To this end, Liem and colleagues randomized 593 patients to either 0.5-mg/day folic acid or no folate supplementation in an open-label fashion. All patients were also on statin therapy and had been for a mean of 3.2 years. To heartwire, Liem confirmed that a blinded placebo-controlled study design was not used because the cost of an approved placebo was prohibitive to a study that no one was interested in sponsoring. In fact, Liem's hospital pharmacy supplied the folic acid for free. To ascertain that patients who did not receive folic acid were not going "immediately to the grocery to buy folic acid themselves," the authors checked folate status regularly to confirm that folate levels did not vary from baseline in the non-folic-acid-treated patients.

At two-year follow-up, plasma homocysteine levels in the 300 patients treated with folic acid had declined by 18%, whereas the 293 patients in the control group experienced no change in homocysteine levels (p<0.001). This change did not, however, appear to effect cardiovascular events: there was no difference in the primary composite end point of all-cause mortality, cardiovascular death, recurrent MI, repeat revascularization, stroke, or TIA.

The authors note that since most patients were on statin therapy before and during the study, this may have masked the beneficial effects of folic-acid supplementation, but as Liem pointed out to heartwire, it would not be possible to conduct a trial today with this group of patients and withhold statins.

Strikingly, baseline levels of plasma homocysteine in this study did correlate with risk of recurrent events, yet lowering levels did not remove this risk.

"The matter of causality of homocysteine in atherosclerosis remains a highly debatable issue," the authors conclude. They note that other laboratory parameters seem more relevant in the prediction of cardiovascular events, one of the most prominent being creatinine clearance, a measure of renal function. Liem et al suggest that since renal function affects homocysteine metabolism, fluctuating levels of homocysteine might speak more to renal function, itself a reflection of cardiovascular disease. As such, "modulating this [homocysteine] marker does not influence cardiovascular prognosis," they write.

The findings do not mean that homocysteine is not a risk factor for cardiovascular disease, but rather that "correcting this risk factor does not seem to reduce upcoming events significantly," Liem said. "One therefore could suggest that homocysteine might just be an epiphenomenon. Just like fever in patients with pneumonia; correcting the fever does not result in a cure."

In a press statement released by the American College of Cardiology, Dr Charles H Hennekens (University of Miami, FL) commented, "This study reaffirms the need for randomized trials to detect reliably whether or not there are small to moderate benefits of agents such as folic acid."

Hennekens points out that the findings seem to overturn the findings from case-control and cohort studies that seemed to lend credence to hypothetical mechanisms by which folate could reduce cardiovascular risk. "This randomized trial, however, does not demonstrate a clinical benefit. Clearly, further research, especially randomized trials of large sample sizes, is needed."