Observational data suggest that high levels of plasma homocysteine are a risk factor for CVD, with supporting experimental data indicating that even mild to moderate elevations in homocysteine cause oxidative stress, damage the endothelium, and enhance thrombogenicity.7 Researchers have examined whether such common elevations could be corrected with vitamin supplementation.
The idea that supplementation with folic acid and vitamins B6 and B12 would lower homocysteine levels and, in turn, lower cardiovascular events received its first blow in 2005 with the results of the Vitamin Intervention for Stroke Prevention (VISP) trial.13,14 Those results failed to show any benefit from vitamin therapy in patients with histories of stroke.
In the HOPE-2 trial,7 some of the same investigators who reported evidence against cardiovascular benefit from vitamin E in the original HOPE trial6 reported data showing no effect from vitamin B (including folic acid) supplementation in preventing cardiovascular events. The HOPE-2 lead author, Eva M. Lonn, MD, of McMaster University in Hamilton, Ontario, Canada, said the following at a press conference at the American College of Cardiology’s 55th Annual Scientific Session in 2006, where the HOPE-27 results were presented8,15:
Because the primary study outcome is neutral, I think we have to conclude that supplementation with high-dose folic acid and vitamins B6 and B12 does not reduce major vascular events in a high-risk population with established vascular disease.
I think they’re important, because we have been often derailed in our efforts to implement secondary prevention adequately, and the focus should be on what has been proven to work—namely, a healthy lifestyle with a good intake of fruits and vegetables, exercise, and, for those who already have had an event, certain drugs such as aspirin, statins, beta blockers, and ACE [angiotensin-converting enzyme] inhibitors, which have proven benefit.
The Norwegian Vitamin (NORVIT) trial16 found no benefit in preventing recurrent cardiovascular events from the use of folic acid and other B vitamins in patients who started taking these supplements within 7 days after myocardial infarction. The researchers, led by principal investigator Kaare Harald Bonaa, MD, of the University of Tromso in Norway, actually reported an increase in cardiovascular events with the combination of folic acid and vitamins B6 and B12.
In an editorial17 accompanying the NORVIT trial,16 Joseph Loscalzo, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, wrote that the consistency of results in three similar, though not identical, patient populations (HOPE-2,7 VISP,13,14 and NORVIT16) “leads 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.”
Results of the NORVIT study16 also suggest that administration of combination B vitamins with the goal of reducing plasma homocysteine levels may actually increase the risk of CVD in patients, and that folic acid alone may increase patients’ risk of cancer. At the Hot Line Session II of the European Society of Cardiology Congress in September 2005, Dr Bonaa noted the following18
The results of the NORVIT trial are important because they tell doctors that prescribing high doses of B vitamins will not prevent heart disease or stroke. B vitamins should be prescribed only to patients who have B vitamin deficiency diseases.
Finally, the American Heart Association19 advises the following regarding B vitamin supplements:
So far, no controlled treatment study has shown that folic acid supplements reduce the risk of atherosclerosis or that taking these vitamins affects the development or recurrence of cardiovascular disease.