Aspirin and Secondary Prevention in Peripheral Artery Disease

Abstract

LOWER EXTREMITY PERIPHERAL ARTERY DISEASE (PAD) is common among older men and women in developed countries and will become increasingly prevalent as populations survive longer with chronic disease. Recent estimates in the United States indicate that 1 in 16 men and women 40 years or older have PAD. In primary care medical practices in the United States, nearly 30% of men and women who are either 70 years or older or aged 50 to 69 years with a history of diabetes or smoking have an ankle-brachial index (ABI) of less than 0.90, consistent with PAD. Multiple epidemiological studies completed during the past 20 years consistently demonstrate increased rates of cardiovascular morbidity and mortality among men and women with PAD compared with those without PAD even after adjusting for cardiovascular disease risk factors and history of cardiovascular events. Therefore, preventing cardiovascular events is a major therapeutic goal for clinicians treating patients with PAD. Current clinical practice guidelines from the American Heart Association and the American College of Cardiology recommend low-dose aspirin (75 to 325 mg/d) to reduce the high risk of cardiovascular morbidity and mortality in patients with PAD. Clopidogrel is recommended as an alternative antiplatelet medication for secondary prevention in PAD. In this issue of JAMA, Berger et al report results of a metaanalysis of 18 randomized controlled clinical trials assessing the effect of aspirin therapy, alone or with dipyridamole, on the risk of cardiovascular events in 5269 patients with PAD. Overall, compared with a control group, aspirin therapy was associated with a 12% relative risk reduction in the primary outcome measure of cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). However, this 12% risk reduction did not achieve statistical significance. For secondary outcomes, aspirin therapy was associated with a statistically significant reduction in nonfatal stroke but was not associated with significant reductions in nonfatal myocardial infarction, cardiovascular mortality, or all-cause mortality. Several characteristics of this meta-analysis must be considered when interpreting the results. First, the sample size is small. The authors report that a sample size of 5000 participants provided 88% power to detect a 25% difference and 70% power to detect a 20% difference between the aspirin and control groups for the primary outcome measure. Therefore, themeta-analysis lacks statisticalpower fordemonstratingclinically meaningful differences of 20% or less between the aspirin and control groups. Second, of the 5269 participants included in the meta-analysis, more than 25% were from 2 studies that included only PAD participants with diabetes mellitus, which is a major risk factor for and is common among those with PAD. However, patients with diabetes mellitus may derive less benefit from aspirin than those without diabetes mellitus, as suggested by results of the Antithrombotic Trialists’ Collaboration meta-analysis and other recent clinical trial data. Third, of the 18 trials included in the meta-analysis, 15 were published prior to 1995; however, the diagnosis and recognition of PAD has changed dramatically in the past 10 years. Although PAD was previously considered synonymous with intermittent claudication, it is now known that most patients with PAD are asymptomatic or present with leg symptoms other than classic intermittent claudication. The results of aspirin clinical trials that enrolled patients with PAD during earlier decades may have limited generalizability to patients with PAD treated by clinicians in the 21st century. Fourth, given the heterogeneity of results, subset analyses stratified by patient characteristics such as age, sex, and diabetes would be informative. However, individual data were not available for these comparisons. The current guideline-recommended dose of 75 to 325 mg ofaspirin forpatientswithPADisderived fromtheAntithrombotic Trialists’ Collaboration meta-analysis of 287 studies involving135 000patientsathighriskofvascularevents. Among all patients, the Antithrombotic Trialists’ Collaboration metaanalysis demonstrated that proportional reductions in vascular events were 19% for daily aspirin doses of 500 to 1500 mg, 26% for aspirin doses of 160 to 325 mg, 32% for aspirin doses