Folic Acid Reduces the Risk of a First Heart Attack by 15%
Results from genetic epidemiological studies suggest that raised serum homocysteine is a cause of ischaemic heart disease, but the results of randomised trials suggest otherwise. We aimed to update meta-analyses on each type of study using the latest published data and test a hypothesis based on antiplatelet therapy use in the trials to explain the discrepancy.
Methods and Findings
Meta-analyses of ischaemic heart disease using (i) 75 studies in which the prevalence of a mutation (CT) in the MTHFR gene (which increases homocysteine) was determined in cases (22,068) and controls (23,618), and (ii) 14 randomised trials (39,597 participants) of homocysteine lowering and ischaemic heart disease events. The summary estimates from the two analyses were compared. Meta-analysis of the MTHFR studies showed a statistically significantly increased risk of ischaemic heart disease in TT compared with CC homozygotes; odds ratio 1.16 (1.04 to 1.29) for a 1.9 µmol/L homocysteine difference (TT minus CC). Meta-analysis of randomised trials showed no significant reduction in IHD risk from folic acid; relative risk 1.00 (0.93 to 1.08), despite a reduction in homocysteine of 3.3 µmol/L. There was a statistically significant difference in risk reduction between the 5 trials with the lowest prevalence of antiplatelet therapy (60% on average, usually aspirin), RR 0.93 (0.84 to 1.05) and the 5 trials with the highest prevalence (91% on average), RR 1.09 (1.00 to 1.19), p = 0.037 for the difference.
Discordant results from MTHFR studies and randomised trials could be explained by aspirin reducing or negating the anti-platelet effect of lowering homocysteine. On this basis, folic acid would have a role in the primary prevention of ischaemic heart disease, when aspirin is not taken routinely, but not in secondary prevention, when it is routine.
From press release:
A perplexing medical paradox now has an explanation according to research undertaken at Barts and The London School of Medicine and Dentistry and published in the current issue of the Public Library of Science. The paradox is that taking folic acid, a B vitamin, lowers homocysteine in the blood which, epidemiological evidence indicates, should lower the risk of heart attack, but clinical trials of folic acid have not shown the expected benefit.
The explanation is surprisingly simple; lowering homocysteine prevents platelets sticking, which stops blood clots…something aspirin also does, so if people in the trials were already taking aspirin there would be no extra benefit in lowering homocysteine with folic acid. Aspirin was in fact widely used by participants in the trials because they were mainly conducted in patients who had already had a heart attack or other cardiovascular diseases.
Research led by Dr David Wald at the Wolfson Institute of Preventive Medicine at Barts and The London School of Medicine and Dentistry showed that there was a difference in the reduction in heart disease events between the five trials with the lowest aspirin use (60 per cent of the participants took aspirin) and the five trials with the highest use (91 per cent took aspirin). The observed risk reduction was six per cent but it would have been 15 per cent if no one had been taking aspirin. Research was based on 75 epidemiological studies involving about 50,000 participants and clinical trials involving about 40,000 participants.
"The explanation has important implications," said Dr David Wald, the lead author of the paper. "The negative clinical trial evidence should not close the door on folic acid -- folic acid may still be of benefit in people who have not had a heart attack because they will generally not be taking aspirin."
David S. Wald*, Joan K. Morris, Nicholas J. Wald.
Reconciling the Evidence on Serum Homocysteine and Ischaemic Heart Disease: A Meta-Analysis
Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine,