Antioxidant supplements to prevent heart disease

Real hope or empty hype?

Thuan L. Tran, MD

VOL 109 / NO 1 / JANUARY 2001 / POSTGRADUATE MEDICINE

CME learning objectives

• To understand the role of free radicals and antioxidants in the development of atherosclerosis
• To be familiar with current clinical studies on antioxidants and prevention of heart disease
• To be able to counsel patients about the use of antioxidant supplements

The author discloses no financial interests in this article.

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Preview: Antioxidants in foods and supplements are being widely promoted for their health benefits. Protection from heart disease is one claim that seems compelling in light of scientific evidence and large-scale observational studies. But will antioxidant supplements help your patients? To examine this question, Dr Tran reviews numerous clinical studies and evaluates the discrepancies between observational and clinical results.
Tran TL. Antioxidant supplements to prevent heart disease: real hope or empty hype? Postgrad Med 2001;109(1):109-114

Public interest in antioxidants has been growing rapidly over the last decade. A recent Internet search yielded more than 50,000 sites mentioning this subject, most of which offered antioxidant products such as vitamins, herbs, minerals, and food extracts. Antioxidants have been promoted as preventive therapy for a wide range of conditions, including cardiovascular disease; therefore, healthcare professionals are often asked about these supplements. This article presents a review of the scientific evidence on antioxidants for prevention of heart disease, with an emphasis on clinical studies involving human subjects in real-life situations.

Scientific rationale

Most heart disease arises from atherosclerosis. A heart attack occurs when atherosclerotic plaque erodes and ruptures, leading to thrombosis (1). Many experimental studies suggest that oxidation of low-density lipoprotein cholesterol by free radicals plays a central role in the formation, progression, and rupture of plaques (2). Antioxidants have been found to inhibit oxidant formation, interfere with the activity of oxidants already formed, and even repair injury caused by oxidants (3). These findings, however, are from molecular- and cellular-level experiments done on animals. The application of such findings to humans requires further examination.

Promising findings in observational studies

Data from epidemiologic and prospective cohort studies of antioxidants and heart disease rates amply support the preventive role of antioxidants in heart disease (table 1). However, these types of studies can show only an associative, not a causative, relationship between antioxidant consumption and reduced rates of heart disease.

Table 1. Outcomes of observational studies on dietary and supplemental antioxidants and heart disease prevention
Study	Antioxidant
	Vitamin E	Vitamin C	Beta carotene
Male health professionals study (8)	+	-	+*
National Health and Nutrition Examination Survey-I (9)		+
Nurses' Health Study (7)	+	-	-
Scottish Heart Health Study (10)
Men	+	+	+
Women	-	-	-
World Health Organization cross-cultural study (4)	+	+
+, benefit; -, no benefit. *Benefit was found in smokers only.

Epidemiologic study evidence
A World Health Organization cross-cultural study (4), which surveyed 12 different populations in Europe, showed a significantly lower rate of cardiac death in groups with high dietary intake of vitamin C or vitamin E. Independent studies from Finland and the United States (5,6) also demonstrated similar beneficial effects of a diet rich in antioxidants, including vitamins C and E, beta carotene, and selenium.

Overall, there is little dispute that the more dietary antioxidants people within a population consume, the lower the rate of heart disease and death.

Prospective cohort study evidence
Outcomes of prospective cohort studies have been inconsistent. The Nurses' Health Study (7), which surveyed more than 88,000 women over an 8-year period, showed that women who consumed the highest amount of vitamin E for more than 2 years, in both diet and supplements, had a much lower risk of heart disease compared with those who took the lowest amount. However, use of vitamin C and beta carotene supplements did not lead to any reduction in heart disease risk. A similar study involving nearly 40,000 male health professionals (8) showed risk reductions of up to 40% in men with the highest vitamin E intakes. Use of beta carotene supplements led to smaller reductions in risk but only in smokers. No benefit was shown for vitamin C supplements.

In contrast, the first National Health and Nutrition Examination Survey (9) reported a significantly lower risk of cardiovascular death in persons with high intakes of vitamin C. This study, however, did not take into consideration other antioxidants that the study participants might have consumed in addition to vitamin C. More perplexing is the Scottish Heart Health Study (10), which reported significant benefits from vitamins C and E and beta carotene but only in men; no benefit was observed in women.

Extreme caution must be used in interpreting data from these cohort studies. Bias is inherent in the selection of participants. For example, people who consume large amounts of fruits and vegetables tend to have more healthful living habits. Diets rich in antioxidants are also lower in saturated fat and cholesterol and higher in fiber. The low incidence of heart disease in these subjects could be the result of their overall lifestyle rather than intake of antioxidants alone.

Disappointing clinical studies

Randomized controlled trials are clinical studies designed to prove or disprove a causative effect. Unfortunately, results of these types of studies on antioxidants and heart disease risk have been disappointing (table 2), especially those investigating primary prevention.

Table 2. Outcomes of randomized controlled trials of antioxidant supplements and heart disease prevention
Antioxidant	Study	Outcome
Vitamin C	Cholesterol Lowering Atherosclerosis Study (CLAS) (16)	0
	Linxian, China, cancer prevention study (14)	0
Vitamin E	Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (11)	-, +*
	Cambridge Heart Antioxidant Study (15)	+*
	CLAS (16)	+*
	Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (17)	0
	Heart Outcomes Prevention Evaluation (18)	0
Beta carotene	ATBC (11)	-
	Beta-Carotene and Retinol Efficacy Trial (12)	-
	Physicians' Health Study (13)	0
Vitamins A, C, and E and beta carotene	Indian Experiment of Infarct Survival-3 (19)	+*
Vitamins C and E and beta carotene	Multivitamins and Probucol Study (20)	0
+, beneficial effect; -, adverse effect; 0, neutral effect. *Secondary prevention.

The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (11) examined the effects of vitamin E and beta carotene over a period of 5 to 8 years in more than 29,000 male smokers in Finland. Overall, no reduction in heart disease or death was found. Moreover, an increase in mortality from hemorrhagic stroke was found with use of vitamin E supplements. An increased incidence of cardiac death was also found in the group taking beta carotene supplements. Similarly, the Beta-Carotene and Retinol Efficacy Trial (12), which involved more than 18,000 men and women, showed that after an average of 4 years of supplementation, the combination of beta carotene and retinol (vitamin A) had no benefit and may have increased the risk of cardiac death.

The Physicians' Health Study (13), which for 12 years followed more than 22,000 male physicians in the United States, showed no significant effect of beta carotene on heart disease. And a randomized study of more than 29,000 residents in rural China (14) over a 5-year period reported no significant benefit of vitamin C supplements in reducing cardiovascular mortality.

Early results of studies on secondary prevention were encouraging. The Cambridge Heart Antioxidant Study (15) showed that in patients with atherosclerotic heart disease confirmed by angiography, high doses of vitamin E could lower the risk of nonfatal heart attack and other cardiovascular events such as stroke, but the overall mortality rate did not improve. The ATBC study, mentioned earlier, also showed that persons with previous heart attack had a lower risk of recurrent heart disease when given vitamin E supplements (11). Again, there was no improvement in the overall rate of mortality. Vitamin E was also shown to slow down the progression of atherosclerotic plaque in patients with coronary artery disease in the Cholesterol Lowering Atherosclerosis Study (16). Whether this reduction might lead to a lower risk of heart attack or death remains to be proved. No benefit was observed with use of vitamin C supplements.

With the release in 1999 of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI) (17) and the Heart Outcomes Prevention Evaluation (HOPE) (18), the role of antioxidants for secondary prevention is again in doubt. The HOPE study reported no reduction in heart attack, stroke, or death in patients with heart disease or diabetes after use of vitamin E supplements for more than 4 years (18). Similarly, the GISSI trial, which followed 11,000 patients with recent heart attacks, showed no benefit from use of vitamin E supplements for up to 2 years (17).

When antioxidants were used in combination, the results were also inconclusive. The Indian Experiment of Infarct Survival (19) suggested that a combination of vitamins A, C, and E and beta carotene could be beneficial in preventing complications and cardiac events in patients with suspected heart attacks. The Multivitamins and Probucol Study (20), however, showed that the combination of vitamins C and E and beta carotene had no effect in reducing the rate of restenosis in patients after angioplasty.

Discrepancy theories

Although scientific rationale and observational studies have been convincing, randomized clinical trials have failed to show a consistent benefit from use of antioxidant supplements; some antioxidant supplements, especially beta carotene, even showed harmful effects on human subjects.

There are many possible explanations for these discrepancies. First, as mentioned previously, the positive outcomes in the observational studies could be from the overall healthful lifestyle of the subjects rather than from the supplements alone. Second, other types of nutrients may be present in fruits and vegetables that act in synergy with antioxidants to provide a protective effect on the heart. Third, the amount of antioxidants in supplements may be so high compared with that in the diet that it leads to a toxic effect. Other explanations may yet be postulated.

As mentioned, antioxidant supplements are not without potential adverse effects. High doses of vitamin E may lead to hemorrhagic stroke. Long-term use of beta carotene supplements may increase the risk of heart disease and cancer. Many medical and health organizations, including the American Heart Association, have cautioned the public about the excessive use of antioxidant supplements, especially beta carotene, based on the overwhelming evidence that it might do more harm than good (21).

Besides vitamins A, C, and E and beta carotene, other antioxidants are being promoted to prevent heart disease: flavonoids, coenzyme Q10 or ubiquinone (Ubiqgel), selenium (Sele-Pak, Selepen), and lycopene, to name a few. Compared with studies of the more common antioxidants, studies of these substances are more scarce and even less conclusive. Clearly, before any definite recommendation can be made, more clinical trials need to be done to clarify the usefulness of antioxidant supplements in the prevention of heart disease.

Conclusion

The notion that antioxidant supplements can prevent heart disease has not been proven or supported by current clinical evidence. Until conclusive scientific evidence is available regarding the efficacy, safety, and appropriate dosage of antioxidants to prevent heart disease, the most prudent recommendation for the general public is to obtain antioxidants from sources that have been clinically proven to be beneficial: fruits, vegetables, and whole grains.

References

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Dr Tran is staff physician, department of family medicine, Southern California Permanente Medical Group, Claremont. Correspondence: Thuan L. Tran, MD, Department of Family Medicine, Southern California Permanente Medical Group, Indian Hill Medical Office, 250 W San Jose St, Claremont, CA 91711.

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