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© 2001 American Heart Association, Inc.
Editorials |
A Time to Stop Prescribing Antioxidant Vitamins to Prevent and Treat Heart Disease?
From the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa.
Correspondence to Lewis H. Kuller, MD, DrPH, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St, Pittsburgh, PA 15261.
The article by Cheung et al,1 "Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL" in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, demonstrates a possibly important and troubling observation. The addition of an antioxidant "cocktail," comprising vitamins E and C, ß-carotene, and selenium, for participants on simvastatin and niacin (SNA) therapy, resulted in a significant blunting of the apoA1 and HDL2c response compared with those on lipid-lowering drugs alone (SN). None of the HDL-related changes for the antioxidant group only were different from those for placebo.
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The unexplained results in a clinical trial are often chance findings, given the numerous possible analyses. The statistical test of significance is not meaningful in such an analysis because there was no prior hypothesis before the data were reviewed. It is probably better to provide a point estimate of the effect and the confidence limits. The unusual findings should not, however, be swept under the rug because they were not part of the planned analysis. The results should be presented so that other investigators can either substantiate or refute these observations with different data sets. The authors did not provide the results of the clinical trial for the primary end points. At the March 2001 American College of Cardiology meeting, the research group from Seattle (Zhao and colleagues2) presented preliminary results of the trial that showed that the combination of antioxidants and lipid-lowering drugs (SNA) not only blunted the HDL response but also had substantial adverse effects with regard to the primary end points of changes in coronary artery disease based on angiography. The SNA group had a 7% increase compared with a 4% decrease in the SN-only group with regard to measures of coronary stenosis, and the antioxidant group alone had a 15% increase compared with a 34% increase for the placebo group.
The initial enthusiasm for antioxidant therapy to prevent or treat cardiovascular disease has been substantially tempered by a series of negative clinical trials for both vitamins E and C and ß-carotene.3 Most of the vitamin E results have been in secondary prevention trials, whereas ß-carotene has not been efficacious even in primary prevention. The only recent trial to show a possible benefit of vitamin E was for secondary prevention in patients with end-stage renal disease. The Alpha Tocopherol Beta Carotene Cancer Prevention Trial reported an increase in cerebral hemorrhage for participants who were taking 50 mg of vitamin E daily compared with placebo.3 There are still ongoing placebo-controlled clinical trials of antioxidant cocktails including vitamin E. These trials are mainly in primary prevention and in lower-risk populations.4–6
If we assume that the results of the study of Cheung et al1 are not random variations, then what may account for the blunting of the HDL2 and apoA1 effect? There were 4 agents in the antioxidant cocktail, and we have no way of determining which 1 or ones are the culprit or whether it is the antioxidants overall that have an adverse effect. Vitamin E apparently increases cholesteryl ester transfer protein activity7 and decreases HDL cholesterol. Vitamin E is transported by lipoproteins.8 Does the binding of vitamin E to HDL cholesterol reduce the transport of cholesterol from the arterial wall to nascent HDL and thus, result in a shortening of the half-life of HDL in plasma? Do the antioxidants adversely affect the esterification of cholesterol by lecithin: cholesterol acyltransferase? The specific biochemical pharmacological effects will require detailed studies. It will be important to determine whether the blunting of the HDL effect is limited to a small subsample, especially those also taking lipid-lowering drugs, or whether it is found in most subjects. There also could be a genetic drug-drug interaction.
What do the results of the study mean for clinical practice? Given the lack of efficacy of antioxidants in clinical trials to date, antioxidant vitamin combinations above the recommended dietary allowances should not be recommended for prevention or treatment of cardiovascular disease. It will be important that physicians advise their patients that the use of antioxidants could be hazardous, especially in combination with lipid-lowering drugs. The next chapter in the antioxidant saga will depend, in part, on the results of ongoing clinical trials.4,5
References
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Cheung MC, Zhao XQ, Chait A, Albers JJ, Brown BG. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol. 2001; 21: 1320–1326.
[Abstract/Free Full Text] - Zhao XQ, Brown BG, Morse JS, Dowdy A, DeAngelis D, Frohlich J, Chait A, Albers JJ. Safety and tolerability of combined niacin plus simvastatin in CAD patients with low HDLc with or without diabetes. J Am Coll Cardiol. 2001; 37: 286A.Abstract.
- Jialal I, Traber M, Devaraj S. Is there a vitamin E paradox? Curr Opin Lipidol. 2001; 12: 49–53.[Medline] [Order article via Infotrieve]
- Christen WG, Gaziano JM, Hennekens CH, for the Steering committee of Physicians’ Health Study II. 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.[Medline] [Order article via Infotrieve]
- Steinberg D. Is there a potential therapeutic role for vitamin E or other antioxidants in atherosclerosis? Curr Opin Lipidol. 2000; 11: 603–607.[Medline] [Order article via Infotrieve]
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Ness AR. Commentary: beyond beta-carotene: antioxidants and cardiovascular disease. Int J Epidemiol. 2001; 30: 143–144.
[Free Full Text] - Arrol S, Mackness MI, Durrington PN. Vitamin E supplementation increases the resistance of both LDL and HDL to oxidation and increases cholesterol ester transfer activity. Atherosclerosis. 2000; 150: 129–134.[Medline] [Order article via Infotrieve]
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Evans RW, Shaten J, Day BW, Kuller LH for the MRFIT Research Group. Prospective association between lipid soluble antioxidants and coronary heart disease in men: The Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1998; 147: 180–186.
[Abstract/Free Full Text]
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