Am Fam Physician. 2000 Sep 15;62(6):1276-1280.
Many patients are frustrated by the mixed messages regarding vitamin supplements. They look to their physicians for guidance, but we often have insufficient or contradictory information because of the complexities of nutritional science and incomplete evidence. Health care recommendations must be based on carefully conducted scientific studies, and the strongest evidence regarding prevention and treatment comes from well-designed, randomized, controlled clinical trials; however, on what do we base our recommendations when clinical trials disagree?
In this issue of American Family Physician, recent clinical evidence regarding vitamin supplements and cardiovascular disease (CVD) prevention is reviewed.1 The authors note that results from two recent clinical trials do not support the use of vitamin E supplementation to reduce CVD events2,3; this is contrary to results from earlier trials that demonstrated a risk reduction from vitamin E supplementation.4,5 They present again the lack of evidence supporting vitamin C and folate supplementation for reduction of CVD events1 and conclude that the available evidence is insufficient to recommend vitamin supplementation for CVD prevention, relating this to a paucity of clinical trials rather than to negative outcomes.
We agree that results from trials do not support the use of vitamin C or beta carotene for reduction of CVD events; in fact, results from several of the trials of beta carotene revealed detrimental effects in the treated group.5 Folate, alone and/or in combination with vitamins B6 and B12, can reduce serum homocysteine that is associated with increased CVD risk; however, results from clinical trials have not been published regarding the role of folate in CVD event reduction.6,7
Nevertheless, scientific evidence from observational, angiographic and clinical trials supports beneficial effects from vitamin E supplementation.5,8 Results from several prospective studies revealed that higher vitamin E intakes from food or supplements were associated with reduced CVD risk.9–11 This, plus other studies,8,10 suggested that clinical trials should test the hypothesis that vitamin E intake could decrease CVD events. The Cambridge Heart Antioxidant Study4 results showed that supplementation of vitamin E from natural sources resulted in impressive reductions in non-fatal myocardial infarctions in patients with known CVD. This study was the first to test higher doses of vitamin E (400 and 800 IU) in contrast to studies that used lower doses and synthetic vitamin E.4,5 Because of the theoretical benefits and the results from positive studies, other studies were conducted to test the effects of vitamin E supplements in preventing CVD. The results revealed no significant benefits or harm.2,3
The lack of congruence of vitamin E trial results is perplexing, but several explanations are possible. First, the Heart Outcomes Prevention Evaluation Study2 included participants with complicated disease and diabetes, while other studies have included participants with only CVD or less risk factors. Vitamin E may not benefit patients with more advanced CVD. Second, the different biologic activities of these compounds, or their combination with other nutrients or foods, may influence their effect. For example, vitamin E consists of eight compounds in two classes (tocopherols and tocotrienols), and different studies used different forms of vitamin E. The type of fat and micronutrients consumed in a daily diet may affect overall risk and lower the effects of vitamin supplementation, such as that seen in the Mediterranean diet common in GISSI participants.3 Current vitamin trials will address the need for combining vitamins12 because most observational studies tested vitamin combinations.
What can we conclude and what do we tell our patients at this point in time? As we suggested previously, all patients should be encouraged to eat a variety of foods, including healthy amounts of fruits, vegetables and whole grains, which contain important micronutrients consistently associated with reduced CVD risk.5,13,14 Pearce and colleagues1,5 agree with our position that available evidence argues against the use of beta carotene and is insufficient regarding vitamin C supplementation for CVD reduction. The controversy remains regarding vitamin E supplementation and secondary prevention of CVD. The two new vitamin E studies would reject a role for vitamin E.2,3 However, as we have previously stated, vitamin E is not harmful at 400 to 800 IU per day and may possibly benefit patients for reasons other than CVD prevention (e.g., improving arterial function).5 We also believe that the lack of toxicity and low costs of folate and vitamin E (in doses of 400 IU or less) allow for patient and physician judgment until further data become available.5–7 We propose that folate use for elevated homocysteine levels in patients at high risk for CVD is reasonable and safe.6,7
Because of the widespread interest and the use of supplements by the public, physicians need to review the potential benefits and risks of vitamin supplements with patients and allow patients to decide for themselves. We eagerly await the outcomes of trials of vitamin supplements and antioxidants that are currently in progress in order to provide a more complete synthesis of clinical information to help guide our recommendations. Until then, we share the confusion and frustration of our patients when the available evidence is contradictory.
Alexandra Adams, M.D., Ph.D., is an associate professor in the Department of Family Medicine at the University of Wisconsin, Madison.
Gail Underbakke, R.D., M.S., is a distinguished senior dietitian in the Department of Medicine (Cardiovascular Section) and Family Medicine at the University of Wisconsin, Madison.
Patrick E. McBride, M.D., M.P.H., is a professor in the Department of Medicine (Cardiovascular Section) and Family Medicine at the University of Wisconsin, Madison.
Address correspondence to Alexandra Adams, M.D., Ph.D. University of Wisconsin, Department of Family Medicine, 777 S. Mills St., Madison, WI 53713.
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2. 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;342:154–60.
3. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447–55.
4. 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. Lancet. 1996;347:781–6.
5. Adams AK, Wermuth EO, McBride PE. Antioxidant vitamins and the prevention of coronary heart disease. Am Fam Physician. 1999;60:895–904.
6. Stein JH, McBride PE. Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment. Arch Intern Med. 1998;158:1301–6.
7. Fallest-Strobl PC, Koch DD, Stein JH, McBride PE. Homocysteine: a new risk factor for atherosclerosis. Am Fam Physician. 1997;56:1607–12.
8. Diaz MN, Frei B, Vita JA, Keaney JF Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337:408–16.
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10. 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.
11. 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.
12. Hercberg S, Galan P, Preziosi P, Roussel AM, Arnaud J, Richard MJ, et al. Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers. SUpplementation en VItamines et Mineraux AntioXydants Study. Int J Vitam Nutr Res. 1998;68:3–20.
13. 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;99:591–5.
14. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779–85.
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