Folic Acid and B Vitamins No Better Than Placebo in Heart Patients and May Cause Harm

Vitamin supplementation with folic acid, vitamin B-6, and vitamin B-12 did not reduce the risk of major cardiovascular outcomes, such as heart attack or stroke, in patients with preexisting cardiovascular disease or after a heart attack according to the results of two studies posted on the web site of the New England Journal of Medicine on Mar. 12, 2006. These studies are available on the Internet (study 1 and study 2).

High levels of homocysteine, like high cholesterol, have been associated with an increased risk of cardiovascular disease and death. Folic acid and B vitamins are known to lower levels of the amino acid homocysteine in the blood. Proponents believed that vitamin supplementation should be used to prevent such events. Often, widely accepted beliefs must be modified in the face of well-done scientific research.

The first of two studies is known as the Heart Outcomes Prevention Evaluation-2, or HOPE-2 for short, was sponsored by the Canadian Institutes of Health Research. This study was a randomized controlled clinical trial — the scientific “gold standard” for determining the effectiveness of medical interventions, including drugs and vitamin supplements.

The HOPE-2 study involved 5,522 patients 55 years of age or older who had existing vascular disease or diabetes. These patients were randomly assigned to receive a daily dose of either 2.5 milligrams of folic acid, 50 milligrams of vitamin B-6, and 1 milligram of vitamin B-12 or a placebo for an average of five years. The researchers’ main interest was the total number of patients who experienced death from cardiovascular causes, heart attacks, or stroke. This is the study’s primary endpoint — the main question about which the study was designed to gather data.

Over the course of the study, as predicted, patients taking the vitamin supplement had decreased homocysteine levels. In patients taking the placebo, homocysteine levels were increased.

At the end of the five years, 18.8 percent of the patients taking the vitamins and 19.8 percent of those given the placebo died from cardiovascular causes, heart attacks, or strokes. The difference between the number of deaths in each group was not statistically significant, meaning that the lower number of deaths in the vitamin group could have been due to chance rather than the effect of the treatment. Compared to the placebo, the vitamins did not significantly decrease the risk death from cardiovascular causes. A similar result was found for heart attacks and stroke.

Of concern was the fact that more patients receiving the vitamins were hospitalized compared to those receiving the placebo for unstable angina (chest pain). The researchers felt that this may have either been due to the difficulty in diagnosing unstable angina or that it was a result due to chance. In our opinion, this finding should not be dismissed as mere chance and must be taken seriously and rigorously investigated.

The HOPE study investigators concluded:

Our results do not support the use of folic acid and B vitamin supplements as a preventive treatment.

The second of the two studies appearing on the New England Journal of Medicine web site is called the Norwegian Vitamin trial, known as NORVIT. The study was funded in part by the Norwegian Research Council.

This study also used the scientific “gold standard” methodology. It involved 3,749 Norwegian men and women who had suffered a heart attack in a seven-day period before being enrolled in the study. The patients were randomly assigned to receive one of the four following treatments daily and were followed for about 40 months:

1. The combination of 0.8 milligrams of folic acid, 0.4 milligrams of vitamin B-12, and 40 milligrams of vitamin B-6.
2. The combination 0.8 milligrams of folic acid plus 0.4 milligrams of vitamin B-12.
3. 40 milligrams of vitamin B-6
4. Placebo

NORVIT examined a combination of new nonfatal and fatal heart attacks, nonfatal and fatal stroke, and sudden death attributed to coronary heart disease.

As was seen in the HOPE-2 study, homocysteine blood levels significantly decreased in those patients in the NORVIT trial taking the vitamins. Also, similar to the HOPE-2 study results, these combinations of vitamins had no statistically significant effect on the primary endpoint. Similarly, treatment with vitamin B-6 alone was not associated with any significant benefit with regard to the study’s primary end point.

In the group given the combination of folic acid, vitamin B-12, and vitamin B-6, there was a non-significant trend toward an increased risk of new nonfatal and fatal heart attacks, nonfatal and fatal stroke, and sudden death attributed to coronary heart disease.

The NORVIT researchers concluded that:

In summary, the NORVIT trial demonstrated that intervention with folic acid, with or without high doses of vitamin B6, did not lower the risk of recurrent cardiovascular disease or death after an acute myocardial infarction [heart attack]. Such therapy may even be harmful after acute myocardial infarction or coronary stenting [a mesh tube inserted into an artery to keep it open] and should therefore not be recommended.

Both the HOPE-2 and NORVIT trials suggest the possibility of harm from combinations of folic acid and B vitamins. These findings could have simply been the result of chance; however, it the possibility that there is a negative effect in some groups of patients cannot be ruled out. The NORVIT researchers offered some plausible explanations for the finding that supplementation may increase the possibility of harm, but without further research, nothing is definitive. The impact of supplementation with folic acid and B vitamins on requires further research. In the meantime, consumers should remember that the belief that vitamins may help but will never harm is not necessarily true.

What You Can Do

You should not use combinations of folic acid and B vitamins to lower blood levels of homocystine with the goal of preventing heart attacks, strokes, or sudden death. There is no evidence of a beneficial effect of these vitamins, and there is a possibility that they may cause harm.