Correspondence
Vitamin E Supplementation and Cardiovascular Events in High-Risk Patients
N Engl J Med 2000; 342:1917-1918June 22, 2000
- Article
To the Editor:
We would like to comment on the design and interpretation of the recent study by the Heart Outcomes Prevention Evaluation (HOPE) investigators on vitamin E supplementation and cardiovascular events (Jan. 20 issue).1 Although this study was undertaken in many geographic areas (the United States, Canada, western Europe, and South America) with different dietary intakes, dietary data (especially on antioxidants) were not reported. In addition, for no subgroup were plasma levels of vitamin E provided to confirm supplementation. Whereas the investigators in the Cambridge Heart Antioxidant Study (CHAOS), the Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) study, and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) study used alpha-tocopherol, the HOPE investigators used natural-source vitamin E, which consists of tocopherols and tocotrienols. Since alpha-tocopherol is the most potent member of the vitamin E family, this could have a bearing on their findings, since there is scanty information on the other forms of vitamin E.
We disagree with the HOPE investigators' interpretation of the prospective studies as they related to alpha-tocopherol supplementation. In the majority of the studies, a positive result was obtained for either a primary end point or a secondary end point. In CHAOS, there was a significant benefit of alpha-tocopherol with regard to the primary end point of cardiovascular death or nonfatal myocardial infarction (a 47 percent reduction). Steiner and coworkers2 showed that in patients with transient ischemic attacks, minor strokes, or residual neurologic deficits, the combination of alpha-tocopherol and aspirin as compared with aspirin alone resulted in a significant reduction in ischemic strokes and recurrent transient ischemic attacks. The ATBC investigators showed that alpha-tocopherol supplementation was associated with a decrease in the incidence of angina pectoris.3 In the GISSI study, alpha-tocopherol supplementation resulted in significant reductions in cardiovascular events, deaths from cardiac causes, deaths from coronary causes, and sudden deaths, even though the primary end point was not significantly affected.4 Thus, we believe that the conclusions of the HOPE investigators — that the prospective studies of alpha-tocopherol do not appear to suggest a benefit — is inappropriate.
4 ReferencesIshwarlal Jialal, M.D., Ph.D.
Sridevi Devaraj, Ph.D.
University of Texas Southwestern Medical Center, Dallas, TX 75390-90731
The Heart Outcomes Prevention Evaluation Study Investigators
Full Text | Web of Science | Medline2
Steiner M ,Glantz M ,Lekos A . Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr 1995;62:Suppl:1381S-1384S
Web of Science | Medline3
Rapola JM ,Virtamo J ,Haukka JK , et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. JAMA 1996;275:693-698[Erratum, JAMA 1998;279:1528.]
CrossRef | Web of Science | Medline4
Jialal I ,Devaraj S ,Huet BA ,Traber MG . GISSI-Prevenzione trial. Lancet 1999;354:1554-1554
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Author/Editor Response
Dr. Yusuf replies:
To the Editor: The comments by Jialal and Devaraj do not alter the primary conclusion of the HOPE study and two other large trials — that vitamin E has not been shown to reduce cardiovascular events. First, epidemiologic studies conducted in North America and western Europe suggested that intake of vitamin E at doses larger than 100 IU per day for more than two years was associated with lower rates of cardiovascular disease.1 In populations recruited from these areas, the HOPE study evaluated vitamin E at doses of 400 IU per day and indicated no evidence of benefit in preventing cardiovascular events over a period of approximately five years. Second, the bioavailability and antioxidant activity of the natural vitamin E preparation used in the HOPE study have been documented to be at least as good as those of synthetic vitamin E.2 Third, Table 4 of our article shows results for the most important composite cardiovascular end point in four major trials involving more than 50,000 subjects. No benefit is evident.
Jialal and Devaraj emphasize differences in selected end points (which are variable among the trials) after a post hoc analysis of several secondary outcomes. CHAOS3 was relatively small, had imbalances in numerous base-line characteristics, and was relatively short (with a median follow-up of 1.3 years, a period during which it is unlikely that atherosclerotic clinical events could be prevented). The differences observed in preventing nonfatal myocardial infarction in CHAOS were based on very few events and could reflect a type I error. Furthermore, Steiner et al.4 did not report a reduction in strokes or myocardial infarction, and the claim of a reduction in ischemic events is based on few events and a selective emphasis on the composite end point of ischemic (not all) strokes and transient ischemic attacks in the “final” (not entire) phase of the study. Both GISSI-Prevenzione,5 based on a predefined analysis of all randomly assigned patients, and the ATBC study6 showed no effect on the end points used in CHAOS or in HOPE. Therefore, the overall data from all the studies show no benefit associated with vitamin E in preventing myocardial infarction, stroke, or death during five years of treatment. We await the results of other ongoing trials as well as data from longer-term follow-up in our trial.
6 ReferencesSalim Yusuf, D.Phil., F.R.C.P.C.
McMaster University, Hamilton, ON L8L 2X2, Canada1
Jha P ,Flather M ,Lonn E ,Farkouh M ,Yusuf S . The antioxidant vitamins and cardiovascular disease: a critical review of epidemiologic data and clinical trial data. Ann Intern Med 1995;123:860-872
Web of Science | Medline2
Burton GW ,Traber MG ,Acuff RV , et al. Human plasma and tissue α-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 1998;67:669-684
Web of Science | Medline3
Stephens NG ,Parsons A ,Schofield PM ,Kelly F ,Cheeseman K ,Mitchinson MJ . Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-786
CrossRef | Web of Science | Medline4
Steiner M ,Glantz M ,Lekos A . Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr 1995;62:Suppl:1381S-1384S
Web of Science | Medline5
GISSI-Prevenzione Investigators
CrossRef | Web of Science | Medline6
The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
Full Text | Web of Science | Medline
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Kyung-Jin Yeum, Robert M. Russell, Giancarlo Aldini. 2010. Antioxidant Activity and Oxidative Stress: An Overview. , 3-19.
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JOYE K. WILLCOX, SARAH L. ASH, GEORGE L. CATIGNANI. (2004) Antioxidants and Prevention of Chronic Disease. Critical Reviews in Food Science and Nutrition 44:4, 275-295
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Ishwarlal Jialal, Sridevi Devaraj. 2003. Prospective Vitamin E Clinical Trials. .
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Andrea Harris, Sridevi Devaraj, Ishwarlal Jialal. (2002) Oxidative stress, alpha-tocopherol therapy, and atherosclerosis. Current Atherosclerosis Reports 4:5, 373-380
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Abdelouahed Khalil. (2002) Mécanisme moléculaire de l'effet protecteur de la vitamine E dans l'athérosclérose. Canadian Journal of Physiology and Pharmacology 80:7, 662-669
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Ishwarlal Jialal, Maret Traber, Sridevi Devaraj. (2001) Is there a vitamin E paradox?. Current Opinion in Lipidology 12:1, 49-53
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Sridevi Devaraj, Ishwarlal Jialal. (2000) Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Radical Biology and Medicine 29:8, 790-792
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