The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) Trial: Factorial Randomised Placebo Controlled Trial of Aspirin and Antioxidants in Patients with Diabetes and Asymptomatic Peripheral Arterial Disease

Abstract

Conclusion: Neither aspirin, antioxidant therapy, nor the combination of aspirin and antioxidant therapy is useful in the primary prevention of cardiovascular events and mortality in patients with diabetes and asymptomatic peripheral arterial disease (PAD). Summary: Patients with asymptomatic PAD are six times more likely to die from cardiovascular disease ≤10 years than patients without PAD (N Engl J Med 1992;326:381-6). Aspirin as a secondary preventative measure in patients with diabetes and cardiovascular disease is well established. This has led to recommendations for use of aspirin as primary preventative therapy as well; however, a meta-analysis has demonstrated no efficacy for aspirin as a primary preventative therapy in patients with diabetes (BMJ 2002;324:71-86). Some evidence also indicates that there is increase in oxidative stress in patients with diabetes, with free radicals increasing platelet aggregation and antioxidants decreasing platelet aggregation. Based on the strength of the data for secondary prevention of cardiovascular events with aspirin therapy, the lack of data investigating aspirin as primary preventative therapy, and potential effects of antioxidants in patients with diabetes, the authors sought to study these agents in a group of patients with diabetes and asymptomatic PAD. The objective was to determine whether aspirin and antioxidant therapy, combined or alone, was more effective than placebo in reducing cardiovascular events in patients with diabetes and asymptomatic peripheral arterial disease. This was a multicenter, randomized, double-blind, two by two, factorial, placebo-controlled trial, It was conducted in 16 hospitals in Scotland and involved 188 primary care groups. Entered into the trial were 1276 adults (aged ≥40 years) with type 1 or type 2 diabetes and an ankle-brachial index <0.99, and no symptoms of cardiovascular disease. The daily regimen was 100 mg of aspirin plus antioxidant capsule in 320 patients, or aspirin plus placebo in 318, or antioxidant plus placebo in 320, or two placebo capsules in 318). The main outcome measures consisted of two composite primary end points: (1) death from coronary heart disease or stroke, nonfatal myocardial infarction or stroke, or amputation above the ankle, and (2) and death from coronary heart disease or stroke. There was no evidence of any benefit of aspirin or antioxidant therapy. There were 638 primary events, of which 116 occurred in the aspirin groups compared with 117 in the no-aspirin group (18.2% vs 18.3%; hazard ratio [HR] 0.98, 95% confidence interval [CI], 0.76-1.26). There were 43 deaths from coronary heart disease or stroke in the aspirin groups compared with 35 deaths in the no-aspirin groups (6.7% vs 5.5%; HR, 1.23, 95% CI, 0.79-1.93). In the antioxidant groups, 117 primary events (18.3%) occurred; whereas in the no-antioxidant therapy groups, 116 (18.2%) occurred (HR, 1.03; 95% CI, 0.79-1.33). There were 42 deaths from coronary heart disease or stroke in the antioxidant groups compared with 36 deaths from coronary heart disease or stroke in the no-antioxidant groups (6.6% vs 5.7%, respectively; HR, 1.21; 95% CI, 0.78-1.89). Comment: Once again, aspirin fails as primary preventative therapy in patients with diabetes. This study extended that conclusion to patients with asymptomatic PAD. The study, however, should not be construed as justification for failure to use aspirin as secondary preventative therapy in patients with cardiovascular disease and diabetes. Aspirin may be a so-called wonder drug, but it does not seem to be good for everything.