Chicago, IL - Authors of one of the longest-duration study looking at folic-acid/B-vitamin supplementation to reduce the risk of cardiovascular events say homocysteine is likely still a useful marker for risk prediction, but the wind has all but gone out of the sails of homocysteine lowering as a means of preventing CV events.

Results of the WAFACS study of homocysteine lowering, first reported at the 2006 AHA meeting, have now been published in the May 7, 2008 issue of the Journal of the American Medical Association [1]. In an interview with heartwire, senior author for the study, Dr JoAnn E Manson (Brigham and Women's Hospital, Boston, MA), emphasized that there are other good reasons for taking folic acid and B vitamins—prevention of birth defects and possible reduction in cognitive decline or macular degeneration. But, particularly on top of other trials that also produced disappointing results, the WAFACS results do not support a strategy of trying to reduce homocysteine to help the heart.

"The findings cast further doubt on the role of folic acid and B vitamins in preventing cardiovascular events, despite their effect on homocysteine lowering," she said. "Even with long duration of treatment, there was no evidence of cardiovascular risk reduction, and we did see a significant reduction in homocysteine."

An accompanying editorial by Dr Eva Lonn (McMaster University, Hamilton, ON) emphasizes that there is "no role for routine screening" for elevated homocysteine and that B-vitamin supplements "cannot currently be recommended for CVD prevention" [2].

As previously reported by heartwire, WAFACS was a randomized controlled study led by Dr Christine Alpert (Brigham and Women's Hospital) comparing the effects of placebo with a daily combination of 2.5-mg folic acid, 50-mg vitamin B₆, and 1-mg vitamin B₁₂ in reducing the risk of major cardiovascular events over seven years in 5442 female health professionals participating in the larger Women's Antioxidant Cardiovascular Study (WACS).

Participants were over the age of 40, and two-thirds of them had a history of CVD; the remainder had three or more risk factors (high-risk primary-prevention subgroup).

The primary end point was a combined outcome of MI, stroke, revascularization, or cardiovascular death. Over an average of 7.29 years of follow-up, there was no difference in the primary end point between the active-treatment group and those receiving placebo, nor was there any difference between the two groups in any of the secondary end points.

On top of disappointing results from other trials, including HOPE-2, NORVIT, and VISP, the authors conclude that the WAFACS results "do not support the use of folic-acid and B-vitamin supplements as preventive interventions for CVD in these high-risk-fortified populations."

To heartwire, Manson offered the caveat that there may yet be a role for targeting high homocysteine levels among higher-risk, undernourished patients in parts of the world with no background fortification of the food supply with folic acid and/or B vitamins, but that this hypothesis would need to be rigorously tested.

Lonn also stopped short of completely denying a role for the strategy, noting that a number of large trials in populations without fortified food supplies in Western Europe, Asia, and Australia are still ongoing. "It is critically important to complete these studies to provide clear answers to some of the remaining questions," she writes. "Until further data become available, it is essential to remain firmly grounded on the available evidence and to admit that, once again, experimental and observational data do not always translate into therapeutic benefits."