VIENNA — Homocysteine lowering with B vitamins and folate didn't reduce mortality or cardiovascular events in the large randomized Western Norway B-vitamin Intervention Trial (WENBIT), Dr. Marta Ebbing reported at the annual congress of the European Society of Cardiology.
WENBIT wasn't the first negative trial of homocysteine lowering as secondary cardiovascular prevention therapy. Completed randomized trials involving nearly 20,000 patients have shown no overall significant benefit, noted Dr. Ebbing of Haukeland University Hospital, Bergen, Norway.
“At this time, vitamin B supplementation is not justified as secondary prevention for coronary artery disease,” she concluded. “Homocysteine is a risk marker, but maybe not a causal factor.”
WENBIT involved 3,090 patients with established coronary heart disease, mostly stable angina and two- or three-vessel disease. They were randomized in a two-by-two factorial design to daily treatment with 0.8 mg of folic acid, 40 mg of B6, plus 0.4 mg of B12; folic acid and B12; B6 only; or placebo. The mean baseline homocysteine level was 10.8 micromol/L. It fell by 28% in the groups receiving folate. There is no mandatory fortification of foods with folate in Norway.
During a median 38 months there was a 13.7% incidence of the combined end point of all-cause mortality, unstable angina, or nonfatal stroke or MI, with no significant difference among the four treatment arms.
Discussant Dr. Salim Yusuf argued that's too early to close the book on homocysteine lowering as preventive therapy. Despite the lack of evidence of an impact on ischemic heart disease events in the nearly 20,000 randomized trial participants to date, there is a modest trend toward fewer strokes, with an average 14% relative risk reduction. WENBIT echoed this trend: there were 9 nonfatal strokes in patients assigned to folic acid plus vitamins B6 and B12, compared with 15 or 16 in each of the other study arms.
The stroke benefit in the studies reported thus far isn't statistically significant, but the studies were underpowered to show such an effect, with the exception of the second Heart Outcomes Prevention Evaluation (HOPE-2), chaired by Dr. Yusuf.
“There was a nominally significant reduction in strokes with homocysteine lowering in HOPE-2, the only study with a significant number of stroke patients followed up longer than 3 years. When we wrote the paper we believed it was due to play of chance because we had looked at many end points, but perhaps we were wrong,” added Dr. Yusuf, director of the Population Health Research Institute and professor of cardiology at McMaster University, Hamilton, Ont.
Homocysteine lowering may have divergent effects in the coronary vascular and cerebrovascular trees. Due to be completed within the next 1–2 years are two major ongoing randomized trials: the Australian VITAmins TO Prevent Stroke (VITATOPS) study, featuring 8,000 patients with recent stroke or transient ischemic attack, and the Oxford University-based Study of the Effectivess of Additional Reductions In Cholesterol and Homocysteine (SEARCH) trial in more than 12,000 patients with various forms of occlusive vascular disease.
“We will have another 20,000 patients' worth of new data, but the key difference is it will be twice as much follow-up. … It would be wise to wait for the results before we pronounce judgment. Like the WENBIT investigators, I would say at the moment there is no reason to lower homocysteine. But it is too early to write off the hypothesis,” he said.
WENBIT was funded by Norwegian nonprofit organizations.
Vitamin B supplementation is not yet justified for use in secondary prevention. Elsevier Global Medical News