London, UK - Flying in the face of recent trial results that have found no benefit of folic acid for the prevention of cardiovascular events, a new commentary in the November 25, 2006 issue of BMJ says the combined evidence from cohort, genetic, and randomized controlled studies is indeed strong enough to support a modest protective effect of this nutrient [1].

Lead author of the new paper, Dr David S Wald (Queen Mary's School of Medicine and Dentistry, London, UK), told heartwire that 0.8 mg of folic acid per day should be used for reduction of cardiovascular events: "It is simple, safe, inexpensive, and undervalued." While he acknowledges that recent interventional trials have not produced positive results, he says that they have been "interpreted as negative when really they have been neutral or inconclusive."

It is naive to believe that folic acid is some nutritional wonder drug, but I don't believe it is dead in the water yet.

While some of the authors of these recent trials are critical of the BMJ paper, other experts sympathize with its arguments but conclude that there is not yet enough evidence to support routine use of folic acid for the prevention of cardiovascular events. Dr Ian Graham (Trinity College, Dublin, Ireland) says: "This is a good debate to have. It is naive to believe that folic acid is some nutritional wonder drug, but I don't believe it is dead in the water yet."

Just two weeks ago, the latest in a line of randomized controlled trials of folic acid was reported at the American Heart Association (AHA) 2006 Scientific Sessions. The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS) joined HOPE-2, NORVIT, and VISP in failing to show any benefit of folic acid on cardiovascular events.

But Wald told heartwire that randomized controlled trials "are only one part of the story. They have all been too small, of too short a duration, and inconclusive—both alone and when we put them together." And, he says, "We must be cautious about our interpretation of randomized controlled trials, as they tend to be deemed positive or negative. In fact [with the folic-acid studies], we don't have enough events to push us one way or another; rather, they leave us in the middle."

The researchers say there are parallels to be drawn between homocysteine and lipid lowering. "An analogy exists with medical judgments made after the early randomized trials of treatment to reduce serum cholesterol concentrations. The early trials achieved only modest reductions in serum cholesterol, and their duration was short; the two years necessary for the near-maximal reduction in ischemic heart disease was not appreciated. Consequently, the modest risk reductions observed were not significant and were widely interpreted as negative. Cholesterol reduction was claimed to be harmful."

For folic acid, the epidemiological data and genetic studies "are most convincing," Wald says, "and our paper addresses the totality of evidence." Although Wald and two of his coauthors have interests in the polypill—which contains folic acid—including patents (granted and pending) in the case of two of them, Wald stressed to heartwire: "I'm not promoting folic acid because of that. We are making conclusions on the basis of evidence."

Their argument centers on meta-analyses of cohort studies showing significant positive associations between serum homocysteine and ischemic heart disease events and on the fact that lower homocysteine concentrations have been shown to have a large effect on CVD risk in patients with homocystinuria.

And in genetic studies of people with a mutation in the methylenetetrahydrofolate reductase gene (MTHFR)—who have moderately raised homocysteine concentrations as a result—meta-analyses have shown up to a 25% excess risk of cardiovascular events, they note.

"These genetic studies avoid the confounding that could affect cohort studies; people with and without the mutation would not be expected to differ in other cardiovascular risk factors, and direct observation indicates that they do not. The studies are, in effect, natural randomized experiments, capable of testing whether moderately raised homocysteine causes ischemic heart disease and stroke," they note.

Folic acid, up to 0.8 mg day, lowers homocysteine concentrations in people with and without this mutation, they say.

Graham says the British researchers have a point. When looking at the effects of antioxidant vitamins, such as vitamin E, "the genetic story does not apply," he says, and therefore it is easier to conclude that they lack benefit.

Wald et al conclude: "In practical terms, folic-acid supplementation will be expected to have a variable effect in preventing cardiovascular disease, with greater prevention in populations with relatively low folate intakes and less prevention in populations with higher folate intakes."

Currently, the AHA does not recommend widespread use of folic-acid and B-vitamin supplements to reduce the risk of heart disease and stroke [3]. It does recommend a daily value of 0.4 mg for prevention of neural tube defects during pregnancy. In the US, wheat flour has been fortified with folic acid since January 1998 to add an estimated 0.1 mg per day to the average diet, and some other Western nations have followed suit.

Wald does concede that any benefit of folic acid is likely to "be relatively modest" but argues that "there is no evidence of harm" and therefore no downside to recommending its use for the prevention of cardiovascular events.

But Graham takes issue with this. While he believes the finding in the NORVIT study—that folic acid may actually increase the risk of MI and stroke in MI survivors—was "very strange" and probably a blip, "there is still a slight niggling worry that folic acid could feed a cancer," he notes.

Graham says the crux of the matter is whether the evidence is sufficiently good it can justify public-health intervention. "For vascular disease, I think it's still a bit too weak."

But, he says, Wald et al "could be right. He's absolutely correct to say that the inability to show benefit does not mean there is no benefit." The death of the homocysteine hypothesis so often cited recently "is premature," he believes.

"We need to wait until there are at least 10 major trials. At the moment there are about five, and the total follow-up is not that long and the numbers are small. What we really need is a megatrial done in a population that does not fortify food and that has a high rate of cardiovascular events—somewhere like Russia—with about 50 000 to 100 000 people followed for 10 years, but it's hard to see how this will be done. There is no profit in folic acid."

When heartwire questioned Canadian researchers involved in the HOPE 2 trial about the conclusions of Wald et al, they were less than enthusiastic.

Lead author Dr Eva Lonn (McMaster University, Hamilton, ON) told heartwire that the review "is outdated; it is based on observational studies only. There are four large randomized trials—about 17 000 people—suggesting no benefit at all. The only data that could justify the use of folic acid would be if any of the ongoing large randomized trials would show different results. For now, there is no rationale for folic acid."

The only data that could justify the use of folic acid would be if any of the ongoing large randomized trials would show different results.

Dr Salim Yusuf (McMaster University) agrees: "The totality of the data rules out any important difference for most populations."

But Dr Eric Rimm (Harvard University, Boston), who reviewed the evidence for folic acid during a session on the science behind nutritional claims at the recent AHA meeting, said: "I agree with the main points made in this editorial, except in some cases they did not go far enough. For example, they focused primarily on homocysteine, yet folate may be beneficial through other metabolic pathways.

"While I don't agree that the trials are underpowered, they are mostly conducted on very high-risk individuals who are also on statins, aspirin, etc. This would attenuate the benefit and likely reduce power for this reason (and because many of the participants will have sufficient folate in their diet)."

Rimm believes there may be a benefit of folic acid in certain susceptible populations, as suggested by subanalyses of the large intervention trials. "B vitamins clearly lower homocysteine, and homocysteine increases the risk of coronary heart disease," he states.

Graham believes that looking at how homocysteine affects other risk factors might provide some answers. "Data have shown that there is an interaction between cholesterol and homocysteine and between smoking and homocysteine. It may be that global risk is important, so that those at very high risk will benefit from folic acid."