Bergen, Norway - The Western Norway B-Vitamin Intervention Trial (WENBIT), showing no benefit of either folate with vitamin B₁₂ or vitamin B₆ in patients with established heart disease, is now published in the August 20, 2008 issue of the Journal of the American Medical Association [1]. First presented at the European Society of Cardiology Congress 2007 by Dr Marta Ebbing (Haukeland University Hospital, Bergen, Norway), as reported by heartwire, the trial is the latest in a series of studies suggesting that B-vitamin supplementation is not justified as secondary prevention in heart disease and that its intended target, homocysteine, is a marker of CHD, rather than a "modifiable cause" of heart disease.

Dr Marta Ebbing

Commenting on the published study to heartwire, Ebbing pointed out that the rigorous design of the WENBIT study makes the results an important addition to the field. Patients underwent coronary angiography before entering the study, were not already taking B vitamins, and Norway, unlike many other countries, does not have folic-acid fortification of foods.

"WENBIT confirms and adds further evidence to results from previously published and similar homocysteine-lowering B-vitamin trials in populations with established or at increased risk of cardiovascular disease," she said.

In WENBIT, 3096 CHD patients were randomized in a 2x2 factorial design to one of four groups to receive a daily oral dose of folic acid (0.8 mg) plus vitamin B₁₂ (0.4 mg) and vitamin B₆ (40 mg); folic acid with vitamin B₁₂ alone; vitamin B₆ alone; or placebo. Homocysteine levels declined by about 30% in the folic-acid/B₁₂ group at one year; the trial, however, was terminated early after results from the NORVIT trial suggested a possible increase in cancer risk with B-vitamin supplementation. After a median follow-up of 38 months, there was no significant difference in the risk of death or major cardiovascular events among the four groups.

But like the NORVIT trial before it, WENBIT hinted at a possible cancer risk—a worrying trend, given that several Western countries have or are considering mandatory folic-acid fortification of staple foods, including cereals, spreads, and flour, to prevent neural-tube defects in babies.

"Both in NORVIT and in WENBIT there was a numerically larger incidence of cancer in the groups treated with folic acid and vitamin B₁₂, and although this could be due to chance, the possible harmful effects of folic-acid treatment/supplementation on cancer development should be explored," Ebbing told heartwire. Researchers in NORVIT and WENBIT are currently working to provide combined results from an extended follow-up of the almost 7000 patients who participated in these trials to explore such possible harmful short- and long-term effects from the intervention.

Furthermore, she said, the B-Vitamin Trialists Treatment Collaboration is planning to collaborate on a meta-analysis of results from completed and ongoing B-vitamin intervention trials. "Incident cancers will be one of the clinical end points in this analysis," she said. 

There is also some suggestion that the incidence of stroke is actually reduced by folic acid/vitamin B₁₂, and this potential effect may also warrant further scrutiny, the WENBIT investigators note.

Dr Salim Yusuf (McMaster University, Hamilton, ON), who discussed the trial when it was first presented last year, pointed out that results from the VITATOPS trial (8000 stroke patients) and the SEARCH trial in 12 000 heart-disease patients will more than double the total database on homocysteine lowering. Echoing Ebbing et al's conclusions, Yusuf stated: "There is no reason now to lower homocysteine levels, but it is still too early to write off the hypothesis completely."