Introduction

Peripheral arterial disease (PAD) is a broad term that encompasses all vascular sites including carotid, vertebral, upper extremity, mesenteric, renal, and lower extremity vessels. To that end, much of the focus of this chapter has been restricted to the antiplatelet management of lower extremity artery disease (LEAD). On the whole, PAD is a common clinical problem, its prevalence rising steeply after the age of 50 years along with the presence of other cardiovascular risk factors [1]. Cigarette smoking, diabetes mellitus, dyslipidemia, and hypertension all significantly increase the risk of PAD [2]. Atherosclerosis is the most common cause of PAD, and since this is a systemic disorder, physicians must be aware of its propensity to affect other vascular beds and lead to critical organ damage. Patients with PAD have markedly increased rates of coronary artery disease (CAD) and cerebrovascular disease [3, 4]. This increased risk of myocardial infarction (MI) and stroke [5] informs the prognosis of PAD, with cardiovascular events being the leading cause of mortality in these patients [6]. The recognition of this cohort of patients as being at high cardiovascular risk has prompted a paradigm shift in their management over recent years: rather than predomination of vascular surgical procedures, it is now appreciated that these patients require comprehensive multidisciplinary medical management with a focus on modification of cardiovascular risk factors and protection against potentially catastrophic coronary and cerebrovascular events. Antiplatelet therapy forms a cornerstone of this management strategy, alongside exercise programs and aggressive risk-factor modification (smoking cessation, blood pressure control, lipid-lowering drugs, and strict glycemic control for patients with diabetes).

Antiplatelet therapy

Having established that patients with PAD are a high cardiovascular risk group, it stands to reason that antiplatelet therapy would be of prognostic benefit. This benefit was most clearly established by a meta-analysis (MA) conducted by the Antithrombotic Trialists’ Collaboration, comparing antiplatelet therapy with control in 135,000 high-risk vascular patients in 287 studies [7]. This included an analysis of 9716 patients with PAD, studied in 42 trials. For these patients, treatment with antiplatelet therapy conferred a 23% reduction in adverse cardiovascular events (vascular death, MI, and stroke). The benefit of antiplatelet therapy was consistent regardless of whether patients had peripheral bypass procedures, peripheral angioplasty, or suffered intermittent claudication. The majority of the trials included in this analysis used aspirin as the antiplatelet agent, and different doses of aspirin were also studied. There was a significantly smaller (13%) reduction in cardiovascular events in patients treated with less than 75 mg daily, but higher doses of aspirin were not beneficial compared to 75–150 mg. Moreover higher doses have been associated with increased gastrointestinal disturbance, including hemorrhage [8]. As well as preventing adverse coronary and cerebrovascular events, MA data has also suggested that antiplatelet therapy leads to a reduction in arterial occlusion and revascularization procedures when used in patients with intermittent claudication [9, 10].

Clopidogrel has been compared to aspirin for the secondary prevention of cardiovascular events in the CAPRIE trial [11]. This study included a subgroup of 6452 patients with PAD and demonstrated that clopidogrel was associated with a statistically significant 23.8% (p = 0.0028) reduction in the composite of ischemic stroke, MI, and vascular death. The effect on overall mortality was minimal, and clopidogrel was at least as well tolerated as aspirin.

The CHARISMA trial [12] is the only large randomized trial to compare a strategy of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel to aspirin alone for the prevention of atherothrombotic events in patients at high risk. The overall study was negative, with no clear benefit of DAPT being proven over and above aspirin alone for the prevention of MI, stroke, or cardiovascular death. A post hoc analysis focusing on PAD patients (n = 3096) was subsequently performed [13]. Here, the composite primary efficacy (cardiovascular death, MI, and stroke) and safety end points occurred with similar frequency in patients treated with either antiplatelet strategy. The combination of clopidogrel with aspirin therapy reduced the rate of MI (2.3% vs. 3.7%; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.42–0.96; P = 0.029) and the rate of hospitalization for ischemic events (16.5% vs. 20.1%; HR, 0.81; 95% CI, 0.68–0.95; P = 0.011) but caused an increased rate of minor bleeding (34.4% vs. 20.8%; odds ratio [OR], 1.99; 95% CI, 1.69–2.34; P < 0.001). The trial investigators suggest therefore that patients perceived to be at a low bleeding but high atherothrombotic risk may gain some added benefit from DAPT.

Oral anticoagulation (OAC) has been shown to reduce major cardiovascular events in patients with CAD [14], and it has therefore been hypothesized that the addition of an anticoagulant to aspirin may also be benefit for PAD patients. MA data has proved inconclusive in establishing the efficacy and safety of OAC with or without aspirin in the context of PAD [15]. The WAVE trial compared a strategy of warfarin (INR 2.0–3.0) in addition to aspirin with aspirin alone in 2161 patients with PAD [16]. Combination therapy was no more effective than aspirin alone for the prevention of MI, stroke, or cardiovascular death. Life-threatening bleeding, however, was significantly increased in the combination therapy group (relative risk, 3.41; 95% CI, 1.84 to 6.35; P<0.001), including fatal bleeds and hemorrhagic stroke.