Research has demonstrated that homocysteine promotes atherosclerosis. It is also closely related to increased risk of developing coronary artery disease. More recently, investigators have observed that homocysteine has a number of effects on the artery that are similar to the mechanisms of percutaneous coronary angioplasty (PTCA) restenosis. Because of this, some researchers have looked at the role of homocysteine in the development of PTCA restenosis. However, conflicting reports have emerged on the role of this heart disease risk factor in restenosis. Some data show that homocysteine also acts on the development of restenosis, while other data do not.

Folic acid, a water soluble vitamin, has gained considerable attention over the last few years for its effects on homocysteine. Adding folic acid to nutrients such as corn flakes can rapidly and substantially decrease blood levels of homocysteine.

There has been some interest in possibly using folic acid to prevent PTCA restenosis. The Swiss Heart Study showed that administering folic acid plus vitamins B6 and B12 decreases homocysteine by 30% and reduces the restenosis rate after angioplasty by 50%. Investigators published these results in 2001 in the New England Journal of Medicine.

Today, some interventionists think these study results support a decision to give folic acid to patients after the first restenosis, or possibly to prevent a first restenosis. However, results of the Folate After Coronary Intervention Trial (FACIT) that show folic acid does not help and may be harmful in patients at risk of restenosis.

Here at ACC, Dr. Lange presented the results of this 2-center study, which enrolled 636 patients who had undergone successful coronary stenting. They were randomly assigned to a group that received folate plus B vitamins for 6 months, or a control group that received placebo. Patients in the vitamin group received 1.2 mg of folate, 48 mg of B6 and 0.06 mg of B12. After an intravenous loading dose including all three vitamins, patients continued taking vitamins orally for 6 months.

The primary endpoint of FACIT was the minimal lumenal diameter and restenosis rate at 6 months. The secondary endpoint was major adverse clinical events such as myocardial infarction or target vessel revascularization.

Unexpectedly, Dr. Lange and colleagues found results exactly the opposite of what they expected. Folic acid had an adverse effect on the development of in-stent restenosis.

The smallest diameter within the stented artery was not larger in the group that received folic acid plus B vitamins. The mean minimal lumenal diameter was 1.59 mm, compared with 1.74 mm in the control group that did not receive vitamin supplementation (p<0.01).

In addition, the restenosis rate was higher after folic acid. Of the vitamin group, 35% had restenosis, versus 27% for the placebo group (p<0.05). Target lesion revascularization occurred in 16% of the vitamin group and only 11% of controls (p<0.05).

Dr. Lange noted that FACIT is one of the few studies that demonstrates vitamin supplementation is not always good and may be harmful in certain settings. The results suggest that a vitamin combination that lowers homocysteine may nevertheless lead to an increase in target vessel revascularization and restenosis after stenting.

Based on these results, Dr. Lange recommended that supplementation with these vitamins should be avoided in patients who have recently received a coronary stent.

A separate question is whether folate supplementation may be useful for secondary prevention of adverse events in patients with established coronary artery disease. Several large studies underway are studying this question. Dr. Lange cautioned that the FACIT study does not provide any conclusions on this subject. However, the negative results of this study at least suggest that an increase in adverse events would be a possible outcome.