ATLANTA — The homocysteine hypothesis for secondary prevention of cardiovascular disease appears to be dead.
Reports in March from two large, separate intervention trials failed to show any benefit from supplements of folic acid and B vitamins in patients with proven vascular disease, even though the supplements cut serum levels of homocysteine by the goal of about 25%.
“We achieved what we set out to do and have to conclude that supplements with folic acid and B vitamins do not reduce cardiovascular events in high-risk populations with established vascular disease,” Dr. Eva M. Lonn said at the annual meeting of the American College of Cardiology.
The trial, led by Dr. Lonn of the Heart Outcomes Prevention Evaluation (HOPE) 2 study, involved more than 5,500 patients aged 55 or older with vascular disease or diabetes who were randomized to either a daily folic acid and B vitamin supplement or placebo. The results were presented at the meeting and were simultaneously released in a paper on the Internet (http://content.nejm.org/cgi/reprint/NEJMoa060900.pdf
The second study, the Norwegian Vitamin (NORVIT) trial, randomized more than 3,700 patients soon after a myocardial infarction to a similar supplement or placebo. Results were first reported last September at the annual meeting of the European Society of Cardiology and were released online along with the HOPE 2 paper (http://content.nejm.org/cgi/reprint/NEJMoa055227.pdf
Both studies were done to test a theory that had become entrenched based on findings from several retrospective and observational studies in the past 25 years. Those studies provided “ample support for the association of mild hyperhomocysteinemia with an elevated risk of atherothrombosis,” wrote Dr. Joseph Loscalzo, chairman of the department of medicine at Brigham and Women's Hospital in Boston, in an editorial that accompanied the two reports (http://content.nejm.org/cgi/reprint/NEJMe068060.pdf
“We may have overestimated the strength of the association between homocysteine and cardiovascular risk in retrospective and cross-sectional studies. We can't always fully adjust for confounding and reverse causality,” said Dr. Lonn, a professor of medicine and cardiology at McMaster University, Hamilton, Ont.
The new findings “address a really important public health issue and will have an impact on practice,” said Dr. Christopher B. Granger, director of the cardiac care unit at Duke University in Durham, N.C.
The HOPE 2 study enrolled 5,522 patients with a history of vascular disease or diabetes and additional risk factors for atherosclerosis; they were randomized to placebo or a single pill daily containing 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12. After an average of 5 years, the rate of cardiovascular death, nonfatal MI, or nonfatal stroke—the primary end point—was 18.8% in patients taking the supplement and 19.8% in the controls, a nonsignificant difference. Significantly fewer patients taking the supplement had strokes, compared with the control group (4.0% compared with 5.3%), but the importance of this isolated benefit was discounted by Dr. Lonn because it came in the context of an otherwise neutral trial.
The NORVIT study enrolled 3,749 patients within 7 days after an MI. Patients were randomized to one of four daily regimens: 0.8 mg folic acid, 40 mg vitamin B6, and 0.4 mg vitamin B12; 0.8 mg folic acid and 0.4 mg vitamin B12; 40 mg vitamin B6; or placebo.
After an average follow-up of 3 years, treatment with folic acid in combination with vitamin B12, with or without vitamin B6, did not significantly reduce the primary end point—the combined rate of sudden coronary death, fatal and nonfatal MI, and fatal and nonfatal stroke. In fact, there was a trend toward an increased rate of events among patients taking B vitamins, especially in the subgroup taking folic acid and vitamins B6 and B12.