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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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
[a] Morris, Carson: Oregon Health & Science University, Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology.
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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.
Current as of June 2003
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