Correspondence
B Vitamins and Restenosis after Coronary Angioplasty
N Engl J Med 2002; 346:1093-1095April 4, 2002
- Article
To the Editor:
Schnyder et al. (Nov. 29 issue)1 suggest that a combination of B vitamins lowers plasma homocysteine levels, which, in turn, reduces the rate of restenosis after coronary angioplasty. This effect is interpreted as evidence of a causal role of hyperhomocysteinemia in the progression of atherosclerotic disease. Observational studies and clinical trials have been unable to rule out the alternative hypothesis that serum folate, vitamin B12, or pyridoxine may have an independent inhibitory effect on atherosclerosis, with a secondary effect on the homocysteine level. Indeed, observational data from large, prospective studies, such as the Atherosclerosis Risk in Communities Study,2 showed a stronger relation between blood pyridoxine levels and coronary end points than between serum homocysteine levels and coronary end points, when plasma levels of homocysteine, folate, B6, and B12 and other risk factors were entered into a multivariate model.
The B vitamins are very biologically active and may also have antioxidant capability.3,4 The importance of a distinction between a pathway through which folate, B6, or B12 acts directly and a pathway through which they act by means of a reduction in the homocysteine level lies in the need to measure homocysteine. Such measurement represents an added expense and would result in a potential barrier to B vitamin treatment if the homocysteine level were “normal.” Moreover, a small proportion (15 to 20 percent) of patients receiving folate therapy have a paradoxical increase in homocysteine levels, a fact that emphasizes the importance of determining whether the low B vitamin levels or the high homocysteine levels are the causal factor.5
5 ReferencesDoru V. Chirieac, M.D.
Thomas A. Pearson, M.D., Ph.D., M.P.H.
University of Rochester Medical Center, Rochester, NY 14642
thomas_pearson@urmc.rochester. edu 1
Schnyder G ,Roffi M ,Pin R , et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600
Full Text | Web of Science | Medline2
Folsom AR ,Nieto FJ ,McGovern PG , et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998;98:204-210
Web of Science | Medline3
Durand P ,Prost M ,Loreau N ,Lussier-Cacan S ,Blache D . Impaired homocysteine metabolism and atherothrombotic disease. Lab Invest 2001;81:645-672
CrossRef | Web of Science | Medline4
Brattstrom L ,Wilcken DE . Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000;72:315-323
Web of Science | Medline5
Malinow MR . Plasma concentrations of total homocysteine predict mortality risk. Am J Clin Nutr 2001;74:3-3
Web of Science | Medline
To the Editor:
In addition to the small number of patients with coronary artery disease studied by Schnyder et al., two major issues not addressed by the study design severely limit the external validity of the reported findings. First, 44 percent of the 231 lesions analyzed had no stent placed. This rate of unstented lesions that were treated with percutaneous transluminal coronary angioplasty (PTCA) is at least twice as high as the rate in the most recent report available from the National Heart, Lung, and Blood Institute Dynamic Registry,1 which covers a representative sample of more than 2000 patients with coronary artery disease in the United States.
Moreover, in a representative sample of 267 U.S. patients with coronary artery disease who were passively exposed to the long-term background effects of grain products fortified with folic acid, the geometric mean of their fasting plasma total homocysteine levels was only 8.3 μmol per liter,2 not the approximately 11.0 μmol per liter reported by Schnyder et al. for patients with coronary artery disease who had not been exposed to such products. Two additional independent controlled trials3,4 involving more than 200 patients have further confirmed that even high-dose treatment with folic acid (i.e., 5 mg per day), either alone3 or in combination with 50 mg of vitamin B6 and 1 mg of vitamin B12 per day,4 reduces the mean fasting total homocysteine level by only 1 μmol per liter among patients with coronary artery disease and long-term exposure to grain products fortified with folic acid. Before anyone can make appropriate, evidence-based recommendations for clinical practice that are relevant to patients in the United States, the findings of Schnyder et al. must be confirmed in a much larger group of patients with coronary artery disease undergoing PTCA with a more typical (i.e., higher) rate of stent placement and long-term exposure to folic-acid–fortified grain products.
4 ReferencesAndrew G. Bostom, M.D.
Barry Sharaf, M.D.
Nicholas Miele, B.S.
Rhode Island Hospital, Providence, RI 02903
abostom@lifespan.org 1
Williams DO ,Vlachos H ,Detre KM ,Cohen H ,Jacobs AK ,Kelsey SF . Patients who are not treated with stents in the stent era: who are they and what is their outcome? J Am Coll Cardiol 2001;37:Suppl A:53A-53A abstract.
CrossRef | Web of Science2
Liaugaudas G ,Jacques PF ,Selhub J ,Rosenberg IH ,Bostom AG . Renal insufficiency, vitamin B(12) status, and population attributable risk for mild hyperhomocysteinemia among coronary artery disease patients in the era of folic acid-fortified cereal grain flour. Arterioscler Thromb Vasc Biol 2001;21:849-851
CrossRef | Web of Science | Medline3
Title LM ,Cummings PM ,Giddens K ,Genest JJ Jr ,Nassar BA . Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2000;36:758-765
CrossRef | Web of Science | Medline4
Bostom AG, Jacques PF, Liaugaudas G, Roger S, Rosenberg IH, Selhub J. Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid fortified cereal grain flour. Arterioscler Thromb Vasc Biol (in press).
Author/Editor Response
The authors reply:
To the Editor: Contrary to the assertion of Drs. Chirieac and Pearson, we did not interpret the beneficial effect of homocysteine-lowering therapy on restenosis “as evidence of a causal role of hyperhomocysteinemia in the progression of atherosclerotic disease.” We refer them to our article, in which we stated that “we cannot be certain whether the benefit seen was due solely to lower homocysteine levels or was also influenced by other effects of folate [plus B6 and B12] treatment.”
Bostom et al. question the “external validity” of our results for a U.S. population. Although our rate of stent placement was 56 percent, it reflects revascularization of a substantial number of lesions in small vessels (the mean diameter of the vessels involved was 2.8 mm). Provisional and not primary stenting is considered the appropriate evidence-based medical practice in this situation, whether in Europe or the United States.1,2 Regardless, results of a subanalysis of our stented lesions, albeit not statistically significant, show a difference of 31 percent in the rate of restenosis in favor of homocysteine-lowering therapy.
As for the call by Bostom et al. for a confirmation of our findings in the context of the current U.S. program of folate fortification of food, we certainly endorse this idea. We would point out, however, that the fortification of food with a small amount of folate (100 μg) has been implemented for women of childbearing age, who most likely have a different diet from that of the average older patient with cardiac disease. Furthermore, 100 μg is believed to be absorbed daily by those in the United States who have an average balanced diet.3 This intake amounts to 10 percent of the 1 mg of folate and none of the vitamin B12 or pyridoxine given to our patients, and there is no basis for assuming that such an intake alone would be adequate to achieve the lowering of the rate of restenosis seen in our study.
3 ReferencesGuido Schnyder, M.D.
Zoltan G. Turi, M.D.
University of California at San Diego Medical Center, San Diego, CA 92103-8784
gschnyder@lycos.com 1
Kastrati A ,Schomig A ,Dirschinger J , et al. A randomized trial comparing stenting with balloon angioplasty in small vessels in patients with symptomatic coronary artery disease. Circulation 2000;102:2593-2598
Web of Science | Medline2
Park S-W ,Lee CW ,Hong MK , et al. Randomized comparison of coronary stenting with optimal balloon angioplasty for treatment of lesions in small coronary arteries. Eur Heart J 2000;21:1785-1789
CrossRef | Web of Science | Medline3
Tice JA ,Ross E ,Coxson PG , et al. Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for the prevention of coronary heart disease: effect of grain fortification and beyond. JAMA 2001;286:936-943
CrossRef | Web of Science | Medline
