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Update on Vitamin Supplements for the Prevention of Coronary Disease and Stroke
Kevin A. PearceDietary antioxidants and folic acid may play a role in the pathophysiology of coronary disease and stroke. We review patient-oriented evidence on the effectiveness of supplementation with antioxidants and/or folic acid in the prevention of myocardial infarction and stroke. Observational data suggest cardiovascular benefit of vitamin E supplementation, but results of controlled clinical trials are inconsistent regarding the effect on nonfatal myocardial infarction. Moreover, studies have not shown a protective effect of vitamin E against fatal myocardial infarction and have not addressed stroke. For vitamin C and folic acid supplementation, observational data are inconsistent and controlled clinical trials are lacking. Thus, the available evidence is insufficient to recommend the routine use of vitamin E, vitamin C or folate supplements for the prevention of myocardial infarction or stroke. The evidence argues against the use of beta carotene supplements for this purpose. The costs and risks associated with these supplements are low, however, and physicians may choose to recommend vitamin E, folate and/or vitamin C supplementation pending conclusive evidence from clinical trials. (Am Fam Physician 2000;62:1359-66.)
Because dietary antioxidants and folic acid (folate) may play a part in the pathophysiology of coronary disease and stroke, interest in the role of vitamin supplements in preventing these diseases is high. This article reviews the evidence from patient-oriented studies to provide information to help physicians decide whether to recommend supplements of antioxidants and/or folate in the prevention of coronary disease and stroke.
Biological Plausibility
Oxidized low-density lipoprotein (LDL) cholesterol attracts and interacts with monocytes, macrophages and platelets to promote atherogenesis in the vascular lining. It also causes endothelial necrosis and interferes with vasorelaxation. Unlike beta carotene, vitamins E and C inhibit LDL oxidation in vitro. Vitamin E reduces monocyte adhesion to endothelium, inhibits platelet activation in vitro and inhibits atherosclerosis in rodents; in humans, angiographic and ultrasonographic studies suggest that vitamin E also inhibits the progression of atherosclerosis.(1)
Homocysteine is an amino acid product of normal protein metabolism. Folate, vitamin B12 and vitamin B6 are all involved in the metabolism of homocysteine. Deficiencies of one or more of these vitamins can lead to hyperhomocysteinemia.(2,3) Homocysteinuria is a rare, congenital enzyme deficiency that results in high serum and urine levels of homocysteine, and persons with this disorder have premature vascular disease and usually die of myocardial infarction (MI), stroke or pulmonary embolus.(2)
Homocysteine, at five to 10 times the normal concentrations, directly damages endothelium, promotes proliferation of vascular smooth muscle cells, exhibits procoagulant activity and increases collagen synthesis.(4) Results of clinical studies reveal that folate and vitamin B12 supplements lower serum homocysteine levels, with mixed results from vitamin B6 supplementation.(2,5) Of these three B vitamins, folate has been studied the most and clearly shows the most powerful effect.(2-5)
Observational Studies
ANTIOXIDANT VITAMINS
Prospective observational studies (Table 1)(6-14) have addressed whether the intake of vitamin C, vitamin E or beta carotene affects cardiovascular risk after adjustment for known major cardiovascular risk factors. Some studies combined dietary and supplemental intakes, while others attempted to separate these sources. Taken together, the results of these studies do not support any conclusions about potential differential effects by vitamin source.
Seven studies(6-12) examined the association of vitamin E intake (from diet and/or supplement sources) with coronary disease. The results of all of these studies except two(10,12) reported a reduction in coronary events associated with higher vitamin E intakes. The only vitamin E study that included stroke6 reported a statistically insignificant trend favoring its use.
Eight studies(7-14) examined the association of vitamin C intake with the incidence of coronary disease. Results were inconsistent between genders and among cohorts, and two of these studies failed to control for vitamin E use.(13,14) The results of one study(14) that investigated stroke revealed an apparent protective effect of vitamin C.
Five prospective cohort studies(7-10,12) examined associations between coronary disease and beta carotene intake. Results of three studies(8-10) revealed no evidence of a protective effect. In the other two studies,(7,12) a protective association was observed only among smokers and ex-smokers.
HOMOCYSTEINE AND FOLATE
Multiple cross-sectional and case-control studies linking plasma homocysteine levels with coronary disease and stroke have been published. The only prospective data come from nested case-control studies involving small subsamples within large cohort studies. Two recent systematic reviews(15,16) have summarized this literature. The first review(15) included 15 studies on coronary disease (involving 5,617 persons) and nine studies addressing stroke (involving 2,547 persons) in a meta-analysis. In all but two of the studies included in this analysis, coronary and stroke risks were higher in persons with higher homocysteine levels. The second review(16) summarized pertinent studies published since the first review. Results of all but five of the 26 studies in this review revealed a positive relationship between plasma homocysteine and coronary disease and/or stroke.
Since the time of these reviews, results of three more prospective studies have been published.(17-19) Among all 12 of the prospective studies now reported, five(17,18,20-22) failed to demonstrate that plasma homocysteine levels were a risk factor for coronary disease or stroke. This lack of consistency among prospective studies makes a causal relationship questionable.
If hyperhomocysteinemia causes cardiovascular disease, then folate supplementation should help prevent it. As yet, there are no reports that link folate intake directly with coronary disease or stroke, but results of interventional studies of folate supplementation have consistently shown a reduction in homocysteine levels, with a plateau effect at a dosage of about 1 mg per day.(5,15)
SUMMARY OF OBSERVATIONAL STUDIES
The prospective observational evidence is fairly consistent for a protective effect of vitamin E against coronary disease. Evidence about the effect of vitamin E on the risk of stroke is sparse. The evidence linking vitamin C to cardiovascular disease is inconsistent, and a protective effect of beta carotene has been observed only among those who smoke. These studies all addressed primary prevention, and absolute risk reductions appear modest at best.
Based on our calculations, if the observed protective effect of vitamin E is real, 170 to 250 persons would need to take vitamin E supplements (or have high dietary vitamin E intake) for 10 years to prevent one MI or stroke. Observational evidence linking homocysteine with cardiovascular disease is less consistent among prospective studies than in cross-sectional or retrospective analyses.
Controlled Clinical Trials
Observational studies cannot prove or disprove a protective effect because they cannot avoid the real possibility that intake of these vitamins is only a marker for other factors or behaviors that are the true modulators of heart attack and stroke. In the case of antioxidant vitamins and cardiovascular disease, results of seven controlled clinical trials have been reported (Table 2).(23-30) Results from controlled clinical trials on the effects of folate supplements in the prevention of MI or stroke have yet to be published.
Neutral or negative effects were reported in all four primary prevention trials.(23,25-27) However, only two of these included vitamin E and at doses that were only about one half of that associated with reduced cardiovascular risk in observational studies. In the Alpha Tocopherol Beta Carotene Cancer Prevention Trial(23) (ATBC), neither vitamin E (50 IU per day) nor beta carotene (20 mg per day) had a significant effect on the risk of a first MI or stroke. In the Beta Carotene and Retinol Efficacy Trial,(26) the combination of 30 mg per day of beta carotene plus 25,000 IU per day of vitamin A increased the risk of death from all causes, with a marginally significant increase in the risk of cardiovascular death.
In a randomized trial(25) restricted to male physicians, beta carotene at a dosage of 50 mg every other day had no effect on the risk of fatal or nonfatal MI or stroke. Among Chinese men and women in a large cancer prevention trial(27) of nutritional supplements, beta carotene (15 mg per day) with vitamin E (30 IU per day) had no effect on coronary deaths (which were rare in this cohort, anyway), but a trend toward fewer strokes was evident. Vitamin C supplementation at a dosage of 120 mg per day also had no effect on cardiovascular mortality.
Four clinical trials(24,28-30) have addressed the use of antioxidant supplements to prevent MI in patients with known coronary disease; none of these trials addressed the secondary prevention of stroke. In the ATBC trial(24) among the subset of male smokers with a past history of MI, the risk of another nonfatal MI in those receiving vitamin E was reduced by 38 percent, with no significant impact on fatal MI. However, the risk of fatal MI in these men was increased with beta carotene use alone or in combination with vitamin E.(24) In the Cambridge Heart Antioxidant Study(28) of men and women with angiographic coronary disease, 400 to 800 IU per day of vitamin E reduced the risk of nonfatal MI by 73 percent but had no effect on fatal MI.
The Health Outcomes Prevention Evaluation(29) study assessed the effect of 400 IU per day of vitamin E on patients with known cardiovascular disease and found no effect on the incidence of MI, stroke or cardiovascular death. Similarly, in the GISSI Prevenzione trial,(30) 300 mg per day of vitamin E had no effect on subsequent MI, stroke or cardiovascular death rates among patients with a recent history of MI.
SUMMARY OF CLINICAL TRIALS
Taken together, the available evidence from randomized controlled trials fails to demonstrate that antioxidant vitamins or folate supplementation is effective for the prevention of coronary disease or stroke. However, this lack of evidence is due more to a paucity of clinical trials than to negative outcomes.
Secondary prevention of coronary disease with vitamin E looked promising based on the first two trials,(24,28) but the efficacy in secondary prevention was not confirmed in either of two larger subsequent trials.(29,30) In addition, the mixed evidence for protective effects of vitamin E against nonfatal MI with no evidence of benefit against fatal MI are unexplained, although a lack of power to detect such effects is plausible.
The available evidence argues against the prescription of beta carotene supplements. Currently, there is no evidence from clinical trials that included disease-specific endpoints to support or refute the potential efficacy of folate, and only one study has investigated vitamin C supplementation, with neutral results.(27)
Safety and Cost of Supplements
If folate or vitamin E supplements prove to reduce cardiovascular risk, the available evidence suggests that vitamin E is best given in a dosage of 100 to 800 IU per day and folate is best given in a dosage of 0.4 to 1 mg per day. The recommended intake of vitamin E is 19 IU per day, and vitamin E doses less than 800 IU per day are safe.(31) However, daily doses of vitamin E greater than 800 IU may adversely affect platelet function, and doses greater than 1,200 IU per day may interfere with vitamin K functions and granulocytic responses.(32-35) The current recommended intake of folate for general health is 0.4 mg per day with a tolerable upper limit of 1 mg per day.(36) The only plausible adverse effects of folate at doses up to 1 mg per day would be masking of vitamin B12 deficiency (in those at risk for B12 malabsorption) and possible interference with zinc absorption.(37,38)
The cardiovascular data on vitamin C are weak but suggest a lower therapeutic threshold of 50 to 100 mg per day. The recommended intake of vitamin C is 75 to 90 mg per day with an upper limit of 2 g per day.(31) Vitamin C toxicity is rare at doses less than 5 g per day, although as little as 500 mg per day may promote oxalate kidney stones.(39,40) Rebound scurvy is possible after abrupt cessation of large doses.(41,42)
Thus, the doses of vitamin E, folate and vitamin C that may have cardiovascular benefit are quite safe and inexpensive. The average wholesale price of vitamin E at a dosage of 800 IU per day is about $3.00 per month; vitamin C at a dosage of 500 mg per day and folate at a dosage of 1 mg per day each cost about $1.50 per month wholesale.(43)
Final Comment
The available evidence is insufficient to recommend the routine use of vitamin E, vitamin C or folate supplements for the prevention of coronary disease or stroke. The evidence argues against the use of beta carotene supplements for this purpose.
Vitamin E at a dose of 100 to 800 IU per day may be useful for secondary prevention, but results from clinical trials are inconsistent. The observational evidence about vitamin C is also inconsistent, and the only reported clinical trial showed no effect. The nonclinical and observational evidence in support of folate supplements is extensive, but evidence from prospective observational studies reveal mixed results (but not harm), and no clinical trial has been completed. On the other hand, the cost and safety profiles for vitamin C, vitamin E and folate supplements are all favorable for empiric use at doses we have discussed.
A similar review regarding antioxidant use has recently been published in this journal.(44) We believe that the evidence supporting the use of antioxidants in the prevention of coronary disease is weaker than this earlier review suggests, and our opinions are more aligned with those of an accompanying editorialist.(45) A heart-healthy diet, emphasizing fruits and vegetables containing antioxidants and B vitamins, may be the best advice in the end.
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(6.) 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;328:1444-9.
(7.) 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;328:1450-6.
(8.) 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;334:1156-62.
(9.) Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180-9.
(10.) Todd S, Woodward M, Tunstall-Perdoe H, Bolton-Smith C. Dietary antioxidant vitamins and fiber in the etiology of cardiovascular disease and all-causes mortality: results the Scottish Heart Health Study. Am J Epidemiol 1999;150:1073-80.
(11.) 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; 64:190-6.
(12.) Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, Boeing H, Hofman A, Grobbee DE, et al. Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam Study. Am J Clin Nutr 1999;69:261-6.
(13.) Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology 1992;3:194-202.
(14.) Gale CR, Martyn CN, Winter PD, Cooper C. Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people. BMJ 1995;310:1563-6.
(15.) Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA 1995;274:1049-57.
(16.) Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31-62.
(17.) Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998;98: 204-10.
(18.) Evans RW, Shaten BJ, Hempel JD, Cutler JA, Kuller LH. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 1997:17:1947-53.
(19.) Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens CH. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999;281:1817-21.
(20.) Verhoef P, Hennekens CH, Allen RH, Stabler SP, Willett, WC, Stampfer MJ. Plasma total homocysteine and risk of angina pectoris with subsequent coronary artery bypass surgery. Am J Cardiol 1997; 79:799-801.
(21.) Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994:25:1924-30.
(22.) Alfthan G, Pekkanen J, Jauhiainen M, Pitkaniemi J, Karvonen M, Tuomilehto J, et al. Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 1994;106:9-19.
(23.) Virtamo J, Rapola JM, Ripatti S, Heinonen OP, Taylor PR, Albanes D, 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; 158:668-75.
(24.) Rapola JM, Virtamo J, Ripatti S, Huttunen JK, Albanes D, Taylor PR, et al. Randomised trial of alphatocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 1997;349:1715-20.
(25.) Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145-9.
(26.) Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996; 334:1150-5.
(27.) Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, 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;85:1483-92.
(28.) 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;347:781-6.
(29.) Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;345:154-60.
(30.) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. GISSI-Prevenzione Investigators. Lancet 1999;354:447-55.
(31.) 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 Intake, Food and Nutrition Board; Institute of Medicine. Washington D.C.: National Academy Press 2000.
(32.) Prasad JS. Effect of vitamin E supplementation on leukocyte function. Am J Clin Nutr 1980;33:606-8.
(33.) Corrigan JJ. Coagulation problems related to vitamin E. Am J Pediatr Hematol Oncol 1979;1:169-73.
(34.) Beahner RL, Boxer LA, Ingraham LM, Butterick C, Haak RA. The influence of vitamin E on human polymorphonuclear cell metabolism and function. Ann N Y Acad Sci 1982;393:237-50.
(35.) Meydani M. Vitamin E. Lancet 1995;345:170-5.
(36.) Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline: a report of the Standing Committee on the Scientific Evaluation of Dietary Refrence Intake and its panel on folate, other B vitamins, choline and Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, Institute of Medicine, Washington, D.C.: National Academy Press, 2000.
(37.) Herbert V. Recommended dietary intakes (RDI) of vitamin B12 in humans. Am J Clin Nutr 1987; 45:671-8.
(38.) Arnaud J, Favier A, Herrmann MA, Pilorget JJ. Effect of folic acid and folinic acid on zinc absorption. Ann Nutr Metab 1992;36:157-61.
(39.) Jacob RA. Vitamin C In: Shils ME, Olson JA, Shike M, eds. Modern nutrition in health and disease. 8th ed. Philadelphia: Lea & Febiger, 1994:432-48.
(40.) Urivetzky M, Kessais D, Smith A. Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis. J Urol 1992;147:1215-8.
(41.) Omaye ST, Skala JH, Jacob RA. Rebound effect with ascorbic acid in adult males [Letter]. Am J Clin Nutr 1988;48:379-80.
(42.) Gerster H, Moser U. Is high does vitamin C associated with systemic conditioning? Nutr Res 1988; 8:1327-2.
(43.) 2000 Drug Topics Redbook. Montvale, N.J.: Medical Economics, 2000:690,859,861.
(44.) Adams AK, Wermuth EO, McBride PE. Antioxidant vitamins and the prevention of coronary heart disease. Am Fam Physician 1999;60:895-904.
(45.) Kininghan R. The value of antioxidant vitamin supplements [Editorial]. Am Fam Physician 1999;60: 742,744.
Members of various medical faculties develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family Practice at the University of Kentucky College of Medicine, Lexington. Guest editors of the series are Bryan F. Yeager, Pharm.D., Thomas Armsey, M.D., and Samuel C. Matheny, M.D., M.P.H.
The Authors
KEVIN A. PEARCE, M.D., M.P.H., is the Michael Rankin professor of family medicine at the University of Kentucky College of Medicine, Lexington. He received his medical degree from the University of Florida College of Medicine, Gainesville, and completed his residency in Family Practice at the Medical College of Virginia/Fairfax Hospital, Fairfax. He received his master of public health degree in epidemiology at the University of Minnesota School of Public Health, Minneapolis.
MARIA G. BOOSALIS, PH.D., M.P.H., R.D., L.D., is an associate professor in the Division of Clinical Nutrition at the University of Kentucky, Lexington. She received her doctor of philosophy degree at the University of Minnesota, Minneapolis and her master of public health degree at the University of California, Berkeley. She is a licensed and registered dietitian with extensive experience in nutritional research and education.
BRYAN YEAGER, PHARM.D., is an assistant professor in the Department of Family Medicine at the Kentucky Clinic and the University of Kentucky College of Pharmacy, Lexington. Dr. Yeager received his bachelor of science degree in pharmacy from the University of Missouri-Kansas City and his doctor of pharmacy degree from the University of Texas, Austin. He completed a postdoctoral residency in Primary Care and Geriatrics at the University of Texas, Austin. He served three years as clinical pharmacy specialist with Kaiser Permanente and as an assistant professor at the University of Colorado, Denver.
Please address correspondence to Kevin A. Pearce, M.D., M.P.H., Department of Family Practice, Room K-302, Kentucky Clinic, University of Kentucky, Lexington, KY 40526-0284. Reprints are not available from the authors.
TABLE 1
Observational Studies of Antioxidant Vitamins
Study Design
Nurse's Health(6) 87,245 women; follow-up
for 8 years
Vitamin E [greater than or equal]
100 IU per day
Health Professionals(7) 39,910 men; follow-up for 4 years
Vitamin E [greater than or equal]
100 IU per day
Beta carotene [greater than or equal]
14,000 IU per day
Vitamin C up to 1,100 mg per day
Iowa Women(8) 34,486 women; follow-up
for 7 years
Vitamin E [greater than or equal]
10 IU per day
Beta carotene [greater than or equal]
13,000 IU per day
Vitamin C [greater than or equal]
196 mg per day
Finnish cohort(9) 5,133 men/women;
follow-up for 14 years
Vitamin E [greater than or equal]
5 IU per day
Vitamin C [greater than] 90 mg per day
Beta carotene
National Health and 11,348 men/women; follow-up
Nutrition Examination for 10 years
Survey (NHANES)(13) Vitamin C [greater than or equal]
50 mg per day
Gale, et al.(14) 730 elderly men/women; follow-up
for 20 years
Vitamin C [greater than or equal]
45 mg per day
Established Populations 11,178 elderly men/women;
for Epidemiologic follow-up for 6 years
Studies of the Elderly Vitamin E supplement use
(EPESE)(11)[*] Vitamin C supplement use
Scottish Heart Health 11,629 men/women; follow-up
Study(10)[] for 8 years
Vitamin E
Vitamin C
Beta carotene
The Rotterdam Study(12)[] 4,802 men/women; follow-up for
4 years
Vitamin E
Vitamin C
Beta carotene
Design Outcomes (95% confidence interval)
87,245 women; follow-up Endpoints: MI or stroke
for 8 years
Vitamin E [greater than or equal]
100 IU per day RR: 0.57 (range: 0.41 to 0.78)
39,910 men; follow-up for 4 years Endpoints: MI or coronary
revascularization
Vitamin E [greater than or equal]
100 IU per day RR: 0.63 (range: 0.47 to 0.84)
Beta carotene [greater than or
equal] 14,000 IU per day RR: 0.30 (range: 0.11 to 0.72)
Vitamin C up to 1,100 mg per day No effect
34,486 women; follow-up Endpoint: fatal MI
for 7 years
Vitamin E [greater than or equal]
10 IU per day RR: 0.38 (range: 0.18 to 0.80)
Beta carotene [greater than
or equal] 13,000 IU per day No effect
Vitamin C [greater than or equal]
196 mg per day No effect
5,133 men/women; Endpoint: fatal MI
follow-up for 14 years
Vitamin E [greater than or equal]
5 IU per day RR: 0.35 (range: 0.14 to 0.88)
Vitamin C [greater than]
90 mg per day RR: 0.49 (range: 0.32 to 0.98)
Beta carotene No effect
11,348 men/women; follow-up Endpoint: cardiovascular death
for 10 years
Vitamin C [greater than or equal]
50 mg per day Men--RR: 0.58 (range: 0.53 to 0.82)
Women--RR: 0.75 (range: 0 .55
to 0.99)
730 elderly men/women; follow-up Endpoints: fatal stroke or MI
for 20 years
Vitamin C [greater than or equal]
45 mg per day RR: 0.50 (range: 0.30 to 0.80),
stroke only
11,178 elderly men/women; Endpoint: fatal MI
follow-up for 6 years
Vitamin E supplement use RR: 0.53 (range: 0.34 to 0.84)
Vitamin C supplement use No effect
11,629 men/women; follow-up Endpoints: MI or coronary
for 8 years revascularization
Vitamin E No significant effect
Vitamin C No significant effect
Beta carotene No significant effect
4,802 men/women; follow-up for MI
4 years
Vitamin E No effect
Vitamin C No effect
Beta carotene RR: 0.55 (range: 0.34 to 0.83)
Design Comments
87,245 women; follow-up Trend towards stroke prevention
for 8 years
Vitamin E [greater than or equal]
100 IU per day
39,910 men; follow-up for 4 years
Vitamin E [greater than or equal]
100 IU per day
Beta carotene [greater than or
equal] 14,000 IU per day Beta carotene benefit in
smokers only
Vitamin C up to 1,100 mg per day
34,486 women; follow-up
for 7 years
Vitamin E [greater than or equal]
10 IU per day Supplement use rare in this
cohort
Beta carotene [greater than or
equal] 13,000 IU per day
Vitamin C [greater than or equal]
196 mg per day
5,133 men/women; Supplement use rare in this
follow-up for 14 years cohort
Vitamin E [greater than or equal]
5 IU per day Benefit among women only
Vitamin C [greater than]
90 mg per day
Beta carotene
11,348 men/women; follow-up Vitamin E intake unaccounted
for 10 years for
Vitamin C [greater than or equal]
50 mg per day
730 elderly men/women; follow-up Vitamin E intake unaccounted
for 20 years for
Vitamin C [greater than or equal]
45 mg per day Fatal MI--no effect
11,178 elderly men/women;
follow-up for 6 years
Vitamin E supplement use RR: 0.53 (range: 0.34 to 0.84)
Vitamin C supplement use No effect
11,629 men/women; follow-up
for 8 years
Vitamin E
Vitamin C Trend toward protection
Beta carotene Trend toward protection
4,802 men/women; follow-up for
4 years
Vitamin E
Vitamin C
Beta carotene Beta carotene benefit in
smokers only
MI = myocardial infarction; RR = relative risk.
[*]--Milligram doses of vitamins E and C in supplements not reported.
[]--Vitamin doses adjusted for dietary energy intakes--doses
in mg per day units not reported.
Information from references 6 through 14.
TABLE 2
Placebo-Controlled Clinical Trials of Antioxidant Vitamins
Study Study population
Alpha Tocopherol Beta 29,133 male smokers;
Carotene Cancer follow-up for 6 years
Prevention
Trial (ATBC)(23)[*](24)[]
Same as above
Physician's Health(25)[*] 22,071 men; follow-up
for 12 years
Beta Carotene and 18,314 men/women;
Retinol Efficacy Trial follow-up for 4 years
(CARET)(26)[*]
Chinese Ca 29,584 men/women;
Prevention(27)[*] follow-up for 5 years
Same as above
Cambridge Heart 2,002 men/women with
Antioxidant Study CHD; follow-up for
(CHAOS)(28)[] 1.5 years
Heart Outcomes 9,541 men/women with
Prevention Evaluation CVD; follow-up for
(HOPE)(29)[] 4.5 years
GISSI-Prevenzione(30)[] 11,324 men/women
secondary prevention
after recent MI;
follow-up for 3.5 years
Study population Treatment
29,133 male smokers; Vitamin E, 50 IU per day
follow-up for 6 years
Same as above Beta carotene, 20 mg per day
22,071 men; follow-up Beta carotene, 50 mg every
for 12 years other day
18,314 men/women; Beta carotene, 30 mg per day
follow-up for 4 years plus vitamin A, 25,000 IU
per day
29,584 men/women; Vitamin E, 30 IU per day,
follow-up for 5 years plus beta carotene, 15 mg
per day
Same as above Vitamin C, 120 mg per day
2,002 men/women with Vitamin E, 400 to 800 IU per
CHD; follow-up for day
1.5 years
9,541 men/women with Vitamin E, 400 IU per day
CVD; follow-up for
4.5 years
11,324 men/women Vitamin E, 300 mg per day[]
secondary prevention
after recent MI;
follow-up for 3.5 years
Study population Endpoint(s)
29,133 male smokers; MI or stroke
follow-up for 6 years
Same as above MI or stroke
22,071 men; follow-up MI or stroke
for 12 years
18,314 men/women; Death--any cause;
follow-up for 4 years cardiovascular death
29,584 men/women; Cardiovascular death
follow-up for 5 years
Same as above Cardiovascular death
2,002 men/women with Fatal or nonfatal MI
CHD; follow-up for
1.5 years
9,541 men/women with MI, stroke or
CVD; follow-up for cardiovascular death
4.5 years
11,324 men/women MI, stroke or
secondary prevention cardiovascular death
after recent MI;
follow-up for 3.5 years
Outcomes (95%
Study population confidence interval)
29,133 male smokers; No effect for primary
follow-up for 6 years prevention
RR: 0.62 (range: 0.41
to 0.96) for nonfatal
MI if past history of MI
Same as above No significant effect
22,071 men; follow-up No effect
for 12 years
18,314 men/women; Marginal increases in
follow-up for 4 years risk for both outcomes
29,584 men/women; No significant effect
follow-up for 5 years
Same as above No effect
2,002 men/women with RR: 0.27 (0.11 to 0.47),
CHD; follow-up for (nonfatal MI only)
1.5 years
9,541 men/women with No effect on any of
CVD; follow-up for these three outcomes
4.5 years
11,324 men/women No effect on any of
secondary prevention these three outcomes
after recent MI;
follow-up for 3.5 years
Study population Comments
29,133 male smokers; Vitamin E dose lower than
follow-up for 6 years observed as protective in
most observational studies
Same as above Trend toward increased risk
22,071 men; follow-up --
for 12 years
18,314 men/women; --
follow-up for 4 years
29,584 men/women; Vitamin E dose low; trend
follow-up for 5 years toward fatal stroke
protection
Same as above --
2,002 men/women with No effect on fatal MI
CHD; follow-up for
1.5 years
9,541 men/women with --
CVD; follow-up for
4.5 years
11,324 men/women Also studied n-3
secondary prevention polyunsaturated fatty
after recent MI; acids, which were
follow-up for 3.5 years protective
MI = myocardial infarction; RR = relative risk;
CHD = coronary heart disease; CVD = cardiovascular disease.
[*]--Primary prevention trials.
[]--Secondary prevention trials.
[]--Vitamin E dosage equivalent: 1 mg = 1.26 IU.
Information from references 23 through 30.
COPYRIGHT 2000 American Academy of Family Physicians
COPYRIGHT 2000 Gale Group