|The antioxidant vitamins and cardiovascular disease: a critical review of epidemiologic and clinical trial data
|Jha P, Flather M, Lonn E, Farkouh M, Yusuf S
To review prospective epidemiological studies and randomised trials regarding the role of antioxidant vitamins (vitamins E and C, and beta-carotene) in the prevention of cardiovascular disease.
Scientific literature was searched for all epidemiological studies (prospective cohort, prospective nested case-control, retrospective case-control, or geographic correlations) and RCTs of antioxidants and cardiovascular disease. Keywords used were 'vitamin E', 'vitamin C', 'beta-carotene', 'vitamins', 'antioxidants', 'coronary heart disease', 'cerebrovascular disease', 'peripheral vascular disease', 'atherosclerosis' and 'mortality'. The cancer literature was searched for studies of the effects of antioxidants on total mortality or other possible cardiovascular outcomes. MEDLINE and the Science Citation Index were searched from 1965 to 1994. In addition, bibliographies of original articles, review articles and textbooks were examined, and researchers were contacted for additional material.
Study designs of evaluations included in the review
The study designs included in the review were prospective cohort studies and randomised control trials (RCTs) using a priori criteria for randomisation and blinding of investigators to treatment assignment. In addition, all randomised trials had to have more than 100 participants. Excluded were retrospective studies, geographical correlations and case series. To be included in the review, studies had to define and quantify the type of intake of antioxidants, whether dietary intake or supplement use. The period of follow-up varied from 4 to 20 years and the daily dose of vitamins differed between studies.
Specific interventions included in the review
Vitamin E, vitamin C and beta-carotene.
Participants included in the review
The participants of studies included in the review varied by sex, age, occupation and health status.
Outcomes assessed in the review
Cardiovascular outcomes such as coronary heart disease, cerebrovascular disease, peripheral vascular disease, atherosclerosis and mortality, were assessed.
How were decisions on the relevance of primary studies made?
The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.
Assessment of study quality
The authors do not report the criteria used to assess quality, or how the quality assessment was performed.
The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction.
Methods of synthesis
How were the studies combined?
A narrative synthesis was undertaken by type of antioxidant and study design. This compared the reduction in risk estimates, dose-response relationships and the Mantel-Haenszel-Peto estimates of relative risk (RR) reduction. A quantitative pooling of the results was precluded due to the differences in patient and study characteristics.
How were differences between studies investigated?
Differences between the studies were evident in study design, participants, interventions and outcomes, and were accommodated through narrative synthesis of results noting the specific differences.
Results of the review
Nineteen studies (217,463 participants) were included in the review, of which 8 (191,541 participants) assessed vitamin E, 11 (83,297 participants) beta-carotene and 9 (94,838 participants) vitamin C.
The results of the review of antioxidants in the prevention of cardiovascular disease were presented by study design and specific antioxidant.
The prospective studies showed that vitamin E, either with supplementation or relatively high levels of dietary intake, and taken for at least 2 years reduced the RR for various cardiovascular end points by between 31 and 65%. The reduction in RR of cardiovascular end points from beta-carotene ranged from between -2 and +46%, with significant benefits limited to a cohort of smokers. Vitamin C reduced the RR of cardiovascular events by between -25 and +51%. The results of the prospective studies should be viewed with caution due to differences in study design, assessment of intake of antioxidants and the end points. Specific differences in lifestyle, dietary and health behaviours not accounted for in the studies, as well as methodological problems of self-reported diet questionnaires, may underlie the apparent variations in cardiovascular outcomes.
The RCTs showed no clear reduction in mortality from cardiovascular disease with supplementation of vitamin E, beta-carotene or vitamin C. As with the prospective studies, the RCTs were limited by differences between the studies, such as variations in dose sizes, a lack of nonfatal cardiovascular end points (studies were designed to assess cancer outcomes) and different start points in terms of the atherosclerotic progression of the patients.
Epidemiological data suggest that high levels of intake of vitamin E that are sustained for 2 or more years, are associated with a reduced risk for fatal and nonfatal cardiovascular disease. Use of beta-carotene or vitamin C is less clearly associated with a reduced risk. Limitations of the epidemiological evidence, such as the differences in health behaviour and dietary intake, may explain much of the observed reduction in risk.
The randomised trials suggest that antioxidants have no beneficial effects on total mortality or mortality from cardiovascular disease. The trials were not specifically designed to assess fatal and nonfatal cardiovascular disease outcomes and probably used sub-optimal doses of vitamin E. The current evidence does not support the routine use of antioxidant vitamins as prevention against cardiovascular disease.
The review lacks essential information necessary for a systematic review. There is no discussion of criteria for assessing the quality of the primary studies included in the review, or the process by which decisions on the relevance of primary studies, judgements of quality or extraction of data were undertaken. In addition, no costing information was provided. Inclusion criteria for participants were not specifically defined, resulting in diverse groups of participants from which generalising proved difficult. Although study design and outcome criteria were defined, the inclusion of RCTs primarily aimed at assessing the influence of antioxidants on cancer end points appears inappropriate. The narrative synthesis of the primary studies appeared appropriate due to the differences underlying the primary studies. The presentation of the methods and results were relatively clear and the authors' conclusions seemed to be supported by the evidence discussed.
Medical Research Council of Canada, grant number 9303UT-25089 and 9303UT-25088.
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. Annals of Internal Medicine 1995; 123(11): 860-872
Subject indexing assigned by NLM
Antioxidants; Ascorbic Acid /physiology; Cardiovascular Diseases /prevention & Carotenoids /physiology; Epidemiologic Methods; Humans; Randomized Controlled Trials as Topic; Vitamin E /physiology; beta Carotene; control
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.