Briefly, atherosclerosis results from adverse interactions between vessel hemodynamics, blood elements, and the vascular intima.² Covering the intimal surface of the vessels, the vascular endothelium regulates several important aspects of vascular homeostasis including vascular tone, leukocyte adhesion and migration, platelet function, and coagulation. Vascular homeostasis is achieved through several autocrine and paracrine factors mediated by endothelial cells. Nitric oxide is released by the endothelium, exerting vasodilatory, antiproliferative, and antithrombotic effects.³ Endothelial dysfunction develops in the presence of cardiovascular risk factors (such as hypertension, diabetes, smoking, and hyperlipidemic disorders) and results in the decreased availability of nitric oxide or an imbalance in vascular homeostasis favoring deleterious circulating factors. The development of endothelial dysfunction promotes atherosclerotic plaque development, hypercoagulability, and thrombosis. The nascent step in atherogenesis involves the endothelial mediated migration of low-density lipoprotein (LDL) from the blood plasma into the vessel intima.^4,5 Subsequent oxidative stress and intimal inflammation lead to the increased expression of leukocyte adhesion molecules along the vascular surface. Once monocyte and T-lymphocyte adherence occurs, chemokines facilitate leukocyte migration into the vessel intima.^{6,7,8,9,10,11}

As monocytes differentiate into macrophages within the vessel intima, they internalize oxidized LDL via scavenger receptors and develop into foam cells. Macrophage colony stimulating factor has been shown to be present in human atherosclerotic lesions and hypothesized to promote macrophage replication within the intima.⁷ Foam cells coalesce to form early atherosclerotic plaques, commonly described as “fatty streaks” (FIGURE 94.1). Activated macrophages and T-lymphocytes cause further plaque progression through the release of inflammatory cytokines and the promotion of smooth muscle cell (SMC) migration and proliferation within the vessel intima. As foam cells, SMCs, and extracellular lipids accumulate, the atherosclerotic plaque continues to organize and grow within the intimal layer. Simultaneously, macrophage and SMC apoptosis within the plaque result in the development of a relatively acellular, collagen-based fibrous cap, which provides stability to the lipid core (FIGURE 94.2). With the continuation of these inflammatory, replicating, and apoptotic processes, the atherosclerotic plaque becomes more complex, creating an abundant extracellular matrix (comprised of interstitial collagen, proteoglycans, and elastin fibers) within the vessel wall, developing calcification, and undergoing neovascularization.⁷

As the atherosclerotic plaque enlarges, an outward, “positive” remodeling phase initially predominates preventing luminal obstruction. However, luminal stenosis eventually develops as the enlarging plaque overcomes the vessel’s capacity to positively remodel. Moreover, proteolytic enzymes exuded from macrophages degrade and weaken the fibrous cap, creating a “vulnerable plaque” susceptible to rupture.¹² With plaque rupture, the thrombogenic inner vessel becomes exposed to circulating platelets and coagulation factors, resulting in thrombosis. If thrombosis results in occlusion of the vessel, acute ischemia develops.⁷ However, repetitive, subclinical thrombotic events also occur; with subsequent healing, and fibrous tissue and collagen fiber formation, resulting in progressive plaque expansion and luminal stenosis.¹² Thus, atherosclerosis progression may span many years without the development of symptoms. However, progressive obstruction of the arterial lumen eventually impedes blood flow through the affected vessel.

Both symptomatic and asymptomatic patients with PAD are at increased risk for adverse cardiovascular events. The prevalence of asymptomatic PAD varies with the age of the population studied, from 3% in 15,106 asymptomatic individuals between the ages of 45 and 60 years¹³ and 4.3% among a population >40 years of age¹⁴ to 29% of higher risk individuals over age 70 with cardiovascular risk factors.¹⁵ The prevalence of symptomatic PAD is 3% to 6% in the general population, also increasing with age (FIGURE 94.3).¹⁶

The natural history of patients with PAD varies widely depending on disease severity and progression of atherosclerosis, with symptoms ranging from intermittent claudication to critical limb ischemia (CLI) and limb loss (FIGURE 94.4). The majority of individuals with PAD have stable leg symptoms, with worsening claudication occurring in approximately 25% of patients,¹⁷ in association with diabetes, smoking, a low initial ankle-brachial index (ABI), and multiple stenotic lesions.¹⁸ CLI is the presenting symptom in 1% to 3% of PAD patients,¹⁷ and 5% to 10% of patients with previously stable PAD develop CLI over a 5-year period; risk factors being diabetes, advanced age, dyslipidemia, smoking, and an ABI of <0.5.¹⁶ In symptomatic individuals, only 1% to 3% require limb amputation over a 5-year period,¹⁷ but individuals with diabetes or those who present with CLI are at increased risk for limb loss.

Between 40% and 65% of patients with PAD are at increased risk for major adverse cardiovascular events (vascular-related death, myocardial infarction, or stroke),^16,19 the annual event rate being 5% to 7% and mortality related to cardiovascular disease being the most common cause of death. Coronary artery disease accounts for 40% to 60% of patient mortality, cerebrovascular disease for 10% to 20%, and other vascular events for 10% of deaths associated with PAD.¹⁶

Platelet activation is a crucial component of vascular atherothrombosis and mediated by several compounds including thromboxane A₂, adenosine diphosphate (ADP), serotonin, and norepinephrine.⁵⁴ The antiplatelet therapies most extensively studied in PAD are acetylsalicylic acid (aspirin) and thienopyridines (clopidogrel and ticlopidine). Aspirin reduces platelet activation through the inhibition of cyclooxygenase, a crucial enzyme for the synthesis of thromboxane A₂. Thienopyridines impair binding of ADP to the P2Y₁₂ receptor, consequently inhibiting platelet activation through the ADP pathway.

Antiplatelet therapy is primarily utilized to reduce the risk of cardiovascular events in patients with PAD. A large meta-analysis by the Antiplatelet Trialists collaboration involving 287 studies examined the effects of antiplatelet agents on cardiovascular outcomes in patients with a history of vascular disease. In a subgroup analysis of 42 studies involving 9,214 patients with PAD, antiplatelet therapy (primarily aspirin, alone or in combination with dipyridamole) was associated with a 23% odds reduction in subsequent vascular events.⁵⁵ In a recent meta-analysis of 18 randomized studies involving 5,269 patients with PAD, Berger et al.⁵⁶ reported a significant reduction in nonfatal cerebrovascular events with aspirin therapy compared to placebo (RR 0.66, 95% CI 0.47 to 0.94). However, no significant differences were demonstrated for all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, or bleeding. Although numerous studies have reported significant improvements in various cardiovascular endpoints with aspirin therapy, recent evidence suggests that the overall cardiovascular benefits demonstrated with aspirin may not be applicable to very low-risk patients who have asymptomatic PAD without concomitant cardiovascular disease. A large, randomized control trial of 28,980 patients with asymptomatic PAD (diagnosed by an ABI of <0.95) failed to demonstrate a reduction in cardiovascular events in participants treated with aspirin 100 mg daily compared to placebo.⁵⁷ However, the low overall mortality rate (1.9%) and mean ABI score (0.86) in the trial suggests a lower risk population compared to those evaluated in previous studies. In PAD patients undergoing revascularization, aspirin improves vessel patency after lower extremity bypass or percutaneous angioplasty. Overall, aspirin is recommended as first-line antiplatelet therapy for the majority of patients with a diagnosis of PAD.

Thienopyridines also benefit patients with PAD. The CAPRIE study showed an 8.7% RR reduction in vascular events with clopidogrel compared to aspirin therapy in patients with atherosclerotic vascular disease, including PAD.⁵⁸ The greatest benefit was demonstrated within the PAD subgroup, achieving a 23.8% RR reduction in vascular events. Thienopyridines also improve symptoms related to PAD. In a randomized study of 151 PAD patients with intermittent claudication, Balsano et al.⁵⁹ reported an improved ABI index, pain-free walking distance, and maximal walking distance with ticlopidine compared to placebo. Current guidelines support the use of clopidogrel as

an alternative antiplatelet agent to aspirin for cardiovascular risk reduction in patients with PAD. The development of severe neutropenia, a potentially fatal side effect, has been reported in 2.1% of patients prescribed ticlopidine, which has significantly limited its use in clinical practice.⁶⁰

The use of dual antiplatelet therapy to reduce secondary events in patients with established cardiovascular disease remains controversial. The CHARISMA study is the largest randomized trial which evaluated dual antiplatelet therapy with aspirin and clopidogrel in patients with known vascular disease or multiple vascular risk factors.⁶¹ Dual antiplatelet therapy did not reduce cardiovascular events compared to aspirin alone and was associated with a significant increase in bleeding events. Given the results of CHARISMA, there is currently insufficient evidence to support the routine use of dual antiplatelet therapy in patients with PAD without secondary indications (i.e., postmyocardial infarction or vascular stent implantation).

While a theoretical rationale exists for improved antithrombotic effects with the addition of an oral anticoagulation agent to antiplatelet therapy, studies examining the combination have failed to demonstrate a benefit and have shown increased bleeding. The WAVE study compared the combination of warfarin and antiplatelet therapy to antiplatelet therapy alone in patients with a history of PAD.⁶² Combination therapy did not reduce cardiovascular events and was associated with increased life-threatening bleeding. Combination therapy has also been studied for the prevention of graft occlusion in patients following peripheral bypass surgery with either venous or arterial grafts. In the Dutch BOA study, there were no significant differences in cardiovascular events or limb salvage with combination therapy compared to antiplatelet therapy alone in patients undergoing infrainguinal bypass.⁶³ Although the Dutch BOA study reported fewer ischemic events with combination therapy in patients with venous grafts, other studies have not demonstrated similar results.⁶⁴ Currently, the routine use of anticoagulants in addition to antiplatelet therapy is not recommended for routine use in patients with PAD to reduce cardiovascular risk or prevent graft occlusion.

As patients with PAD are a high-risk population for major cardiovascular events, aggressive lipid management is recommended. HMG coenzyme A reductase inhibitors (statins) are the principal agents for risk reduction in patients with vascular disease, with each reduction of 1 mmol/L of LDL with statin therapy associated with a 20% reduction in cardiovascular events.⁶⁵ Large randomized control trials demonstrate profound benefits with statin therapy in patients with cardiovascular disease or vascular risk factors. The Heart Protection Study compared simvastatin 40 mg to placebo in 20,536 individuals with cardiovascular disease, including 6,748 patients with PAD.⁶⁶ Simvastatin was associated with significant reduction in all-cause mortality (12.9% vs. 14.7%, P = 0.0003), primarily driven by a decrease in coronaryrelated death (5.7% vs. 6.9%, P = 0.0005). Moreover, aggressive lipid control provides further benefit compared to moderate lipid control in patients with cardiovascular disease. The Treat to New Targets study reported significant improvements in cardiovascular events with a reduction in LDL to <1.8 mmol/L (<170 mg/dL), compared to moderate LDL control in patients with coronary artery disease (RR 0.78, 95% CI 0.69 to 0.89).⁶⁷ Current PAD guidelines recommend aggressive LDL reduction in PAD patients to <2.59 mmol/L (100 mg/dL).¹⁶ A number of lipid guidelines advocate for even lower LDL targets to <1.8 to 2.0 mmol/L (70 to 77 mg/dL) in patients with established vascular disease.⁶⁵

Clinical studies suggest that statins may improve cardiovascular outcomes by reducing vascular inflammation, an important mediator of atherosclerosis progression. The PROVE-IT study reported significant reductions in C-reactive protein (CRP) levels with high-dose compared to low-dose statin therapy amongst 3,745 patients presenting with acute coronary syndromes who were followed over a mean period of 24 months. Patients with a reduced CRP had significantly fewer cardiovascular events compared to those with an increased CRP, regardless of LDL concentration.⁶⁸ Complementary results were reported in the REVERSAL study, which examined the effects of high-dose statin therapy on atherosclerosis progression in CAD patients by coronary intravascular ultrasound.⁶⁹ Participants who received high-dose statin therapy had reduced coronary atherosclerosis progression compared to those who received moderate-dose statin therapy, atheroma progression being directly related to changes in both LDL and CRP. Both PROVE-IT and REVERSAL provide support for the additional vascular benefits statins provide as potent mediators of vascular inflammation. Statin therapy also exerts positive effects on endothelial activity, likely mediated through increased endothelial nitric oxide synthase expression.^70,71 Tsunekawa et al.⁷² demonstrated increased brachial artery flow-mediated vasodilation and plasma nitrate levels in prediabetic patients treated with statin therapy compared to placebo. Additional proposed vascular effects of statins include decreased oxidative stress through the downregulation of angiotensin II and NAD(P)H oxidase; and the stimulation of circulating endothelial progenitor cells which assist in ischemic tissue neorevascularization and repair.⁷³ In addition to cardiovascular risk reduction, several studies have reported improvements in claudication symptoms and walking performance with statin therapy in patients with PAD.^74,75,76

Individuals with PAD frequently have further disorders of lipid metabolism, such as reduced HDL and elevated triglycerides. Although epidemiologic studies have demonstrated that both HDL and triglyceride disorders are associated with increased cardiovascular events, there is limited evidence supporting targeted therapy to improve HDL or triglycerides in the current era of aggressive LDL lowering using statin therapy. Lifestyle modifications, including exercise and weight loss, have beneficial effects on both HDL and triglycerides. Niacin therapy can increase HDL up to 15% to 25%, and reduce LDL by an additional 20% in patients, and may be considered as a second agent in patients with persisting lipid abnormalities despite adequate statin therapy.⁶⁵ Niacin improves surrogate markers of cardiovascular disease such as carotid artery intimal thickness, although whether this translates to a reduction in cardiovascular events in patients already receiving statin therapy remains uncertain.⁷⁷ Fibric acid derivatives (fibrates) may be considered in patients with severe hypertriglyceridemia or those with persistently increased triglycerides despite statin therapy and lifestyle modification.

Aggressive blood pressure is recommended in all patients with vascular disease. The intersociety consensus for the management of PAD (TASC II) guidelines suggest that patients with PAD should have blood pressure controlled to <140/90, or <130/80, in the presence of diabetes or renal impairment.¹⁶ Weight reduction, limitation of alcohol consumption, and dietary changes are important lifestyle modifications which reduce blood pressure. In separate populations of overweight individuals, a weight reduction of 10 lbs resulted in a significant reduction in blood pressure ranging from 5 to 20 mm Hg.^78,79,80 Maintenance of a normal body weight (BMI 18.5 to 24.9 kg/m²) should be targeted in all patients to improve blood pressure and reduce overall cardiovascular risk.^80,81 Alcohol consumption should be limited to no more than 2 drinks per day in men, and no more than 1 drink per day in women.⁸⁰ Dietary salt intake should be limited to 65 to 100 mmol per day in hypertensive individuals. Consumption of a diet rich in fruits, vegetables, and low-fat dairy products with limited saturated fat has been shown to lower blood pressure.^80,82,83

Several classes of medications may be used alone or in combination for hypertension treatment in patients with PAD. Angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics are considered first-line therapies for hypertension management in PAD patients. Ostergren et al.⁸⁴ evaluated the effects of ramipril in a subset of 3,099 patients with PAD enrolled in the HOPE study. Ramipril was associated with a 25% RR reduction in vascular events in individuals with clinical PAD, with similar benefits also demonstrated in those without clinical PAD but a reduced ABI. Long-acting calcium channel blockers and angiotensin receptor blockers (ARBs) can also be used as initial monotherapy for hypertension treatment. Despite previous concerns of worsening claudication symptoms with β-adrenergic blocking drugs, multiple studies have demonstrated their safety and effectiveness in patients with PAD.¹⁶ However, the antihypertensive effects of β-adrenergic blocking drugs are diminished in patients >60 years of age. ACE inhibitors and ARBs should not be routinely used in combination due to the increased risks of renal dysfunction and hyperkalemia.