Homocysteine and Coronary Restenosis
Source: Schnyder G, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345:1593-1600.
An association between elevated total plasma homocysteine levels and restenosis after percutaneous coronary angioplasty has been demonstrated. This study was designed to evaluate the effect of lowering plasma homocysteine levels on restenosis after coronary angioplasty.
A combination of folic acid (1 mg), vitamin B12 (400 mcg), and pyridoxine (10 mg)—referred to as folate treatment—or placebo was administered to 205 patients (mean [±SD] age, 61 ± 11 years) for six months after successful coronary angioplasty in a prospective, double-blind, randomized trial. The primary endpoint was restenosis within six months as assessed by quantitative coronary angiography. The secondary endpoint was a composite of major adverse cardiac events.
Base-line characteristics and initial angiographic results after coronary angioplasty were similar in the two study groups. Twenty-two percent of the patients were women; the mean age was 61 years, and the distribution of cardiovascular risk factors was typical of a population in central Europe. The primary endpoint with respect to efficacy was the presence or absence of restenosis of 50% or more at follow-up examination.
Folate treatment significantly lowered plasma homocysteine levels from 11.1 ± 4.3 micromol/L to 7.2 ± 2.4 micromol/L (P < 0.001). At follow-up, the minimal luminal diameter was significantly larger in the group assigned to folate treatment (1.72 ± 0.76 mm vs. 1.45 ± 0.88 mm, P = 0.02), and the degree of stenosis was less severe (39.9% ± 20.3% vs. 48.2% ± 28.3%, P = 0.01). The rate of restenosis was significantly lower in patients assigned to folate treatment (19.6% vs. 37.%, P = 0.01), as was the need for revascularization of the target lesion (10.8% vs. 22.3%, P = 0.047).
There was a correlation between late loss of luminal diameter and homocysteine levels at follow-up (r = 0.27, P < 0.001; a loss of 0.1 mm of luminal diameter per 1.7 micromol of plasma homocysteine per liter). This correlation was stronger for lesions treated with balloon angioplasty only (r = 0.48, P < 0.001; 0.1 mm loss of luminal diameter per 1.2 micromol of plasma homocysteine per liter). This correlation was not reproducible for stented lesions (r = 0.07, P = 0.44).
One patient assigned to folate treatment discontinued the study medication because of pruritus. The 28 patients without angiographic follow-up data and the nine patients without clinical follow-up data did not differ significantly from the remaining population.
Treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduces homocysteine levels and decreases the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. This inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty.
Comment
Restenosis after angioplasty is far too common. Because total plasma homocysteine correlates with coronary artery disease (CAD) severity, and low (less than 9 micromol/L) levels have been observed to restenose at half the rate of patients with higher levels, the investigators decided to try to actively decrease the rate of restenosis—prospectively, using folic acid (vitamin B9), B12, and B6 as medication.
To make a long story short, it worked. Importantly, patients with an occluded graft and patients taking multivitamins (presumably to avoid excessive vitamin levels) were excluded, so these results must be taken with those caveats.
Why is homocysteine elevated in CAD? Genetic defects (one out of seven), renal failure, or B-vitamin deficiencies. What harm does homocysteine do? It increases thrombogenicity, thickens arterial intima, promotes collagen deposition, inhibits vasodilation that is endothelium-dependent, and encourages the vascular smooth-muscle cells to proliferate. All in all, it’s bad for vasculature.
What does this study add? Real clinical benefit—not just endothelial functional enhancement. Of course, it would be helpful to know that the benefit lasts, and gives rise to less angina, fewer myocardial infarctions, and fewer deaths. It would be even better to know that these B vitamins are protective in those who do not yet have clinically significant coronary disease but do have elevated homocysteine levels. But those studies have not yet been done.
Recommendation
Even in those patients with average homocysteine levels (the upper limit in most labs is 12-14 micromol/L) with CAD post-angioplasty, these B vitamins (folic acid [1 mg], vitamin B12 [400 mcg], and pyridoxine [10 mg]) should be prescribed, right along with aspirin, once daily.
La Puma J. Homocysteine and coronary restenosis. Altern Med Alert 2002;5:36.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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