Vitamin E Supplementation in the Prevention of Coronary Heart Disease
2001; Elsevier BV; Volume: 76; Issue: 11 Linguagem: Inglês
10.4065/76.11.1131
ISSN1942-5546
AutoresSandhya Pruthi, Thomas G. Allison, Donald D. Hensrud,
Tópico(s)Nutritional Studies and Diet
ResumoVitamin E consists of a number of compounds, tocopherols and tocotrienols, that function as lipid-soluble antioxidants. A hypothesis is that vitamin E may slow the progression of atherosclerosis by blocking the oxidative modification of low-density lipoprotein cholesterol and thus decrease its uptake into the arterial lumen. Basic science and animal studies have generally supported this hypothesis. Observational studies have primarily assessed patients with no established coronary heart disease (CHD), and results have generally supported a protective role of vitamin E in CHD. Early primary and secondary prevention clinical trials (Alpha-Tocopherol, Beta-Carotene Cancer Protection study and Cambridge Heart Antioxidant Study) showed mixed results. Despite years of encouraging evidence from basic science and observational studies, 3 large randomized clinical trials (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico, Heart Outcomes Prevention Evaluation, and Primary Prevention Project) with a combined total of more than 25,000 patients failed to show a significant benefit with vitamin E taken as a dietary supplement for the prevention of CHD. Four large randomized primary prevention trials currently under way should add to our knowledge. The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but has made no recommendations regarding vitamin E supplementation for the general population. Although vitamin E supplementation seems to be safe for most people, recommendations from health care professionals should reflect the uncertainty of established benefit as demonstrated in clinical trials. Vitamin E consists of a number of compounds, tocopherols and tocotrienols, that function as lipid-soluble antioxidants. A hypothesis is that vitamin E may slow the progression of atherosclerosis by blocking the oxidative modification of low-density lipoprotein cholesterol and thus decrease its uptake into the arterial lumen. Basic science and animal studies have generally supported this hypothesis. Observational studies have primarily assessed patients with no established coronary heart disease (CHD), and results have generally supported a protective role of vitamin E in CHD. Early primary and secondary prevention clinical trials (Alpha-Tocopherol, Beta-Carotene Cancer Protection study and Cambridge Heart Antioxidant Study) showed mixed results. Despite years of encouraging evidence from basic science and observational studies, 3 large randomized clinical trials (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico, Heart Outcomes Prevention Evaluation, and Primary Prevention Project) with a combined total of more than 25,000 patients failed to show a significant benefit with vitamin E taken as a dietary supplement for the prevention of CHD. Four large randomized primary prevention trials currently under way should add to our knowledge. The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but has made no recommendations regarding vitamin E supplementation for the general population. Although vitamin E supplementation seems to be safe for most people, recommendations from health care professionals should reflect the uncertainty of established benefit as demonstrated in clinical trials. The popularity of dietary supplements to promote health and prevent disease has increased substantially in recent years. Sales of dietary supplements almost doubled in the 1990s, increasing from $3.3 billion per year in 1990 to $6.5 billion per year in 1996.1Kurtzweil P An FDA guide to dietary supplements.Available at: http://www.fda.gov/fdac/features/1998/598_guid.htmlGoogle Scholar Vitamin E is one of the most common supplements consumed,2F-D-C Reports/The Hartman Group: Dietary Supplement Market View.Available at: http://www.fdcreports.com/dsmvc1.htmlGoogle Scholar3Hensrud DD Engle DD Scheitel SM Underreporting the use of dietary supplements and nonprescription medications among patients undergoing a periodic health examination.Mayo Clin Proc. 1999; 74: 443-447PubMed Scopus (135) Google Scholar primarily because of its purported effects of decreasing the risk of coronary heart disease (CHD) and multiple other diseases. For a decade or more, vitamin E has been an essential element in the overall strategy for prevention of CHD not only in the minds of the general population but also of medical professionals. However, the recent publication of 3 large randomized clinical trials, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione trial,4GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial [published correction appears in Lancet. 2001;357:642].Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3729) Google Scholar the Heart Outcomes Prevention Evaluation (HOPE) Study,5Yusuf S Sleight P Pogue J Bosch J Davies R Dagenais G Heart Outcomes Prevention Evaluation Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:748, 1376].N Engl J Med. 2000; 342: 145-153Crossref PubMed Scopus (8157) Google Scholar and the Primary Prevention Project (PPP),6Collaborative Group of the Primary Prevention Project Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice.Lancet. 2001; 357: 89-95Abstract Full Text Full Text PDF PubMed Scopus (963) Google Scholar has challenged the claim that vitamin E prevents CHD. This article first reviews background information on vitamin E. The early favorable evidence for primary and secondary prevention of CHD with vitamin E is then discussed, and the more recent GISSI, HOPE, and PPP trials are reviewed. Vitamin E consists of a group of 8 molecules belonging to 2 classes designated as tocopherols and tocotrienols. Both tocopherols and tocotrienols possess 4 structurally similar forms designated α, β, γ, and δ. In the past it was believed that each of these forms had a different degree of biological activity, with α-tocopherol having the greatest.7Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council.in: Recommended Dietary Allowances. 10th rev ed. National Academy Press, Washington, DC1989: 99-107Google Scholar More recently it was demonstrated that only the α-tocopherol form, specifically the 2R-stereoisomers, is maintained in plasma.8Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. National Academy Press, Washington, DC2000Google Scholar The other forms are not converted to α-tocopherol in humans and do not contribute toward meeting the vitamin E requirement. The isomer of α-tocopherol found in nature is RRR-α-tocopherol (old term d-α-tocopherol), while the synthetic form is a mixture of 8 stereoisomers referred to as all-rac-α-tocopherol (old term d,l-α-tocopherol). Four of these 8 stereoisomers are of the 2R form (including RRR-α-to-copherol) and possess biological activity. Therefore, 1 mg of RRR-α-tocopherol from natural food sources is equivalent in vitamin E activity to 2 mg of all-rac-α-tocopherol from synthetic supplemental vitamin E. Vitamin E supplements usually contain synthetic all-rac-α-tocopherol, although natural vitamin E supplements containing RRR-α-tocopherol are also sold. Supplements labeled mixed to-copherols and tocotrienols contain combinations of these natural compounds. The absorption of vitamin E is dependent on dietary fat and aided by bile salts and pancreatic enzymes. Vitamin E is transported in blood on plasma lipids. Therefore, circulating tocopherol concentration is dependent on plasma lipid concentration. In patients with extremely high or low lipids, vitamin E levels should be interpreted with respect to their ratio with total plasma lipids (normal >0.8 mg of α-tocopherol per gram of total lipid).9Traber MG Vitamin E.in: Shils ME Olson JA Shike M Ross AC Modern Nutrition in Health and Disease. 9th ed. Williams & Wilkins, Baltimore, Md1999: 347-362Google Scholar For example, a low plasma vitamin E in the setting of low serum lipids does not necessarily indicate deficiency. The uptake of vitamin E from plasma to tissue occurs by a low-density lipoprotein (LDL) receptor mechanism and lipoprotein lipase–mediated lipoprotein catabolism. Biological activities of vitamin E include promoting normal formation of red blood cells and normal function of the nervous and immune systems. The role of vitamin E as a lipid-soluble antioxidant in cellular membranes and lipo-proteins is important. Free radicals are highly reactive oxygen species due to 1 or more unpaired electrons and are formed during normal metabolism and inflammatory processes. Free radicals can bind to any adjacent normal cellular component, including polyunsaturated fatty acids (PUFAs) or DNA, and oxidize or "steal" an electron, causing damage to that component. Lipid peroxyl radicals, formed by the attack of free radicals on PUFA, can propagate indefinitely in a chain reaction.10Diplock AT Antioxidant nutrients and disease prevention: an overview.Am J Clin Nutr. 1991; 53: 189S-193SPubMed Google Scholar Vitamin E is capable of protecting fatty acids by scavenging the peroxyl radical and stopping this reaction; thus, vitamin E is described as a "chain-breaking" antioxidant. Other major nutrients that are part of the antioxidant defense system include vitamin C and selenium.10Diplock AT Antioxidant nutrients and disease prevention: an overview.Am J Clin Nutr. 1991; 53: 189S-193SPubMed Google Scholar Vitamin C appears to act in conjunction with vitamin E by regenerating reduced vitamin E.11Niki E Action of ascorbic acid as a scavenger of active and stable oxygen radicals.Am J Clin Nutr. 1991; 54: 1119S-1124SPubMed Google Scholar Beta carotene appears to have the ability to quench singlet oxygen.10Diplock AT Antioxidant nutrients and disease prevention: an overview.Am J Clin Nutr. 1991; 53: 189S-193SPubMed Google Scholar However, randomized studies evaluating beta carotene supplementation have shown no significant benefit, and among smokers the risk of lung cancer and overall mortality was increased.12Virtamo J Rapola JM Ripatti S et al.Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease.Arch Intern Med. 1998; 158: 668-675Crossref PubMed Scopus (255) Google Scholar13Omenn GS Goodman GE Thornquist MD et al.Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.N Engl J Med. 1996; 334: 1150-1155Crossref PubMed Scopus (3108) Google Scholar The nomenclature of vitamin E activity can be confusing. The Institute of Medicine has recommended that the old nomenclature using α-tocopherol equivalents be abandoned. This is based on their review of data that indicate only the 2R-stereoisomers of α-tocopherol possess biological activity. With use of current conversions, 1 IU is equivalent to 0.67 mg of RRR-α-tocopherol or 0.45 mg of all-rac-α-tocopherol. The recommended dietary allowance is now set at 15 mg of α-tocopherol, primarily from food sources.8Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. National Academy Press, Washington, DC2000Google Scholar This is equivalent to 22 IU of RRR-α-tocopherol or 33 IU of allrac-α-tocopherol. The requirements for vitamin E increase as the dietary intake of PUFA increases.7Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council.in: Recommended Dietary Allowances. 10th rev ed. National Academy Press, Washington, DC1989: 99-107Google Scholar However, vitamin E is often found in association with PUFA; thus, vitamin E intake increases proportionately with PUFA intake. The upper limit of intake is 1000 mg/d of any form of supplemental α-tocopherol, including all 8 stereoisomers of allrac-α-tocopherol.8Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. National Academy Press, Washington, DC2000Google Scholar This is equivalent to 1500 IU of RRR-α-tocopherol or 1100 IU of all-rac-α-tocopherol. The upper limit is consistent with 1 study reporting increased erythrocyte peroxidation in subjects ingesting 1050 mg of RRR-α-tocopherol daily.14Brown KM Morrice PC Duthie GG Erythrocyte vitamin E and plasma ascorbate concentrations in relation to erythrocyte peroxidation in smokers and nonsmokers: dose response to vitamin E supplementation.Am J Clin Nutr. 1997; 65: 496-502PubMed Google Scholar Because RRR-α-tocopherol has twice the activity of allrac-α-tocopherol, it has been suggested that supplementation with natural RRR-α-tocopherol is preferred over synthetic all-rac-α-tocopherol. However, all 2R-stereoisomers contribute similarly toward vitamin E activity. In addition, the amount of vitamin E contained in supplements is usually many times greater than the recommended dietary allowance. The amount of vitamin E necessary to decrease the susceptibility of LDL to oxidation or protect against cardiovascular disease has been estimated at 100 to 400 IU/d.15Jialal I Fuller CJ Huet BA The effect of a-tocopherol supplementation on LDL oxidation: a dose-response study.Arterioscler Thromb Vasc Biol. 1995; 15: 190-198Crossref PubMed Scopus (343) Google Scholar, 16Rimm EB Stampfer MJ Ascherio A Giovannucci E Colditz GA Willett WC Vitamin E consumption and the risk of coronary heart disease in men.N Engl J Med. 1993; 328: 1450-1456Crossref PubMed Scopus (2137) Google Scholar, 17Stampfer MJ Hennekens CH Manson JE Colditz GA Rosner B Willett WC Vitamin E consumption and the risk of coronary disease in women.N Engl J Med. 1993; 328: 1444-1449Crossref PubMed Scopus (1917) Google Scholar Therefore, because most supplementation is at pharmacological rather than physiological doses, the issue of supplementation with RRR-α-tocopherol rather than allrac-α-tocopherol may be debatable. Vegetable, nut, and seed oils are good sources of tocopherols.18Sheppard AJ Weihrauch JL Pennington JAT Analysis and distribution of vitamin E in vegetable oils and foods.in: Packer L Fuchs J Vitamin E in Health and Disease. Marcel Dekker, New York, NY1993: 9-31Google Scholar Commonly consumed food sources of α-tocopherol and their concentrations include canola oil (21 mg/100 g), olive oil (12 mg/100 g), margarine (16–24 mg/100 g), almonds (45 mg/100 g), and peanuts (11 mg/100 g).18Sheppard AJ Weihrauch JL Pennington JAT Analysis and distribution of vitamin E in vegetable oils and foods.in: Packer L Fuchs J Vitamin E in Health and Disease. Marcel Dekker, New York, NY1993: 9-31Google Scholar Median daily intakes of α-tocopherol in the United States are approximately 7 to 10 mg for men and 5 to 8 mg for women, although these may be underestimated.8Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. National Academy Press, Washington, DC2000Google Scholar Despite these low intakes, overt dietary vitamin E deficiency is uncommon because of its relatively wide distribution in foods commonly consumed. In premature neonates, people with fat malabsorption, or people with genetic conditions such as abetalipoproteinemia, vitamin E deficiency can develop.9Traber MG Vitamin E.in: Shils ME Olson JA Shike M Ross AC Modern Nutrition in Health and Disease. 9th ed. Williams & Wilkins, Baltimore, Md1999: 347-362Google Scholar Several studies of vitamin E that have used dosages as high as 3200 IU/d and a follow-up of more than 10 years have reported minimal toxicity.19Ovesen L Vitamin therapy in the absence of obvious deficiency: what is the evidence?.Drugs. 1984; 27: 148-170Crossref PubMed Scopus (30) Google Scholar Adverse effects described in published individual case reports or uncontrolled studies with intakes of vitamin E higher than 400 IU/d include fatigue, muscle weakness, coagulation disorders, and gastrointestinal symptoms such as cramps and diarrhea. These adverse effects were generally not observed in larger well-controlled studies.20Bendich A Machlin LJ Safety of oral intake of vitamin E.Am J Clin Nutr. 1988; 48: 612-619PubMed Google Scholar Oral intake of vitamin E does not result in blood coagulation abnormalities in healthy people. In patients with vitamin K deficiency, such as malabsorption syndromes or with use of anticoagulation drugs such as warfarin, high doses of vitamin E can exacerbate coagulation defects.21Corrigan Jr, JJ Marcus FI Coagulopathy associated with vitamin E ingestion.JAMA. 1974; 230: 1300-1301Crossref PubMed Scopus (101) Google Scholar The precise mechanism by which this occurs is unknown but may be due to inhibition of platelet aggregation, interference of vitamin E directly with vitamin K, or inhibition of vitamin E quinone 2 with vitamin K–dependent carboxylase.22Freedman JE Farhat JH Loscalzo J Keaney Jr, JF α-Tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism.Circulation. 1996; 94: 2434-2440Crossref PubMed Scopus (280) Google Scholar23Dowd P Zheng ZB On the mechanism of the anticlotting action of vitamin E quinone.Proc Natl Acad Sci U S A. 1995; 92: 8171-8175Crossref PubMed Scopus (116) Google Scholar Early interest in the use of vitamin E supplementation in patients with CHD came from the enthusiastic reports of a London, Ontario, physician, Evan Shute, who recommended vitamin E for all his patients with CHD and presented case series showing significant benefit in reducing symptoms of angina pectoris.24Shute EV Proposed study of vitamin E therapy.Can Med Assoc J. 1972; 106: 1057PubMed Google Scholar However, his data were not placebo controlled or blinded and were based only on subjective reports. The mechanism of benefit was proposed to be improved myocardial efficiency rather than reduced progression of atherosclerosis–a proposed benefit that occurred later when the role and mechanisms of LDL cholesterol in atherosclerosis were elucidated experimentally. A small (48 patients in a crossover design) randomized clinical trial funded by the National Institutes of Health to determine the effects of vitamin E supplementation on angina and exercise tolerance in patients with established symptomatic CHD was ultimately performed.25Anderson TW Reid DB A double-blind trial of vitamin E in angina pectoris.Am J Clin Nutr. 1974; 27: 1174-1178PubMed Google Scholar The results were negative, thus dampening early enthusiasm for vitamin E in the treatment of CHD. More recently, interest in vitamin E was renewed with the development of the hypothesis that atherosclerosis may be prevented by blocking the oxidative modification of LDL cholesterol and thus decrease its uptake into the arterial lumen.26Steinberg D Parthasarathy S Carew TE Khoo JC Witztum JL Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity.N Engl J Med. 1989; 320: 915-924Crossref PubMed Google Scholar Basic science and animal studies have documented beneficial effects of vitamin E on several stages of the atherosclerotic process.27Hensrud DD Heimburger DC Antioxidant status, fatty acids, and cardiovascular disease.Nutrition. 1994; 10: 170-175PubMed Google Scholar The Health Professionals Follow-up Study was a prospective investigation of 39,910 male health professionals free of CHD, diabetes, or hypercholesterolemia at baseline. Those who took at least 100 IU/d of vitamin E for more than 2 years had a 37% lower risk of CHD compared with men who did not take vitamin E.16Rimm EB Stampfer MJ Ascherio A Giovannucci E Colditz GA Willett WC Vitamin E consumption and the risk of coronary heart disease in men.N Engl J Med. 1993; 328: 1450-1456Crossref PubMed Scopus (2137) Google Scholar The Nurses' Health Study, a prospective study of 87,245 nurses, reported that among middle-aged women the use of vitamin E supplements for more than 2 years was associated with a 41% lower risk of CHD.17Stampfer MJ Hennekens CH Manson JE Colditz GA Rosner B Willett WC Vitamin E consumption and the risk of coronary disease in women.N Engl J Med. 1993; 328: 1444-1449Crossref PubMed Scopus (1917) Google Scholar The Established Populations for Epidemiologic Studies of the Elderly found a decreased risk of CHD mortality and overall mortality among 11,178 elderly persons age 67 to 105 years who used vitamin E supplements.28Losonczy KG Harris TB Havlik RJ Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly.Am J Clin Nutr. 1996; 64: 190-196PubMed Google Scholar The Iowa Women's Health Study, a prospective cohort study of 34,486 postmenopausal women free of heart disease at baseline, revealed that the intake of vitamin E from food was inversely associated with the risk of death from CHD.29Kushi LH Folsom AR Prineas RJ Mink PJ Wu Y Bostick RM Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women.N Engl J Med. 1996; 334: 1156-1162Crossref PubMed Scopus (846) Google Scholar Of interest, that study showed no effect with vitamin E supplements. In the Cholesterol Lowering Atherosclerosis Study (CLAS), 156 men were examined who had undergone coronary artery bypass grafting with serial quantitative coronary angiography.30Hodis HN Mack WJ LaBree L et al.Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis.JAMA. 1995; 273: 1849-1854Crossref PubMed Scopus (314) Google Scholar Those with self-selected intake of at least 100 IU/d of vitamin E had less coronary artery disease progression over 2 years. Overall, these results from observational studies appear to support a protective role of vitamin E for CHD. Before GISSI, HOPE, and PPP, 3 randomized clinical trials evaluated the role of vitamin E in the prevention of CHD. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, 29,133 male smokers in southwestern Finland were assigned to receive 50 mg/d of vitamin E (all-rac-α-tocopherol acetate) or placebo and 20 mg/d of beta carotene or placebo in a 2 × 2 design.12Virtamo J Rapola JM Ripatti S et al.Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease.Arch Intern Med. 1998; 158: 668-675Crossref PubMed Scopus (255) Google Scholar The primary hypothesis was that antioxidant supplementation would reduce the incidence of lung cancer in this high-risk population, although cardiovascular events were also collected and reported. After a median treatment of 6.1 years, no significant reduction was noted in nonfatal myocardial infarction or CHD mortality. A randomized trial conducted in China involved 29,584 adults from Linxian Province.31Blot WJ Li JY Taylor PR et al.Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population.J Natl Cancer Inst. 1993; 85: 1483-1492Crossref PubMed Scopus (1514) Google Scholar Subjects were randomly assigned to receive daily supplementation of 30 mg of vitamin E (α-tocopherol), 15 mg of beta carotene, and 50 µg of selenium vs placebo and were followed up for a mean of 5.2 years. Those receiving the nutrient supplements experienced a significant 9% decrease in death from all causes with no significant reduction in cardiovascular events. Because of the other supplements involved, it is difficult to attribute this benefit to vitamin E. Moreover, the nutritional status of this population differs from that of Western populations, and the observed benefit may have been due to correcting preexisting deficiencies. The Cambridge Heart Antioxidant Study (CHAOS) reported that vitamin E supplementation (400–800 IU/d of RRR-α-tocopherol) in 2002 patients with angiographically proven coronary atherosclerosis reduced the risk of the primary trial end point of combined cardiovascular death and nonfatal myocardial infarction by 47% after a mean of 17 months.32Stephens 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: 781-786Abstract PubMed Scopus (1658) Google Scholar The entire benefit was seen in patients with nonfatal myocardial infarctions, which were decreased by 77%. No significant difference was noted in cardiovascular or overall mortality between patients who took vitamin E compared with those who took placebo. The GISSI-Prevenzione trial involved 11,324 patients who were randomized within 3 months of experiencing a myocardial infarction to receive 300 mg/d of vitamin E (all-rac-α-tocopherol), 1 g/d of ω-3 fatty acids, both or placebo in a 2 × 2 design.4GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial [published correction appears in Lancet. 2001;357:642].Lancet. 1999; 354: 447-455Abstract Full Text Full Text PDF PubMed Scopus (3729) Google Scholar Supplementation with ω-3 PUFA significantly decreased the risk of the primary end point of combined stroke, nonfatal myocardial infarction, and overall mortality. Supplementation with vitamin E showed no significant benefit. However, based on secondary analyses of the end point of cardiovascular death, a possible benefit of vitamin E cannot be excluded or dismissed. The HOPE Study reported no apparent effect of vitamin E supplementation on cardiovascular outcomes in high-risk patients.5Yusuf S Sleight P Pogue J Bosch J Davies R Dagenais G Heart Outcomes Prevention Evaluation Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:748, 1376].N Engl J Med. 2000; 342: 145-153Crossref PubMed Scopus (8157) Google Scholar This study consisted of 2545 women and 6996 men 55 years of age or older who had documented vascular disease or diabetes plus 1 other coronary risk factor. Subjects were randomized in a 2 × 2 factorial design to receive 400 IU/d of vitamin E from natural sources, an angiotensin-converting enzyme inhibitor (ramipril), both, or placebo. After a mean treatment period of 4.5 years, no significant differences were noted between vitamin E and placebo in myocardial infarction, stroke, or death from cardiovascular disease. Of note, ramipril was associated with a significant decrease in cardiovascular morbidity and mortality in all subgroups.5Yusuf S Sleight P Pogue J Bosch J Davies R Dagenais G Heart Outcomes Prevention Evaluation Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:748, 1376].N Engl J Med. 2000; 342: 145-153Crossref PubMed Scopus (8157) Google Scholar In the PPP, 4495 men and women with 1 or more coronary risk factors were randomized to receive 100 mg/d of aspirin, 300 mg/d of vitamin E (all-rac-α-tocopherol), both or placebo in an open 2 × 2 factorial design.6Collaborative Group of the Primary Prevention Project Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice.Lancet. 2001; 357: 89-95Abstract Full Text Full Text PDF PubMed Scopus (963) Google Scholar The primary end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Although aspirin was associated with a 29% reduction in the primary end point, no reduction occurred with vitamin E. In the 5 large clinical trials (ATBC, CHAOS, GISSI, HOPE, PPP), the total number of events reported in the vitamin E group was 2098 vs 2140 in the placebo group for a relative risk of 0.98, suggesting that the benefit of vitamin E supplementation was small or absent. Four large clinical trials (1 secondary and 3 primary prevention) studying the effect of vitamin E supplementation, either alone or in combination with other antioxidants, are under way. The Women's Health Study is investigating the effects of 100 mg of aspirin, 600 IU of vitamin E, and 50 mg of beta carotene, all given on alternate days in a 2 × 2 × 2 design, in 39,876 healthy female health professionals.33Manson JE Gaziano JM Spelsberg A WACS Research Group et al.A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women: rationale, design, and methods.Ann Epidemiol. 1995; 5: 261-269Abstract Full Text PDF PubMed Scopus (87) Google Scholar In a companion study, the Women's Antioxidant and Cardiovascular Study, 8000 women with preexisting cardiovascular disease are being randomized in the same 2 × 2 × 2 design.33Manson JE Gaziano JM Spelsberg A WACS Research Group et al.A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women: rationale, design, and methods.Ann Epidemiol. 1995; 5: 261-269Abstract Full Text PDF PubMed Scopus (87) Google Scholar The Physicians' Health Study II is randomizing 15,000 healthy male physicians in a 2 × 2 × 2 × 2 design of alternate days of vitamin E (400 IU), vitamin C (500 mg), beta carotene (50 mg), and a multivitamin.34Christen WG Gaziano JM Hennekens CH Design of Physicians' Health Study II—a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials.Ann Epidemiol. 2000; 10: 125-134Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar The Heart Protection Study has randomized 20,436 high-risk men and women in a 2 × 2 treatment design to receive 40 mg/d of simvastatin or placebo and a daily antioxidant combination of 600 mg of vitamin E, 20 mg of beta carotene, and 250 mg of vitamin C or placebo.35MRC/BHF Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience.Eur Heart J. 1999; 20: 725-741Crossref PubMed Scopus (254) Google Scholar Results of these 4 trials should provide further information on potential benefits and risks of vitamin E supplementation. The strategy of combining vitamin E with other antioxidants vs administration of only vitamin E, as was done in all 3 of the recently published clinical trials, will be addressed. Differential effects of vitamin E in women vs men, primary vs secondary prevention, and in older vs younger individuals will also be evaluated in these ongoing investigations. In 2 randomized trials, vitamin E intake was associated with a slight improvement in dementia36Sano M Ernesto C Thomas RG Alzheimer's Disease Cooperative Study et al.A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease.N Engl J Med. 1997; 336: 1216-1222Crossref PubMed Scopus (2294) Google Scholar and a decreased risk of prostate cancer37Heinonen OP Albanes D Virtamo J et al.Prostate cancer and supplementation with a-tocopherol and -carotene: incidence and mortality in a controlled trial.J Natl Cancer Inst. 1998; 90: 440-446Crossref PubMed Scopus (783) Google Scholar; thus, these considerations may influence a patient's decision to take vitamin E. In addition, prospective studies have shown that multivitamin supplementation, in particular vitamin E, improves immune function and decreases incidence of infections in elderly subjects.38Meydani SN Vitamin/mineral supplementation, the aging immune response, and risk of infection.Nutr Rev. 1993; 51: 106-109PubMed Google Scholar39Meydani SN Meydani M Blumberg JB et al.Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial.JAMA. 1997; 277: 1380-1386Crossref PubMed Google Scholar The evidence in the scientific literature evaluating the role of vitamin E supplementation on the reduction of CHD has been of great interest, particularly as patients take supplements for disease prevention. Experimental studies have identified potential mechanisms by which atherosclerosis may be inhibited by vitamin E supplementation. Observational studies have primarily assessed patients with no established coronary artery disease and suggest some benefit. However, the data from randomized trials performed to date generally do not support the results from basic science, animal, and observational studies. The 3 most recently published trials, GISSI, HOPE, and PPP, showed no benefit of only vitamin E in the prevention of CHD. Although GISSI was strictly a secondary prevention study and PPP a primary prevention study, HOPE included subjects with and without established CHD (although all were at high risk). Prior trials, the large ATBC and Linxian Province studies, both of which used small doses of vitamin E, and the smaller CHAOS trial, showed equivocal results, with suggestion of a slight benefit from vitamin E. The overall record of the clinical trials of CHD prevention with vitamin E is disappointing in light of the enthusiasm raised by observational and experimental studies. The evidence from these large randomized trials must be considered the strongest evidence in evaluation of the clinical benefit of vitamin E.
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