This is a multicenter, double-masked, randomized, controlled clinical trial to determine whether the addition of a multivitamin with high dose folic acid, pyridoxine, and cyanocobalamine contributes to best medical management and risk factor modification reduction of recurrent cerebral infarction (primary endpoint) and myocardial infarction (secondary endpoint) in patients with a first non-diabling cerebral infarction (NDCI) and elevated homocysteine levels. The eligibility criteria are occurrence of a first-ever NDCI within 30 days prior to randomization and homocysteine >9.5 nmol/ml at the screening visit. Patients will be randomly assigned to receive a daily multivitamin containing a high or low dose of folic acid, pyridoxine, and cyanocobalamin in addition to standard multivitamins. Patients will also receive a methionine loading test. All patients will receive the best management for risk factor reduction. The study will recruit 3600 patients (1800 in each group) over a 2-year period for 80% power for detection of a 30% treatment effect. Follow-up will continue until recurrent stroke, death, or a maximum of 2 years. Data analysis will use an intent-to-treat analysis using the log-rank test of difference in survival-without-endpoint curves. The incidence of second stroke in patients with a first stroke is between 7-10% per year. Myocardial infarction adds a major increment to morbidity and mortality. Because homocysteine may be a major contributor to the etiology of atherothrombotic disease and an independent risk factor for these conplications, its reduction with vitamin supplements could reduce the impact of recurrent stroke, myocardial infarction and vascular death. This inexpensive intervention has the potential for being added to other customary risk factor reduction therapy. It may substitute for more dangerous and complicated managements which include Warfarin or more expensive therapies such as Ticlopidine which are commonly advocated for secondary prevention of stroke, particularly for patients who experience ischemic symptoms while treated with aspirin. The long-term effects and putative toxicity to vitamin supplementation will be delineated. There are now 56 participating centers. Approximately 1020 patients have been enrolled throughout all centers.
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