Lowering homocysteine levels with folic acid and vitamin B12 supplements does not reduce the risk of cardiovascular events or stroke in patients who have suffered an MI, a major study has concluded.

SEARCH was a randomised controlled trial of 12,064 survivors of MI in the UK. Participants were randomised to 2 mg folic acid and 1 mg vitamin B12 daily or placebo.

The vitamin group achieved a mean reduction in homocysteine of 3.8µmol/L, a 28% reduction from baseline. The follow-up period was 6.7 years with a composite primary endpoint of first major vascular event (coronary death, MI, any revascularisation, or stroke).

The results showed no significant difference in the primary endpoint between the two groups, relative risk (RR) 1.04 (95% CI: 0.97-1.12). Furthermore, there was no significant difference for any of the individual endpoints or deaths from nonvascular causes.

Earlier studies had raised the possibility of increasing cancer risk by lowering homocysteine. This has been refuted by SEARCH with no significant difference seen between the two groups, RR 1.07 (95% CI: 0.96-1.19).

Observational studies had previously shown an association between increased homocysteine levels and increased cardiovascular risk. However, no definite protective effects of lowering homocysteine with folic acid and vitamin B12 supplementation had been demonstrated to date in seven randomised trials.

Commentators had raised questions regarding insufficient numbers of events, short duration of treatment and the possible attenuation of any effects by population-wide folic acid fortification. This had resulted in ongoing uncertainty to which the SEARCH trial hoped to provide a definitive answer.

Therefore, it would appear that SEARCH has finally laid the homocysteine theory to rest. Raised levels may be associated with increased cardiovascular risk but this would not appear to be a causal association.

The authors also noted that a recently submitted meta-analysis of individual patient data from eight homocysteine lowering trials, including SEARCH, with data on 37,485 individuals, confirms that folic acid supplementation has no significant effect on major vascular events, RR 1.01 (95% CI: 0.97-1.05).

I wouldn't stop eating the fruit and vegetables just yet but their beneficial effects on cardiovascular health are unlikely to be produced through folic acid and lowering of homocysteine.

Dr Peter Savill