Overview of lower extremity peripheral artery disease

INTRODUCTION — Atherosclerosis results in the accumulation of lipid and fibrous material between the layers of the arterial wall and causes disease of the coronary, cerebral, and peripheral arteries. Atherosclerotic disease often involves the arteries providing flow to the lower extremities, referred to as lower extremity peripheral artery disease (PAD). Atherosclerosis can lead to acute or chronic symptoms due to embolism from more proximal disease, or due to thrombosis of an artery that has been progressively narrowed.

Management of patients with lower extremity PAD should include medical therapies aimed at reducing the risk for future cardiovascular and limb events related to atherothrombosis, such as myocardial infarction, stroke, and amputation, and also to improve limb symptoms and quality of life.

An overview of atherosclerotic disease affecting the lower extremities is provided here. Disease affecting the upper extremity is reviewed separately. (See "Upper extremity atherosclerotic disease".)

ANATOMY AND PATHOPHYSIOLOGY — The subintimal accumulation of lipid and fibrous material (ie, plaque) can narrow the vessel lumen, which can thrombose, or the plaque can rupture, causing occlusion of downstream vessels. Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction, enhanced platelet activity, dyslipidemia, inflammatory and immunologic factors, and tobacco use. (See "Pathogenesis of atherosclerosis".)

The symptoms related to atherosclerotic narrowing of the aorta or lower extremity arteries depend upon the location and severity of disease. Within any arterial segment (aortoiliac, femoropopliteal, tibial), the plaque tends to occur in the proximal or mid-segments (eg, proximal bifurcation leading to that vascular bed). Atherosclerotic disease follows anatomic patterns, which also have a bearing on the natural history and progression of disease. Patients with diabetes or with end-stage kidney disease generally present with more distal disease.

Patients with PAD develop changes in their muscles with reduced calf skeletal muscle area and increased calf muscle fat infiltration and fibrosis. The presence of PAD also reduces calf muscle perfusion and impairs mitochondrial activity, and greater walking impairment is associated with smaller myofibers. Small clinical trials have shown that these changes are reversible with intervention. Patients with PAD have been shown to suffer from sarcopenia. Sarcopenia is a type of muscle loss that occurs with aging and/or immobility and is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss depends on exercise level, comorbidities, nutrition, and other factors. All the etiological factors that have been associated with sarcopenia are present in PAD. Both sarcopenia and PAD are accompanied by oxidative stress, skeletal muscle mitochondrial impairments, inflammation, inhibition of specific pathways regulating muscle synthesis or protection (ie, insulin-like growth factor-1, reperfusion injury salvage kinase [RISK], and Survivor Activating Factor Enhancement [SAFE]), and activation of molecules associated with muscle degradation [1-4].

EPIDEMIOLOGY AND RISK FACTORS — The overall prevalence of lower extremity PAD varies widely depending upon the population studied but is estimated to be approximately 10 percent of adults older than 55 years [5]. Data from the 2010 United States census suggested that the overall burden of PAD among adults in the United States is greater for women compared with men [6]. Well-defined risk factors are associated with the development of PAD and include older age, hypertension, tobacco use, diabetes, and hypercholesterolemia, among others [7-9]. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

CLINICAL PRESENTATIONS — The clinical manifestations of PAD (claudication, rest pain, ulceration, and gangrene) are predominantly due to progressive luminal narrowing (stenosis/occlusion), although thrombosis or embolism of unstable atherosclerotic plaque or thrombotic material can also occur [10]. The natural history of those who present with mild-to-moderate claudication is generally benign with respect to the limb, which contrasts with the more progressive clinical course seen in those who present with ischemic rest pain or ulceration. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

Single-level disease (ie, aortoiliac, superficial femoral) more frequently manifests initially as claudication. Multilevel disease can manifest as claudication when collateral circulation is adequate (figure 1), but often manifests as ischemic rest pain or lower extremity ulceration when a well-developed collateral circulation is inadequate or absent [11]. Severe manifestations can occur without an intervening history of claudication, particularly in older patients with diabetes or chronic kidney disease.

Asymptomatic — Evidence of underlying atherosclerotic occlusive disease may be present in the absence of symptoms. It is estimated that there are three times as many asymptomatic patients with lower extremity PAD as symptomatic patients [12]. Although those with asymptomatic PAD may not report exertional leg discomfort by definition (ie, claudication), lower extremity physiological function may be impaired compared with matched controls without PAD [13]. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Asymptomatic patients screened for PAD' and "Asymptomatic peripheral artery disease".)

Among asymptomatic patients, atherosclerotic disease of the iliac and femoral arteries is most prevalent [14]. Due to the fact that PAD may predict risk for future cardiovascular events, screening for PAD in asymptomatic high-risk individuals using the ankle-brachial index (ABI) is advocated by some, but not all, expert groups [12,15-21]. (See "Screening for lower extremity peripheral artery disease".)

Claudication — Exertional pain in patients with lower extremity PAD is termed "claudication," which is derived from the Latin word "claudico" (to limp). Claudication is a reproducible discomfort of a defined group of muscles that is induced by exercise and relieved with rest. Claudication can present unilaterally or bilaterally, as buttock and hip, thigh, calf, or foot pain, singly or in combination. The severity of symptoms depends upon the number and degree of arterial narrowings, the collateral circulation, and the vigor of extremity use. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Intermittent claudication and atypical lower extremity pain'.)

Chronic limb-threatening ischemia — Chronic limb-threatening ischemia (CLTI) is a clinical syndrome defined by the presence of PAD in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. CLTI is the preferred term replacing the terms critical limb ischemia (CLI) or severe limb ischemia [22]. The use of the term CLTI reflects changes in arterial disease patterns and the concept that CLTI is a spectrum of disease, a concept that is especially applicable to patients with diabetes. The nature of the clinical manifestations depends upon the wound extent, the presence or absence of infection, and the time course over which arterial narrowing or occlusion occurs; the latter in turn affects the extent to which the collateral circulation can develop (figure 1). Acute-on-chronic reductions in limb perfusion, which may be due to atheroembolism, cholesterol embolism, or thrombotic occlusion of a stenotic vessel, cause diffuse limb pain [5]. Chronic severe reductions in limb perfusion present as ischemic rest pain, typically localized to the forefoot and toes, or as tissue loss (nonhealing ulcer, gangrene).

●(See "Clinical features and diagnosis of acute lower extremity ischemia", section on 'Acute-on-chronic limb ischemia'.)

●(See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Symptoms'.)

DIAGNOSIS — In patients with an appropriate history and physical examination, the diagnosis of PAD is established with the measurement of an ankle-brachial index (ABI) ≤0.9. The ABI is a comparison of the resting systolic blood pressure at the ankle to the higher systolic brachial pressure (algorithm 1A-B). An ABI of 0.9 to 0.99 is classified as borderline normal; the pressure is normally higher in the ankle than in the arm (ie, ABI >1 to 1.3). For patients with symptoms suggestive of PAD, but a normal or borderline ABI, we obtain an ABI following exercise testing. We also obtain additional vascular studies (eg, toe-brachial index) for an ABI >1.3, which suggests the presence of noncompressible calcified vessels. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Exercise testing'.)

Duplex ultrasonography is commonly used in conjunction with the ABI to identify the location and severity of arterial obstruction [23]. Advanced vascular imaging (computed tomographic [CT] angiography, magnetic resonance [MR] angiography, catheter-based arteriography) is usually reserved for patients in whom there remains uncertainty following noninvasive testing, or in whom intervention is anticipated [24,25]. (See 'Revascularization' below.)

CLASSIFICATION — Classification of lower extremity PAD, by grading symptoms and the anatomic lesions responsible for these symptoms, provides an objective measure by which to follow patients clinically, and provides consistency when comparing medical and interventional treatment strategies in clinical studies. The main classifications are listed below and reviewed in more detail separately.

●Claudication is classified functionally by the initial and absolute walking distance and on the Society of Vascular Surgery Rutherford scale graded from 1 to 3. (See "Classification of acute and chronic lower extremity ischemia", section on 'Rutherford'.)

●Atherosclerotic patterns of disease in the lower extremities have previously been classified by TASC-II criteria according to their anatomic distribution, multiplicity of lesions, and the nature of the lesion (stenosis or occlusion) [26]. (See "Classification of acute and chronic lower extremity ischemia", section on 'TASC classification'.)

●The Global Vascular Guidelines for the management of chronic limb-threatening ischemia recommend staging the limb using the Society for Vascular Surgery (SVS) lower extremity threatened limb classification system, WIfI (Wound, Ischemia, foot Infection) [22]. WIfI classifies the severity of limb threat in a manner that is intended to more accurately reflect important clinical considerations that impact management and amputation risk (figure 2) [27,28]. WIfI restaging can also be used to help to assess the adequacy of intervention [27]. (See "Classification of acute and chronic lower extremity ischemia", section on 'WIfI (Wound, Ischemia, foot Infection)'.)

●GLASS – The Global Anatomic Staging System (GLASS) is an anatomic classification (table 1) that grades the level of disease in the femoropopliteal and infrapopliteal segments of the preferred target artery path (TAP) [22]. These are combined to provide an overall grade of complexity for lower extremity interventions. (See "Classification of acute and chronic lower extremity ischemia", section on 'GLASS classification'.)

MANAGEMENT — The management of patients with lower extremity PAD is aimed at relieving symptoms and lowering the risk of cardiovascular disease progression and complications. Patients with PAD exhibit a wide range of symptoms and associated effects on daily function. The treatment of symptomatic lower extremity PAD is based on a careful assessment of risk factors, medical comorbidities, compliance with pharmacologic treatments and follow-up care, and the subjective values and goals of the patient. Patients with ischemic pain or ulceration may necessarily require early intervention for limb salvage. (See 'Revascularization' below.)

Medical management involves cardiovascular risk factor reduction, lifestyle modification, and other pharmacologic therapies to reduce the risk of atherosclerotic disease progression [12,29] With aggressive medical management, regression of noncalcified atherosclerotic lesions may be possible [30]. Regular exercise and weight reduction are also important. (See 'Risk factor modification' below and 'Claudication' below and 'Ischemic rest pain or tissue loss' below.)

Risk factor modification — PAD is regarded as a coronary heart disease risk equivalent. We agree with major cardiovascular practice guidelines for the management of patients identified with PAD (asymptomatic or symptomatic) that recommend secondary prevention measures to reduce the risk of future cardiovascular events and potentially limit the progression of atherosclerosis [12,29,31-33]. Preventive strategies are appropriate for asymptomatic or symptomatic patients with lower extremity PAD.

Preventive therapies include antiplatelet therapy, smoking cessation, lipid-lowering therapy, and treatment of diabetes and hypertension. Prevention of cardiovascular disease events is reviewed separately. Some of these treatments can also reduce the risk of periprocedural complications and also may improve symptoms or the patency of interventions. Management of medications in the periprocedural period is reviewed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Management of cardiac risk for noncardiac surgery" and 'Adjuncts to improve patency of revascularization' below.)

Antithrombotic therapy — Long-term antithrombotic therapy has established benefit in the secondary prevention of atherosclerotic cardiovascular disease. Based upon randomized trials showing a significantly reduced risk for future adverse cardiovascular events, we agree with major cardiovascular consensus guidelines that recommend long-term antiplatelet therapy (eg, aspirin, clopidogrel) for patients identified with symptomatic lower extremity PAD [12,29,31]. For individuals identified with PAD who are asymptomatic, antithrombotic therapy is individualized, accounting for overall cardiovascular risk and weighing the potential risk reduction with the potential increase in bleeding. We do not recommend dual antiplatelet therapy in patients with PAD in the absence of other indications (eg, drug-eluting stent) given the increased risk of bleeding in the absence of proven benefit.

The effectiveness of antiplatelet therapy for the secondary prevention of adverse cardiovascular events (eg, myocardial infarction [MI], stroke, vascular death) was demonstrated in the Antithrombotic Trialists' Collaboration [34-36]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Specifically among patients with PAD, in a meta-analysis that included 18 trials involving 5269 patients with PAD (symptomatic and asymptomatic), aspirin therapy (alone or in combination with dipyridamole) was associated with a nonsignificant reduction for the primary endpoint (composite endpoint of nonfatal MI, nonfatal stroke, and cardiovascular death) but a significant reduction in the secondary outcome of nonfatal stroke (relative risk [RR] 0.66; 95% CI 0.47-0.94) [37]. There were no significant differences in other individual secondary outcomes (nonfatal MI, major bleeding).

Either aspirin or clopidogrel monotherapy are appropriate choices [29]. Other antiplatelet agents (ticagrelor, vorapaxar) have also been studied specifically in the PAD patient population [38-45].

●In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel (75 mg/day) had a modest, although significant, advantage over aspirin (325 mg/day) for reducing the risk for the combined outcome of ischemic stroke, MI, or vascular death in 19,185 patients with a recent stroke, MI, or symptomatic PAD (relative risk reduction 8.7 percent, 95% CI 0.3 to 16.5 percent) [46]. In a subgroup analysis, the benefit for clopidogrel over aspirin was mainly driven by patients with PAD, for whom there was a 23.8 percent relative risk reduction (95% CI 8.9 to 36.2 percent).

●Some trials suggest that ticagrelor may provide additional benefit for preventing cardiovascular events [39-41]. Direct comparisons between ticagrelor and clopidogrel in patients with symptomatic PAD have found no significant differences [42,44].

•In the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, 13,885 patients with predominantly symptomatic PAD were randomly assigned to single-agent therapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily) [43,44,47]. The rate of ischemic stroke was significantly reduced for ticagrelor compared with clopidogrel (1.9 versus 2.4 percent; HR 0.78, 95% CI 0.62-0.98), but there were no significant differences between the groups for the composite primary outcome (cardiovascular death, MI, or ischemic stroke; 10.8 versus 10.6 percent) or other outcomes (death, MI, acute limb ischemia, the need for revascularization, major bleeding). More patients receiving ticagrelor discontinued treatment due to dyspnea or minor bleeding.

•In the PEGASUS-TIMI 54 trial, 21,162 patients with prior MI one to three years prior were randomly assigned to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin [39]. Among PAD patients with prior MI (1143 patients; 5 percent of the total), ticagrelor reduced the absolute rate of major adverse cardiovascular event by 4.1 percent and significantly reduced the risk for peripheral revascularization (hazard ratio [HR] 0.63, 95% CI 0.43-0.93). However, there was a 0.12 percent absolute excess of major bleeding.

●Vorapaxar is a novel antagonist of protease-activated receptor (PAR-1), which is located on platelets, vascular endothelium, and smooth muscle and is the primary receptor for thrombin on human platelets [48]. In the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50), among patients with symptomatic lower extremity PAD, vorapaxar (administered with other antiplatelet agents) reduced the rate of first acute limb ischemia events, particularly among those who had undergone revascularization [49-52]. (See 'Adjuncts to improve patency of revascularization' below.)

No benefit over aspirin has been established for vitamin K antagonists for reducing mortality in those with PAD. A systematic review that identified nine small trials involving 4889 patients noted no significant difference in mortality for anticoagulation versus aspirin or versus control following lower extremity bypass procedures, and the rate of major bleeding events was increased [53]. Similarly, in the later Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, a combination of warfarin (target international normalized ratio [INR] 2 to 3) plus antiplatelet therapy was not more effective compared with aspirin alone for preventing cardiovascular morbidity in patients with PAD [54].

Data suggest a benefit for combined aspirin and low-dose rivaroxaban (a direct oral anticoagulant) for individuals with PAD, though with an increased risk for bleeding [55-58]. Before rivaroxaban could be considered for all patients with PAD, a direct comparison between low-dose rivaroxaban plus aspirin and clopidogrel would be useful. An essential clinically important question is whether the observed improvements in cardiac and limb outcomes outweigh the risk of bleeding, and if so, for which PAD patients.

●A multicenter trial (COMPASS) randomly assigned over 27,000 patients with stable coronary heart disease or PAD to a low dose of rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice daily) plus placebo, or aspirin (100 mg once a day) plus placebo [56]. At a mean follow-up of 23 months, primary composite of cardiovascular death, stroke, or MI, and individual endpoints of cardiovascular mortality and ischemic stroke were significantly reduced for rivaroxaban plus aspirin compared with aspirin alone. In a prespecified subgroup analysis among 7470 subjects with PAD, the composite endpoint of cardiovascular death, myocardial infarction, or stroke was significantly reduced for rivaroxaban plus aspirin compared with aspirin alone (5 versus 7 percent; HR 0.72, 95% CI 0.57-0.90), as were major adverse limb events (1 versus 2 percent; HR 0.54, 95% CI 0.35-0.82) [57]. Rivaroxaban alone compared with aspirin alone did not significantly reduce the composite endpoint, but there was a trend toward reduced major adverse cardiovascular events. Rivaroxaban increased the risk of major bleeding (3 versus 2 percent) whether used alone or in combination.

●In the Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial, 6564 patients with PAD who had undergone prior revascularization were randomly assigned to rivaroxaban (2.5 mg twice a day) plus aspirin, or placebo plus aspirin [59]. Low-dose rivaroxaban plus aspirin reduced the composite endpoint of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes (17.3 versus 19.9 percent); the incidence of acute limb ischemia (5.2 versus 7.8 percent); and the need for index-limb revascularization for recurrent limb ischemia (20.0 versus 22.5 percent). Major bleeding, as defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification, was 2.7 percent in the rivaroxaban group and 1.9 percent in the placebo group (HR 1.43, 95% CI 0.97-2.10). The incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding was significantly increased for the rivaroxaban group compared with the placebo group (5.94 versus 4.06 percent; HR 1.42, 95% CI 1.10-1.84). Approximately 14 percent of patients discontinued treatment prematurely, which may have had an impact on the observed benefits and risks. Concomitant clopidogrel treatment, which was permitted for up to six months after the intervention, did not affect the primary efficacy or safety outcomes [60]. However, there was a trend toward more ISTH major bleeding within 365 days with clopidogrel use >30 days compared with shorter durations (p for trend = 0.06).

The role of oral anticoagulation for preventing graft thrombosis is discussed below. (See 'Adjuncts to improve patency of revascularization' below.)

Smoking cessation — Numerous epidemiological and observational studies show that smoking cessation reduces adverse cardiovascular events and the risk for limb loss in patients with PAD, but smoking cessation may be difficult to accomplish. We agree with consensus guidelines that recommend smoking cessation for all patients with PAD. The patient should be assessed for willingness to quit smoking and assisted in finding resources (eg, behavioral modification) to help with this goal. Follow-up for smoking cessation therapy should also be arranged. Nicotine replacement therapy and use of other pharmacologic adjuncts (varenicline or bupropion) should be considered. Nicotine replacement therapy does not appear to be associated with any increase in adverse cardiovascular events. (See "Cardiovascular risk of smoking and benefits of smoking cessation" and "Overview of smoking cessation management in adults" and "Cardiovascular effects of nicotine".)

Lipid-lowering therapy — Lipid-lowering therapy with at least a moderate dose of a statin, irrespective of the baseline LDL cholesterol, is recommended for all patients with atherosclerotic cardiovascular disease. The evidence for benefit and the appropriate goals for cholesterol lowering in patients with all forms of cardiovascular disease are discussed in more detail elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome".)

Examples of outcomes with the use of statin therapy among patients with PAD include the following [61-65]:

●In the Heart Protection Study, among 6748 patients who had PAD, there was a 22 percent relative risk reduction in the first major vascular event for those randomized to simvastatin (40 mg) compared with placebo [62]. The absolute reduction in first major vascular event was 63 (standard error [SE] 11) per 1000 patients with PAD and 50 (SE 7) per 1000 without preexisting PAD.

●In a five-year prospective study, patients undergoing major lower extremity amputations and who were on medium-intensity and high-intensity statin therapy had improved survival at one year compared with those who were not on similar statin therapy [66].

●The effect of statin therapy in patients with chronic limb-threatening ischemia was evaluated in a retrospective study of 931 patients (1019 affected limbs) who underwent first-time revascularization (endovascular or surgical) over a nine-year period (2005 to 2014) [63]. Discharge on the recommended intensity of statin therapy was associated with lower mortality (HR 0.73; 95% CI 0.60-0.99) and lower major adverse limb event rate (HR 0.71; 95% CI 0.51-0.97) over a median follow-up of 380 days.

●The effect of PCSK9 inhibition with evolocumab was evaluated in 3642 patients with PAD from the FOURIER trial [67]. The primary composite endpoint (cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, coronary revascularization) was significantly reduced for those with PAD randomized to evolocumab compared with placebo (HR 0.79; 95% CI 0.66-0.94). Evolocumab also reduced the risk of major adverse limb events in all patients (HR 0.58; 95% CI 0.38-0.88) with consistent effects among those with and without known PAD.

●In a prespecified analysis of the ODYSSEY OUTCOMES trial [68], alirocumab significantly reduced PAD events defined as critical limb ischemia, limb revascularization, or amputation for ischemia not planned at time of randomization in patients with recent acute coronary syndrome (HR 0.69, 95% CI 0.54–0.89). In the subgroup of 759 PAD patients with recent ACS, alirocumab reduced PAD events by 41 percent (HR 0.59, 95% CI 0.40-0.86), corresponding to an 8.6 percent absolute risk reduction at three years [61]. Patients with a history of PAD contributed 46.7 percent of all PAD events while comprising only 4.0 percent of the study population.

Glycemic control — Glycemic control in patients with diabetes and peripheral artery disease is reviewed separately. (See "Overview of peripheral artery disease in patients with diabetes mellitus", section on 'Glycemic control' and "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Summary and recommendations'.)

Blood pressure control — Hypertension is a major risk factor for PAD. However, there are no data evaluating whether antihypertensive therapy alters the progression of PAD. In the EUCLID trial, poor blood pressure control and high systolic blood pressure were associated with worse limb outcomes [43,44,47]. Nevertheless, hypertension should be controlled to reduce morbidity from cardiovascular and cerebrovascular disease [26]. Goals for blood pressure lowering therapy and choice of antihypertensive therapy are discussed in detail separately. (See "Overview of hypertension in adults".)

While there has been some concern that an aggressive blood pressure-lowering target may lead to worsened limb outcomes in those with PAD [69,70], a review of data from the EUCLID trial does not support this contention. Among over 13,000 participants with symptomatic PAD in the EUCLID trial, a clinical history of hypertension was present in 78 percent [71]. During follow-up (median 30 months), average systolic blood pressure (SBP) was 135 mmHg. Every 10 mmHg increase in SBP >125 mmHg was associated with a significant increase in the risk of major adverse cardiac events (hazard ratio [HR] 1.10, 95% CI 1.06–1.14) and an increased risk of major adverse limb events/lower extremity revascularization (HR 1.08, 95% CI 1.04–1.11). Every 10 mmHg decrease in SBP ≤125 mmHg was associated with a significant increase in the risk of major adverse cardiac events (HR 1.19, 95% CI, 1.09–1.31]), but not major adverse limb events or major adverse limb events/lower extremity revascularization.

In the Appropriate Blood-Pressure Control in Diabetes (ABCD) trial, intensive blood pressure lowering to an average of 128/75 mmHg was associated with a reduction of cardiovascular events in those with diabetes mellitus and PAD [72]. Similarly, in a post hoc analysis of the International Verapamil-SR/Trandolapril Study (INVEST) trial, which included 2699 hypertensive patients with concomitant PAD and coronary artery disease, major adverse cardiovascular events, the primary composite outcome, occurred in significantly more patients with PAD compared with those without PAD (16.3 versus 9.2 percent; adjusted HR 1.26, 95% CI 1.13-1.40) [73]. Reduced major adverse cardiac events were observed in patients with a systolic blood pressure between 135 and 145 mmHg and a diastolic blood pressure between 60 and 90 mmHg. Higher and lower systolic blood pressure were associated with an increased risk of major adverse cardiovascular events. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril (10 mg per day) significantly reduced the rates of death, MI, and stroke in a broad range of patients, including those with asymptomatic or symptomatic PAD [74]. In a follow-up study looking at the PAD patients, the relative benefit of ramipril was similar in patients subdivided by levels of ABI [75]. Given that event rates were higher in those with an ABI <0.9, the absolute benefits are approximately twice as large in this group (50 per 1000 events prevented) compared with those with an ABI >0.9 (24 per 1000 events prevented). (See "Goal blood pressure in adults with hypertension" and "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Reduction in GFR' and "Management of claudication due to peripheral artery disease", section on 'Risk for progression and risk modification'.)

Diet and exercise — Healthy diets are associated with lower cardiovascular disease events. Guidelines from the American Heart Association/American College of Cardiology (AHA/ACC) and European Society of Cardiology (ESC) on lifestyle management are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.)

Obesity — The relationship between obesity and PAD is unclear. In two small studies, obesity independently predicted more severe PAD [76,77]. In a study of 46 older patients with PAD, obesity was associated with a decreased time to claudication symptoms and delayed postexercise hemodynamic recovery [76]. In a small prospective cohort study, obesity was independently associated with the severity of PAD as measured by ankle-brachial pressure index, initial claudication distance, and mean walking distance [77]. Metabolic syndrome was independently associated only with mean walking distance. By 24 months, outcome events occurred in 37 and 43 percent of patients with metabolic syndrome or obesity, respectively, compared with 0 and 11 percent of those without these diagnoses. A subsequent, larger observational study suggested that body mass indicator is an independent risk factor for PAD, but only in women [78]. In a review of data from the Atherosclerosis Risk in Communities (ARIC) study, higher body mass index was associated with increased incident hospitalized PAD after adjusting for potential confounders, particularly for more severe ischemia [79].

However, obesity has been associated with lower risk for death in patients with PAD. In a review of a national German database of over 5 million individuals aged 18 years or older with PAD, those classified as obese were younger (70 versus 73), more frequently female (36.7 versus 35.1 percent), had less cancer (4.9 versus 7.9 percent), and had less frequent major amputation (2.6 versus 3.2 percent) compared with the nonobese reference group [80]. In-hospital mortality was 5 percent overall. Obese patients with PAD had lower mortality rate (3.2 versus 5.1 percent), and a reduced risk for in-hospital mortality (odds ratio 0.62, 95% CI 0.61-0.63) compared with those who were normal weight or overweight. This obesity survival paradox was independent of age, sex, and comorbidities and was seen in all obesity classes. (See "Overweight and obesity in adults: Health consequences", section on 'Obesity paradox'.)

Asymptomatic PAD — Although those with asymptomatic PAD (defined as an abnormal ABI without typical limb pain) may not report exertional pain, lower extremity function may nonetheless be impaired as evidenced by slow walking speed or poor balance. Whether those with asymptomatic PAD should undergo ABI testing and with what frequency has not been established, but testing or repeat testing may be useful in higher-risk patients. It is also important to note that some asymptomatic PAD patients, particularly those with diabetes, can develop limb-threatening ischemia without an antecedent history of claudication.

It is unknown if specific therapies, in addition to risk factor modification, can improve functional ability or quality of life. As an example, it is unclear if antiplatelet therapy is beneficial for these patients. In trials of patients with asymptomatic PAD, aspirin compared with placebo did not significantly reduce the incidence of cardiovascular events [81-83]. Nevertheless, given the systemic nature of atherosclerotic disease, it is reasonable to treat patients with PAD who do not exhibit symptoms. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Claudication — The initial treatment for exertional lower limb pain (ie, claudication) is a supervised exercise program (algorithm 2) [12,29]. Patients must be screened for sufficient cardiopulmonary reserve and other medical comorbidities for their ability to tolerate an exercise program. The addition of the phosphodiesterase inhibitor, cilostazol, may also improve symptoms. Statin therapy may also improve pain-free walking time in patients with claudication, but the evidence for this is conflicting. There is no evidence that beta blocker therapy for treatment of high blood pressure worsens claudication. (See "Management of claudication due to peripheral artery disease".)

Without treatment, the natural history of claudication is a slow progressive decline in the distance the individual is able to walk before the onset of pain. However, with intensive medical management (risk factor reduction, exercise therapy, pharmacologic therapy), among patients with claudication and no diabetes or renal dysfunction, less than 5 percent will develop any signs of limb-threatening ischemia, and the risk of major amputation is exceedingly low (<1 percent per year). The risk for other adverse cardiovascular events (eg, stroke, heart attack) is greater than the risk for adverse limb outcomes.

Symptoms should be reevaluated after conservative treatments (risk factor reduction, exercise therapy, pharmacologic therapy) have been instituted and allowed to have an effect. If claudication symptoms persist and the patient has been responsive to adjusting his/her lifestyle, the patient may be a candidate for an endovascular or open intervention depending on the location and severity of lesions and medical risk. (See 'Revascularization' below and "Approach to revascularization for claudication due to peripheral artery disease".)

Patients with symptomatic PAD are at risk for developing new or worsening lesions in the same or other vascular beds, which underscores the need for ongoing follow-up.

Ischemic rest pain or tissue loss — Once a patient develops ischemic rest pain or tissue loss, the natural history often involves a persistent decline and an increased risk of major limb amputation unless there is some form of intervention to improve arterial perfusion. (See 'Revascularization' below.)

The presence of ischemic ulcers/gangrene influences the timing of debridement, revascularization, and definitive coverage/closure. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds".)

In general:

●For patients with wet gangrene or abscess, the wound should be debrided or drained immediately regardless of the anticipated need for revascularization. The dressing choice depends upon the level of anticipated drainage and the size of the wound. Dead space is usually managed with gauze packing. The extremity should be revascularized as soon as safely possible, if needed, after drainage/debridement and control of the infection.

●For patients with dry gangrene without cellulitis, the limb should be revascularized first. The wound dressing is protective, reducing the risk for trauma or infection. The wound should be lightly wrapped with a bulky dry gauze bandage, avoiding excess pressure that could aggravate ischemia. Following revascularization, the wound should be monitored closely for signs of healing, or for tissue necrosis/drainage that may indicate a need for further debridement.

Some patients are poor candidates for any type of revascularization procedure (endovascular, surgical) because of concomitant diseases or unfavorable anatomy. Medical therapies would be desirable in such patients. Therapies that have been investigated include prostaglandins, therapeutic angiogenesis, stem cell therapy, and spinal cord stimulation; however, none of these are recommended. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease".)

In the interim prior to intervention, and for those who are not candidates for intervention, it is appropriate to aggressively manage the patient's pain. (See "Approach to the management of chronic non-cancer pain in adults".)

REVASCULARIZATION

Indications

●For those with significant or disabling symptoms of claudication unresponsive to lifestyle adjustment and pharmacologic therapy, intervention (percutaneous, surgical) may be reasonable. In the absence of limb-threatening ischemia, symptoms of PAD tend to remain stable with medical therapy. Performing prophylactic intervention, whether percutaneous or surgical, in patients with minimal claudication provides little benefit, may cause harm, and is not indicated. (See "Management of claudication due to peripheral artery disease".)

●For patients with chronic limb-threatening ischemia (eg, rest pain, ulceration), revascularization is a priority to improve arterial blood flow [26]. Some patients with acute thrombosis superimposed on chronic stenosis or occlusion (ie, acute-on-chronic ischemia) may benefit from thrombolytic therapy. The Global Vascular Guidelines for the management of chronic limb-threatening ischemia provide a framework for evidence-based lower extremity revascularization, including recommendations for endovascular intervention or lower extremity surgical bypass [12,22]. The role for thrombolytic therapy and revascularization for chronic limb-threatening ischemia is reviewed separately. (See "Clinical features and diagnosis of acute lower extremity ischemia", section on 'Acute-on-chronic limb ischemia' and "Management of chronic limb-threatening ischemia" and "Intra-arterial thrombolytic therapy for the management of acute limb ischemia".)

Once the decision has been made to intervene, a three-step integrated approach (PLAN) is suggested that includes Patient risk estimation, Limb staging using WIfI [27], and determining the ANatomic pattern of disease using the Global Anatomic Staging System (GLASS) [22]. (See "Classification of acute and chronic lower extremity ischemia", section on 'WIfI (Wound, Ischemia, foot Infection)' and "Classification of acute and chronic lower extremity ischemia", section on 'GLASS classification'.)

For patients over 65 years of age, comprehensive geriatric assessment may improve outcomes following elective lower extremity bypass. In a trial that included 176 patients undergoing lower extremity bypass surgery or abdominal aortic aneurysm (AAA) repair, length of stay was reduced for those randomly assigned to comprehensive geriatric assessment and optimization versus standard preoperative assessment (3.32 versus 5.53 days) [84]. Although the outcomes were not stratified by the type of surgery, the major benefit shown was more likely to have occurred in the bypass group. The comprehensive assessment increased the number of new diagnoses (eg, pulmonary disease, chronic kidney disease, cognitive impairment) and influenced the number of patients who did not undergo surgery. There was a lower incidence of complications, including cardiac complications (8 versus 27 percent), bladder/bowel complications (33 versus 55 percent), and delirium (11 versus 24 percent). Patients in the comprehensive assessment group were also less likely to require discharge to a higher level of dependency. This trial underscores the need to accurately assess medical risk prior to undertaking elective vascular surgery in older adults. (See "Evaluation of cardiac risk prior to noncardiac surgery" and "Management of cardiac risk for noncardiac surgery" and "Anesthesia for infrainguinal revascularization", section on 'Preanesthetic assessment'.)

Choice of intervention — Among those with appropriate indications for intervention, determining whether percutaneous or surgical revascularization is the more appropriate initial treatment depends upon a myriad of factors, including symptomatology, WIfI stage, patient risk, available conduit, anatomic location and extent of disease, the patient's comorbidities (including frailty) and functional status, risk for the intervention, and patient preference.

Endovascular interventions have a lower short-term periprocedural risk, but durability has not been comparable to surgical revascularization.

●For patients with claudication, the Society for Vascular Surgery suggests that a minimal effectiveness threshold for invasive therapy should be a >50 percent likelihood of sustained clinical improvement for at least two years [12]. Freedom from hemodynamically significant restenosis in the treated limb is considered a prerequisite for this goal.

●The majority of patients presenting with chronic limb-threatening ischemia (CLTI) can be offered a reasonable attempt at limb salvage. Freedom from pain or sustained healing of areas of tissue loss may be acceptable goals even in the absence of sustained patency of the treated arterial lesion. Overall, approximately 25 percent of patients with CLTI require amputation within one year. However, for some patients, primary amputation may be the best course of therapy.

For most focal lesions, given the widespread availability of percutaneous procedures, initial percutaneous revascularization is supported by major vascular society guidelines. Surgery is generally reserved for those with arterial anatomy for which a percutaneous approach is not likely to provide a durable clinical success, provided the patient has an acceptable risk for surgery [5,22-25].

For patients with CLTI, the Best Endovascular versus Best Surgical Therapy for Patients with Critical Limb Ischemia trial showed that an available single segment of suitable great saphenous vein positively impacted the outcomes of revascularization [85]. The BASIL-2 study, which will compare vein bypass surgery and best endovascular treatment, is pending.

Lesions that display unfavorable anatomy for a percutaneous approach have one or more of the following features, which reflect more extensive disease and are typically associated with more severe symptoms:

●Long-segment stenosis

●Multifocal stenosis

●Eccentric, calcified stenosis

●Long segment occlusions

The issues regarding the choice of intervention differ depending upon clinical manifestations, goals of care, and the affected vascular bed.

●(See "Management of claudication due to peripheral artery disease" and "Approach to revascularization for claudication due to peripheral artery disease".)

●(See "Management of chronic limb-threatening ischemia".)

Perioperative medication management — The general management of cardiovascular medications and other medications prior to vascular surgery or intervention is reviewed separately. (See "Perioperative medication management".)

Whether to continue or discontinue antiplatelet agents prior to vascular surgical intervention is controversial [86,87]. Few studies have focused specifically on vascular surgery patients who should be taking aspirin (or clopidogrel) as a recommended strategy for long-term cardiovascular risk reduction. We generally maintain patients on prescribed antiplatelet therapies. (See 'Antithrombotic therapy' above.)

In the PeriOperative ISchemic Evaluation 2 (POISE-2) trial, perioperative aspirin use increased the risk of bleeding but had no effect on perioperative (30 day) mortality. Whether these results apply to vascular surgery patients was addressed in a subgroup analysis of POISE-2 that included 603 patients [88]. Among these were 272 patients undergoing surgery for peripheral occlusive disease. Excluded from the POISE-2 trial were patients with carotid occlusive disease and patients with bare metal coronary stents placed fewer than six weeks before the surgery or drug-eluting coronary stents less than one year before surgery. As with the overall results, there was no significant difference for the primary outcome (composite of death or myocardial infarction at 30 days) for those allocated to aspirin compared with placebo (15.8 versus 13.6 percent; hazard ratio [HR] 1.16, 95% CI 0.62-2.17). In the subgroup analysis of those with a prior coronary stent, there appeared to be a benefit for aspirin [89]. Perioperative withdrawal of chronic aspirin therapy did not appear to increase vascular occlusive complications. However, while there was an increased risk of major or life-threatening bleeding, the difference was not statistically significant among vascular surgery patients taking aspirin. The results of this study (positive and negative) need to be viewed with caution as the number of events was small and the subgroup analysis was underpowered.

Adjuncts to improve patency of revascularization

Antithrombotic therapy — Definitive data to support the use of antithrombotic therapy (antiplatelet agents, systemic anticoagulation) to improve the patency of lower extremity revascularization are overall lacking. Antiplatelet therapy may benefit those undergoing prosthetic bypass. Whether the addition of another antiplatelet agent to aspirin (ie, dual antiplatelet therapy) offers any additional benefit for those who have undergone lower extremity percutaneous revascularization remains debated. (See "Lower extremity surgical bypass techniques", section on 'Antithrombotic therapy' and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.)

Paclitaxel-coated devices — Several medical therapies are aimed at preventing restenosis, but only local delivery of the drug paclitaxel has been shown to improve the longevity of endovascular interventions for lower extremity PAD. Long-term efficacy paclitaxel-coated devices and their safety are reviewed separately. (See "Endovascular techniques for lower extremity revascularization", section on 'Concern over paclitaxel'.)

Outcome measures — Outcomes of revascularization may be measured anatomically, hemodynamically, and functionally. While anatomic patency and hemodynamic success are important, the primary reason to perform an intervention is symptom relief and long-term clinical success. Following intervention, clinical success is often higher than anatomic success. Clinical failures are only partially related to anatomic patency of the treated area, and other factors, such as progression of disease in the inflow vessels, in the treated vessel, and in the outflow tract, are also implicated.

The Society for Vascular Surgery (SVS) has adopted objective performance goals to assess cross-platform interventions in a patient-centric manner [90,91].

●Major adverse cardiovascular events (MACE)

●30-day major adverse limb events (MALE)

●30-day amputation rate

●Amputation-free survival

●Freedom from MALE

Anatomically, the patency of the intervention, as defined by the SVS reporting standards, allows one to assess the time to primary failure (ie, occlusion or need for intervention) and the time to final failure after multiple interventions and revisions.

●Primary patency – Refers to patency that is obtained without the need for an additional or secondary surgical or endovascular procedure.

●Assisted primary patency – Refers to patency achieved with the use of an additional or secondary endovascular procedure as long as occlusion of the primary treated site has not occurred.

●Secondary patency – Refers to patency obtained with the use of an additional or secondary surgical procedure once occlusion occurs.

Hemodynamic success is defined as an increase in ankle-brachial index (ABI) of at least 0.15. Immediate and long-term hemodynamic success (ABI >0.15) after percutaneous procedures is directly related to tibial runoff [92]. Most studies have shown an appropriate increase in ABI after intervention. The magnitude of change may or may not correlate with symptomatic improvement.

Quality of life — Patient Reported Outcome Measures (PROMs) are an important and developing metric to evaluate a patient’s subjective perception of their health and wellbeing before and after medical intervention. Patients with claudication have decrements in perceived health status and quality of life (QoL), which worsens with disease progression. After a period of supervised exercise therapy (SET), objective improvement in health status and in the physical and overall domains of QoL have been observed in patients with claudication [93-99].

The Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) trial compared optimal medical care alone, optimal medical care plus SET, and optimal medical care plus endovascular revascularization in patients with claudication and documented aortoiliac occlusive disease [93]. While the primary outcome of walking distance was improved more for the SET group compared with the endovascular revascularization group, PROMs were improved more in the endovascular group compared with SET or optimal medical therapy alone.

In the Low Intensity Exercise Intervention in Peripheral Artery Disease (LITE) clinical trial, 305 patients with claudication were randomized to low-intensity home-based walking, home-based high-intensity walking, or nonexercise control [94]. At 12-month follow-up, low-intensity walking was significantly less effective compared with high-intensity walking and was not significantly different from the nonexercise control when the six-minute walk distance was assessed. However, QoL was significantly improved for either exercise intervention compared with no exercise. There was no significant difference in change in QoL between exercise at an intensity inducing ischemic leg symptoms and exercise at a comfortable pace without ischemic leg symptoms.

For patients with chronic ischemia, undergoing revascularization provides modest QoL benefits with similar outcomes for open or endovascular intervention [97]. However, major lower extremity amputation and ongoing conservative management also appear to maintain QoL. For patients who are nonambulatory, those with advanced age, and those with renal failure, revascularization provides limited QoL benefits.

Surveillance following revascularization — Following revascularization, periodic clinical evaluation and postprocedure surveillance help identify problems that can contribute to thrombosis and potentially limb loss. For patients with chronic limb-threatening ischemia, the SVS WIfI Classification is recommended to initially stage the limb and to assess the response to therapy [27]. The surveillance schedule depends on the type of intervention (angioplasty/stenting, vein bypass, prosthetic bypass). (See "Endovascular techniques for lower extremity revascularization", section on 'Surveillance after endovascular interventions' and "Lower extremity surgical bypass techniques", section on 'Graft surveillance'.)

The main complications following revascularization are graft or stent thrombosis, vein graft stenosis, in-stent stenosis, and new native vessel stenotic lesions. There are three major time periods for failure after intervention.

●Failure in the immediate or early postoperative period (<30 days) is most often due to technical complications or judgment errors. Other causes include inadequate outflow, infection, and an unrecognized hypercoagulable state.

●Failure between 30 days and two years is most often the result of myointimal hyperplasia within the endovascular treated areas, within the vein graft or at anastomotic sites.

●Late endovascular and late graft failure is usually due to the natural progression of atherosclerotic disease.

PROGNOSIS — The overall prognosis of the patient with PAD depends on the specific risk factors for PAD, the specific vascular beds that are more predominantly affected, and the presence of coronary heart disease and other comorbidities.

Estimates for limb and cardiovascular outcomes at five years in patients with claudication are as follows:

●For limb morbidity – Stable claudication in 70 to 80 percent, worsening claudication in 10 to 20 percent, and chronic limb-threatening ischemia (ie, critical limb ischemia) in 1 to 2 percent [29,100].

●For cardiovascular morbidity and mortality – An association between cardiovascular disease and PAD has been noted in multiple studies [101-105]. In a review of over 5000 subjects, the mortality rate was 59 percent at 10 years. Among those who died, cardiovascular disease (eg, ischemic heart disease, cerebrovascular disease, heart failure) was the main cause in 44.6 percent [103]. The importance of PAD as a marker for coexistent coronary artery disease cannot be overstated.

Among the 1 to 2 percent of patients who develop chronic limb-threatening ischemia (CLTI), outcomes have improved over time, related to improved medical management [106-108], and possibly the more liberal use of endovascular intervention [109]. Even among those without a revascularization option, amputation-free survival has improved [110]. Overall (all comers), at one year, 45 percent of patients will be alive with both limbs, 30 percent will have undergone amputation, and 25 percent will have died. At five years, more than 60 percent of patients with CLTI will have died. For patients with nonreconstructible disease at one year, approximately 55 percent will be alive without amputation (range 40 to 69 percent); 20 percent of patients will have died (range: 12 to 32 percent), and 34 percent will have undergone major amputation (range: 25 to 45 percent) [110].

These general estimates do not apply equally to all patients. Atherosclerotic vascular disease tends to be more aggressive in patients with diabetes and lower extremity PAD with amputation rates that are higher compared with patients with PAD who do not have diabetes [111]. Sensory neuropathy and increased susceptibility to infection contribute to the increased amputation rate. The prognosis for both limb loss and survival is significantly worse in patients with diabetes and end-stage kidney disease, and those who continue to smoke [111,112]. (See "Overview of peripheral artery disease in patients with diabetes mellitus".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Peripheral artery disease and claudication (The Basics)")

●Beyond the Basics topics (see "Patient education: Peripheral artery disease and claudication (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Peripheral artery disease".)

SUMMARY AND RECOMMENDATIONS

●Peripheral artery disease – Atherosclerotic disease often involves the arteries providing flow to the lower extremities, referred to as lower extremity peripheral artery disease (PAD). PAD is a growing clinical problem due to the aging population and the epidemic of diabetes in the United States and other developed countries. (See 'Introduction' above.)

●Risk factors – As with atherosclerotic disease that develops in other vascular beds (eg, coronary, cerebral), risk factors for lower extremity PAD include smoking, hypertension, hyperlipidemia, diabetes, and metabolic syndrome. (See 'Epidemiology and risk factors' above.)

●Clinical presentations – The natural history of lower extremity PAD in patients who present initially as asymptomatic or with mild-to-moderate exertional pain (claudication) is relatively benign, which contrasts with the more rapid deterioration often seen in those who initially present with ischemic rest pain or extremity ulceration. (See 'Clinical presentations' above.)

●Diagnosis – Noninvasive vascular testing is an extension of the vascular history and physical examination and is used to confirm a diagnosis of arterial disease and determine the level and extent of disease. (See 'Diagnosis' above.)

●Cardiovascular risk reduction – Medical management of PAD is aimed at improving symptoms, lowering the risk of future cardiovascular events and limb complications, and to potentially limit the progression of atherosclerosis.

•We recommend initiation of cardiovascular risk reduction strategies for all individuals identified with PAD. Long-term antithrombotic therapy (eg, aspirin, clopidogrel) has established benefit in the secondary prevention of atherosclerotic cardiovascular disease. Smoking cessation, lipid-lowering therapy, and treatment of diabetes and hypertension are also recommended. (See 'Risk factor modification' above.)

•Alternative antithrombotic therapies that may provide additional benefits in symptomatic patients with PAD include: clopidogrel rather than aspirin, and rivaroxaban 2.5 mg twice a day (ie, low dose) in addition to aspirin. Rivaroxaban plus aspirin is associated with an increased risk for bleeding compared with aspirin alone. For those who are asymptomatic, a decision for aspirin therapy is individualized, taking into account overall cardiovascular risk and weighing the potential risk reduction with the potential increase in bleeding. (See 'Antithrombotic therapy' above.)

●Exercise therapy – For most patients with lower extremity PAD, in addition to cardiovascular risk reduction strategies, we recommend exercise therapy (for those who can participate), and possibly pharmacologic therapy, rather than initial vascular intervention (Grade 1B). For patients who can participate in exercise therapy, we suggest supervised rather than unsupervised exercise therapy, where available (Grade 2B). For patients who have been compliant with risk reduction strategies, but six months to one year of exercise therapy and adjunctive pharmacotherapy have failed to provide satisfactory improvement, referral for possible revascularization is appropriate. (See 'Management' above and 'Revascularization' above and "Management of claudication due to peripheral artery disease", section on 'Exercise therapy'.)

●Limb salvage – For patients with chronic limb-threatening ischemia (CLTI; ischemic rest pain or ulceration), where the limb is at risk of amputation, revascularization is a priority to restore perfusion and limit tissue loss. The Society for Vascular Surgery (SVS) Wound, Infection, foot Infection (WIfI) Classification is recommended to stage the limb in patients with CLTI and to assess the response to therapy. Some patients with acute thrombosis superimposed on chronic stenosis or occlusion may benefit from thrombolytic therapy. The role of thrombolytic therapy in such patients is discussed separately. (See 'Management' above and 'Classification' above and 'Revascularization' above.)

●Revascularization options – Among patients with indications for revascularization, options include percutaneous intervention, surgical bypass, or a combination (hybrid approach) of these. The choice depends upon the level of obstruction (aortoiliac, femoropopliteal), severity of disease, the patient's risk for the intervention, and the goals for care. For patients with lesions that have anatomic features associated with durable clinical success with a percutaneous approach (single, short segment, uniform), we agree with guidelines that suggest an initial attempt at percutaneous revascularization rather than initial surgical revascularization. (See 'Revascularization' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.