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Vitamin E Supplementation in the Prevention of Coronary Heart Disease
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Review
Vitamin E Supplementation in the Prevention of Coronary Heart Disease SANDHYA PRUTHI, MD; THOMAS G. ALLISON, PHD, MPH; AND DONALD D. HENSRUD, MD, MPH 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. Mayo Clin Proc. 2001;76:1131-1136 ATBC = Alpha-Tocopherol, Beta-Carotene Cancer Prevention; CHAOS = Cambridge Heart Antioxidant Study; CHD = coronary heart disease; GISSI = Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico; HOPE = Heart Outcomes Prevention Evaluation; LDL = low-density lipoprotein; PUFA = polyunsaturated fatty acid; PPP = Primary Prevention Project
T
he 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 1996.1 Vitamin E is one of the most common supplements consumed,2,3 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,4 the Heart Outcomes Prevention Evaluation (HOPE) Study,5 and the Primary Prevention Project (PPP),6 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. CHEMISTRY AND BIOLOGICAL ACTIVITY 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.7 More recently it was demonstrated that only the α-tocopherol form, specifically the 2R-stereoisomers, is maintained in plasma.8 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-αtocopherol (old term d-α-tocopherol), while the synthetic form is a mixture of 8 stereoisomers referred to as all-racα-tocopherol (old term d,l-α-tocopherol). Four of these 8 stereoisomers are of the 2R form (including RRR-α-tocopherol) and possess biological activity. Therefore, 1 mg of RRR-α-tocopherol from natural food sources is equiva-
From the Division of General Internal Medicine (S.P.), Division of Cardiovascular Diseases and Internal Medicine (T.G.A.), and Division of Preventive and Occupational Medicine and Internal Medicine and Division of Endocrinology, Metabolism, Nutrition and Internal Medicine (D.D.H.), Mayo Clinic, Rochester, Minn. Address reprint requests and correspondence to Sandhya Pruthi, MD, Division of General Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Mayo Clin Proc. 2001;76:1131-1136
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© 2001 Mayo Foundation for Medical Education and Research
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lent 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-αtocopherol are also sold. Supplements labeled mixed tocopherols 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 αtocopherol per gram of total lipid).9 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. ANTIOXIDANT PROPERTIES 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 lipoproteins 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.10 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.10 Vitamin C appears to act in conjunction with vitamin E by regenerating reduced vitamin E.11 Beta carotene appears to have the ability to quench singlet oxygen.10 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.12,13 DOSING AND REQUIREMENTS 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
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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.8 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.7 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.8 This is equivalent to 1500 IU of RRR-αtocopherol 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-αtocopherol daily.14 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.15-17 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. DIETARY SOURCES AND DEFICIENCY Vegetable, nut, and seed oils are good sources of tocopherols.18 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).18 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.8 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.9 ADVERSE EFFECTS 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
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reported minimal toxicity.19 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 wellcontrolled studies.20 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.21 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.22,23 ROLE OF VITAMIN E IN THE PREVENTION OF CHD 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.24 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.25 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.26 Basic science and animal studies have documented beneficial effects of vitamin E on several stages of the atherosclerotic process.27 Observational Studies 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
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men who did not take vitamin E.16 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.17 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.28 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.29 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.30 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. Early Randomized Controlled Trials 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.12 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.31 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.
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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.32 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. Recent Clinical Trials 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.4 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.5 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 angiotensinconverting 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.5 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.6 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.
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Ongoing Trials 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.33 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.33 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.34 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.35 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. EFFECTS OF VITAMIN E ON OTHER CONDITIONS In 2 randomized trials, vitamin E intake was associated with a slight improvement in dementia36 and a decreased risk of prostate cancer37; 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.38,39 CONCLUSIONS 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
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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. The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidantrich fruits and vegetables but has not made population-wide recommendations regarding vitamin E supplementation.40 The most recent recommendations acknowledged encouraging results from early clinical trials for secondary prevention but did not recommend vitamin E supplementation. The 3 most recently published studies should not change this lack of recommendation. An important issue regarding dietary supplements in general is that no regulation or quality control exists other than voluntarily from the manufacturer. Additionally, as yet unrecognized drug-nutrient interactions are possible. Overall, however, vitamin E has few associated adverse effects, except the potential for affecting coagulation in people with vitamin K deficiency or in those taking warfarin. A remaining issue is whether vitamin E is beneficial in combination with other antioxidants because the effects of vitamin E may vary depending on the milieu in which it is given. Ongoing trials are evaluating this issue and further defining the overall role, if any, of vitamin E in the prevention of CHD. Although vitamin E supplementation is probably safe for most people, recommendations from health care professionals should reflect the lack of established benefit as demonstrated in currently completed and published clinical trials.
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GISSI-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; 354:447-455. Yusuf 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;342:145153. Collaborative 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;357:89-95. Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council. Recommended Dietary Allowances. 10th rev ed. Washington, DC: National Academy Press; 1989:99-107. Dietary 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. Washington, DC: National Academy Press; 2000. Traber MG. Vitamin E. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore, Md: Williams & Wilkins; 1999:347-362. Diplock AT. Antioxidant nutrients and disease prevention: an overview. Am J Clin Nutr. 1991;53(1, suppl):189S-193S. Niki E. Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am J Clin Nutr. 1991;54(6, suppl):1119S1124S. Virtamo 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;158:668675. Omenn 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;334:1150-1155. Brown 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;65:496-502. Jialal I, Fuller CJ, Huet BA. The effect of α-tocopherol supplementation on LDL oxidation: a dose-response study. Arterioscler Thromb Vasc Biol. 1995;15:190-198. Rimm 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;328:1450-1456. Stampfer 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;328:1444-1449. Sheppard AJ, Weihrauch JL, Pennington JAT. Analysis and distribution of vitamin E in vegetable oils and foods. In: Packer L, Fuchs J, eds. Vitamin E in Health and Disease. New York, NY: Marcel Dekker; 1993:9-31. Ovesen L. Vitamin therapy in the absence of obvious deficiency: what is the evidence? Drugs. 1984;27:148-170. Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin Nutr. 1988;48:612-619. Corrigan JJ Jr, Marcus FI. Coagulopathy associated with vitamin E ingestion. JAMA. 1974;230:1300-1301.
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Freedman JE, Farhat JH, Loscalzo J, Keaney JF Jr. α-Tocopherol inhibits aggregation of human platelets by a protein kinase Cdependent mechanism. Circulation. 1996;94:2434-2440. Dowd P, Zheng ZB. On the mechanism of the anticlotting action of vitamin E quinone. Proc Natl Acad Sci U S A. 1995;92:81718175. Shute EV. Proposed study of vitamin E therapy. Can Med Assoc J. 1972;106:1057. Anderson TW, Reid DB. A double-blind trial of vitamin E in angina pectoris. Am J Clin Nutr. 1974;27:1174-1178. Steinberg 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;320:915-924. Hensrud DD, Heimburger DC. Antioxidant status, fatty acids, and cardiovascular disease. Nutrition. 1994;10:170-175. Losonczy 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;64:190196. Kushi 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;334:11561162. Hodis HN, Mack WJ, LaBree L, et al. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA. 1995;273:1849-1854. Blot 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;85:1483-1492. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in pa-
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tients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781-786. Manson JE, Gaziano JM, Spelsberg A, et al, WACS Research Group. A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women: rationale, design, and methods. Ann Epidemiol. 1995;5:261-269. Christen 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;10:125-134. MRC/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;20:725-741. Sano M, Ernesto C, Thomas RG, et al, Alzheimer’s Disease Cooperative Study. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med. 1997; 336:1216-1222. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with α-tocopherol and β-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440446. Meydani SN. Vitamin/mineral supplementation, the aging immune response, and risk of infection. Nutr Rev. 1993;51:106-109. Meydani 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;277:1380-1386. Tribble DL, Nutrition Committee. Antioxidant consumption and risk of coronary heart disease: emphasis on vitamin C, vitamin E, and β-carotene: a statement for healthcare professionals from the American Heart Association. Circulation. 1999;99:591-595.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
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Review
Vitamin E Supplementation in the Prevention of Coronary Heart Disease SANDHYA PRUTHI, MD; THOMAS G. ALLISON, PHD, MPH; AND DONALD D. HENSRUD, MD, MPH 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. Mayo Clin Proc. 2001;76:1131-1136 ATBC = Alpha-Tocopherol, Beta-Carotene Cancer Prevention; CHAOS = Cambridge Heart Antioxidant Study; CHD = coronary heart disease; GISSI = Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico; HOPE = Heart Outcomes Prevention Evaluation; LDL = low-density lipoprotein; PUFA = polyunsaturated fatty acid; PPP = Primary Prevention Project
T
he 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 1996.1 Vitamin E is one of the most common supplements consumed,2,3 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,4 the Heart Outcomes Prevention Evaluation (HOPE) Study,5 and the Primary Prevention Project (PPP),6 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. CHEMISTRY AND BIOLOGICAL ACTIVITY 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.7 More recently it was demonstrated that only the α-tocopherol form, specifically the 2R-stereoisomers, is maintained in plasma.8 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-αtocopherol (old term d-α-tocopherol), while the synthetic form is a mixture of 8 stereoisomers referred to as all-racα-tocopherol (old term d,l-α-tocopherol). Four of these 8 stereoisomers are of the 2R form (including RRR-α-tocopherol) and possess biological activity. Therefore, 1 mg of RRR-α-tocopherol from natural food sources is equiva-
From the Division of General Internal Medicine (S.P.), Division of Cardiovascular Diseases and Internal Medicine (T.G.A.), and Division of Preventive and Occupational Medicine and Internal Medicine and Division of Endocrinology, Metabolism, Nutrition and Internal Medicine (D.D.H.), Mayo Clinic, Rochester, Minn. Address reprint requests and correspondence to Sandhya Pruthi, MD, Division of General Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Mayo Clin Proc. 2001;76:1131-1136
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© 2001 Mayo Foundation for Medical Education and Research
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lent 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-αtocopherol are also sold. Supplements labeled mixed tocopherols 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 αtocopherol per gram of total lipid).9 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. ANTIOXIDANT PROPERTIES 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 lipoproteins 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.10 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.10 Vitamin C appears to act in conjunction with vitamin E by regenerating reduced vitamin E.11 Beta carotene appears to have the ability to quench singlet oxygen.10 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.12,13 DOSING AND REQUIREMENTS 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
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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.8 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.7 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.8 This is equivalent to 1500 IU of RRR-αtocopherol 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-αtocopherol daily.14 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.15-17 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. DIETARY SOURCES AND DEFICIENCY Vegetable, nut, and seed oils are good sources of tocopherols.18 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).18 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.8 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.9 ADVERSE EFFECTS 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
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reported minimal toxicity.19 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 wellcontrolled studies.20 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.21 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.22,23 ROLE OF VITAMIN E IN THE PREVENTION OF CHD 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.24 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.25 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.26 Basic science and animal studies have documented beneficial effects of vitamin E on several stages of the atherosclerotic process.27 Observational Studies 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
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men who did not take vitamin E.16 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.17 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.28 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.29 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.30 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. Early Randomized Controlled Trials 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.12 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.31 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.
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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.32 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. Recent Clinical Trials 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.4 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.5 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 angiotensinconverting 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.5 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.6 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.
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Ongoing Trials 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.33 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.33 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.34 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.35 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. EFFECTS OF VITAMIN E ON OTHER CONDITIONS In 2 randomized trials, vitamin E intake was associated with a slight improvement in dementia36 and a decreased risk of prostate cancer37; 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.38,39 CONCLUSIONS 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
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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. The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidantrich fruits and vegetables but has not made population-wide recommendations regarding vitamin E supplementation.40 The most recent recommendations acknowledged encouraging results from early clinical trials for secondary prevention but did not recommend vitamin E supplementation. The 3 most recently published studies should not change this lack of recommendation. An important issue regarding dietary supplements in general is that no regulation or quality control exists other than voluntarily from the manufacturer. Additionally, as yet unrecognized drug-nutrient interactions are possible. Overall, however, vitamin E has few associated adverse effects, except the potential for affecting coagulation in people with vitamin K deficiency or in those taking warfarin. A remaining issue is whether vitamin E is beneficial in combination with other antioxidants because the effects of vitamin E may vary depending on the milieu in which it is given. Ongoing trials are evaluating this issue and further defining the overall role, if any, of vitamin E in the prevention of CHD. Although vitamin E supplementation is probably safe for most people, recommendations from health care professionals should reflect the lack of established benefit as demonstrated in currently completed and published clinical trials.
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For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.