
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.
Biological Plausibility
Observational Studies
ANTIOXIDANT VITAMINS
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 |
HOMOCYSTEINE AND FOLATE
SUMMARY OF OBSERVATIONAL STUDIES
Controlled Clinical Trials
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 |