Intervention Studies in Humans with Clinical Endpoints
Observational studies, of course, only infer a cause-and-effect relationship. Even in the most well:designed observational studies, the amount of uncontrolled and uncontrollable confounding could easily be as large as the small to moderate reductions in risk that are most plausible. Individuals who select higher intakes of antioxidants may also adopt other dietary or nondietary lifestyle characteristics that account for the apparent benefits of antioxidants seen in observational studies. Prospective studies v.ith a clinical endpoint are required, and only randomized trials of sufficient sample size, dose, and duration of treatment and follow-up can provide reliable data. The limitations of intervention trials are that they can often only be interpreted for the particular study population, and for the antioxidant dose provided during the trial.
Numerous intervention studies designed to test the hypothesis that increased antioxidan intake will protect against atherosclerosis are currently in progress. In general, these studie~ are using supplements of antioxidant vitamins or other antioxidants, and results so far have been encouraging. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Tria1.(ATBC), nducted among 29, 133 male heavy smokers in FiIlland, found no reduction in CHD morbidity mortality during 5-8 yr of treatment with vitamin E (50 mg/d) or (3-carotene (20 mg/d). ose assigned vitamin E had no significant decrease in CHD deaths, but a 50% excess of ';eaths from cerebral hemorrhage, whereas those assigned to l3-carotene experienced an 11% crease in CHD deaths. In a further analysjs, a subgroup of the original subjects with a previous MI were considered.
The endpoint of this substudy was the first major coronary event after randomization. e proportion of major coronary events was not decreased with either a-tocopherol or 13otene supplements. In fact, l3-carotene conferred an excess of fatal CHD (75% increase in risk). There was a beneficial effect of vitamin E on nonfatal MI with a risk reduction of 38%. The CARET (Beta-Carotene and Retinol Efficacy TriaD, designed to test the effects of a mbined supplement of 30 mg (3-carotene and 25,000 IU retinol daily among 18,314 cigarette 31llokers and individuals with occupational asbestos exposure, was ended early when researchers detected an elevated risk of death from lung cancer in those receiving l3-carotene and, again, no beneficial effect on cardiovascular disease (C VD) was found. For C VD mortality, there was a nonsignificant 26% increase in the treated group (p = 0.06). The Physicians Health "'tudy followed more than 22,000 US male doctors treated with 50 mg l3-carotene or placebo every other day for an average of 1.2 yr.
The trial appears to have been conducted meticulously and its results would seem to seriously question any beneficial effect with such supplementation on CVD in well-nourished populations. There were no significant effects on indi-vidual outcomes, or on a combined endpoint of nonfatal MI, nonfatal stroke, and cardiovascular death, for which the relative risk was 1.0. There was also no evidence of harm (or benefit) among the 11% of participants who were current smokers at baseline. Greenberg and associates studied the effect of l3-carotene supplementation (50 mg/d) in 1720 male and female subjects for a median period of 4.3 yr with a median follow-up of 8.2 yr. Subjects whose plasma levels of l3-carotene were in the highest quartile at the beginning of the study had the lowest risk of death from all causes compared with those in the lowest quartile. Supplementation, however, had no effect on either all-cause or cardiovascular mortality. Thus for l3-carotene supplementation, it would appear that there are no overall benefits among individuals with a good nutritional status who are at low or average risk of developing CHD. The situation may be different, however, for those with a previous history of such disease.
