Overview of lower extremity peripheral artery disease

INTRODUCTION — 

Peripheral artery disease (PAD) is a cause of significant morbidity, mortality, and disability. PAD predominantly describes the presence of atherosclerosis in the vascular beds of the extremities (this occurs predominantly in the lower extremities, but it can also occur in the upper extremities). Symptomatic lower extremity PAD manifests with claudication (pain on walking short distances), reduced walking capacity, ischemic rest pain (pain in the feet), impaired wound healing, or tissue loss (ulcers, gangrene).

Medical therapies aim to control and improve symptoms and long-term outcomes in patients with PAD, weighing cardiovascular protection and limb preservation benefits against the risk of the various potential treatments. Some treatments can also reduce the risk of periprocedural complications in treating vascular disease and may also improve symptoms or the patency of vascular interventions.

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

ANATOMY AND PATHOPHYSIOLOGY — 

Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction, enhanced platelet activity, dyslipidemia, inflammatory and immunologic factors, hyperglycemia, and tobacco use. (See "Pathogenesis of atherosclerosis".)

The subintimal accumulation of lipid and fibrous material (ie, plaque) can narrow the vessel lumen, which results in decreased distal perfusion. Any resultant thrombosis formation may embolize distally. (See "Thromboembolism from aortic plaque" and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".)

The symptoms related to atherosclerotic narrowing of the aorta or lower extremity arteries depend upon the location and severity of the disease. Atherosclerotic disease follows anatomic patterns, which also have a bearing on the natural history and progression of the disease. Within any arterial segment (eg, aortoiliac, femoropopliteal, tibial, pedal), the plaque tends to occur in the more proximal bed or the mid-segment. Patients with diabetes or with end-stage kidney disease generally present with disease of the tibioperoneal arteries. These patients are often asymptomatic for many years and, upon initial presentation, often have more severe disease. (See "Asymptomatic peripheral artery disease", section on 'Disease patterns and associated vascular beds'.)

Patients with PAD also develop changes in their musculature with a reduced volume of calf skeletal muscle and increased fat infiltration and fibrosis of the muscle. These changes, along with reduced calf muscle perfusion and impaired mitochondrial activity, lead to greater walking impairment. Small clinical trials have shown that these changes are reversible with intervention. Patients with PAD have been shown to have sarcopenia, which is a muscle loss that occurs with aging and/or immobility and is characterized by muscular atrophy and degradation of quality and strength. It can occur as a result of aging, hormonal changes, chronic diseases, lifestyle changes, and social and economic factors, which are also characteristics of the PAD population. Both sarcopenia and PAD are accompanied by increased oxidative stress, skeletal muscle mitochondrial impairment, inflammation, inhibition of specific pathways regulating muscle synthesis or protection (ie, insulin-like growth factor-1, reperfusion injury salvage kinase, and survivor activating factor enhancement), and activation of molecules associated with muscle degradation [1-4].

EPIDEMIOLOGY AND RISK FACTORS — 

The global prevalence of lower extremity PAD varies widely depending upon the population studied, but it was estimated in 2019 at 1.52 percent, impacting 113 million people over the age of 40, but estimates vary widely even among those analyzing the same databases [5-7]. Well-defined risk factors are associated with the development of PAD and include older age, hypertension, tobacco use, diabetes, and hypercholesterolemia, among others. A greater emphasis on frailty assessment is commonplace, as frailty is associated with further walking impairment in patients with PAD [8]. Artificial intelligence-generated risk factor stratification may allow for a greater prediction of outcomes long term [9,10]. (See "Peripheral artery disease: Prevalence and risk factors".)

CLINICAL PRESENTATIONS — 

The clinical manifestations of PAD (claudication, impaired walking capacity, rest pain, ulceration, and gangrene) are predominantly due to progressive luminal narrowing (stenosis/occlusion). However, thrombosis or embolism of unstable atherosclerotic plaque or thrombotic material can also occur [11]. 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 "Lower extremity peripheral artery disease: Clinical features and diagnosis" and "Asymptomatic peripheral artery disease", section on 'Activity level not sufficient to provoke symptoms'.)

Single-level disease (ie, aortoiliac, superficial femoral) can be asymptomatic or manifest 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 [12]. Severe manifestations can occur without an intervening history of claudication, particularly in older patients and those 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 [13]. 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 [14]. (See "Asymptomatic peripheral artery disease".)

Among asymptomatic patients, atherosclerotic disease of the iliac and femoral arteries is most prevalent [15]. 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 is advocated by some, but not all, expert groups [13,16-21]. (See "Asymptomatic peripheral artery disease", section on 'Abnormal ABI'.)

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 stenoses, the collateral circulation, and the vigor of extremity use.

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" or "severe limb ischemia" [22]. The nature of the clinical manifestations depends on the presence and extent of wounds or infection and the time course over which the arterial disease occurred, which 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 [23]. Chronic severe reductions in limb perfusion present as ischemic rest pain or as tissue loss (nonhealing ulcer, gangrene). Ischemic rest pain is a throbbing discomfort or numbness typically localized to the forefoot occurring when a person is resting or lying supine.

●(See "Lower extremity peripheral artery disease: Clinical features and diagnosis".)

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

DIAGNOSIS — 

In patients with an appropriate history, the diagnosis of PAD can be established with a physical examination or an ankle-brachial index (ABI). (See "Lower extremity peripheral artery disease: Clinical features and diagnosis", section on 'Physical examination'.)

The vascular examination should include assessing for signs of reduced circulation, including:

●Skin temperature, discoloration or paleness, hair loss, skin atrophy, and changes in nails.

●Palpation of pulses, including the femoral, popliteal, dorsalis pedis, and posterior tibial arteries. Reduced or absent pulses can be evaluated using a handheld Doppler.

●Evaluation of nonhealing wounds or ulcers.

●Auscultation for arterial bruits.

The ABI is a ratio of the resting systolic blood pressure at the ankle to the systolic pressure of the brachial artery (algorithm 1A-B). The arm with the higher systolic pressure should be used in the calculation. An ABI ≤0.9 is abnormal. An ABI of 0.9 to 0.99 is classified as borderline normal, with normal being an ABI >1 to 1.3, as the pressure is typically higher in the ankle than in the arm. For patients with symptoms suggestive of PAD but a normal or borderline ABI, we obtain an ABI testing following exercise. We also obtain additional vascular studies (eg, toe-brachial index) for an ABI >1.3, which suggests the presence of noncompressible calcified vessels as commonly seen in older patients and those with diabetes or chronic kidney disease. In these patients, ABI may not be diagnostic, and toe brachial index is preferred. (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. Advanced vascular imaging (computed tomographic angiography, magnetic resonance angiography, catheter-based arteriography) is usually reserved for patients in whom there remains uncertainty following noninvasive testing or in whom intervention is anticipated.

●(See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Duplex ultrasound'.)

●(See 'Revascularization' below and "Advanced vascular imaging for lower extremity peripheral artery disease".)

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 separately in more detail.

●Claudication is classified functionally by the initial and absolute walking distance and on the Society for Vascular Surgery (SVS) Rutherford scale. Symptoms can also be classified using the Fontaine classification. (See "Classification of acute and chronic lower extremity ischemia", section on 'Chronic extremity ischemia'.)

●The Global Vascular Guidelines for the management of chronic limb-threatening ischemia (CLTI) recommend staging the limb using the 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 in patients with CLTI (figure 2) [24,25]. WIfI restaging can also be used to help assess the adequacy of intervention [24]. (See "Classification of acute and chronic lower extremity ischemia", section on 'WIfI (Wound, Ischemia, foot Infection)'.)

●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 [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'.)

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

MANAGEMENT — 

The management of PAD is based on a careful, patient-specific assessment of risk factors, symptomatology, medical comorbidities, the subjective values and goals of the patient, and shared decision-making.

Treatment is aimed at controlling and relieving symptoms, improving quality of life, and lowering the risk of overall cardiovascular disease progression, mortality, and complications such as:

●Disease progression within the symptomatic extremity

●Presence of disease within the contralateral extremity

●Disease in other vascular beds, including cardiac, cerebrovascular, or visceral vascular beds

●Atheroembolism

●Adverse limb events following intervention (eg, reintervention, amputation)

Lifestyle modification and other pharmacologic therapies aim to reduce the risk of atherosclerotic disease progression and improve long-term outcomes [13,27,28] Regular exercise and weight reduction are key components of lifestyle modification. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Lifestyle modifications'.)

General approach by PAD severity

●Asymptomatic PAD – Although those with asymptomatic PAD (defined as an abnormal ankle-brachial index [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 screening and with what frequency has not been established but has been advocated in higher-risk patients. It is also important to note that some asymptomatic PAD patients, particularly those with diabetes and end-stage kidney disease, can develop limb-threatening ischemia without an antecedent history of claudication.

It is unclear if pharmacologic treatment, in addition to risk factor modification, alters outcomes in asymptomatic individuals, as the risk of bleeding often offsets any decrease in incidence in ischemic events. In trials of patients with asymptomatic PAD, aspirin, compared with placebo, did not significantly reduce the incidence of cardiovascular events [29-31]. Nevertheless, given the systemic nature of atherosclerotic disease, it is reasonable to treat patients with asymptomatic PAD (eg, aspirin or clopidogrel monotherapy) to reduce the risk of major adverse cardiovascular events (MACE) [32]. (See 'Antithrombotic therapy' below and "Asymptomatic peripheral artery disease", section on 'Management'.)

●Claudication – In addition to cardiovascular risk reduction, the initial treatment to improve walking distance is a supervised exercise program (algorithm 2) [13]. 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 improve symptoms and walking distance. Statin therapy may also improve pain-free walking time in patients with claudication, but the evidence for this is conflicting. Treatment of hypertension using beta-blocker therapy does not appear to worsen claudication. (See 'Management' above.)

Without treatment, the natural history of claudication is a slow progressive decline in the distance the individual can 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 kidney dysfunction, less than 5 percent will develop signs of limb-threatening ischemia, and the risk of major amputation is exceedingly low (<1 percent per year). The risk of MACE (eg, stroke, myocardial infarction) is overall much higher than the risk for adverse limb outcomes.

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. Thus, symptoms should be reevaluated after medical treatments (risk factor reduction, exercise therapy, pharmacologic therapy) have been instituted and allowed to have an effect. If claudication symptoms persist and impact the quality of life despite exercise therapy, lifestyle modification, and cilostazol, the patient may be a candidate for an 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".)

●Ischemic rest pain or tissue loss – Once a patient develops ischemic rest pain or tissue loss, the natural history is often a persistent decline in function with an increased risk of major limb amputation unless revascularization (open, endovascular) is performed to improve arterial perfusion. (See 'Revascularization' below.)

The presence of ischemic ulcers/gangrene influences the timing of revascularization and definitive wound coverage/closure. (See "Management of chronic limb-threatening ischemia", section on 'General care' and "Overview of treatment of chronic wounds", section on 'Ischemic ulcers and gangrene'.)

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 extremity should be revascularized as soon as safely possible, if needed, after control of the infection.

•For patients with dry gangrene without cellulitis, the limb should be revascularized first. 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.

•For some patients with significant infection or without revascularization options, limb salvage is not possible, and major amputation or a staged major amputation is recommended.

Some patients are poor candidates for any type of revascularization procedure because of concomitant diseases or unfavorable anatomy. Medical therapies combined with advanced wound care to improve wound healing would be desirable in such patients. Many therapies that have been investigated; however, none of these have been shown to have consistent results. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease".)

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

Medical therapies — PAD is regarded as a coronary artery disease risk equivalent. Patients with PAD and coronary artery disease (CAD) have a much higher risk of cardiovascular mortality than CAD alone. 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 [13,27,28]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)".)

Treatment includes antithrombotic therapy, lipid-lowering therapy, and treatment of hypertension and diabetes, as well as lifestyle modifications such as smoking cessation and attention to diet, exercise, and maintaining an optimal weight. Some of these treatments can also reduce the risk of periprocedural complications and may also improve symptoms or the patency of interventions.

Successful risk factor reduction is associated with improved long-term survival [33]. Even though secondary prevention is a mainstay, patients with PAD are often undertreated. In addition, optimal control of cardiovascular risk factors can be more difficult in patients with PAD compared with those with CAD and cerebrovascular disease. (See 'Compliance' below.).

The overall prognosis of the patient with PAD depends on the specific risk factors for PAD, the specific vascular beds that are predominantly affected, and the presence of coronary artery disease and other comorbidities (eg, diabetes, chronic kidney disease) [33,34].

Antithrombotic therapy — Long-term antithrombotic therapy has established benefits in the secondary prevention of atherosclerotic cardiovascular disease. The selection of treatment varies based on the presenting symptoms, prior history of antithrombotic therapies or revascularization, medical comorbidities, and the risk for bleeding.

The effectiveness of antithrombotic therapies for reducing symptoms, MACE, and major adverse limb events (MALE) are summarized below and reviewed in detail in the linked topics.

●Asymptomatic PAD – For individuals identified with PAD who are asymptomatic, treatment is individualized, accounting for overall cardiovascular risk and weighing the potential risk reduction with the potential increase in bleeding. It may be reasonable to treat patients with asymptomatic PAD with aspirin or clopidogrel. (See "Asymptomatic peripheral artery disease", section on 'Potential medical therapies'.)

●Symptomatic PAD – Based on randomized trials showing a significantly reduced risk for MACE, we agree with major cardiovascular guidelines that recommend long-term antiplatelet therapy for patients identified with symptomatic PAD [13,27,28]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Antiplatelet therapy'.)

For PAD, the agent selected depends on the presenting symptoms, medical comorbidities, and bleeding risk. (See "Management of symptomatic peripheral artery disease: Claudication", section on 'Antithrombotic therapy' and "Management of chronic limb-threatening ischemia", section on 'General care'.)

•For most patients with symptomatic PAD (mild-to-moderate claudication, no high-risk comorbidities), either aspirin (75 to 100 mg orally once daily) or clopidogrel (75 mg orally once daily) monotherapy are appropriate choices. Other antiplatelet agents (eg, ticagrelor, vorapaxar) have also been studied in patients with PAD but have not gained broad attention.

•For symptomatic patients with PAD and a low risk for bleeding, low-dose rivaroxaban (2.5 mg orally twice daily) plus aspirin (100 mg orally once daily) may be preferred for patients with more severe symptoms, and those at risk for MALE (eg, prior revascularization) or MACE (ie, one or more high-risk comorbidities [heart failure, diabetes, kidney insufficiency, polyvascular disease]). In these patients, the benefit of reducing MALE may justify the increased risk of bleeding associated with rivaroxaban.

There is no evidence that dual antiplatelet therapy in symptomatic PAD is beneficial; however, in patients with symptomatic PAD following revascularization, it is reasonable to consider dual antiplatelet therapy [32,35,36]. (See 'Periprocedural antithrombotic therapy' below.)

Lipid-lowering therapy — Lipid-lowering therapy with at least a moderate dose of a statin, irrespective of the baseline low-density lipoprotein cholesterol (LDL-C), is recommended for all patients with atherosclerotic cardiovascular disease. The administration of goal-directed statin therapy (eg, >50 percent reduction LDL-C or target LDL <70 mg/dL) among patients with PAD is associated with a significant reduction in all-cause mortality, cardiovascular mortality, MACE, the risk for amputation, or loss of patency of peripheral interventions.

In patients who have been unable to reach target LDL goals, it is reasonable to consider the addition of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor [32,37-39]. PCSK9 inhibitors and ezetimibe effectively lower LDL-C levels, which is a major risk factor for PAD progression, potentially reducing the risk of MACE and MALE in patients with PAD [39,40]. We agree with guidelines that recommend considering PCSK9 inhibitors and ezetimibe in high-risk patients with PAD and elevated LDL-C levels, especially those with a history of MACE. The overall efficacy of statins in patients with PAD is reviewed separately. (See "Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

In a large retrospective cohort study, despite having a high risk for atherosclerotic cardiovascular disease events, patients with PAD were less likely to be taking a statin versus those with coronary or cerebrovascular disease [41]. Interestingly, females with PAD have lower odds of receiving any statins or being statin-adherent [42]. 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.

Examples of outcomes with the use of statin therapy among patients with PAD include the following [37,39,43-54]:

●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 [52]. The absolute reduction in the first major vascular event was 63 per 1000 patients with PAD (standard error [SE] 11) and 50 without pre-existing PAD (SE 7) per 1000.

●The effect of PCSK9 inhibition with evolocumab was evaluated in 3642 patients with PAD from the FOURIER trial [39]. 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 (hazard ratio [HR] 0.79, 95% CI 0.66-0.94). Evolocumab also reduced the risk of MALE in all patients (HR 0.58, 95% CI 0.38-0.88), with consistent effects among those with and without known PAD.

●In an observational study of 691 symptomatic PAD patients, multivariate analysis showed that adherence to newly prescribed statin therapy or an increase in the statin dose predicted reduced mortality [45,55-57]. Studies have demonstrated a reduction in adverse limb events with statin administration. However, statin therapy alone is not associated with improved walking distance unless additional medications are added to the regimen.

●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 nine years (2005 to 2014) [53]. Discharge on the recommended intensity of statin therapy was associated with lower mortality (HR 0.73, 95% CI 0.60-0.99) and lower MALE rate (HR 0.71, 95% CI 0.51-0.97) over a median follow-up of 380 days.

●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 [43].

Antihypertensive therapy — Hypertension is a major risk factor for PAD [58]. Hypertension should be controlled to reduce morbidity from cardiovascular and cerebrovascular disease [26]. While 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 [44,59,60]. The goals for blood pressure lowering therapy (table 2) and choice of antihypertensive therapy are discussed in detail separately. (See "Goal blood pressure in adults with hypertension".)

In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril (10 mg per day) significantly reduced the rates of death and stroke in a broad range of patients, including those with asymptomatic or symptomatic PAD [61]. In a follow-up study of patients with PAD, the relative benefit of ramipril was similar in patients categorized by levels of ABI [62]. However, given that event rates were higher in those with an ABI <0.9, the absolute benefits were approximately twice as large in this group compared with those with an ABI >0.9 (50 versus 24 events per 1000 events prevented).

Lifestyle modification

Smoking cessation — We agree with the guideline recommendations regarding smoking and vaping cessation, in general, and in particular for patients with PAD [13,27,28]. (See "Cardiovascular risk of smoking and benefits of smoking cessation" and "Overview of smoking cessation management in adults" and "Cardiovascular effects of nicotine".)

Patients with PAD may find tobacco product cessation difficult to accomplish. The patient should be assessed for willingness to quit smoking and assisted in finding resources to help with this goal. (See "Overview of smoking cessation management in adults".)

●All patients should be strongly advised to stop smoking or vaping by their physicians.

●All patients should be offered pharmacotherapy, behavior modification, referral to a smoking cessation program, and counseling.

●All patients who are smokers or former smokers should be asked about the status of tobacco use at every visit.

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".)

Diet, exercise, and weight loss — Healthy diets are associated with lower cardiovascular disease events and should be encouraged as part of risk factor modification. Guidelines on lifestyle management are discussed separately [13,27,28]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention)", section on 'Diet'.)

The relationship between obesity and PAD is unclear. In several studies, obesity independently predicted more severe PAD [63-66]. In a study of 46 older patients with PAD, obesity was associated with a decreased time to claudication symptoms and delayed post-exercise hemodynamic recovery [64]. In a small prospective cohort study, obesity was independently associated with the severity of PAD as measured by ankle-brachial index, initial claudication distance, and mean walking distance [65]. Metabolic syndrome was independently associated with only 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 index is an independent risk factor for PAD, but only in females [66].

However, obesity has been associated with a lower risk of 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 [67]. In-hospital mortality was 5 percent overall. Obese patients with PAD had a 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'.)

Glycemic control — Glycemic control in patients with diabetes and PAD is reviewed separately. (See "Glycemic management and vascular complications in type 1 diabetes mellitus", section on 'Summary and recommendations'.)

Compliance — Adherence to cardiovascular risk reduction strategies decreases early during treatment [68-73]. It is estimated that after the initial 12-week module, 50 percent of individuals discontinue ongoing participation in cardiac rehabilitation programs within the first year and that 16 to 50 percent of patients discontinue antihypertensive medication within the first year of treatment. For those enrolled in smoking cessation programs, 79 percent relapse in the first six months.

The 16‐center PORTRAIT (Patient‐Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories) registry, which enrolled 1275 patients with new symptoms or exacerbation of PAD symptoms (2011 to 2015), demonstrated that even in specialty PAD clinics, adherence to guideline‐recommended therapy is not optimized [74-76]. This has also been demonstrated in the Vascular Quality Initiative registry. Attempts at person-centered, nurse-led follow-up programs for PAD risk factor modification have not shown improved adherence to secondary preventive medications.

REVASCULARIZATION

Indications

●For those with significant or disabling symptoms of claudication unresponsive to lifestyle adjustment and pharmacologic therapy, intervention (percutaneous or 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 symptomatic peripheral artery disease: Claudication".)

●For patients with chronic limb-threatening ischemia (CLTI; eg, rest pain, ulceration), revascularization is a priority to improve arterial blood flow and prevent limb loss [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 CLTI provide a framework for evidence-based lower extremity revascularization, including recommendations for endovascular intervention or lower extremity surgical bypass [13,22]. The role of thrombolytic therapy and revascularization for CLTI is reviewed separately. (See "Clinical features and diagnosis of acute arterial occlusion of the lower extremities", 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 (Wound, Ischemia, foot Infection) [24], 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, the 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) [77]. 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 many factors, including symptomatology, 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. For example, the availability of a single segment of suitable great saphenous vein positively impacts the outcomes of lower extremity revascularization in patients with CLTI [78]. (See "Management of chronic limb-threatening ischemia", section on 'Approach to revascularization'.)

Endovascular interventions have a lower short-term periprocedural risk and can be associated with greater initial cost but have lower durability to surgical revascularization in the optimal candidate.

●For patients with claudication, the Society for Vascular Surgery (SVS) suggests that a minimal effectiveness threshold for invasive therapy should be a >50 percent likelihood of sustained clinical improvement for at least two years [13]. Freedom from hemodynamically significant restenosis in the treated limb is considered a prerequisite for this goal. (See "Management of symptomatic peripheral artery disease: Claudication" and "Approach to revascularization for claudication due to peripheral artery disease".)

●The majority of patients presenting with 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. For some patients, primary amputation may be the best course of therapy. (See "Management of chronic limb-threatening ischemia".)

For most focal lesions, given the widespread availability of percutaneous procedures, initial percutaneous revascularization is supported by major vascular society guidelines [13,27,28]. 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 [22,23,79-81].

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

Periprocedural antithrombotic therapy — 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 [82,83]. Few studies have focused specifically on vascular surgery patients 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 did not affect 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 [84]. Among these were 272 patients undergoing surgery for PAD. 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 1.16, 95% CI 0.62-2.17). In the subgroup analysis of those with a prior coronary stent, aspirin appeared to be beneficial [85]. Perioperative withdrawal of chronic aspirin therapy did not appear to increase vascular 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.

The potential benefits of post-procedural antithrombotic therapy are reviewed separately. (See "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy' and "Lower extremity surgical bypass techniques", section on 'Antithrombotic therapy'.)

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 the anatomic patency of the treated area, and other factors, such as the progression of disease in the inflow vessels, in the treated vessel, and the outflow tract, are also implicated.

The SVS has adopted objective performance goals to assess cross-platform interventions in a patient-centric manner [86,87].

●Major adverse cardiovascular events

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

●Assisted primary patency – This 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 – This refers to patency obtained with the use of an additional or secondary surgical procedure once occlusion of the treated anatomic segment 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 [88]. 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 well-being 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 the physical and overall domains of QoL have been observed in patients with claudication [89-95].

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 [89]. While the primary outcome of walking distance was improved more for the SET group compared with the endovascular revascularization group, interestingly, 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 [90]. At the 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 CLTI, revascularization provides modest QoL benefits with similar outcomes for open or endovascular intervention [93]. However, major lower extremity amputation and ongoing conservative management also appear to maintain QoL. For nonambulatory patients, those with older age, and those with kidney 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 CLTI, the SVS WIfI Classification is recommended to initially stage the limb and assess the response to therapy [24]. 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 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 neointimal hyperplasia within the endovascular treated areas, within the vein graft, or at anastomotic sites.

●Late endovascular and late graft failure (>2 years) is usually due to the natural progression of atherosclerotic disease.

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 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 tobacco use, hypertension, hyperlipidemia, diabetes, and metabolic syndrome. (See 'Epidemiology and risk factors' above.)

●Clinical presentations and diagnosis – The clinical presentations of PAD include no apparent symptoms, pain with exertion (ie, claudication), forefoot pain without exertion (ie, ischemic rest pain), ulceration, and gangrene. These symptoms are predominantly due to progressive luminal narrowing (stenosis/occlusion), although thrombosis or embolism of unstable atherosclerotic plaque or thrombotic material can also occur. The diagnosis of PAD is established with the measurement of an ankle-brachial index (ABI) ≤0.9 in a patient with appropriate risk factors for atherosclerotic disease. (See 'Clinical presentations' above and 'Diagnosis' above.)

●Medical management – Medical management of symptomatic PAD is aimed at improving symptoms, lowering the risk of future cardiovascular events and limb complications, and potentially limiting the progression of atherosclerosis. (See 'Management' above.)

•Cardiovascular risk reduction – For all patients diagnosed with PAD, we recommend initiation of cardiovascular risk reduction strategies, including lifestyle modifications (smoking cessation, proper nutrition, exercise, and weight loss, if applicable) and pharmacologic therapies (ie, antithrombotic therapy, lipid-lowering therapy, maintenance of blood pressure and glucose at recommended levels).

•Antithrombotic therapy – Long-term antithrombotic therapy (eg, aspirin, clopidogrel, rivaroxaban) has established benefits in the secondary prevention of atherosclerotic cardiovascular disease. Whether to offer therapy and the agent selected depends on the presenting symptoms and the balance of the potential benefits versus the bleeding risk. (See 'Antithrombotic therapy' above.)

-Asymptomatic PAD – For asymptomatic patients, a decision to treat is individualized; aspirin (75 mg, 81 mg, or 325 mg orally once daily) or clopidogrel (75 mg orally once daily) monotherapy may be reasonable.

-Symptomatic PAD – For most symptomatic patients with PAD, aspirin (75 to 325 mg orally once daily) or clopidogrel (75 mg orally once daily) are effective for reducing the incidence of future major adverse cardiac events.

In addition to reducing major adverse cardiac events, low-dose rivaroxaban provides additional benefits in reducing major adverse limb events (MALE), although with a higher risk of bleeding complications compared with aspirin alone. For those with a low risk for bleeding, rivaroxaban (2.5 mg orally twice daily) plus aspirin (100 mg orally once daily) may be preferred when PAD symptoms are more severe. In these patients, the benefit of reducing MALE may justify the increased bleeding risk.

●Approach to intervention – The general approach to managing symptoms varies by PAD severity. (See 'General approach by PAD severity' above.)

•Claudication – For most patients with claudication, in addition to cardiovascular risk reduction strategies, supervised exercise therapy (for those who can participate) and possibly pharmacologic therapy are prescribed to improve walking prior to any consideration for intervention. For those who are unresponsive to these measures and with significant or disabling symptoms of claudication, intervention (percutaneous, surgical) may be reasonable. (See "Management of symptomatic peripheral artery disease: Claudication".)

•Chronic limb-threatening ischemia – For patients with chronic limb-threatening ischemia (CLTI; ischemic rest pain, ulceration, or gangrene), where the limb is at risk for 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 used to stage the limb and to assess the response to therapy. (See "Management of chronic limb-threatening ischemia".)

●Revascularization options – Among patients with indications, options for revascularization include endovascular intervention (eg, angioplasty, stenting), surgical bypass, or a combination of these (hybrid approach). The choice depends upon the level of obstruction (aortoiliac, femoropopliteal, tibial), the severity of the 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), an initial attempt at percutaneous revascularization rather than initial surgical revascularization is appropriate. (See 'Revascularization' above.)

ACKNOWLEDGMENT — 

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