"Since folic acid reduces homocysteine concentrations, to an extent dependent on background folate levels, it follows that increasing folic acid consumption will reduce the risk of heart attack and stroke by an amount related to the homocysteine reduction achieved," wrote lead author David Wald in the British Medical Journal.
A range of studies has linked increased blood levels of the amino acid homocysteine to an increased risk of cardiovascular disease (CVD). It has been suggested that by lowering the levels of homocysteine in the blood with B-vitamins, people could cut the risk of CVD.
However, a number of high profile randomised intervention trials have reported negative or null effects, most notably the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), the Heart Outcomes Prevention Evaluation (HOPE) 2 trial and the Norwegian Vitamin (NORVIT) trial reported that B-vitamin supplements did lower homocysteine levels but did not reduce the risk of certain cardiovascular diseases.
"If the only evidence available were the trial results, we would still be in the dark," said Wald.
Reviewing the evidence, Wald and his colleagues from the Wolfson Institute for Preventive Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry report that while such randomized trials are important, they are not the only source of evidence.
Indeed, reviewing cohort studies led them to state that a three micromole per litre decrease in serum homocysteine levels, said to be achievable with a daily folic acid intake with 0.8 milligrams, lowers the risk of heart attack and stroke by 15 and 24 per cent.
Moreover, some randomised trials have reported similar effects, but the reviewers state: "Folic acid is expected to reduce cardiovascular disease events by only about 10-15 per cent (compared, for example, to about an 80 per cent reduction in neural tube defects from taking five millgrams folic acid daily)."
In studies looking at genetic mutations of the methylenetetrahydrofolate reductase (MTHFR) gene, which affects one in ten people, influences folate metabolism and is associated with increased homocysteine levels, the researchers report that high homocysteine levels were associated as causal for the risk of stroke.
"The dose-response relation in the genetic studies is particularly relevant in suggesting a causal effect," wrote the reviewers.
"The summary estimate from the trials is consistent with a short term protective effect of 12 per cent on ischaemic heart disease events and 22 per cent on stroke, or a larger long terms effect.
"We therefore take the view that the evidence is now sufficient to justify action on lowering homocysteine concentrations, although the position should be reviewed as evidence from on-going trials emerges," they concluded.
It should be noted that three of the four reviewers report an interest in "Polypill", a cocktail of compounds, including statins, folic acid, aspirin, and three blood pressure lowering drugs marketed as a way of reducing the risk of mortality from heart attack and stroke by 80 per cent.
Folate is found in foods such as green leafy vegetables, chick peas and lentils, and an overwhelming body of evidence links has linked folate deficiency in early pregnancy to increased risk of neural tube defects (NTD) - most commonly spina bifida and anencephaly - in infants.
This connection led to the 1998 introduction of public health measures in the US and Canada, where all grain products are fortified with folic acid - the synthetic, bioavailable form of folate.
While preliminary evidence indicates that the measure is having an effect with a reported 15 to 50 per cent reduction in NTD incidence, parallel measures in European countries, including the UK and Ireland, are still on the table.
The main reason not to proceed that is cited by those not in favour of the measure is that upping folate levels across the entire population may mask a form of aenemia in elderly people that is cause by vitamin B12 deficiency, and can cause dementia.
Source: British Medical Journal Volume 333, 25 November 2006, Pages 1114-1117 Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence
Authors: David Wald, Joan Morris, Malcolm Law, Nicholas Wald