 |
 |
|
Home |
Current Issue |
Past Issues |
In the Clinic |
ACP Journal Club |
CME |
Collections |
Audio/Video |
Mobile |
Subscribe |
Tools |
Help |
ACP Online
|
1 December 1995 | Volume 123 Issue 11 | Pages 860-872
Purpose: To review prospective epidemiologic studies and randomized trials regarding the role of antioxidant vitamins (vitamins E and C and ß-carotene) in the prevention of cardiovascular disease, with emphasis on differences in results obtained by these two types of studies. REVIEW
The Antioxidant Vitamins and Cardiovascular Disease: A Critical Review of Epidemiologic and Clinical Trial Data
|
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 ß-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 ß-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.
Methods
|
|---|
 Top Methods Author & Article InfoReferences |
|---|
We searched the scientific literature for all epidemiologic studies (prospective cohort, prospective nested case–control, retrospective case–control, or geographic correlations) and randomized clinical trials of antioxidants (using the terms vitamin E, vitamin C, ß-carotene, vitamins, and antioxidants) and cardiovascular disease (using the terms coronary heart disease, cerebrovascular disease, peripheral vascular disease, atherosclerosis, and mortality). We also examined all reports in the cancer literature to identify any studies of the effects of antioxidants on total mortality or other possible cardiovascular outcomes. We searched the MEDLINE database and the Science Citation Index for articles published from 1965 to 1994. We identified additional studies by examining bibliographies of original articles, review articles, and textbooks and by personally contacting the researchers. We also provide in the Appendix a list of the most relevant reviews as a supplement to the references.
Study Selection
We included only studies that specifically defined the type of intake of antioxidants, that is, studies that quantified the components of dietary intake or supplement use. We excluded studies that did not quantify intake (such as intake of fruits and vegetables or randomized trials of different diets). We used standard definitions to define epidemiologic studies [5] and did not consider case series. Randomized clinical trials were those in which previously established criteria [6] were used to randomly assign patients and to blind the investigators to treatment assignment.
Study Synthesis
We only selected prospective cohort studies; the rationale for this decision was consistent with discussions of epidemiologic causality [5]. The epidemiologic cohort studies varied greatly in terms of study design, sample size, and assessment of antioxidant intake. To consistently summarize the results of these studies, we emphasized the consistency of the reductions in risk estimates across studies and antioxidant groups; when possible, we reviewed dose-response relations. We excluded retrospective studies because they cannot determine whether reported antioxidant intake or biological levels were altered by the development of cardiovascular disease. We also excluded broad geographic correlations of population-based intake of antioxidants and cardiovascular disease rates because such correlations are retrospective in nature; in addition, extrapolation of these results to individual clinical decisions is difficult. These two types of studies have been reviewed previously [7].
We included all randomized trials with more than 100 participants; only five randomized trials had fewer than 100 participants. These five trials consisted of a total of 268 patients, and all trials had a maximum treatment duration of 6 months. Thus, their exclusion did not alter our results. To consistently present results for randomized clinical trials, we used the one-step modified Mantel-Haenszel-Peto method [6] to estimate a relative risk reduction (RRR) for each trial.
Mechanisms of Antioxidants
|
|---|
-tocopherol) and ß-carotene, a precursor of vitamin A. The major water-soluble antioxidant vitamin is vitamin C (ascorbic acid). Vitamin E is important in preventing oxidation of LDL cholesterol. In vitro studies have shown that this process does not begin until oxidative stress depletes the host vitamin E content [11]. ß-Carotene prevents oxidation of LDL cholesterol [12], although this finding is inconsistent [13]. Vitamin C prevents oxidation of LDL cholesterol and preserves vitamin E and ß-carotene levels during oxidative stress [14]. A combination of antioxidants is not believed to be clearly more efficacious in preventing oxidation of LDL cholesterol than any one antioxidant alone [13]. Supple-mentation with daily doses greater than 200 IU of vitamin E, 1000 mg of vitamin C, and 25 mg of ß-carotene increase blood levels of the corresponding vitamin to the same extent as do higher doses of these vitamins [15-17] (1.49 IU of vitamin E equals 1 mg; 10 IU of ß-carotene equals 1 µg of retinol, which equals 1 retinol equivalent. Vitamin C is expressed in mg rather than IU). Antioxidant vitamins presumably exert their effects through protection of oxidation; however, some studies have shown that the vitamins may also preserve endothelial function [18], affect hemostasis [19], and lower both LDL cholesterol levels [20, 21] and blood pressure [22].
Epidemiologic Studies of Antioxidant Vitamins and Cardiovascular Disease
|
|---|
Vitamin E
Prospective Cohort Studies
In a large prospective cohort study, the U.S. Nurses' Health Study [23] (Table 1, Figure 1), 87000 female nurses were followed for an average of 8 years. About 13% of women regularly used vitamin E supplements. These women had a statistically significant RRR of 31% (95% CI, 3% to 51%) for nonfatal myocardial infarction and death from cardiovascular disease compared with women who did not use the supplements, after adjustment for age, smoking, alcohol use, menopausal status, hormone use, exercise, aspirin use, hypertension, cholesterol intake, diabetes, caloric intake, and vitamin C and ß-carotene intake. The absolute risk reduction was 3.4 per 10000 years of follow-up (8.5 compared with 5.2 per 10000 years of follow-up).
|
|
Use of vitamin E supplements was found to offer similar protection in another cohort study in which 39000 male health professionals were followed for 4 years [24]. About 17% of the men took vitamin E supplements. Compared with men in the lower quintile of vitamin E intake (median intake, 6 IU/d), men in the upper quintile (median intake, 419 IU/d) had a 40% RRR (CI, 19% to 56%) for nonfatal myocardial infarction, death from coronary heart disease, or coronary revascularization after adjustment for age, smoking, body mass, caloric intake, fiber intake, alcohol use, hypertension, aspirin use, exercise, family history, profession, and vitamin C and ß-carotene use. The absolute risk reduction was 6.0 per 10000 years of follow-up (50.9 compared with 44.9 per 10000 years of follow-up) among persons using vitamin E supplements. Use of vitamin E supplements for less than 2 years was not associated with a reduced risk for cardiovascular events (RRR, 5%; P > 0.05). As in the Nurses' Health Study, only the two upper quintiles of vitamin E intake were associated with significant risk reductions; the intakes in these quintiles were at least four times the intake in the lowest quintile.
In a prospective cohort study in Finland [25], 2748 men and 2385 women were followed for a mean of 14 years. During follow-up, 186 men and 58 women died of coronary heart disease. Only 3% of the study sample took vitamin supplements. Compared with men in the lowest tertile of intake (intake of vitamins through diet and supplements, <4.5 IU/d), men with the highest intake of vitamin E (mean, >6.0 IU/d) had a nonsignificant RRR of 34% (CI, –11% to 58%) after adjustment for age, smoking, serum cholesterol levels, hypertension, body mass index, and energy intake. Compared with women in the lowest tertile of vitamin E intake (mean, <3.5 IU/d), women in the highest tertile (mean, >4.7 IU/d) had an RRR of 65% (CI, 12% to 86%). The long follow-up period for this study (14 years) suggests that prolonged differences were seen in the intake of vitamin E between persons who died of coronary heart disease and those who did not; however, such differences were not reported.
Of note, the intake seen in the highest tertile in this study was similar to that in the lowest quintiles in the Nurses' [23] or Health Professionals [24] studies, suggesting that the association between vitamin E and coronary heart disease can be seen with both high and low intakes. The relative difference between the intake levels needed to observe benefit was only about 40% higher in the Finnish study [25]. This percentage, however, refers to differences in tertile ranges; true differences in median levels of intake are probably higher. In addition, these investigators did not fully adjust for dietary factors and did not adjust for intake of vitamin C or ß-carotene.
Nested Case-Control Studies
Two studies examined archived blood samples among patients who subsequently developed cardiovascular disease and those who did not [26, 27]. Neither study found vitamin E levels to be significantly lower in persons who developed disease. However, these studies tested blood more than 7 years after collection. Because antioxidant vitamin levels tend to decrease with time in archived blood [28, 29], these studies probably underestimate the strength of the association between antioxidant vitamins and cardiovascular disease. Moreover, single blood measurements cannot distinguish short-term use from long-term use, a distinction that seems to be necessary to measure the effect on cardiovascular disease [29].
ß-Carotene
Prospective Cohort Studies
In the Health Professionals Study [24] (Table 2 and Figure 2), which included more than 39 000 men, participants in the highest quintile of carotene intake (mean, 19 034 IU/d) had a RRR of 29% (CI, 14% to 47%) for coronary revascularization, myocardial infarction, and death from coronary heart disease compared with those in the lowest quintile (mean, 3969 IU/d) after adjustment for cardiovascular risk factors and intake of vitamins E and C. Significantly reduced risk was seen only in the highest quintile compared with the lowest quintile, corresponding to a 4.8-fold difference. The benefit was largely confined to current smokers (RRR, 70%), with no benefit seen in nonsmokers (RRR, –9%). The reasons for this are unclear, although previous studies have shown that smoking reduces ß-carotene levels [30].
|
|
In another study of male pharmaceutical employees [31], mortality from coronary heart disease was nonsignificantly higher in men with low baseline carotene levels (relative risk, 1.53 [CI, 1.07 to 2.20]). Investigators of the Lipid Research Clinics follow-up study of 1899 middle-aged men with type IIa hyperlipidemia [32] found that patients with serum carotenoid levels in the highest quartile (mean, more than 3.2 µmol/L) had a RRR of 36% (CI, 8% to 56%) compared with those in the lowest quintile (mean, less than 2.3 µmol/L). In a small prospective study of 1299 elderly nursing home residents [33], risk for death from cardiovascular disease was reduced among residents with a high dietary intake of ß-carotene (RRR, 46% [CI, 13% to 66%]). The Nurses' study did not show significant risk reductions associated with carotene intake once intake of vitamins E and C was considered [23].
Nested Case-Control Studies
In a study in which archived blood samples were used, ß-carotene levels were lower among patients who had had myocardial infarction than among hospitalized controls [34]. Investigators of two other similar studies did not find any association between death from coronary heart disease and baseline vitamin A levels [26, 27].
Vitamin C
In a prospective population-based study of 11 348 U.S. adults, investigators found a 34% lower standardized mortality rate (CI, 18% to 47%) among persons who received 50 mg of vitamin C per day or more (by diet or supplements) compared with persons who received less vitamin C [35] (Table 3; Figure 3). However, these researchers did not consider vitamin E intake; the intake of this vitamin has been correlated with vitamin C intake [23]. In a small cohort study of 730 elderly persons in the United Kingdom followed for 20 years [36], stroke among persons in the highest tertile of vitamin C intake (mean, >45 mg/d) was significantly reduced (RRR, 50% [CI, 20% to 70%]) compared with the lowest tertile (mean, <28 mg/d); however, no such reduction was seen in mortality from coronary heart disease (RRR, 20% [CI, –20% to 40%]). However, in the Nurses' study, persons using vitamin C did not have a significantly lower risk for myocardial infarction or death from coronary heart disease once vitamin E was considered [23]. Similarly, the Health Professionals study showed no reduced risk for coronary revascularization, myocardial infarction, or death from coronary heart disease among persons using vitamin C (excess RRR, –25% [CI, –71% to 9%]) after adjustment for cardiovascular disease risk factors and vitamin E intake [24].
|
|
In the Finnish study, vitamin C intake was associated with a significantly reduced risk for death from coronary heart disease among women (RRR, 51% [CI, 2% to 76%] for differences between persons receiving 91 mg/d and those receiving less than 61 mg/d) [25]. However, no such reduction was seen for men (RRR, 0% [CI, –45% to 32%] for differences between men receiving 91 mg/d and those receiving less than 61 mg/d). The investigators of the Finnish study did not adjust for intake of vitamin E or carotene.
Three other small cohort study among adults in California [37], Switzerland [31], and Sweden [38] have shown no reductions in risk for death from coronary heart disease with vitamin C intake. Vitamin C has not been studied in nested case–control studies because vitamin C degrades quickly in stored samples [29].
Summary and Limitations of the Prospective Observational Studies
The magnitude of benefit from epidemiologic studies is difficult to precisely estimate because of differences in study design, assessment of intake of antioxidants, and end points. However, broad consistencies in risk reductions associated with high levels of antioxidant intake may be examined. On the basis of confirmation in all independent, large [more than 50 000 years of follow-up], and prospective cohort studies, the most consistent and reliable effect is seen with vitamin E, either with supplementation or relatively high levels of dietary intake. The RRR for various cardiovascular end points seems to range from 31% to 65%. This intake apparently needs to be sustained for at least 2 years before risk reductions may be detected. Use of ß-carotene is less clearly associated with a reduced risk; ß-carotene was found to provide significant protection in only one of the three large cohort studies. In that study, its benefits seemed to be largely confined to smokers. ß-Carotene has provided inconsistent protection in the smaller cohort studies. The RRR for the large and small studies ranged from –2% to 46%). Vitamin C clearly reduced risk in only one of the large cohort studies, in which vitamin E intake was not ascertained, and in none of the small cohort studies. The RRR in these studies ranged from –25% to 51%.
These findings do not provide conclusive evidence that vitamin E reduces cardiovascular disease, because the studies have potentially important methodologic problems that limit their interpretation. First, lifestyle and dietary patterns probably differ significantly between persons who use and do not use antioxidant vitamins. For example, in four of the larger studies [23, 24, 35, 37], persons using antioxidant vitamins were, on aggregate and in relative percentages, 24% less likely to be current smokers, 29% more likely to exercise regularly, and 10% less likely to have hypertension than persons who did not use the vitamins. Persons using antioxidant vitamins also consumed more alcohol.
These findings suggest that persons using antioxidant vitamins may have other health and lifestyle behaviors that reduce their risk for cardiovascular disease. The absolute difference in these behaviors is not large enough to significantly alter the risk reductions seen for vitamin E or vitamin C intake; in addition, these differences have been considered in most of the cohort studies we examined, either by stratification or adjustment in statistical models. However, such adjustment may be unreliable if these other variables were measured poorly (such as a single unreliable blood pressure reading). Moreover, it is impossible to adjust for unmeasured health behaviors that probably exist, given the more healthy profile of persons using antioxidant vitamins. The relative homogeneity of the Nurses' [23] and Health Professional [24] study samples was confirmed by the smaller differences in health behaviors between the persons in these samples who used and did not use vitamin supplements than among participants in the nationally representative study [35]. Although this homogeneity tends to increase the internal validity of the risk reductions associated with vitamin E, it does limit generalization to broader populations (for example, the mortality rate in the Nurses' and Health Professionals studies was less than one third the U.S. national average [1]).
Second, vitamin E intake may only be a marker for the intake of another as-yet unidentified protective factor. However, that a benefit was seen specifically for vitamin E and not for vitamin C or ß-carotene in the two largest studies partially argues against this theory. In addition, investigators of the two largest studies (the U.S. Nurses' and Health Professionals studies) adjusted their risk estimates for measured dietary factors such as fiber and caloric intake. However, vitamin E intake may still correlate best with intake of an undetermined protective factor.
In a prospective study of 805 men aged 65 years or older, intake of flavonoids, the natural antioxidants found in many of the same foods as vitamin E, was inversely correlated with mortality from coronary heart disease (P = 0.015 for the trend) [39]. Intake of vitamin E, vitamin C, and ß-carotene was significantly higher in persons with the highest intake of flavonoids. Similarly, in a retrospective case–control study of antioxidants in persons with advanced age-related macular degeneration, intake of specific carotenoids—lutein and zeaxanthin (primarily obtained from dark green, leafy vegetables)—provided the most protection against macular degeneration, whereas the intake of preformed vitamin A (retinol) provided no protection [40]. Although the significance of both flavonoids, lutein and zeaxanthin, in preventing cardiovascular disease is unclear, these two studies show that antioxidant vitamins may be markers for other protective factors. Further indirect evidence has been provided by observational studies of antioxidants and cancer, which have noted that whereas a broad intake of fresh fruits and vegetables offers protection, more specific intake of ß-carotene and vitamin C offers less protection [41]. Phyloestrogens, flavonoids, other carotenoid compounds, and phenol-derived substances have been less extensively studied [9, 42].
Self-reported diet questionnaires generally underestimate biological levels of antioxidant vitamins and have varying reproducibility within the same person [43]. Both these factors would tend to underestimate the strength of the association between antioxidant vitamins and cardiovascular disease.
Completed Randomized Trials of Antioxidant Vitamins
|
|---|
Vitamin E
In the ATBC trial [44] (Table 4; Figure 1), vitamin E did not significantly reduce total mortality (RRR, –2% [CI, –9% to 5%]) or mortality from cardiovascular disease (RRR, 2% [CI, –8% to 11%]). Vitamin E supplementation led to a marginally significant increase in mortality from hemorrhagic stroke (RRR, –49% [CI, –217% to –3%]) and a nonsignificant reduction in mortality from ischemic stroke (RRR, 16% [CI, –19% to 41%]). Both stroke outcomes were based on small numbers of events and may have arisen by chance. This trial did not report data on nonfatal cardiovascular disease events. The results of this large trial (> 1700 deaths from cardiovascular disease) appear to directly contradict the findings that were based on the epidemiologic data.
|
This trial, however, had several limitations, primarily the low vitamin E dose used. The 50-mg vitamin E dose increased serum levels by only 1.4-fold, a much lower increase than the fourfold or greater differences that epidemiologic studies suggest are needed to see a reduction in cardiovascular disease [23, 24].
Second, the population studied, middle-aged male long-term smokers in Finland, is not representative of general populations or their state of atherosclerosis. In other studies, smoking has been shown to reduce antioxidant vitamin levels [30]. Other completed trials of vitamin E in cardiovascular disease have been much smaller and have had treatment durations of less than 1 year. In a trial of 100 patients who had had angioplasty and were randomly assigned to receive 1200 IU of vitamin E daily or placebo for 4 months, the RRR for restenosis was 46% (P = 0.06; absolute risk reduction for restenosis, 15%: 50% in the placebo group compared with 35% in the vitamin E group) [47].
Vitamin E in Combination with Other Antioxidants
In the Chinese trial [45], the combination of vitamin E with ß-carotene and selenium led to a marginally significant reduction in mortality (RRR, 9% [CI, 0% to 17%]); however, this reduction was largely due to reductions in the number of stomach cancers. A trend toward a reduction in mortality from cerebrovascular disease was also seen (RRR, 9% [CI, –8% to 24%]). It is impossible, however, to evaluate which substance—ß-carotene, vitamin E, or selenium—contributed most to the trend toward lower mortality from cerebrovascular disease.
Significant 15-fold differences in serum levels were noted with 15 mg of ß-carotene per day. Although vitamin E levels were not reported, it is probable that, as in the ATBC study, the 30-mg daily dose of vitamin E did not increase serum levels above 1.5-fold. A further limitation of this trial was that only 1% of the deaths in this population were caused by coronary heart disease (or only about 10% to 15% of the rate in the general population of that age group [2]); this finding limits the power of the trial to assess this coronary outcome. Finally, the Chinese trial was done in an area with low antioxidant intake, much less than that in Western populations, which limits the generalizability of the findings to populations with a higher intake of antioxidants.
ß-Carotene
In the ATBC trial [44] (Table 5; Figure 2), ß-carotene supplementation led to significant increases in total mortality (RRR, –9% [CI, –17% to –2%] and a nonsignificant increase in mortality from cardiovascular disease (RRR, –11% [CI, –23% to 1%]). No significant reductions were seen in mortality from stroke or other cardiovascular disease. The 20-mg ß-carotene dose increased serum levels 15-fold, suggesting that suboptimal dosing did not cause the lack of benefit. A possible limitation of this trial may have been the unblinding of ß-carotene use. Yellowing of the skin was seen in 34% of persons in the ß-carotene group and in 7% of persons in the placebo group. The group assigned to receive ß-carotene may have felt protected and therefore increased their tobacco use or other adverse behaviors, which in turn led to cardiovascular disease. In the smaller trial of ß-carotene in 1805 patients with skin cancer, total mortality was not reduced, even though only 151 patients died [46]. According to a Physicians Health Study subgroup analysis in 333 men with evidence of angina at baseline, supplementation with 50 mg of ß-carotene every other day for a mean of 5 years reduced the incidence of cardiovascular events by 54% (CI, 15% to 76%) [48]. Although interesting, this was a data-derived finding in a subgroup of the larger sample of 21 000 men; the larger study is continuing, and the investigators should report its results in 1996 or 1997.
|
In the Chinese trial [45] (Table 5; Figure 2), the combination of vitamin C and molybdenum did not reduce total mortality (RRR, –1% [CI, –10% to 7%]) or mortality from cerebrovascular disease (RRR, –4% [CI, –24% to 12%]). The 120-mg vitamin C dose led to significant fivefold increases in serum levels of vitamin C, suggesting that suboptimal dosing did not cause the lack of benefit. In a small trial of 578 patients admitted to a geriatric hospital, supplementation with 200 mg of vitamin C did not reduce total mortality at 6 months [49].
Summary of Completed Randomized Trials
Completed randomized trials, primarily designed for cancer outcomes, have shown no clear reduction in mortality from cardiovascular disease with supplementation lasting as long as 6 years for vitamin E, ß-carotene, or vitamin C. Several factors can explain these "negative" findings. First, the vitamin E doses used in the larger trials were probably not large enough to detect plausible reductions in the risk for cardiovascular disease. In contrast, the ß-carotene and vitamin C doses used in these trials were sufficient, yielding substantial increases in blood levels.
Second, in the epidemiologic studies, benefit was seen for both nonfatal and fatal end points. The trials were of sufficient size and statistical power to detect reductions in risk for death from cardiovascular disease that were as large as those found in epidemiologic studies (approximately 30%). However, unlike the epidemiologic studies, the trials did not report findings on nonfatal myocardial infarction or strokes.
Third, none of the trials was specifically designed to detect differences in cardiovascular outcomes. The outcome measures and sample size determination were not designed for cardiovascular end points, and the proportion of cardiovascular end points to total end points in these trials may be lower than ideal. In addition, the mechanism of the benefit of antioxidants may differ between cancer and cardiovascular disease.
Finally, it is important to note that randomized trials evaluate the reduction in cardiovascular disease when supplementary antioxidant vitamins are used for a specified duration (usually a few years), usually starting in middle age; by this time atherosclerosis may be well established. By contrast, the epidemiologic studies address the relation of reduction in disease when high dietary intake (including supplementation) of antioxidant vitamins is sustained for much longer periods (at least several years or even decades), often starting at much younger ages, that is, the early part of atherosclerotic progression. Thus, the epidemiologic results probably also reflect differences in health behaviors and dietary habits between persons who use and do not use antioxidant vitamins. These results may also reflect differing effects of antioxidant supplementation on the initiation or progression or rupture of atherosclerotic plaques [10]. These data suggest that the magnitude of benefit seen in the epidemiologic data (range, 20% to 60%) is probably larger than the magnitude of plausible therapeutic benefit expected from vitamin E, ß-carotene, and vitamin C supplementation of a few years' duration. This may further indicate that the duration of supplementation may have to extend beyond 6 years before reductions can be detected.
Safety of Antioxidant Vitamins
|
|---|
Ongoing Randomized Trials
|
|---|
|
The UK Heart Protection Study (Peto R. Personal communication) will assess a combination of vitamin E, ß-carotene, and vitamin C in 20 000 patients with established cardiovascular disease. The Heart Outcomes Protection Study [53] is assessing vitamin E in 9000 similar patients. The Women's Antioxidant Cardiovascular Study will assess a factorial of vitamin E, vitamin C, and ß-carotene in 8000 nurses with established cardiovascular disease (Hennekens CH. Personal communication). The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Acuto) prevention trial will assess vitamin E in 12 000 patients who have had recent myocardial infarction (Tognoni GT. Personal communication). The Women's Health Study [54] is assessing vitamin E and ß-carotene in a factorial design among 40 000 postmenopausal nurses. In all trials of vitamin E, doses greater than 300 IU/d are being used; such doses should be sufficient to increase serum levels at least two- to threefold [17]. A future meta-analysis or a systematic overview of the cumulative numbers from these trials (an estimated 40 000 patients receiving secondary prevention and 86 000 patients receiving primary prevention) should, by the end of the decade, provide clear answers about the efficacy and safety of the various antioxidant vitamins. Such an overview would also provide data on the size of the effect, the treatment duration needed, and effects in different groups (for example, men compared with women, older patients compared with younger patients, smokers compared with nonsmokers, diabetic patients compared with nondiabetic patients).
Summary and Current Clinical Implications
|
|---|
The completed randomized trials suggest that no antioxidant beneficially affects total mortality or mortality from cardiovascular disease. However, these trials have probably used suboptimal doses of vitamin E, and none was specifically designed to assess fatal or nonfatal cardiovascular disease outcomes. Within a few years, ongoing and planned randomized trials will help resolve many of these uncertainties. The combined evidence currently does not support the routine use of antioxidant vitamins as prevention against cardiovascular disease. Individual choices and public policy guidelines should await the result of the large trials, which will provide more information on the efficacy and safety of antioxidant vitamins as protection against cardiovascular disease [55].
Drs. Flather, Lonn, and Yusuf: Division of Cardiology, McMaster University, Hamilton General Hospital, HGH McMaster Clinic, 237 Barton Street, Hamilton L8L 2X2, Ontario, Canada.
Dr. Farkouh: Division of Area Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
Author and Article Information
|
|---|
|
TopMethodsAuthor & Article InfoReferences |
|---|
References
|
|---|
|
TopMethodsAuthor & Article InfoReferences |
|---|
1. American Heart Association. 1993 Heart and Stroke Facts Statistics. Dallas, TX: American Heart Association; 1993:2-16.
2. World Bank. World Development Report 1993: Investing in Health. Oxford: Oxford University Pr; 1993:26-7.
3. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum J. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989; 320:915-24.
4. Steinberg D. Antioxidants in the prevention of human atherosclerosis. Summary of the proceedings of a National Heart, Lung, and Blood Institute Workshop: September 5-6, 1991, Bethesda, Maryland. Circulation. 1992; 85:2337-44.
5. Rothman K. Modern Epidemiology. Boston: Little, Brown; 1987:31-66.
6. "Early Breast Cancer Trialists' Collaborative Group. Treatment of Early Breast Cancer. Volume 1: Worldwide Evidence 1985-1990. Oxford: Oxford University Pr; 1990:8-19.".
7. Gaziano JM, Hennekens CH. Vitamin antioxidants and cardiovascular disease. Curr Opin Cardiol. 1992; 3:291-4.
8. Chisolm GM 3d. Antioxidants and atheroscerlosis: a current assessment. Clin Cardiol. 1991; 14:I25-30.
9. Harris WS. The prevention of atherosclerosis with antioxidants. Clin Cardiol. 1992; 15:636-40.
10. Steinberg D. Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet. 1995; 346:36-8.
11. Jessup W, Rankin SM, De Whalley CV, Hoult JR, Scott J, Leake DS. Alpha-tocopherol consumption during low-density-lipoprotein oxidation. Biochem J. 1990; 265:399-405.
12. Jialal I, Norkus EP, Cristol L, Grundy SM. ß-Carotene inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta. 1991; 1086:134-8.
13. Reaven PD, Khouw A, Beltz WF, Parthasarathy S, Witztum JL. Effect of dietary antioxidant combinations in humans. Protection of LDL by vitamin E but not by ß-carotene. Arterioscler Thromb. 1993; 13:590-600.
14. Sato K, Niki E, Shimasaki H. Free radical-mediated chain oxidation of low density lipoproteins and its synergistic inhibition by vitamin E and vitamin C. Arch Biochem Biophys. 1990; 279:402-5.
15. Willett WC, Stampfer MJ, Underwood BA, Taylor JO, Hennekens CH. Vitamins A, E, and carotene: effects of supplementation on their plasma levels. Am J Clin Nutr. 1983; 38:559-66.
16. Green J. Interrelationships between vitamin E and other vitamins and the ubiquinones. Vitam Horm. 1962; 20:485-94.
17. Farrell PM, Bieri JG. Megavitamin E supplementation in man. Am J Clin Nutr. 1975; 28:1381-6.
18. Keaney JF Jr, Gaziano JM, Xu A, Frei B, Curran-Celentano J, Shwaery GT, et al. Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits. Proc Natl Acad Sci U S A. 1993; 90:11880-4.
19. Khaw KT, Woodhouse P. Interrelation of vitamin C, infection, haemostatic factors, and cardiovascular disease. BMJ. 1995; 310:1559-63.
20. Trout DL. Vitamin C and cardiovascular risk factors. Am J Clin Nutr. 1991; 53:322S-5S.
21. Jacques PF. Effects of vitamin C on high-density lipoprotein cholesterol and blood pressure. J Am Coll Nutr. 1992; 11:139-44.
22. Stamler J, Ruth KJ, Liu K, Shekkele RB. Dietary antioxidants and blood pressure change in the western electric study [Abstract]. 34th Annual Conference on Cardiovascular Disease Epidemiology and Prevention. Tampa, Florida; 1993.
23. 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.
24. 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.
25. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol. 1994; 139:1180-90.
26. Kok FJ, de Bruijn AM, Vermeeren R, Hofman A, de Bruin M, Hermus RJ, et al. Serum selenium, vitamin antioxidants and cardiovascular mortality: a 9-year follow-up study in the Netherlands. Am J Clin Nutr. 1987; 45:462-8.
27. Salonen JT, Salonen R, Penttila I, Herranen J, Jauhianinen M, Kantola M, et al. Serum fatty acids, apolipoproteins, selenium and vitamin antioxidants and the risk of death from coronary artery disease. Am J Cardiol. 1985; 56:226-31.
28. Driskell WJ, Lackey AD, Hewett JS, Bashor MM. Stability of vitamin A in frozen sera. Clin Chem. 1984; 30:1171-3.
29. Comstock GW, Alberg AJ, Helzlsouer KJ. Reported effects of long-term freezer storage on concentrations of retinol, ß-carotene, and -tocopherol in serum or plasma summarized. Clin Chem. 1993; 39:1075-8.
30. Riemersma RA, Wood DA, MacIntyre CC, Elton RA, Gey KF, Oliver MR. Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet. 1991; 337:1-5.
31. Gey KF, Moser UK, Jordan P, Stahelin HB, Eichholzer M, Ludin E. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C. Am J Clin Nutr. 1993; 57(5 Suppl):787S-97S.
32. Morris DL, Kritchevsky SB, Davis CE. Serum carotenoids and coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study. JAMA. 1994; 272:1439-41.
33. Gaziano JM, Manson JE, Branch LG, LaMott GA, Colditz GA, Buring JE, et al. Dietary ß-carotene and decreased cardiovascular mortality in an elderly cohort [Abstract]. J Am Coll Cardiol. 1992; 19(Suppl A):377A.
34. Street DA, Comstock GW, Salkeld RM, Shuep W, Klag M. A population-based case–control study of the association of serum antioxidants and myocardial infarction. Am J Epidemiol. 1991; 134:719-20.
35. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992; 3:194-202.
36. Gale CR, Martyn CN, Winter PD, Cooper C. Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people. BMJ. 1995; 310:1563-6.
37. Enstrom JE, Kanim LE, Breslow L. The relationship between vitamin C intake, general health practices, and mortality in Alameda County, California. Am J Public Health. 1986; 76:1124-30.
38. Lapidus L, Andersson H, Bengtsson C, Bosaeus I. Dietary habits in relation to incidence of cardiovascular disease and death in women: a 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. Am J Clin Nutr. 1986; 44:444-5.
39. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993; 342:1007-11.
40. Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, et al. Dietary carotenoids, vitamins A, C, and E, and advanced agerelated macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994; 272:1413-20.
41. Ziegler RG, Subar AF, Craft NE, Ursin G, Patterson BH, Graubard BI. Does ß-carotene explain why reduced cancer risk is associated with vegetable and fruit intake? Cancer Res. 1992; 52(7 Suppl):2060s-6s.
42. Ziegler RG. A review of epidemiological evidence that carotenoids reduce the risk of cancer. J Nutr. 1989; 119:116-22.
43. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility and validity of an expanded self-administered semi-quantitative food frequency questionnaire among male health professionals. Am J Epidemiol. 1992; 135:1114-26.
44. "The effect of vitamin E and ß-carotene on the incidence of lung cancer and other cancers in male smokers. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994; 330:1029-35.".
45. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and diseasespecific mortality in the general population. J Natl Cancer Inst. 1993; 85:1483-92.
46. Greenberg ER, Baron JA, Stukel TA, Stevens MM, Mandel JS, Spencer SK, et al. A clinical trial of ß-carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group. N Engl J Med. 1990; 323:789-95.
47. DeMaio SJ, King SB 3d, Lembo NJ, Roubin GS, Hearn JA, Bhagavan HN, et al. Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). J Am Coll Nutr. 1992; 11:68-73.
48. Gaziano JM, Manson JE, Ridker PM, Buring JE, Hennekens CH. Beta carotene therapy for chronic stable angina [Abstract]. Circulation. 1990; 82:III-201.
49. Wilson TS, Datta SB, Murrell JS, Andrews CT. Relation of vitamin C levels to mortality in a geriatric hospital: a study of the effect of vitamin C administration. Age Aging. 1973; 2:163-71.
50. Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin Nutr. 1988; 48:612-9.
51. Hennekens CH, Eberlein K. A randomized trial of aspirin and ß-carotene among U.S. physicians. Prev Med. 1985; 14:165-8.
52. Thornquist MD, Omenn GS, Goodman GE, Grizzle JE, Rosenstock L, Barnhart S, et al. Statistical design and monitoring of the Carotene and Retinol Efficacy Trial (CARET). Control Clin Trials. 1993; 14:308-24.
53. "The Heart Outcomes Prevention Evaluation (HOPE) study. The design for a large, simple randomized trial of an angiotensin converting enzyme inhibitor and vitamin E in patients at high risk of cardiovascular events. Can J Cardiol. 1995; [In press].".
54. Buring JE, Hennekens CH. The Women's Health Study: summary of the study design. Journal of Myocardial Ischemia. 1992; 4:27-9.
55. Bulpitt CJ. Vitamin C and vascular disease [Editorial]. BMJ. 1995; 310:1548-9.
Related articles in Annals:
This article has been cited by other articles:
 |
|
 |
|
  S.S. Young, B. Eskenazi, F.M. Marchetti, G. Block, and A.J. Wyrobek The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men Hum. Reprod., May 1, 2008; 23(5): 1014 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-N. Vercambre, A. Fournier, M.-C. Boutron-Ruault, F. Clavel-Chapelon, V. Ringa, and C. Berr Differential Dietary Nutrient Intake according to Hormone Replacement Therapy Use: An Underestimated Confounding Factor in Epidemiologic Studies? Am. J. Epidemiol., December 15, 2007; 166(12): 1451 - 1460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. K Rudolph, K. Ruempler, E. Schwedhelm, J. Tan-Andresen, U. Riederer, R. H Boger, and R. Maas Acute effects of various fast-food meals on vascular function and cardiovascular disease risk markers: the Hamburg Burger Trial Am. J. Clinical Nutrition, August 1, 2007; 86(2): 334 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Buse, H. N. Ginsberg, G. L. Bakris, N. G. Clark, F. Costa, R. Eckel, V. Fonseca, H. C. Gerstein, S. Grundy, R. W. Nesto, et al. Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus: A Scientific Statement From the American Heart Association and the American Diabetes Association Circulation, January 2, 2007; 115(1): 114 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Buse, H. N. Ginsberg, G. L. Bakris, N. G. Clark, F. Costa, R. Eckel, V. Fonseca, H. C. Gerstein, S. Grundy, R. W. Nesto, et al. Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus: A scientific statement from the American Heart Association and the American Diabetes Association Diabetes Care, January 1, 2007; 30(1): 162 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, M. H Gail, Y.-q. Wang, L. M. Brown, K.-f. Pan, J.-l. Ma, H. Amagase, W.-c. You, and R. Moslehi A randomized factorial study of the effects of long-term garlic and micronutrient supplementation and of 2-wk antibiotic treatment for Helicobacter pylori infection on serum cholesterol and lipoproteins. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 912 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Stranges, J. R. Marshall, M. Trevisan, R. Natarajan, R. P. Donahue, G. F. Combs, E. Farinaro, L. C. Clark, and M. E. Reid Effects of Selenium Supplementation on Cardiovascular Disease Incidence and Mortality: Secondary Analyses in a Randomized Clinical Trial Am. J. Epidemiol., April 15, 2006; 163(8): 694 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H. Tan, P. Sagoo, C. Chan, J. B. Yates, J. Campbell, S. C. Beutelspacher, B. M. J. Foxwell, G. Lombardi, and A. J. T. George Inhibition of NF-{kappa}B and Oxidative Pathways in Human Dendritic Cells by Antioxidative Vitamins Generates Regulatory T Cells J. Immunol., June 15, 2005; 174(12): 7633 - 7644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 The HOPE and HOPE-TOO Trial Investigators Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer: A Randomized Controlled Trial JAMA, March 16, 2005; 293(11): 1338 - 1347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Genkinger, E. A. Platz, S. C. Hoffman, G. W. Comstock, and K. J. Helzlsouer Fruit, Vegetable, and Antioxidant Intake and All-Cause, Cancer, and Cardiovascular Disease Mortality in a Community-dwelling Population in Washington County, Maryland Am. J. Epidemiol., December 15, 2004; 160(12): 1223 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Knekt, J. Ritz, M. A Pereira, E. J O'Reilly, K. Augustsson, G. E Fraser, U. Goldbourt, B. L Heitmann, G. Hallmans, S. Liu, et al. Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts Am. J. Clinical Nutrition, December 1, 2004; 80(6): 1508 - 1520. |
Article
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.