• BACKGROUND: Several nonrandomized, observational studies have suggested that antioxidant vitamins decrease vascular disease, cancer, and mortality. However, large randomized trials are needed to counter biases such as the “healthy user effect” often seen in observational studies.

• POPULATION STUDIED: The investigators studied 20,536 adults (mostly men from the United Kingdom) aged 40 to 80 years with diabetes, peripheral artery disease, or coronary artery disease. Patients were included if their total cholesterol concentration was above 3.5 mmol/L (135 mg/dL) and they were at a “substantial risk” for more than 5 years of death from coronary disease due to the presence of known cardiovascular disease (coronary artery disease, peripheral artery disease, cerebrovascular disease), diabetes, or hypertension. Patients were excluded if they had other life-threatening illnesses, diagnosed cancer, or were already taking high-dose vitamin E supplements.

• STUDY DESIGN AND VALIDITY: Patients in this impressive placebo-controlled, double-blind randomized (masked allocation via central telephone system) trial received antioxidant supplementation (vitamin E 600 mg, vitamin C 250 mg, and beta-carotene 20 mg daily) or matching placebo. This study was part of the MRC/BHF study on simvastatin. All patients in the vitamin treatment group also received simvastatin. In an 8- to 10-week “prerandomization run-in” phase eligibility and compliance with the 5-year study protocol was assessed. Patients were seen at 4, 8, and 12 months, and then every 6 months during a 5-year period.

  The intervention and placebo groups were similar in baseline characteristics. Subjects were analyzed according to the groups to which they were assigned (“intention-to-treat” analysis). Follow-up was available for 77% of subjects in both groups. The design allowed assessment of the separate effects of simvastatin and of the antioxidant vitamins, and enabled information about their combined effects to be obtained.

• OUTCOMES MEASURED: The primary outcomes measured were “major coronary events” (nonfatal myocardial infarction or death from coronary disease) and fatal coronary heart disease. Secondary outcomes measured were effects on major coronary events and major vascular events and nonfatal or fatal stroke. Other outcomes included site-specific cancer, cerebral hemorrhage, vascular procedures, and hospitalization for various causes.

• RESULTS: Patients taking vitamins had significantly higher levels of these vitamins in their blood. Despite this increase no difference was noted in all-cause mortality or deaths due to vascular or nonvascular causes. There were no differences in nonfatal myocardial infarctions, coronary death, nonfatal or fatal stroke, or coronary or noncoronary revascularization. No differences were noted in cancer incidence or hospitalization for any other nonvascular cause.

RECOMMENDATIONS FOR CLINICAL PRACTICE

This impressive placebo-controlled, double-blind randomized trial clearly shows that antioxidants, specifically vitamin E and C and beta-carotene, should not be recommended for secondary prevention of heart disease in high-risk patients. Site-specific cancers were not affected in this study. However, the study was too short (5 years) to be able to conclusively comment about the antioxidants’ effects on cancer.