STOCKHOLM—Findings from the Norwegian Vitamin Trial (NORVIT) have called into question the popular notion that elevated homocysteine is a risk factor for myocardial infarction, and that it can be reduced by taking folic acid.
The study, a multicenter, double-blind trial involving more than 3,700 patients recovering from myocardial infarctions, compared folic acid, 0.8 mg per day, folic acid plus vitamin B6, 0.4 mg per day, vitamin B6 alone at 40 mg per day, or placebo, to see if these interventions would prevent second MI, stroke, and/or cardiovascular death in this high-risk population. The patients, aged 30 to 84, were followed for 3.5 years; compliance was upward of 90%.
As expected, all the patients taking folate showed plasma homocysteine reductions within 2 months. Throughout the study, they maintained homocysteine levels 28% lower than patients on placebo or vitamin B6 alone. The surprise, though, was that neither folic acid alone, nor folic acid plus B6 had any measurable impact on incidence of fatal or non-fatal MI or stroke.
Cardiovascular events occurred at a rate of approximately 18% in all four groups, prompting lead investigator Kaare Harald Bonaa, MD, to state that, “The homocysteine hypothesis is dead.” Dr. Bonaa, of the University of Trondheim, Tromso, Norway, presented the data at the annual meeting of the European Society of Cardiology. The NORVIT study has yet to be published.
The data run sharply counter to expectations based on several large epidemiologic studies showing a strong correlation between homocysteine and cardiovascular events. That evidence prompted many physicians to believe that lowering homocysteine, easily done via folate supplementation, would improve cardiovascular health and prevent premature deaths.
The homocysteine hypothesis had strong traction among holistic and naturopathic physicians because homocysteine appeared to be a risk factor easily ameliorated through a simple, inexpensive nutritional intervention.
According to Dr. Bonaa, homocysteine is an “innocent bystander,” with no causal connection to MI or stroke. He advised doctors to abandon the practice of recommending folic acid for cardiovascular protection, largely on the basis of another surprising NORVIT finding: that the incidence of cancer was higher among the patients receiving folic acid.
There were 12 cancer deaths per thousand person-years in the patients on folic acid plus B6, and 11.9 among those on folic acid alone, compared with only 8 in the B6 group, and 9 in the placebo arm.
These numbers are small, the differences were not statistically significant, and this study was not designed to evaluate the effects of vitamins on cancer risk. But Dr. Bonaa believes it wise to err on the side of caution, especially given the data showing no measurable cardiovascular benefit from the vitamin intervention.
Professor Ian M. Graham, of the Royal College of Surgeons, Dublin, who discussed Dr. Bonaa’s paper at the ESC conference, agreed that currently there is no ground for recommending B vitamins in post-infarction patients. However, he stopped short of dismissing the homocysteine hypothesis altogether. Lack of evidence of benefit in one trial is not definitive proof that there is no benefit, Dr. Graham said. NORVIT, it must be remembered, was a secondary prevention trial in patients who already had CVD; it is difficult to draw a meaningful conclusion about the potential for lowering homocysteine as a primary preventive measure in people who do not yet have frank heart disease.
Nutritionally-minded physicians are questioning the overall validity of the NORVIT findings, and few seem willing to sideline folic acid in the management of CVD. According to Leo Galland, MD, a New York City internist and director of the Foundation for Integrated Medicine, the issue is one of patient selection.
“Reducing homocysteine from 20 to 14 may have a greater effect than lowering it from 10 to 7, though each would be a 30% reduction. In the patients I see, (baseline) homocysteine levels of 10 are far more common than levels of 20. So a trial in all my patients could potentially miss the benefits,” Dr. Galland told Holistic Primary Care. “It is also possible that 3 years is not a long enough period in which to see an effect, and that the effect of homocysteine lowering may be confined to people who have not already experienced vascular damage.”
Lee Lipsenthal, MD, president of the American Board of Holistic Medicine and a leader in the field of nutrition and lifestyle change to prevent heart disease, believes NORVIT’s folate doses were too low.
“While the study design was of good quality, the dose of folate used (0.8 mg per day) was fairly low. The usual treatment dose is 2 mg per day. The 0.8 mg dose lowered homocysteine from what appears to be a pre-treatment average of just over 13 micromoles/ liter to just above 9 micromoles/liter. In multiple studies showing the effectiveness of lowering homocysteine, levels were brought below 7 micromoles/liter. Thus the low dosing of folate and marginal effect of that dose may not have been enough to demonstrate a reasonable treatment effect.”
There are a number of other folate trials currently underway that could soften the blow delivered by the NORVIT data. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, a massive UK study involving more than 12,000 post-infarction trials is testing the impact of 2 mg folate plus 1 mg vitamin B12. Data are expected at some point next year.
