, community hospitals, private neurology practices, and Veterans Affairs medical centers across the United States, Canada, and Scotland.
Patients were randomly assigned to receive once-daily doses of the high-dose formulation (n = 1827), containing 25 mg of vitamin B6, 0.4 mg of vitamin B12, and 2.5 mg of folic acid; or the low-dose formulation (n = 1853), containing 200 micrograms of vitamin B6, 6 micrograms of vitamin B12, and 20 micrograms of folic acid.
Mean reduction of total homocysteine was greater in the high-dose vitamin group than in the low-dose group, but there was no treatment effect on any end point. The chance of an event (stroke, CHD [coronary heart disease] or death) within 2 years was 18.0 percent in the high-dose group and 18.6 percent in the low-dose group. The risk of ischemic stroke within 2 years was 9.2 percent for the high-dose and 8.8 percent for the low-dose groups.
However, the authors did discover that "there was a persistent and graded association between baseline total homocysteine level and outcomes. A 3-micromol/liter lower total homocysteine level was associated with a 10 percent lower risk of stroke, a 26 percent lower risk of CHD events, and a 16 percent lower risk of death in the low-dose group and a nonsignificantly lower risk in the high-dose group by 2 percent for stroke, 7 percent for CHD events, and 7 percent for death."
"In summary, [this] trial showed that moderate reduction of total homocysteine level after ischemic stroke had no effect on vascular outcomes during the 2 years of follow-up. However, because of the consistent findings of an association of total homocysteine level with vascular risk, further exploration of the hypothesis is warranted and longer trials in different populations with elevated total homocysteine may be necessary," the researchers conclude.
Editor's Note: This trial was supported by the National Institute of Neurological Disorders and Stroke. The raw materials for the vitamins were supplied by Roche Inc, Paramus, N.J.
EDITORIAL: THE CHALLENGE OF STROKE PREVENTION
In an accompanying editorial, Daniel F. Hanley, M.D., of Johns Hopkins Medical Institutions, Baltimore, examines the topic of stroke prevention.
"Smoking cessation, exercise, and blood pressure reduction are all appropriate and important stroke risk reduction interventions. Even more evidence is now available that aggressive treatment of these individual risk factors leads to stroke reduction. Despite knowledge of benefit, clinicians apparently have not yet accepted the need to aggressively optimize the medical and behavioral factors that lead to risk reduction.
"One research avenue worth strong consideration is to find novel means to address established, unameliorated stroke risk factors with validated treatment regimens. Such an approach would have to address multiple factors simultaneously but should be explored to improve the period of independent living for the aging population at risk of stroke," he writes.
(JAMA. 2004;291:621-622. Available post-embargo at JAMA.com.)
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