Contemporary Medical Management of Peripheral Artery Disease

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis with common treatment approaches to reduce cardiovascular risk. Risk factors that drive atherogenesis in peripheral arteries overlap those associated with atherosclerosis in other circulations, including smoking, hyperlipidemia, hypertension, and diabetes.¹ Thus, patients with PAD often have coexistent coronary or cerebrovascular disease, referred to as polyvascular disease, and are at heightened risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. For example, in the EUCLID trial (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease trial), in the 13 855 patients with PAD: 44% had clinical atherosclerotic disease in other territories, including 19% with coronary artery disease (CAD), 15% with cerebrovascular disease, and 10% with atherosclerotic disease in all 3 territories.² The presence of polyvascular disease identifies the highest risk patient group for MACE, and those most likely to derive the greatest benefit with effective therpies.^3–5

Patients with PAD also have impaired walking capacity and symptoms of intermittent claudication and are at risk of critical limb ischemia leading to major adverse limb events (MALE), such as peripheral revascularization or amputation. In the patients with PAD participating in the REACH (The REduction of Atherothrombosis for Continued Health) Registry, there was a 22% risk of peripheral revascularization and a 6% risk of amputation over 4 years.⁶ Patients with PAD and prior peripheral revascularization or amputation are at increased risk for recurrent MALE relative to patients with PAD with no prior revascularization.^7,8 It is well established that there is a decreased risk of MACE and MALE among patients with PAD who are treated with risk factor modifying and antithrombotic therapies. Unfortunately, patients with PAD remain undertreated compared with patients with CAD,^9,10 underscoring the importance of raising the awareness among medical professionals of PAD. A key health goal important for health equity is the improved management of PAD to reduce the incidence of nontraumatic amputations.¹¹ This review highlights the medical therapies currently available to improve outcomes in patients with PAD.

Pathophysiologic Drivers of Clinical PAD

Complex layers of underlying pathophysiologic processes drive the clinical manifestations of PAD as illustrated in Figure 1. Key modifiable risk factors including cigarette smoking, poor diet quality, obesity, and physical inactivity along with underlying genetic factors all contribute to lower extremity atherosclerosis.¹² Arterial obstruction in the limb is a core feature of PAD leading to diminished blood flow and ischemia.¹³ However, the symptoms of PAD including claudication, functional limitation, and critical limb ischemia are not fully determined by reduced ankle brachial index (ABI).¹⁴ Vascular dysfunction with abnormal endothelium-mediated vasodilation impairs augmentation of blood supply during exercise and reduces functional capacity in patients with PAD.^15–17 Inflammatory activation with increased circulating biomarkers relates to both incident disease and the rate of decline in walking distance in patients with PAD.^18,19 Multiple risk factors for PAD including smoking, hypercholesterolemia, and diabetes induce oxidative stress that accelerates arterial damage and injury to skeletal muscle.^20,21 Chronic ischemia produces alterations in the leg skeletal muscle that limit walking ability.²² The skeletal muscle myopathy of PAD is characterized by impaired oxygen metabolism, mitochondrial dysfunction, skeletal muscle fiber changes, and atrophy.

Severe chronic restriction in blood flow along with local factors in the foot contribute to the transition to critical limb ischemia. Microvascular disease synergizes with obstructive PAD to markedly increase amputation rates indicating the importance of targeting specific risk factors including chronic kidney disease and diabetes.²³ Inadequate angiogenesis with reduced capillary density is associated with advanced PAD and highlights the potential for developing therapies that augment microvascular growth.²⁴ Microembolization may also contribute to microvascular loss evidenced by small vessel thrombotic obstruction in amputated limbs from patients with critical limb ischemia.²⁵ Acute limb ischemia is an important contributor to MALE, particularly in patients with prior revascularization, and seems to be largely driven by arterial thrombosis (in situ and artery to artery embolism).

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