Folic acid-based multivitamin therapy to prevent stroke: the jury is still out.

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There is a large body of observational and laboratory evidence suggesting but not proving that increasing plasma concentrations of total homocysteine (tHcy) is a causal risk factor for atherothromboembolic ischemic stroke and other vascular events.1–9 Recent publication of the results of the landmark Vitamins in Stroke Prevention (VISP) Trial is the first evidence from a large randomized controlled trial (RCT) of the effect of lowering tHcy via folic acid–based multiple B vitamin supplementation on the incidence of “hard” clinical events, such as recurrent stroke, in patients with recent ischemic stroke.10,11 In contrast to what was expected from the epidemiological evidence, the VISP Trial did not identify a significant treatment effect of lowering tHcy by vitamin therapy on recurrent stroke, coronary events, or death, despite confirming a consistent and graded association between baseline tHcy and vascular risk (particularly the probability of stroke over time).11 Recruiting primarily from North America, VISP enrolled 3680 recent (3 to 120 days) survivors of nondisabling, noncardiogenic, ischemic stroke with baseline tHcy above the 25th percentile of the North American stroke population into a double-blind, randomized comparison of high versus low doses of a combination of 12 different vitamins, including folic acid, vitamin B12, vitamin B6, and riboflavin, which are cofactors for enzymes responsible for metabolizing homocysteine.11 After 2 years of follow-up, there was no significant difference in the cumulative incidence of the primary outcome event of recurrent cerebral infarction: 8.4% of 1814 patients who were allocated to high-dose multivitamins [including 2.5 mg of folic acid, 0.4 mg of vitamin B12, and 25 mg of vitamin B6] versus 8.1% of 1835 patients allocated to low-dose multivitamins [including 0.02 mg of folic acid, 0.006 mg of vitamin B12, 0.2 mg of vitamin B6 …