FACIT enrolled 626 patients who underwent successful coronary stenting procedures. Patients were randomly assigned placebo or 1.2 mg folic acid in combination with 4.8 mg pyridoxine (vitamin B₆) and 0.06 mg vitamin B₁₂. Vitamin therapy to lower homocysteine levelsa risk factor for CADis recommended as a cost-effective way to treat elevated homocysteine levels, said Lange.

We are confident that folate in this particular setting is clearly harmful.

FACIT was designed to explore whether supplemental folic-acid therapy can limit the renarrowing of coronary stents in patients during the six months following implantation. The angiographic end pointsminimal lumen diameter, late loss, and restenosis ratewere assessed at six months by coronary angiography.

Investigators found higher rates of restenosis in the folate-treated group. After six months, the rate of restenosis was 35% compared with 27% in the group receiving placebo. Higher rates of TVR were also reported in the group of patients receiving vitamin supplements.

The detrimental effect of folic acid supplementation was most pronounced in patients without diabetes, in men, and in patients with a low homocysteine level at baseline, report investigators.

Surprisingly, the adverse effects of folic acid and vitamin therapy on restenosis are opposite the findings of the Swiss Heart Study, a study published in the Journal of the American Medical Association in 2002.2 In that study, homocysteine-lowering therapy with folic acid, vitamin B₆, and vitamin B₁₂ improved outcomes after PCI, reducing the need for repeat vascularization and decreasing the overall incidence of major adverse events one year after successful coronary angioplasty.

"Clearly, the two studies are a little different," said Lange. "There were some differences in dose, especially B₆, which was higher in our study, and there were a few more smokers and diabetics in the Swiss population. But I'm really not so convinced this is the reason for the difference in the results."

Folate, in some patients, is a double-edged sword.

While half the patients in the Swiss study received stents, most of the benefit was observed in those patients undergoing balloon angioplasty alone, possibly explaining the different results between the two trials. Thrombus formation within intimal cracks and vascular remodeling are important processes of restenosis after angioplasty and are more susceptible to the folate-induced effects of homocysteine lowering compared with the restenosis processes after stenting, said Lange.

"Folate, in some patients, is a double-edged sword," said Lange. "You have a positive effect from lowering homocysteine, which may play a greater role in angioplasty than in stent patients, but on the other hand you have a strong proliferative effect on cell growth with folate. It increases cell metabolism and promotes neointimal hyperplasia."

Lange told heartwire that it is hoped that a third study would answer the unresolved question of the benefit of folic acid and vitamin B supplementation after PCI. A large Norwegian trial known as NORVIT is investigating B vitamins in MI but has a large stenting study arm with folate supplementation.

In an editorial accompanying the published study, Dr Howard C Herrmann (University of Pennsylvania, Philadelphia) attempts to reconcile the strikingly different results between the Swiss Heart Study and FACIT.3 Even with the slight differences between the two studieshigher doses of vitamins and lower baseline homocysteine levels in FACIT, as well as a different patient populationthe evidence supporting folate therapy is not there, he concludes.

Folic acid, vitamin B₆, and vitamin B₁₂ should not be routinely administered to patients receiving coronary stents in an effort to reduce the risk of restenosis.

"On the basis of these differences and the potential for harm demonstrated by the current study, folic acid, vitamin B₆, and vitamin B₁₂ should not be routinely administered to patients receiving coronary stents in an effort to reduce the risk of restenosis," writes Herrmann. "Studies are needed to clarify the optimal dose, route, and timing of administration and the subgroups of patients who might benefit most from this treatment."

Herrmann points out the recent and widespread adoption of drug-eluting stentswhich lower the need for TVR to about 5% and were not used in either trialhas made the consideration of folate therapy to prevent restenosis moot. Instead, clinicians need to start focusing on the underlying disease process to treat vulnerable plaques and atherosclerosis. The focus should be shifting to prevent cardiac events, as well as new and progressive atherosclerotic lesions, he writes.

"Although percutaneous coronary intervention can dramatically improve a patient's clinical condition in the short term, both the physician and the patient must remain focused on the long-term consequences of subsequent progression and use all available strategies to attenuate it," Herrmann concludes.