January 2003 / Vol. 52, No. 1

• BACKGROUND: Should patients with coronary artery disease and high homocysteine levels take folic acid? Plasma homocysteine levels predict outcome after coronary angioplasty, and lowering plasma homocysteine levels significantly decreases restenosis after coronary angioplasty.

  Treatment with folic acid, vitamin B₁₂, and vitamin B₆ decreases homocysteine levels and lowers the short-term incidence of restenosis when given after angioplasty. This study evaluated long-term effects.

• STUDY POPULATION: The investigators enrolled 553 participants who had successfully undergone angioplasty for at least one significant coronary stenosis (≥50%). Subjects in the treatment and control groups were predominantly male (79% and 82%), and had mean ages of 62 and 63 years. Patients were excluded if they had unstable angina, subacute myocardial infarction (within the previous 2 weeks), renal insufficiency (serum creatinine >1.8 mg/dL), or were taking vitamins.

• STUDY DESIGN AND VALIDITY: The study was a randomized, double-blind, placebo-controlled trial. After successful angioplasty, defined as residual diameter stenosis less than 35% with normal flow pattern (TIMI III criteria), patients were randomly assigned to receive a supplement containing folic acid (1 mg), vitamin B₁₂ (400 μg), and vitamin B₆ (10 mg) or placebo daily for 6 months. Treatment was discontinued after 6 months and the participants were then followed for another 6 months. Fasting total plasma homocysteine levels were measured on admission and at 6 months.

  Clinical follow-up, including noninvasive stress testing and resting electrocardiography, were performed at 6 and 12 months or sooner if symptoms recurred. All analyses were by intention to treat. Outcome data were included until the dropout time points for patients who were lost to follow-up.

  The study was well designed. Consecutive patients were enrolled in a double-blinded fashion (allocation concealment unknown). Groups were similar with respect to age, smoking status, diagnosis of diabetes mellitus, hypertension, lipid profiles, previous cardiac history and drug therapy, and represented typical cardiac patients with the exceptions noted above. For a subset of patients who received follow-up invasive testing, those reading the angiograms were blinded to treatment group. It is not explicit whether those interpreting outcomes through noninvasive means were similarly blinded. If not, some investigator bias could have been introduced. Separate effects of folic acid and vitamins B₁₂ and B₆ as well as the effects of different doses of these vitamins could not be established.

• OUTCOMES MEASURED: The main outcomes evaluated were death, cardiac death (defined as sudden, unexpected death or death related to myocardial infarction), nonfatal myocardial infarction (new Q-wave in 2 or more electrocardiogram leads), the need for repeat revascularization for proven ischemia demonstrated by either follow-up cardiac events or a positive noninvasive stress test with significant angiographic stenosis of at least 50%, or a composite of these outcomes.

• RESULTS: The composite outcomes of death, cardiac death, recurrence, or need for revascularization was significantly decreased with the vitamin therapy (hazard ratio, 0.68; 95% confidence interval [CI], 0.48–0.96). For the 6 months after the angioplasty, one outcome would have been avoided for every 13 patients treated. Individually, only the need for repeat revascularization was significantly affected by therapy (hazard ratio, 0.62; 95% CI, 0.40–0.97). Adjustment for multiple risk factors including age, sex, and variables known to influence the need for target lesion revascularization after coronary angioplasty (use of stents, treatment of restenotic lesions, vessel size, post procedural minimal luminal diameter, target lesion location, and use of glycoprotein IIb/IIIa inhibitors) did not significantly change the relationship between homocysteine-lowering therapy and the need for repeat target lesion revascularization.

PRACTICE RECOMMENDATIONS

All patients with known coronary artery disease should take prescription strength (1 mg/d) folic acid, vitamin B₁₂ (400 μg/d), and vitamin B₆ (10 mg/d), which have few if any known adverse effects. In this study, therapy to reduce homocysteine levels with prescription strength folic acid (1 mg) and vitamins B₁₂ and B₆ for 6 months following coronary angioplasty reduced the risk of need for revascularization of target lesions and of overall adverse cardiac events at least 6 months following cessation of therapy.

Based on this study, it is unknown whether the benefit is related to baseline homocysteine levels or whether there is further benefit to continuing treatment beyond 6 months. Over-the-counter folic acid supplements (800 μg or less) were not studied and may not be as beneficial.