Folate Therapy and In-Stent Restenosis After Coronary Stenting - Folate Therapy and In-Stent Restenosis After Coronary Stenting


The goal of the study was to evaluate the effect of a combination of folic acid, vitamin B6, and vitamin B12 (i.e., folate therapy) on the risk of angiographic restenosis after coronary stent placement.

Study Design

Study Design:

Patients Enrolled: 636
Mean Follow Up: Six months
Mean Patient Age: Mean age 61 years
Female: 23

Patient Populations:

Performance of successful coronary stenting


In-stent restenosis, significant left-main-artery stenosis and bifurcation lesions, MI <24 hours before enrollment, renal dysfunction (defined by a serum creatinine level of >1.3 mg/dl), and current intake of vitamins

Primary Endpoints:

Primary angiographic endpoint: MLD within the target lesion at follow-up.
Primary clinical endpoints were events related to restenosis: death from cardiac causes, target-vessel MI, and TVR.

Secondary Endpoints:

Late luminal loss and restenosis

Drug/Procedures Used:

Patients were randomized to folate therapy (n=316) or placebo (n=320). Folate therapy included 1 mg of folic acid, 5 mg of vitamin B6, and 1 mg of vitamin B12 intravenously, followed by daily oral doses of 1.2 mg of folic acid, 48 mg of vitamin B6, and 60 µg of vitamin B12 for six months.

Concomitant Medications:

All patients received 300 mg of clopidogrel orally immediately after the procedure, followed by 75 mg daily for four weeks, and 100 mg of aspirin daily.

Principal Findings:

Treatment was discontinued in 13.3% of patients in the folate group and 15.3% of patients in the placebo group (p=0.47). There was no difference in statin use at six months (40.6% vs. 45.5%, respectively, p=0.22). Compared to baseline, homocysteine levels were lower in the folate group at one month (from 12.2 to 8.7 µmol/l, p<0.001) and six months (9.0 µmol/l, p<0.001), but levels did not change in the placebo group.

Minimal luminal diameter (MLD) at six-month follow-up was smaller in the folate group compared with the placebo group (1.59 ± 0.62 vs. 1.74 ± 0.64 mm, p=0.008), while late lumen loss was greater in the folate group (0.90 ± 0.55 vs. 0.76 ± 0.58 mm, p=0.004). The restenosis rate was greater in the folate group (34.5% vs. 26.5%, relative risk 1.30, 95% confidence interval 1.00-1.69, p=0.05), as was the percent diameter stenosis (45.1% vs. 41.0%, p=0.01). With the exception of females, diabetics, and patients with high baseline homocysteine, folate therapy was associated with higher restenosis rates in all subgroups.

The repeat target vessel revascularization (TVR) rate by 250 days was higher in the folate group (15.8% vs. 10.6%, p=0.05). There was no difference in death (0.3% in each arm, p=0.99) or myocardial infarction (MI) (0.9% vs. 0.6%, p=0.64), but the major adverse cardiac events composite was higher in the folate arm (16.8% vs. 10.9%, p=0.03), driven primarily by TVR.


Among patients who underwent successful coronary stenting, treatment with folate therapy was associated with smaller MLDs and increased restenosis and TVR at six-month follow-up compared with placebo, despite lowering of homocysteine levels in the folate group. Homocysteine levels were not associated with restenosis in the present trial, a finding that differed from some earlier studies. However, some of the earlier studies were conducted primarily in patients who underwent balloon angioplasty without coronary stenting, unlike the present trial in which all patients were stented.

While folate therapy may inhibit intimal hyperplasia caused by high homocysteine levels, it may also increase intimal hyperplasia in the absence of elevated homocysteine levels. Additionally, the present study used a relatively high dose of vitamin B6 compared with the earlier trials.


Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004;350:2673-81.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Statins

Keywords: Vitamin B 6, Myocardial Infarction, Folic Acid, Constriction, Pathologic, Vitamin B 12, Hyperplasia, Diabetes Mellitus, Stents

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