Folate Therapy Reduces Homocysteine Levels, Restenosis – NEJM Study

Folate therapy's ability to lower homocysteine levels and reduce the risk of restenosis in patients who have undergone coronary angioplasty could make it a viable alternative to using stents, Swiss researchers suggest in the Nov. 29 New England Journal of Medicine.

In a randomized, double-blind trial of 205 coronary angioplasty patients, "the lowering of plasma homocysteine levels was of particular benefit in non-stented lesions, potentially challenging the current trend of primary stenting," Guido Schnyder, MD, Swiss Cardiovascular Center, University Hospital, Bern, et al., state.

Among 101 individual lesions treated with balloon angioplasty only, Schnyder et al. found a 76% lower risk of restenosis in patients on folate treatment. A 10.3% rate of restenosis was observed in the folate group after six months, compared with a 41.9% rate in the placebo cohort.

Although the researchers also discerned a lower restenosis rate with folate therapy in lesions treated with stents, the risk reduction was significantly smaller. Among the 130 patients with stented lesions, there was a 20.6% rate of restenosis in the folate group and a 29.9% rate in the placebo arm.

Regardless of treatment type, however, the results indicate folate "should be considered as adjunctive therapy for patients undergoing coronary angioplasty," the researchers aver, since positive results were obtained "with minimal side effects and at a very low cost."

Schnyder et al. emphasize that "although other therapeutic approaches, such as radiation therapy, have been proposed to achieve similar results, the low cost and risk-benefit ratio of folate therapy is appealing."

The prospective trial randomly assigned patients to receive daily either a combination of 1 mg folic acid, 400 mcg vitamin B12 and 10 mg pyridoxine or placebo. Researchers recruited participants "who had undergone successful angioplasty of at least one coronary stenosis of 50% or more."

Coronary angiograms were conducted to assess restenosis after six months of treatment. The study's primary endpoint was the presence or absence of restenosis of 50% or more; the secondary endpoint was a combination of major cardiac events.

Schnyder et al. selected the folate combination based on prior studies showing "plasma homocysteine can be reliably lowered 25%-30% with a daily dose of at least 500 mcg of folic acid" in combination with vitamin B12 and pyridoxine.

Since elevated total plasma homocysteine has been linked to restenosis, the researchers hypothesized that lowering plasma homocysteine levels with folate treatment would decrease the rate of restenosis after coronary angioplasty.

As predicted, Schnyder et al. found homocysteine levels at follow-up to be significantly lower in patients receiving folate treatment than in those assigned to placebo (7.2 vs. 9.5 mcg/liter).

Moreover, the researchers reported a 19.6% rate of restenosis in the folate group after six months compared with a 37.6% rate in the control group, resulting in a 47.9% lower risk of restenosis in participants on folate treatment.

Reviews of individual lesions showed a 15.7% rate of restenosis in the group assigned to folate treatment, compared with a 34.5% rate in the control group, which corresponds to a 54% risk reduction, the investigators report.

Assessing the secondary endpoints, Schnyder et al. found folate treatment significantly lowered the incidence of major cardiac events in patients with coronary angioplasty. After six months, participants assigned to daily folate therapy had a 10.8% rate of revascularization of the target lesion, compared to 22.3% in the placebo group.

After considering other adverse events such as death from cardiovascular causes and nonfatal myocardial infarction, AE rates were 12.7% in the folate group and 24.5% in the placebo arm, the researchers report.

Schnyder et al. discuss several limitations of their study, noting a "critical question" is whether the strong association between the lowering of plasma homocysteine levels and the decrease in the rate of restenosis actually "reflects causality."

The researchers found a "nonsignificant trend toward a greater use of stents in the control group," which might have skewed results since stent use has been shown to reduce the rate of restenosis. However, Schnyder et al. point out "despite this, the rate of restenosis was higher in the control group," which "may be seen to strengthen our findings indirectly."