U.S. Preventive Services Task Force banner
U.S. Preventive Services Task Force


There is minimal evidence that any single vitamin supplement, combined antioxidant supplement, or multivitamin combination has a significant benefit in the primary or secondary prevention of CVD (Table 4). For vitamin A and C supplements, the lack of consistent, clear benefit in cohort studies does not support future randomized clinical trials. No observational study has examined beta-carotene and coronary death or events. However, in the clinical trials of beta-carotene designed for primary prevention of cancer, there is no evidence for cardiovascular risk reduction and some evidence supporting an increase in overall mortality. Secondary prevention analyses demonstrate similar results.

For vitamin E in particular, the promise of benefit from basic science and animal studies, correlation studies of plasma vitamin levels and CVD, and nutritional surveys was not borne out in RCTs. Why have these findings not been confirmed in clinical trials? Examination of potential explanations requires exploration of the broader questions of nutrition and chronic disease.

Is it possible that the observational studies are correct, that the clinical trials are in error, and that vitamin E can treat and prevent CVD? In general, supplementation of vitamin E in clinical trials has been of relatively short duration: 6 years in the ATBC trial,32 4.5 years in the HOPE study,35 and 4 years in the Primary Prevention Project.36 In contrast, observational studies have assessed 15 years of supplementation, although in small numbers of participants. It is noteworthy that in two observational studies, at least 2 years of supplement use were necessary to observe an effect, and there was a trend (albeit nonsignificant) for decreasing cardiovascular events with increasing duration of use.18,20 Given that, it is reasonable to assume that the duration of supplementation in these 3 clinical trials was sufficient. However, because the dose and duration of supplementation vary considerably more in observational studies than in clinical trials, it is possible that longer periods of supplementation may reduce CVD risk.

A second explanation is that in randomized trials, dosages may have been suboptimal or pharmacologic delivery may have been inappropriate and may not have increased plasma or cellular levels sufficiently to induce a change in cardiovascular risk. A supplement is delivered as an isolated nutrient source, but in addition to usual dietary intake. For some nutrients, such as vitamins C and E, the usual supplement is many times greater than dietary intake, thus overpowering any effect of diet. In at least one cohort study, there was no evident dose response, indicating a potential threshold for vitamin E.18

Many clinical trials, such as CARET and the ATBC study, were begun for primary prevention of cancer rather than CVD. While there is no evidence of misclassification of cardiovascular end points or less avid assessment compared with cancer end points, the issue of secondary analyses must be considered. Observational studies, such as the Nurses' Health Study,18,19 the Iowa Women's Study,21 and the Health Professionals' Study,20 have also analyzed multiple end points far more extensively than most clinical trials; this is an often-cited strength of observational cohorts. However, it is possible that the results of these trials are spurious because of the sheer number of analyses.

Many trials of supplementation were carried out in high-risk samples, whereas observational studies were conducted in general, broad-risk samples. Cohorts for the ATBC study43 included only male smokers, and the HOPE trial,35 Heart Protection Study,40 and Primary Prevention Project36 included older persons with known coronary artery or vascular disease or cardiovascular risk factors. Although conducting a randomized trial in a high-risk population reduces the required sample size because of the higher event rate, it is possible that, because of age and risk characteristics, such participants are less amenable to cardiovascular event reduction with antioxidant supplementation. However, in the HOPE trial, the Heart Protection Study and the Primary Prevention Project trial, the cointerventions significantly reduced cardiovascular events within the same population.

Is it more likely that the clinical trials are correct and the observational studies are in error? Considerable attention has been paid to this comparison.60,61 Because individuals who choose to take supplements differ in many ways from those who do not, observational studies are more subject to misleading associations because of confounding. Persons who use vitamin supplements tend to be more highly educated, and of higher socioeconomic status, are likely to have lower body mass index, are less likely to smoke, are more likely to perform vigorous exercise, are less likely to consume alcohol, are less likely to have familial history of early coronary disease, and are more likely to use hormone replacement therapy.18,19,62 Although these analyses have been adjusted for obvious differences, it is entirely possible that unmeasured differences remain between users of vitamin supplements and non-users. Confounding may also be incompletely controlled in the cohort analyses. Because of this, greater weight must be given to results from randomized trials in consideration of evidence.63

Evidence involving folic acid supplementation is more complex than that for other supplements. Positive effects of multivitamin supplementation are often ascribed to folic acid in the absence of other evidence. Consistent data in several cohorts link low plasma folate levels and high homocysteine levels with fatal coronary heart disease and link multivitamin use with the lowered risk of cardiovascular events.64,65 However, these studies were undertaken prior to the U.S. food supply was fortified with folate. Monitoring the effect of this fortification on population folate or homocysteine levels will provide important evidence about whether vitamin supplementation would be beneficial in the new food composition environment. Clinical trials of folic acid supplementation for primary prevention of cardiovascular disease are needed.

Five to 10 major clinical trials of antioxidant use for primary prevention of CVD are ongoing in North America and Europe. These trials will include tens of thousands of participants and will examine major cardiovascular events. Several small trials will examine coronary atherosclerosis. At the conclusion of these trials, sufficient data should exist to analyze the effects of antioxidant use on cardiovascular outcomes in different racial, ethnic, gender, and other minority groups. There is a similar number of ongoing studies of vitamin supplementation for secondary prevention of CVD in the United States and in Europe. These somewhat smaller trials are evaluating antioxidants as well as folic acid supplements.

Randomized placebo-controlled trials remain the gold standard for medical therapeutics.63 However, evaluating the role of vitamin supplementation in the early stages of CVD requires trials of many years' duration. Epidemiologic cohort studies will continue to be extremely important in guiding the role of vitamin supplementation in prevention of chronic disease. The largest established cohorts (the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Iowa Women's Study) are now reaching a stage of maturity that will allow them to provide information on risks and benefits associated with behaviors taking place early in the atherosclerosis process.18-21 Conclusions drawn from epidemiologic studies will always be limited by concerns about underlying differences between users and nonusers. Attempts to analyze the large cohort studies in ways that replicate clinical trial designs would be extremely useful in elucidating the differences between findings from clinical trials and cohort studies. Understanding these sources will permit scientists to better use the cohort study data and to better design long-term clinical trials.

Return to Contents


The study on which this article is based was conducted by the Oregon Health & Science University Evidence-based Practice Center, under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0018, task order No. 2).

The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

The authors wish to thank Janet Allan and Steven Woolf of the U.S. Preventive Services Task Force, Cheryl Ritenbaugh and Kelly Streit of Kaiser Permanente Center for Health Research, and Mark Helfand of the Oregon Health & Science University Evidence-based Practice Center, for their contributions to this project.

Return to Contents


1. American Heart Association. 1999 Heart and Stroke Statistical Update Dallas: American Heart Association; 1998.

2. Alaimo K, McDowell MA, Briefel RF, et al. (National Center for Health Statistics). Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey. Phase 1, 1988-01. November 3, 1994.

3. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Dietetic Assoc. 1996;96:1027-39.

4. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362(6423):801-9.

5. Tribble DL. AHA Science Advisory. Antioxidant consumption and risk of coronary heart disease: emphasis on vitamin C, vitamin E, and beta-carotene: A statement for healthcare professionals from the American Heart Association. Circulation. 1999;99(4):591-5.

6. Diaz MN, Frei B, Vita JA, Keaney JF, Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337(6):408-16.

7. Jha P, Flather M, Lonn E, Farkouh M, Yusuf S. The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data. Ann Intern Med. 1995;123(11):860-72.

8. Kushi LH. Vitamin E and heart disease: a case study. Am J Clin Nutr. 1999;69(6):1322S-1329S.

9. Jialal I, Traber MG, Devaraj S. Is there a vitamin E paradox? Curr Opin Lipidol. 2001;12:49-53.

10. Price JE, Fowkes FG. Antioxidant vitamins in the prevention of cardiovascular disease. The epidemiological evidence. Eur Heart J. 1997;18(5):719-27.

11. Pearce KA, Boosalis MG, Yeager B. Update on vitamin supplements for the prevention of coronary disease and stroke. Am Fam Physician. 2000;62:1359-66.

12. Rimm EB, Stampfer MJ. Antioxidants for vascular disease. Med Clin North Am. 2000;84:239-49.

13. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults; scientific review. JAMA. 2002;287:3116-26.

14. Hercberg S, Galan P, Preziosi P. Antioxidant vitamins and cardiovascular disease: Dr Jekyll or Mr Hyde? [editorial]. Am J Public Health. 1999;89(3):289-91.

15. Asplund K. Antioxidant vitamins in the prevention of cardiovascular disease: a systematic review. J Intern Med. 2002;251:372-92.

16. Harris R, Helfand M, Woolf S, et al. Current methods of the U.S. Preventive Services Task Force. Am J Prev Med. 2001;20(3S):21-35.

17. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.

18. 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(20):1444-9.

19. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279(5):359-64.

20. 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(20):1450-6.

21. 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(18):1156-62.

22. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992;3(3):194-202.

23. 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(2):190-6.

24. Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, et al. Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam Study. Am J Clin Nutr. 1999;69(2):261-6.

25. Watkins ML, Erickson JD, Thun MJ, Mulinare J, Heath CW, Jr. Multivitamin use and mortality in a large prospective study. Am J Epidemiol. 2000;152(2):149-62.

26. 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(12):1180-9.

27. Muntwyler J, Hennekens CH, Manson JE, Buring JE, Gaziano JM. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch Intern Med. 2002;162(1472-76).

28. 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(23):1849-54.

29. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. New Engl J Med. 1996;334:1145-9.

30. Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999;91(24):2102-6.

31. Greenberg ER, Baron JA, Karagas MR, et al. Mortality associated with low plasma concentration of beta-carotene and the effect of oral supplementation. JAMA. 1996;275:699-703.

32. The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. New Engl J Med. 1994;330:1029-35.

33. Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta-carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial [published erratum appears in JAMA 1998 May 20;279(19):1528]. JAMA. 1996;275(9):693-8.

34. 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(6):668-75.

35. 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;342(3):154-60.

36. 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.

37. 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(18):1150-5.

38. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled clinical trial of high-dose supplementation with vitamins C and E and beta-carotene for age-related cataract and vision loss: AREDS Report No. 9. Arch Ophthalmol. 2001;119:1439-52.

39. Hodis HN, Mack WJ, LaBree L, et al. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis; the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002;106:1453-9.

40. Heart Protection Study Collaboration Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23-33.

41. Gaziano JM, Manson JE, Ridker PM, Buring JE, Hennekens CH. Beta carotene therapy for chronic stable angina (abstract). Circulation. 1990;Suppl 82:III-201.

42. Gaziano JM, Manson JE, Ridker PM, Buring JE, Hennekens CH. Beta carotene therapy for chronic stable angina. Circulation. 1996;94 (suppl 1):I-508.

43. Rapola JM, Virtamo J, Ripatti S, et al. Effects of alpha tocopherol and beta-carotene supplements on symptoms, progression, and prognosis of angina pectoris. Heart. 1998;79(5):454-8.

44. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infraction. Lancet. 1997;349(9067):1715-20.

45. Anderson TW, Reid DB. A double-blind trial of vitamin E in angina pectoris. Am J Clin Nutr. 1974;27(10):1174-8.

46. Gillilan RE, Mondell B, Warbasse JR. Quantitative evaluation of vitamin E in the treatment of angina pectoris. Am Heart J. 1977;93(4):444-9.

47. DeMaio SJ, King SB, di Lembo NJ, et al. Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). J Am Coll Nutr. 1992;11(1):68-73.

48. 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(9004):781-6.

49. 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. Lancet. 1999;354(9177):447-55.

50. Tardif JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med. 1997;337(6):365-72.

51. Rodes J, Cote G, Lesperance J, et al. Prevention of restenosis after angioplasty in small coronary arteries with probucol. Circulation. 1998;97(5):429-36.

52. Brown BG, Zhao X, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary artery disease. N Engl J Med. 2001;345:1583-92.

53. Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine. N Engl J Med. 2001;345:1593-1600.

54. Tomoda H, Yoshitake M, Morimoto K, Aoki N. Possible prevention of postangioplasty restenosis by ascorbic acid. Am J Cardiol. 1996;78(11):1284-6.

55. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. JAMA. 2002;288:2432-40.

56. Winder AF. Antioxidants, cholesterol, and ischaemic heart disease: CHAOS or confusion? J Clin Pathol. 1997;50(4):269-70.

57. Lee IM, Cook NR, Manson JE, Buring JE. Randomised beta-carotene supplementation and incidence of cancer and cardiovascular disease in women: is the association modified by baseline plasma level? Brit J Cancer. 2002;86:698-701.

58. Redlich CA, Chung JS, Cullen MR, Blaner WS, Van Bennekum AM, Berglund L. Effect of long-term beta-carotene and vitamin A on serum cholesterol and triglyceride levels among participants in the Carotene and Retinol Efficacy Trial (CARET) [corrected and republished article originally printed in Atherosclerosis 1999 Apr;143(2):427-34]. Atherosclerosis. 1999;145(2):425-32.

59. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst. 1996;88:1550-1559.

60. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med. 2000;342:1878-86.

61. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research design. N Engl J Med. 2000;342:1887-92.

62. Bender MM, Levy AS, Schucker RE, Yetley EA. Trends in prevalence and magnitude of vitamin and mineral supplement usage and correlation with health status. J Am Dietetic Assoc. 1992;92:1096-101.

63. Pocock SJ, Elbourne DR. Randomized trials or observational tribulations? N Engl J Med. 2000;342:1907-9.

64. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274(13):1049-57.

65. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases. Circulation. 1999;99:178-82.


Author Affiliations

[a] Morris, Carson: Oregon Health & Science University, Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology.

Copyright and Source Information

This document is in the public domain within the United States. Requests for linking or to incorporate content in electronic resources should be sent via the USPSTF contact form.

Source: Morris CD, Carson S. Routine Vitamin Supplementation to Prevent Cardiovascular Disease. A summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003;139(1):56-70.

Return to Contents

Current as of June 2003

Internet Citation:

Morris CD, Carson S. Routine Vitamin Supplementation to Prevent Cardiovascular Disease. A summary of the evidence for the U.S. Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/3rduspstf/vitamins/vitcvdsum.htm


USPSTF Program Office   540 Gaither Road, Rockville, MD 20850