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Analysis And Comment Cardiovascular disease

Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence

BMJ 2006; 333 doi: (Published 23 November 2006) Cite this as: BMJ 2006;333:1114
  1. David S Wald, senior lecturer and consultant cardiologist,
  2. Nicholas J Wald, professor of epidemiology and preventive medicine,
  3. Joan K Morris, reader in medical statistics,
  4. Malcolm Law, professor of environmental and preventive medicine
  1. 1Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and The London, Queen Mary's School of Medicine and Dentistry, London EC1M 6BQ
  1. Correspondence to: D S Wald d.s.wald{at}
  • Accepted 21 September 2006

Increasing intake of folic acid would be a relatively cheap and simple way of reducing heart disease, if it works. Can we draw a definitive conclusion from the current evidence?

Debate remains over whether raised serum homocysteine concentrations cause ischaemic heart disease and stroke and whether folic acid, which lowers homocysteine, will help reduce the risk of these disorders. Different groups of researchers have used the same evidence to reach opposite conclusions.1 2 We examine why the differences have occurred and draw conclusions using evidence from the various types of study used to investigate the relation.

Cohort studies

Meta-analyses of cohort studies show significant positive associations between serum homocysteine concentrations and ischaemic heart disease events (fatal and non-fatal myocardial infarction and sudden cardiac death) and stroke. A 3 µmol/l decrease in serum homocysteine (achievable with 0.8 mg/day folic acid) lowers the risk of myocardial infarction by 15% and stroke by 24%.1 3 These estimates were adjusted for confounding by other cardiovascular risk factors.

Evidence from patients with homocystinuria

Lowering homocysteine concentrations has been shown to have a large effect on cardiovascular disease risk in patients with homocystinuria. Untreated people who are homozygous for this rare genetic disorder have homocysteine concentrations about five times above the average for unaffected people and about a 50% chance of a vascular event by age 30.4 In two studies, homozygous patients taking treatment to reduce homocysteine concentrations had only two vascular events when 59 would have been expected from previous observations in untreated patients.5 6 Although these were not randomised trials, selection bias is unlikely to explain so large a difference. The absence of a threshold in the dose-response relation between homocysteine and cardiovascular disease over a wide range3 7 suggests that lowering moderately raised homocysteine concentrations would also have a preventive effect.

Evidence from genetic polymorphism studies

Moderately raised homocysteine concentrations …

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