Context In observational studies, elevated plasma total homocysteine levels
have been positively associated with ischemic stroke risk. However the utility
of homocysteine-lowering therapy to reduce that risk has not been confirmed
by randomized trials.
Objective To determine whether high doses of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12), given to lower total homocysteine
levels, reduce the risk of recurrent stroke over a 2-year period compared
with low doses of these vitamins.
Design Double-blind randomized controlled trial (September 1996–May 2003).
Setting and Participants 3680 adults with nondisabling cerebral infarction at 56 university-affiliated
hospitals, community hospitals, private neurology practices, and Veterans
Affairs medical centers across the United States, Canada, and Scotland.
Interventions All participants received best medical and surgical care plus a daily
multivitamin containing the US Food and Drug Administration's reference daily
intakes of other vitamins; patients were randomly assigned to receive once-daily
doses of the high-dose formulation (n = 1827), containing 25 mg of pyridoxine,
0.4 mg of cobalamin, and 2.5 mg of folic acid; or the low-dose formulation
(n = 1853), containing 200 µg of pyridoxine, 6 µg of cobalamin,and 20 µg of folic acid.
Main Outcome Measures Recurrent cerebral infarction (primary outcome); coronary heart disease
(CHD) events and death (secondary outcomes).
Results Mean reduction of total homocysteine was 2 µmol/L greater in the
high-dose group than in the low-dose group, but there was no treatment effect
on any end point. The unadjusted risk ratio for any stroke, CHD event, or
death was 1.0 (95% confidence interval [CI], 0.8-1.1), with chances of an
event within 2 years of 18.0% in the high-dose group and 18.6% in the low-dose
group. The risk of ischemic stroke within 2 years was 9.2% for the high-dose
and 8.8% for the low-dose groups (risk ratio, 1.0; 95% CI, 0.8-1.3) (P = .80 by log-rank test of the primary hypothesis of difference
in ischemic stroke between treatment groups). There was a persistent and graded
association between baseline total homocysteine level and outcomes. A 3-µmol/L
lower total homocysteine level was associated with a 10% lower risk of stroke
(P = .05), a 26% lower risk of CHD events (P<.001), and a 16% lower risk of death (P = .001) in the low-dose group and a nonsignificantly lower risk in
the high-dose group by 2% for stroke, 7% for CHD events, and 7% for death.
Conclusions In this trial, moderate reduction of total homocysteine after nondisabling
cerebral infarction had no effect on vascular outcomes during the 2 years
of follow-up. However, the consistent findings of an association of total
homocysteine with vascular risk suggests that further exploration of the hypothesis
is warranted and longer trials in different populations with elevated total
homocysteine may be necessary.