Pharmacologic Management of Intermittent Claudication

Nature of the Problem

Ischemic intermittent claudication becomes asymptomatic when metabolic demands in exercising muscles exceed the oxygen and nutrient supply. The relative ischemia presumably elicits a maximal endogenous vasodilator response. Theoretically, numerous pharmacologic avenues can benefit patients in this setting, including augmenting vasodilation with exogenous vasodilators, altering skeletal muscle metabolic demands, enhancing blood flow by altering flow characteristics of the blood itself, and improving the endothelial dysfunction in atherosclerotic vessels. Pharmacologic therapies addressing each of these physiologic avenues have been proposed.

Concomitant Coronary Artery Disease

The most important aspect of pharmacologic treatment for this disease is the recognition that coronary artery disease (CAD) accompanies peripheral artery disease in the majority of patients. CAD represents the greatest cause of morbidity and mortality for these patients; estimated to be as high as 25% to 30% over 5 years in symptomatic PAD. Measures to prevent myocardial infarction (MI) are strongly indicated. In fact, it is generally agreed that patients with PAD, even without documented or known CAD, should be treated as if they had known CAD, with the same appropriate secondary prevention measures. These include routine use of antiplatelet agents, smoking cessation, aggressive treatment of diabetes, appropriate control of hypertension, and, most importantly, aggressive lipid lowering.

Antiplatelet agents have specifically been shown to improve outcomes in patients with cardiovascular disease and also to improve patency of peripheral bypass grafts. However, more recent studies have called the efficacy of antiplatelet agents in the PAD population specifically into question. A meta-analysis of aspirin use in controlled trials specifically looking at PAD treatment failed to find significant reductions in cardiovascular events. However, in studies that evaluated aspirin use alone (versus in combination with dipyridamole), there was a strong trend toward reduction in total cardiovascular events (relative risk [RR], 0.75; 95% confidence interval [CI], 0.48–1.18), as well as a statistically significant reduction in stroke risk (RR, 0.64; 95% CI, 0.42–0.99). Likely, such meta-analyses suffer from being underpowered, because there are not many randomized trials of aspirin use specifically in PAD.

Similarly, smoking cessation is associated with improved outcomes in peripheral vascular disease, although for obvious reasons, randomized, controlled trials do not exist. Observational studies have clearly shown an improvement in outcomes for patients with PAD and other forms of vascular disease who quit smoking over those who do not quit. Every patient seen in a vascular clinic, or by vascular specialists, should be asked about smoking status, and smokers should be offered smoking cessation therapy.

Lipid-lowering therapy has been shown to decrease the incidence of MI and cardiovascular death, as well as stroke, in patients with hyperlipidemia, PAD, and CAD. More specifically, the Heart Protection Study demonstrated a 24% reduction in the endpoint of MI, MI-related death, stroke, or revascularization in all these patient groups. This was particularly evident in patients with PAD and no known CAD. Two studies even demonstrated that lipid-lowering with statin therapy lessened claudication symptoms as well.