Background: Persons with diabetes or peripheral arterial disease have markedly increased risks of myocardial infarction (MI), stroke, and death. Because aspirin is an effective antiplatelet agent for secondary prevention of cardiovascular events in these populations, its use has been extrapolated for primary prevention. Despite a lack of evidence of any benefit in primary prevention, daily aspirin use has become part of several guidelines, including those from the American Heart Association and the American Diabetes Association. The use of antioxidants in primary prevention has also been studied because they may counteract the platelet aggregating effects of free radicals. Belch and colleagues studied whether aspirin or antioxidants, alone or in combination, are more effective than placebo in preventing first cardiovascular events in patients with diabetes and asymptomatic peripheral arterial disease.

The Study: The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial included 16 hospital centers in Scotland and 1,276 patients in a randomized, double-blind, placebo-controlled study. Allocation was concealed, and patients were randomized to daily therapy with 100 mg of aspirin plus an antioxidant tablet, aspirin with a placebo antioxidant tablet, placebo aspirin plus an antioxidant tablet, or two placebo tablets. The antioxidant tablet contained alphatocopherol (200 mg), ascorbic acid (100 mg), pyridoxine hydrochloride (25 mg), zinc sulphate (10 mg), nicotinamide (10 mg), lecithin (9.4 mg), and sodium selenite (0.8 mg). Participants were at least 40 years of age, had type 1 or 2 diabetes, and had asymptomatic peripheral artery disease (defined as an ankle-brachial index of 0.99 or less).

The primary outcomes were the composite end point of death from coronary heart disease or stroke, nonfatal MI or stroke, or lower extremity amputation for ischemia; and death from MI or stroke. Participants were screened at baseline and every six months to record cardiovascular events and interventions.

Results: The groups were similar in number of patients and baseline characteristics. The median length of follow-up was 6.7 years. Overall, 233 participants experienced the composite end point (event rate of 2.9 per 100 patient-years), and 78 patients died from coronary heart disease or stroke (event rate of 1.0 per 100 patient-years). There were no differences in outcomes among the groups. Compared with placebo, neither aspirin nor antioxidant use affected the composite end point or death rate in this population.

Conclusion: Aspirin and antioxidants, alone or in combination, did not prevent a first cardiovascular event or death in patients with diabetes and asymptomatic peripheral disease. This contradicts recommendations from many guidelines. The authors conclude that aspirin should continue to be recommended for secondary prevention of cardiovascular disease in patients with diabetes.