Am Fam Physician. 2000;62(6):1359-1366
Dietary antioxidants and folic acid may play a role in the pathophysiology of coronary disease and stroke. We review patient-oriented evidence on the effectiveness of supplementation with antioxidants and/or folic acid in the prevention of myocardial infarction and stroke. Observational data suggest cardiovascular benefit of vitamin E supplementation, but results of controlled clinical trials are inconsistent regarding the effect on nonfatal myocardial infarction. Moreover, studies have not shown a protective effect of vitamin E against fatal myocardial infarction and have not addressed stroke. For vitamin C and folic acid supplementation, observational data are inconsistent and controlled clinical trials are lacking. Thus, the available evidence is insufficient to recommend the routine use of vitamin E, vitamin C or folate supplements for the prevention of myocardial infarction or stroke. The evidence argues against the use of beta carotene supplements for this purpose. The costs and risks associated with these supplements are low, however, and physicians may choose to recommend vitamin E, folate and/or vitamin C supplementation pending conclusive evidence from clinical trials.
Because dietary antioxidants and folic acid (folate) may play a part in the pathophysiology of coronary disease and stroke, interest in the role of vitamin supplements in preventing these diseases is high. This article reviews the evidence from patient-oriented studies to provide information to help physicians decide whether to recommend supplements of antioxidants and/or folate in the prevention of coronary disease and stroke.
Biological Plausibility
Oxidized low-density lipoprotein (LDL) cholesterol attracts and interacts with monocytes, macrophages and platelets to promote atherogenesis in the vascular lining. It also causes endothelial necrosis and interferes with vasorelaxation. Unlike beta carotene, vitamins E and C inhibit LDL oxidation in vitro. Vitamin E reduces monocyte adhesion to endothelium, inhibits platelet activation in vitro and inhibits atherosclerosis in rodents; in humans, angiographic and ultrasonographic studies suggest that vitamin E also inhibits the progression of atherosclerosis.1
Homocysteine is an amino acid product of normal protein metabolism. Folate, vitamin B12 and vitamin B6 are all involved in the metabolism of homocysteine. Deficiencies of one or more of these vitamins can lead to hyperhomocysteinemia.2,3 Homocysteinuria is a rare, congenital enzyme deficiency that results in high serum and urine levels of homocysteine, and persons with this disorder have premature vascular disease and usually die of myocardial infarction (MI), stroke or pulmonary embolus.2
Homocysteine, at five to 10 times the normal concentrations, directly damages endothelium, promotes proliferation of vascular smooth muscle cells, exhibits procoagulant activity and increases collagen synthesis.4 Results of clinical studies reveal that folate and vitamin B12 supplements lower serum homocysteine levels, with mixed results from vitamin B6 supplementation.2,5 Of these three B vitamins, folate has been studied the most and clearly shows the most powerful effect.2–5
Observational Studies
ANTIOXIDANT VITAMINS
Prospective observational studies (Table 1)6–14 have addressed whether the intake of vitamin C, vitamin E or beta carotene affects cardiovascular risk after adjustment for known major cardiovascular risk factors. Some studies combined dietary and supplemental intakes, while others attempted to separate these sources. Taken together, the results of these studies do not support any conclusions about potential differential effects by vitamin source.
| Study | Design | Outcomes (95% confidence interval) | Comments |
|---|---|---|---|
| Nurse's Health6 | 87,245 women; follow-up for 8 years | Endpoints: MI or stroke | Trend towards stroke prevention |
| Vitamin E ≥100 IU per day | RR: 0.57 (range: 0.41 to 0.78) | ||
| Health Professionals7 | 39,910 men; follow-up for 4 years | Endpoints: MI or coronary revascularization | |
| Vitamin E ≥100 IU per day | RR: 0.63 (range: 0.47 to 0.84) | ||
| Beta carotene ≥14,000 IU per day | RR: 0.30 (range: 0.11 to 0.72) | Beta carotene benefit in smokers only | |
| Vitamin C up to 1,100 mg per day | No effect | ||
| Iowa Women8 | 34,486 women; follow-up for 7 years | Endpoint: fatal MI | |
| Vitamin E ≥10 IU per day | RR: 0.38 (range: 0.18 to 0.80) | Supplement use rare in this cohort | |
| Beta carotene ≥13,000 IU per day | No effect | ||
| Vitamin C ≥196 mg per day | No effect | ||
| Finnish cohort9 | 5,133 men/women; follow-up for 14 years | Endpoint: fatal MI | Supplement use rare in this cohort |
| Vitamin E ≥5 IU per day | RR: 0.35 (range: 0.14 to 0.88) | Benefit among women only | |
| Vitamin C > 90 mg per day | RR: 0.49 (range: 0.32 to 0.98) | ||
| Beta carotene | No effect | ||
| National Health and Nutrition Examination Survey (NHANES)13 | 11,348 men/women; follow-up for 10 years | Endpoint: cardiovascular death | Vitamin E intake unaccounted for |
| Vitamin C ≥50 mg per day | Men—RR: 0.58 (range: 0.53 to 0.82) | ||
| Women—RR: 0.75 (range: 0 .55 to 0.99) | |||
| Gale, et al.14 | 730 elderly men/women; follow-up for 20 years | Endpoints: fatal stroke or MI | Vitamin E intake unaccounted for |
| Vitamin C ≥45 mg per day | RR: 0.50 (range: 0.30 to 0.80), stroke only | Fatal MI—no effect | |
| Established Populations for Epidemiologic | 11,178 elderly men/women; follow-up for 6 years | Endpoint: fatal MI | |
| Studies of the Elderly(EPESE)11 * | Vitamin E supplement use | RR: 0.53 (range: 0.34 to 0.84) | |
| Vitamin C supplement use | No effect | ||
| Scottish Heart Health Study10 † | 11,629 men/women; follow-up for 8 years | Endpoints: MI or coronary revascularization | |
| Vitamin E | No significant effect | ||
| Vitamin C | No significant effect | Trend toward protection | |
| Beta carotene | No significant effect | Trend toward protection | |
| The Rotterdam Study12 † | 4,802 men/women; follow-up for 4 years | MI | |
| Vitamin E | No effect | ||
| Vitamin C | No effect | ||
| Beta carotene | RR: 0.55 (range: 0.34 to 0.83) | Beta carotene benefit in smokers only |
Seven studies6–12 examined the association of vitamin E intake (from diet and/or supplement sources) with coronary disease. The results of all of these studies except two10,12 reported a reduction in coronary events associated with higher vitamin E intakes. The only vitamin E study that included stroke6 reported a statistically insignificant trend favoring its use.
Eight studies7–14 examined the association of vitamin C intake with the incidence of coronary disease. Results were inconsistent between genders and among cohorts, and two of these studies failed to control for vitamin E use.13,14 The results of one study14 that investigated stroke revealed an apparent protective effect of vitamin C.
HOMOCYSTEINE AND FOLATE
Multiple cross-sectional and case-control studies linking plasma homocysteine levels with coronary disease and stroke have been published. The only prospective data come from nested case-control studies involving small sub-samples within large cohort studies. Two recent systematic reviews15,16 have summarized this literature. The first review15 included 15 studies on coronary disease (involving 5,617 persons) and nine studies addressing stroke (involving 2,547 persons) in a meta-analysis. In all but two of the studies included in this analysis, coronary and stroke risks were higher in persons with higher homocysteine levels. The second review16 summarized pertinent studies published since the first review. Results of all but five of the 26 studies in this review revealed a positive relationship between plasma homocysteine and coronary disease and/or stroke.
Since the time of these reviews, results of three more prospective studies have been published.17–19 Among all 12 of the prospective studies now reported, five17,18,20–22 failed to demonstrate that plasma homocysteine levels were a risk factor for coronary disease or stroke. This lack of consistency among prospective studies makes a causal relationship questionable.
If hyperhomocysteinemia causes cardiovascular disease, then folate supplementation should help prevent it. As yet, there are no reports that link folate intake directly with coronary disease or stroke, but results of interventional studies of folate supplementation have consistently shown a reduction in homocysteine levels, with a plateau effect at a dosage of about 1 mg per day.5,15
SUMMARY OF OBSERVATIONAL STUDIES
The prospective observational evidence is fairly consistent for a protective effect of vitamin E against coronary disease. Evidence about the effect of vitamin E on the risk of stroke is sparse. The evidence linking vitamin C to cardiovascular disease is inconsistent, and a protective effect of beta carotene has been observed only among those who smoke. These studies all addressed primary prevention, and absolute risk reductions appear modest at best.
Based on our calculations, if the observed protective effect of vitamin E is real, 170 to 250 persons would need to take vitamin E supplements (or have high dietary vitamin E intake) for 10 years to prevent one MI or stroke. Observational evidence linking homocysteine with cardiovascular disease is less consistent among prospective studies than in cross-sectional or retrospective analyses.
Controlled Clinical Trials
Observational studies cannot prove or disprove a protective effect because they cannot avoid the real possibility that intake of these vitamins is only a marker for other factors or behaviors that are the true modulators of heart attack and stroke. In the case of antioxidant vitamins and cardiovascular disease, results of seven controlled clinical trials have been reported (Table 2).23–30 Results from controlled clinical trials on the effects of folate supplements in the prevention of MI or stroke have yet to be published.
| Study | Study population | Treatment | Endpoint(s) | Outcomes (95% confidence interval) | Comments |
|---|---|---|---|---|---|
| Alpha Tocopherol Beta Carotene Cancer Prevention Trial (ATBC)23 *24 † | 29,133 male smokers; follow-up for 6 years | Vitamin E, 50 IU per day | MI or stroke | No effect for primary prevention | Vitamin E dose lower than observed as protective in most observational studies |
| RR: 0.62 (range: 0.41 to 0.96) for nonfatal MI if past history of MI | |||||
| Same as above | Beta carotene, 20 mg per day | MI or stroke | No significant effect | Trend toward increased risk | |
| Physician's Health25 * | 22,071 men; follow-up for 12 years | Beta carotene, 50 mg every other day | MI or stroke | No effect | — |
| Beta Carotene and Retinol Efficacy Trial (CARET)26 * | 18,314 men/women; follow-up for 4 years | Beta carotene, 30 mg per day plus vitamin A, 25,000 IU per day | Death—any cause; cardiovascular death | Marginal increases in risk for both outcomes | — |
| Chinese Ca Prevention27 * | 29,584 men/women; follow-up for 5 years | Vitamin E, 30 IU per day, plus beta carotene, 15 mg per day | Cardiovascular death | No significant effect | Vitamin E dose low; trend toward fatal stroke protection |
| Same as above | Vitamin C, 120 mg per day | Cardiovascular death | No effect | — | |
| Cambridge Heart Antioxidant Study(CHAOS)28 † | 2,002 men/women with CHD; follow-up for 1.5 years | Vitamin E, 400 to 800 IU per day | Fatal or nonfatal MI | RR: 0.27 (0.11 to 0.47), (nonfatal MI only) | No effect on fatal MI |
| Heart Outcomes Prevention Evaluation(HOPE)29 † | 9,541 men/women with CVD; follow-up for 4.5 years | Vitamin E, 400 IU per day | MI, stroke or cardiovascular death | No effect on any of these three outcomes | — |
| GISSI-Prevenzione30 † | 11,324 men/women secondary prevention after recent MI; follow-up for 3.5 years | Vitamin E, 300 mg per day‡ | MI, stroke or cardiovascular death | No effect on any of these three outcomes | Also studied n-3 polyunsaturated fatty acids, which were protective |
Neutral or negative effects were reported in all four primary prevention trials.23,25–27 However, only two of these included vitamin E and at doses that were only about one half of that associated with reduced cardiovascular risk in observational studies. In the Alpha Tocopherol Beta Carotene Cancer Prevention Trial23 (ATBC), neither vitamin E (50 IU per day) nor beta carotene (20 mg per day) had a significant effect on the risk of a first MI or stroke. In the Beta Carotene and Retinol Efficacy Trial,26 the combination of 30 mg per day of beta carotene plus 25,000 IU per day of vitamin A increased the risk of death from all causes, with a marginally significant increase in the risk of cardiovascular death.
In a randomized trial25 restricted to male physicians, beta carotene at a dosage of 50 mg every other day had no effect on the risk of fatal or nonfatal MI or stroke. Among Chinese men and women in a large cancer prevention trial27 of nutritional supplements, beta carotene (15 mg per day) with vitamin E (30 IU per day) had no effect on coronary deaths (which were rare in this cohort, anyway), but a trend toward fewer strokes was evident. Vitamin C supplementation at a dosage of 120 mg per day also had no effect on cardiovascular mortality.
Four clinical trials24,28–30 have addressed the use of antioxidant supplements to prevent MI in patients with known coronary disease; none of these trials addressed the secondary prevention of stroke. In the ATBC trial24 among the subset of male smokers with a past history of MI, the risk of another nonfatal MI in those receiving vitamin E was reduced by 38 percent, with no significant impact on fatal MI. However, the risk of fatal MI in these men was increased with beta carotene use alone or in combination with vitamin E.24 In the Cambridge Heart Antioxidant Study28 of men and women with angiographic coronary disease, 400 to 800 IU per day of vitamin E reduced the risk of nonfatal MI by 73 percent but had no effect on fatal MI.
The Health Outcomes Prevention Evaluation29 study assessed the effect of 400 IU per day of vitamin E on patients with known cardiovascular disease and found no effect on the incidence of MI, stroke or cardiovascular death. Similarly, in the GISSI Prevenzione trial,30 300 mg per day of vitamin E had no effect on subsequent MI, stroke or cardiovascular death rates among patients with a recent history of MI.
SUMMARY OF CLINICAL TRIALS
Taken together, the available evidence from randomized controlled trials fails to demonstrate that antioxidant vitamins or folate supplementation is effective for the prevention of coronary disease or stroke. However, this lack of evidence is due more to a paucity of clinical trials than to negative outcomes.
Secondary prevention of coronary disease with vitamin E looked promising based on the first two trials,24,28 but the efficacy in secondary prevention was not confirmed in either of two larger subsequent trials.29,30 In addition, the mixed evidence for protective effects of vitamin E against nonfatal MI with no evidence of benefit against fatal MI are unexplained, although a lack of power to detect such effects is plausible.
The available evidence argues against the prescription of beta carotene supplements. Currently, there is no evidence from clinical trials that included disease-specific endpoints to support or refute the potential efficacy of folate, and only one study has investigated vitamin C supplementation, with neutral results.27
Safety and Cost of Supplements
If folate or vitamin E supplements prove to reduce cardiovascular risk, the available evidence suggests that vitamin E is best given in a dosage of 100 to 800 IU per day and folate is best given in a dosage of 0.4 to 1 mg per day. The recommended intake of vitamin E is 19 IU per day, and vitamin E doses less than 800 IU per day are safe.31 However, daily doses of vitamin E greater than 800 IU may adversely affect platelet function, and doses greater than 1,200 IU per day may interfere with vitamin K functions and granulocytic responses.32–35 The current recommended intake of folate for general health is 0.4 mg per day with a tolerable upper limit of 1 mg per day.36 The only plausible adverse effects of folate at doses up to 1 mg per day would be masking of vitamin B12 deficiency (in those at risk for B12 malabsorption) and possible interference with zinc absorption.37,38
The cardiovascular data on vitamin C are weak but suggest a lower therapeutic threshold of 50 to 100 mg per day. The recommended intake of vitamin C is 75 to 90 mg per day with an upper limit of 2 g per day.31 Vitamin C toxicity is rare at doses less than 5 g per day, although as little as 500 mg per day may promote oxalate kidney stones.39,40 Rebound scurvy is possible after abrupt cessation of large doses.41,42
Thus, the doses of vitamin E, folate and vitamin C that may have cardiovascular benefit are quite safe and inexpensive. The average wholesale price of vitamin E at a dosage of 800 IU per day is about $3.00 per month; vitamin C at a dosage of 500 mg per day and folate at a dosage of 1 mg per day each cost about $1.50 per month wholesale.43
Final Comment
The available evidence is insufficient to recommend the routine use of vitamin E, vitamin C or folate supplements for the prevention of coronary disease or stroke. The evidence argues against the use of beta carotene supplements for this purpose.
Vitamin E at a dose of 100 to 800 IU per day may be useful for secondary prevention, but results from clinical trials are inconsistent. The observational evidence about vitamin C is also inconsistent, and the only reported clinical trial showed no effect. The nonclinical and observational evidence in support of folate supplements is extensive, but evidence from prospective observational studies reveal mixed results (but not harm), and no clinical trial has been completed. On the other hand, the cost and safety profiles for vitamin C, vitamin E and folate supplements are all favorable for empiric use at doses we have discussed.
A similar review regarding antioxidant use has recently been published in this journal.44 We believe that the evidence supporting the use of antioxidants in the prevention of coronary disease is weaker than this earlier review suggests, and our opinions are more aligned with those of an accompanying editorialist.45 A heart-healthy diet, emphasizing fruits and vegetables containing antioxidants and B vitamins, may be the best advice in the end.