No effect of B vitamins on vascular risk

The final nail has been driven into the homocysteine-lowering coffin as a means to prevent recurrent coronary events. The results from the homocysteine-lowering arm of the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial found no benefit to folic acid combined with vitamin B₁₂ in preventing major vascular events in heart attack survivors, announce researchers from the United Kingdom.

Epidemiologic studies of blood homocysteine indicate a positive association with the risk of occlusive vasular disease, but evidence from randomized controlled trials about the effects on risk of lowering blood homocysteine levels is lacking, says Jane Armitage, MD, a SEARCH co-investigator and a senior research fellow and honorary consultant in public health medicine at the University of Oxford, U.K.

The overall SEARCH study was conducted in 88 U.K. hospitals and included 12,064 survivors of myocardial infarction (MI). One-third of the patients were older than 70 years at trial entry and about 20% were women. They were randomized in a 2x2 factorial design to either 20 mg/day or 80 mg/day of simvastatin to assess the effect of more vs. less intensive lipid-lowering treatment, and separately to homocysteine lowering with folic acid, 2 mg/day, plus vitamin B₁₂, 1 mg/day, or matching placebo.

After a median follow-up of 6.7 years, despite a reduction in blood homocysteine of 28% in the active treatment group, there was no effect of folic acid/vitamin B₁₂ on the primary endpoint in the study, a composite of nonfatal MI or coronary death, any stroke, or any arterial revascularization. The hazard ratio of 1.02 observed in the active treatment group relative to placebo was consistent with prior smaller studies of shorter duration that showed a null effect of B vitamins on the risk of major vascular events, says Dr. Armitage.

“With the totality of the evidence, we now rule out unequivocally the claim from observational epidemiology about the effects of homocysteine lowering on major vascular events,” says co-investigator Rory Collins, MBBS, MSc, professor of medicine and epidemiology at the Clinical Trail Service Unit at the University of Oxford.

Even patients with the highest homocysteine levels at baseline derived no benefit from homocysteine lowering in the study. There was no emerging trend toward benefit with longer treatment with folic acid/vitamin B₁₂ in any group, he says.

There had been concerns that folic acid may increase the risk of certain types of cancer, says Dr. Collins, but SEARCH was reassuring in that no excess cancer of any type was detected with folic acid/vitamin B₁₂. There were 250 cancer deaths in the treatment group and 251 in the control group.