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June 28, 2010

SEARCH published: No CV benefit on reducing homocysteine

From www.theheart.org

June 22, 2010 | Sue Hughes

Oxford, UK – Substantial long-term reductions in blood homocysteine levels with folic-acid and vitamin-B12 supplementation did not have beneficial effects on vascular outcomes in the large-scale SEARCH trial [1]. But a silver lining of good news from the trial is that the vitamin supplements were not associated with any increase in cancer risk, which had been suggested in a previous study.

The trial, published in the June 23, 2010 issue of the Journal of the American Medical Association, was conducted by a team led by Dr Jane M Armitage (University of Oxford, UK).

Results from SEARCH were first reported by heartwire at the 2008 AHA meeting.

End of an era

Armitage told heartwire that this large randomized trial “rounds off an era of trials with folic acid, which together suggest no benefit in reducing cardiovascular events.”

While there is no doubt about the association between increased homocysteine levels and increased heart disease risk, our results suggest that this is not a causal association.

“This is another example of findings from observational studies leading us up the wrong path. While there is no doubt about the association between increased homocysteine levels and increased heart-disease risk, our results suggest that this is not a causal association. Lowering homocysteine does not reduce that risk. There is probably a third party involved that increases risk of heart disease and increases homocysteine at the same time. So lowering homocysteine should no longer be the focus of our attention,” Armitage commented.

She added: “That is not to say that foods high in folic acid will not be beneficial. Folic acid is found in fruit and vegetables, and these of course are good for you, but not necessarily because they contain folic acid.”

On the cancer findings, Armitage said: “Our cancer results are reassuring. Most other trials have also shown no significant risk of cancer with folic-acid supplementation, but there was one trial that suggested a small increase in risk, which has probably received overselective emphasis. But it is important to be sure, as folate is added to food in some countries and is given to pregnant women to prevent neural-tube defects. While we can never say never, our data do provide reassurance on the risk of cancer. But it would still be good to see longer-term data when considering cancer risk. We had seven-year follow-up in this study, but we are going to continue to follow our patients well into the future to provide even longer-term data.”

While we can never say never, our data do provide reassurance on the risk of cancer.

In the paper, the researchers explain that observational studies have consistently indicated that patients with vascular disease have higher blood levels of homocysteine than do controls, and these differences precede the onset of disease and are independent of other risk factors. Daily supplementation with folic acid typically lowers homocysteine levels by about 25%, and the addition of vitamin B12 lowers it by a further 7%, and as these vitamins are inexpensive, there is considerable interest in using them to reduce the incidence of vascular disease.

They add that no definite protective effects of these vitamins have been seen in seven previous large-scale randomized trials, but it has been unclear whether this was due to insufficient numbers of events, too short a duration of treatment, attenuation of any effects by populationwide folic-acid fortification, or lack of real benefit. However, a subgroup analysis of the HOPE-2 trial and a meta-analysis of other trials have suggested a protective effect on stroke. To look at this issue further, they conducted the SEARCH trial, in which 12 064 UK survivors of MI were randomized to 2-mg folic acid plus 1-mg vitamin B12 daily or matching placebo.
28% reduction in homocysteine

Results showed that allocation to the study vitamins reduced homocysteine by a mean of 3.8 µmol/L (28%). During 6.7 years of follow-up, there was no difference in the primary end point of first major vascular event (coronary death, MI, any revascularization, or stroke) between the two groups. There was also no difference in other major secondary end points or in the incidence of cancer between the two groups.

SEARCH results: Effect of folic acid/vitamin B12 on major end points

End point Foil acid + vitamin B12 (%) Placebo (%) Risk ratio
Primary end pointfirst major vascular event 25.5 24.8 1.04 (0.97-1.12)
Major coronary events 20.4 19.6 1.05 (0.97-1.13)
Stroke 4.5 4.4 1.02 (0.86-1.21)
Noncoronary revascularizations 3.0 2.5 1.18 (0.95-1.46)
Vascular death 9.6 9.3 1.04 (0.92-1.16)
Nonvascular death 6.7 6.5 1.04 (0.90-1.19)
Cancer incidence 11.2 10.6 1.07 (0.96-1.19)
To download table as a slide, click on slide logo above

The authors note that a meta-analysis of individual patient data from eight homocysteine lowering trials (including SEARCH), which has been submitted for publication and includes data on 37 485 individuals, confirms that folic-acid supplementation has no significant effects on major vascular events (RR 1.01) or any of its separate components.

Armitage commented to heartwire: “This meta-analysis gives an even more definitive answer that there is no benefit on heart disease of folic acid and should be the end of this issue,” she said.

On the cancer findings, the researchers explain that there have been concerns that folic acid may play a role in carcinogenesis and suggestions that the introduction of folic-acid fortification in the US was linked to an increase in colorectal-cancer incidence during the late 1990s. While previous trials have shown mixed results in this issue, they state: “By contrast, with more than 1300 incident cancers during up to seven years of treatment with 2-mg folic acid and 1-mg vitamin B12 daily, SEARCH provides no evidence of adverse effects on cancer at any particular site.”

The SEARCH trial was funded by Merck, as it was also evaluating two different doses of simvastatin. Armitage and other coauthors from the University of Oxford declare no financial conflicts, but the university does receive grants from Merck and other pharmaceutical companies to conduct independent research. Coauthor Dr Peter Sleight (University of Oxford) reports receiving speaker or data safety monitoring board fees from Abbott, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, Boehringer Mannheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Knoll, Medscape, Menarini, Merck, Monarch, MSD, Novartis, Pfizer, Pharmacia, Sanofi-Aventis, and Servier.

  1. Armitage J M et al on behalf of the SEARCH Collaborative Group. Effect of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors. JAMA 2010; 303:2486-2494.