Abstract & Commentary
Elevated plasma homocysteine is an independent risk factor for the development of coronary artery disease (CAD) and has previously been shown to correlate with outcomes in the presence of established CAD. In previous reports, Schnyder and colleagues have demonstrated an association between elevated plasma homocysteine levels and restenosis after percutaneous coronary intervention (PCI), and that treatment with a combination of folic acid, vitamin B12, and pyridoxine reduces homocysteine levels as well as angiographic restenosis and the need for target lesion revascularization (TLR) within 6 months of follow-up.1 The present study, which includes the patients from their original report, expands on these results, demonstrating that 6 months of homocysteine-lowering therapy decreases the frequency of adverse clinical events out to 1 year after successful PCI.
This is a randomized, double-blind, placebo-controlled trial. The study population consisted of 553 patients who underwent successful PCI at the University of Bern between May 1998 and April 1999. Patients with unstable angina, recent myocardial infarction (MI), renal insufficiency (serum creatinine > 1.8 mg/dL), or who were taking vitamin supplementation were excluded from the study. Patients were randomized to receive homocysteine-lowering therapy with folic acid (1 mg/d), vitamin B12 (400 mg/d), and vitamin B6 (10 mg/d) or placebo for 6 months. Clinical follow-up was performed at 6 months and 1 year, or earlier if recurrent symptoms warranted. Follow-up included stress testing and electrocardiography (as well as 6-month coronary angiography for the 205 patients in the previously published subgroup analysis).1 Major adverse events were defined as death, nonfatal Q-wave MI, and need for repeat revascularization for documented ischemia. The primary end point was a composite of major adverse events at 1 year of follow-up.
The folate + B12+B6 and placebo groups were well matched in terms of baseline clinical and angiographic characteristics. Baseline homocysteine levels were comparable in the 2 groups. Twenty-nine percent of patients had mild-to-moderately elevated homocysteine levels (> 1.62 mg.L) at baseline. No patient had severe hyperhomocystinemia (> 13.5 mg/L) at baseline. Not surprisingly, patients treated with folate + B12+B6 had significantly lower mean homocysteine levels than those treated with placebo (1.01 mg/L vs 1.36 mg/L) at 6 months.
The mean duration of follow-up was 11 months. The composite end point was significantly lower in patients receiving homocysteine lowering therapy (15.4% vs 22.8%; P = 0.03). This was attributable primarily to the lower rates of TLR (9.9% vs 16.0%; P = 0.03), though trends toward lower rates of death and MI were also noted in the patients treated with folate + B12+B6. Adjustment for multiple demographic and angiographic factors known to be associated with higher rates of TLR (such as diabetes, vessel size, use of stents, treatment of restenotic lesion) did not alter the relationship between homocysteine lowering therapy and outcome, and in fact, resulted in an adjusted P value of 0.01. The benefit of folate + B12+B6 therapy was present in all subgroups of traditional risk factors, and was greatest in the patients with the highest terciles of total cholesterol and LDL (Schnyder G, et al. JAMA. 2002;288:973-979).
Comment by Sarah M. Vernon, MD
This study demonstrates that homocysteine lowering therapy using folate + B12+B6 improves clinical outcomes in patients undergoing PCI, primarily by reducing the need for ischemia driven target lesion revascularization. This benefit persists out to 1 year of follow-up after a 6-month course of therapy. This study adds to a growing body of data demonstrating the value of homocysteine lowering therapy for lowering the risk of atherosclerotic coronary events even in patients without overtly elevated homocysteine levels. Schnyder et al acknowledge that the use of a folate + B12+B6 "cocktail" makes it difficult to determine the precise mechanism of this effect. Despite this imprecision, there is little downside to the folate + B12+B6 therapy. It is inexpensive, readily available, and well tolerated. In addition, the use of "vitamins" is likely to be embraced by many patients in an era when dietary supplements are somewhat in "fashion." All this and a therapy that seems to actually reduce restenosis and clinical events.
Dr. Vernon is Assistant Professor of Medicine Director, VAMC Cardiac Catherization Laboratory, University of New Mexico, Health Sciences Center, Albuquerque, NM.
Reference
1. Schnyder G, et al. N Engl J Med. 2001;345:1593-1600.
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