This multicenter, double-blind, randomized, controlled clinical trial has been designed to determine whether the addition of a multivitamin with high dose folic acid, pyridoxine, and cyanocobalamin to best medical management and risk factor modification reduces recurrent cerebral infarction (primary endpoint) and myocardial infarction (secondary endpoint) in patients with a first nondisabling cerebral infarction (NDCI) who have elevated homocyst(e)ine levels. The fundamental eligibility criteria are the occurrence of a first-ever NDCI within 30 days prior to randomization and homoeyst(e)ine >10.5 nmo1/m1 at screening visit. Patients will be randomly assigned to receive a daily multivitamin containing, in addition to standard multivitamins, a high or low dose of folic acid, pyridoxine, and cyanocobalamin. Randomized patients will also receive a methionine loading test. All patients will receive best management for risk factor reduction. The study is designed to recruit 3600 patients (1800 in each group) over a 2-year-period for 80% power for detection of a 30% treatment effect. Follow-up continues until recurrent stroke, death, or a maximum of 2 years. Analysis will be in terms of original randomization (intent-to-treat analysis) using the log-rank test of difference in survival-without-endpoint curves. The incidence of second stroke in patients who have had a first stroke is between 7-10% per year. Myocardial infarction adds a major increment to morbidity and mortality. Because homocyst(e)ine may be a major contributor to the etiology of atherothrombotic disease and is an independent risk factor for these complications, its reduction by appropriate intervention 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 risk factor reduction customary 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 in patients who are aspirin resistant. The long term effects and putative toxicity to vitamin supplementation will be delineate.
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