HOPE 2: can supplementation with folic acid and B vitamins reduce cardiovascular risk?

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Observational data have indicated that raised homocysteine levels could increase an individual's cardiovascular risk. Daily supplementation with folic acid and vitamins B6 and B12 can dramatically lower homocysteine levels and therefore could, in theory, reduce cardiovascular risk.


To find out whether long-term supplementation with folic acid and vitamins B6 and B12 can lower major vascular event risk in individuals at high risk of cardiovascular events.


The multicenter, double-blind, placebo-controlled Heart Outcomes Prevention Evaluation (HOPE) 2 trial prospectively enrolled individuals at least 55 years old with diabetes. Patients had to have additional atherosclerotic risk factors, or previous coronary, cerebrovascular or peripheral vascular disease. The study excluded individuals who were taking greater than 0.2 mg folic acid dietary supplementation daily.


Participants were randomized to 2.5 mg folic acid, 50 mg vitamin B6 and 1 mg vitamin B12 in a combined pill, or placebo daily. Follow-up was by interview every 6 months and folate, vitamin B6, vitamin B12 and total homocysteine levels were recorded at randomization and again at 2 years. Only the total homocysteine measurement was repeated at the end of the study. All analyses were done on the basis of intention to treat.


The main outcome was a composite of stroke, myocardial infarction and cardiovascular-related mortality.


Of the 5,522 patients enrolled, 2,758 received folic acid and vitamins B6 and B12, and 2,764 received placebo. On average participants were followed up for 5 years. At study start, levels of folate, vitamin B6, vitamin B12 and total plasma homocysteine were similar in both treatment groups. After 2 years, the levels had not changed in the placebo group; however, individuals in the supplementation group had approximately double the folate and vitamin B12 levels and approximately four times the vitamin B6 levels, compared with levels at study start. Similarly, at study end, mean homocysteine level had decreased by 2.4 μmol/l in patients receiving supplementation and had increased by 0.8 μmol/l in patients receiving placebo (total difference of 3.2 μmol/l between two groups). There was no significant difference in the composite occurrence of stroke, myocardial infarction and cardiovascular-related death between patients receiving supplementation and the patients receiving placebo (519 [18.8%] versus 547 [19.8%]; relative risk 0.95, 95% CI 0.84-1.07; P=0.41). When analyzed separately there was no difference in death, cardiovascular-related death or rate of myocardial infarction between the two groups; however, supplementation did reduce the occurrence of stroke compared with placebo (111 [4.0%] versus 147 [5.3%]; relative risk 0.75, 95% CI 0.59-0.97; P=0.03).


Although total homocysteine levels and stroke rate were reduced, long-term supplementation with folic acid and vitamins B6 and B12 did not reduce mortality or the incidence of myocardial infarction in high-risk patients with vascular disease.

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