Epidemiological studies have linked increased blood levels of homocysteine to an increased risk of cardiovascular disease (CVD). It has been suggested that by lowering the levels of homocysteine in the blood, people could cut the risk of CVD.
The two new studies, the Heart Outcomes Prevention Evaluation (HOPE) 2 trial and the Norwegian Vitamin (NORVIT) trial, looked at the effects of B-vitamin supplements for patients recovering from heart attacks or suffering from heart disease.
Published on-line in the prestigious New England Journal of Medicine (doi: 10.1056/NEJMoa060900), the HOPE 2 trial randomly assigned 5522 patients with heart disease or diabetes to receive either a combination of 2.5 mg of folic acid, 50 mg of vitamin B6 and 1mg of vitamin B12, or a placebo.
3982 patients were from Canada and the US (countries with folate fortification programs) and 1540 patients were from Western Europe, Brazil and Slovakia (countries with no compulsory fortification program).
Mandatory fortification of certain food with folic acid was introduced in the US and Canada to reduce the occurrence of birth defects, and has been successful in cutting the number of children born with neural tube defects by over 25 per cent.
Patients were tested every six months for five years, with blood samples taken at the start, after two years, and at the end of the study.
"In our study, daily administration of the combination of folic acid, vitamin B6, and vitamin B12 lowered homocysteine levels significantly but did not reduce the incidence of death from cardiovascular causes, myocardial infarction, and stroke," wrote lead author Eva Lonn from Hamilton General Hospital in Ontario, Canada.
Blood levels of homocysteine decreased by 2.4 micromoles per litre (0.3 milligrams per litre) during the five years of supplementation, while the placebo group's homocysteine levels increased by 0.8 micromoles per litre (0.1 milligrams per litre) during the same period.
The researchers reported that, as expected, the patients from regions without folate fortification showed greater difference between supplements and placebo - 4.1 micromoles per litre (0.6 milligrams per litre) compared to 2.9 micromoles per litre (0.4 milligrams per litre).
Despite decreases in homocysteine levels for the supplementation group, no link was found between B-vitamin intake and the risk of death.
"The risk of death from any cause was similar in the active-[supplement] group and the placebo group," said Lonn.
Interestingly, when subgroups were analysed, the researchers observed that fewer patients from the supplementation group had non-fatal strokes, compared to the placebo group, an effect that did not differ significantly between regions with and without folate fortification of food.
The researchers however were not convinced by the link between B-vitamins and the reduction of non-fatal strokes: "We believe that the apparent beneficial effect of B vitamin supplements on stroke in our trial may represent either an overestimate of the real effect of a spurious result due to the play of chance."
The NORVIT trial reported similar results for the 3749 patients who had suffered an acute heart attack within a week of the start of the randomised trial.
In this trial, supplementation was divided into four groups. The first group received a combination of folic acid (0.8 mg), vitamin B6 (40 mg), and vitamin B12 (0.4 mg). The second group received folic acid (0.8 mg) and vitamin B12 (0.4 mg). The third group received only vitamin B6 (40 mg), and the fourth group received a placebo.
In the group supplemented with all three B vitamins, or with folic acid and B12, the researchers observed a 27 per cent reduction in homocysteine levels (3.5 micromoles per litre).
Supplementation of vitamin B6 alone did not effect total serum homocysteine levels, while the placebo group's levels increased by 0.4 micromoles per litre.
Supporting the results of the HOPE 2 trial, the supplementation with B vitamins did not affect the risks of death from recurrent cardiovascular disease or death. Indeed, taking vitamin B6 alone was linked to a 17 per cent increase in further heart attack.
The main conclusion to draw from the studies appears that the combination of B vitamins for these high risk groups cannot be recommended.
Joseph Loscalzo from Brigham and Women's Hospital in Boston stated the same in an accompanying editorial: "The results lead to the unequivocal conclusion that there is no clinical benefit of the use of folic acid and vitamin B12 (with or without the addition of vitamin B6) in patients with established vascular disease."
The studies also draw into question the link between homocysteine and the risk of CVD, a question raised by Loscalzo. The HOPE 2 researchers proposed that "homocysteine could be a marker, but not a cause, of vascular disease."
It should be made clear however that the results are not applicable to healthy people, a point supported by Dr. Annette Dickinson, consultant and past president of US trade organisation The Council for Responsible Nutrition (CRN).
"While these studies contribute importantly to the research base, they have limited application for the general population. These studies did not test whether B vitamin used by healthy people can help keep them healthy. Vitamins should not be expected to perform like drugs - their greatest promise is in prevention," said Dickinson.
"This is a well-designed and executed trial for the purpose for which it was created. If there is a fundamental flaw, it is in the reasoning that is the underpinning of many clinical trials on nutrient intervention.
We need to remember that [these trials] are not necessarily testing a hypothesis that led us to undertake the trials in the first place. Scientific research does not always provide the yes or no answers that some would like. Our best advice to healthy consumers is not to throw away your vitamins based on the study du jour."