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David S. Wald, MRCP; Lucy Bishop, MRCP; Nicholas J. Wald, DSc(Med); Malcolm Law, FRCP; Enid Hennessy, MSc; Donald Weir, FRCP; Joe McPartlin, PhD; John Scott, ScD

Arch Intern Med. 2001;161:695-700.

Background  Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear.

Methods  We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued.

Results  Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 µmol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical.

Conclusions  A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

From the Department of Cardiology, St Richard's Hospital, Chichester, West Sussex, England (Drs D. Wald and Bishop); Wolfson Institute of Preventive Medicine, London, England (Drs N. Wald and Law and Ms Hennessy); Department of Clinical Medicine, St James's Hospital, Dublin, Ireland (Drs Weir and McPartlin); and Department of Biochemistry, Trinity College, Dublin (Dr Scott).

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