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The Antioxidant Vitamins and Cardiovascular Disease: A Critical Review of Epidemiologic and Clinical Trial Data

Prabhat Jha, MD, DPhil; Marcus Flather, MBBS, MRCP; Eva Lonn, MD, FRCPC; Michael Farkouh, MD, FRCPC; and Salim Yusuf, DPhil, FRCP
[+] Article and Author Information

From McMaster University, Hamilton, Ontario, Canada. Acknowledgments: The authors thank Lauren Ptito for providing editorial assistance on the manuscript and the reviewers for their comments on the paper. Grant Support: In part by a joint university-industry grant from the Medical Research Council of Canada (9303UT-25089 and 9303UT-25088), a fellowship from the Heart and Stroke Foundation of Ontario, Canada, and a Scientist Award from the Medical Research Council of Canada. The Heart Outcomes Protection Study is conducted independently of the industrial sponsors (Hoechst-Roussell and Astra Pharmaceuticals and the Natural Vitamin E Association), which have no access to any study data before publication. AppendixRequests for Reprints: Prabhat Jha, MD, Human Development Department, The World Bank, 1818 H Street NW, Washington, DC 20433. Current Author Addresses: Dr. Jha: The World Bank, Human Development Department, 1818 H Street NW, Washington, DC 20433.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(11):860-872. doi:10.7326/0003-4819-123-11-199512010-00009
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Purpose: To review prospective epidemiologic studies and randomized trials regarding the role of antioxidant vitamins (vitamins E and C and β-carotene) in the prevention of cardiovascular disease, with emphasis on differences in results obtained by these two types of studies.

Data Sources: Computerized and manual searches of the literature on antioxidant vitamins and cardiovascular disease.

Study Selection: Prospective epidemiologic studies and randomized trials that included 100 or more participants and provided quantified estimates of antioxidant vitamin intake.

Data Synthesis: Comparisons of relative risk reductions (RRR) across observational studies and randomized trials, including assessment of dose-response relations.

Results: All three large epidemiologic cohort studies of vitamin E noted that high-level vitamin E intake or supplementation was associated with a significant reduction in cardiovascular disease (RRR range, 31% to 65%), as measured by various fatal and nonfatal cardiovascular end points. To obtain these reductions, vitamin E supplementation must last at least 2 years. Less consistent reductions were seen in studies of β-carotene (RRR range, −2% to 46%) and vitamin C (RRR range, −25% to 51%). Considerable biases in observational studies, such as different health behaviors of persons using antioxidants, may account for the observed benefit. By contrast, none of the completed randomized trials showed any clear reduction in cardiovascular disease with vitamin E, vitamin C, or β-carotene supplementation. The trials were not specifically designed to assess cardiovascular disease, did not provide data on nonfatal cardiovascular end points, may have had insufficient treatment durations, and used suboptimal vitamin E doses. The completed trials were of adequate size to indicate that the true therapeutic benefit of vitamin E and other antioxidants in reducing fatal cardiovascular disease (a survival benefit as long as 5 years) is probably more modest than the epidemiologic data suggest.

Conclusion: The epidemiologic data suggest that antioxidant vitamins reduce cardiovascular disease, with the clearest effect for vitamin E; however, completed randomized trials do not support this finding. Much of this controversy should be resolved by the ongoing large-scale and long-term randomized trials designed specifically to evaluate effects on cardiovascular disease.

Figures

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Figure 1.
Prospective observational studies and randomized trials of vitamin E: effects on cardiovascular end points.

The horizontal bars represent 95% Cls. The size of the square showing the reduction is approximately proportional to the square root of the overall sample size multiplied by the number of events. ATBC equals α-Tocopherol, Beta-Carotene and Cancer Prevention Study; CHD equals coronary heart disease; CVD equals cardiovascular disease; MI equals myocardial infarction; NA equals not applicable. *The minimum dose ratio refers to the minimum relative differences in intake levels or antioxidant vitamin doses between comparison groups (for observational studies) and between treatment groups (for randomized trials); see the tables for more details. † Risk reduction is the relative reduction in the odds ratio, standardized mortality ratio, or relative risk (see the tables for details).

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Figure 2.
Prospective observational studies and randomized trials of β-carotene: effects on cardiovascular end points.

The horizontal bars represent 95% Cls. The size of the square showing the reduction is approximately proportional to the square root of the overall sample size multiplied by the number of events. ATBC equals α-Tocopherol, Beta-Carotene and Cancer Prevention Study; CHD equals coronary heart disease; CVD equals cardiovascular disease; LRC equals Lipids Research Clinic; NA equals not applicable; MI equals myocardial infarction; SCPS equals Skin Cancer Prevention Study. *The minimum dose ratio refers to the minimum relative differences in intake levels or antioxidant vitamin doses between comparison groups (for observational studies) and between treatment groups (for randomized trials); see the tables for more details. † Risk reduction is the relative reduction in the odds ratio, standardized mortality ratio, or relative risk (see the tables for details). ‡ The size of the square for the study by Gaziano and colleagues is estimated.

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Figure 3.
Prospective observational studies and randomized trials of vitamin C: effects on cardiovascular end points.

The horizontal bars represent 95% Cls. The size of the square showing the reduction is approximately proportional to the square root of the overall sample size multiplied by the number of events. CHD equals coronary heart disease; CVD equals cardiovascular disease; MI equals myocardial infarction; NA equals not applicable; NHANES equals National Health and Nutrition Examination Survey. *The minimum dose ratio refers to the minimum relative differences in intake levels or antioxidant vitamin doses between comparison groups (for observational studies) and between treatment groups (for randomized trials); see the tables for more details. † Risk reduction is the relative reduction in the odds ratio, standardized mortality ratio, or relative risk (see the tables for details).

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