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    Content 1

    • The diagnosis of peripheral artery disease (PAD) is based on clinical presentation and noninvasive testing that includes measurement of the ankle–brachial index.

    • Conventional computed tomography or magnetic resonance angiography is useful in planning for revascularization.

    • Ultrasound combined with Doppler (duplex scanning) is commonly used to assess stent or graft patency after revascularization.

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    Current Therapy

    • The main goals in managing patients with PAD are to reduce risks of adverse cardiovascular outcomes by high-intensity statin and antiplatelet therapy, improve functional capacity by a supervised exercise program, and preserve limb viability.

    • Cilostazol (Pletal) may be useful as an adjunct to increase walking distance, and revascularization is indicated if there is a suboptimal response.

    Peripheral artery disease includes several disease entities that affect noncardiac, non-intracranial (peripheral) arteries. The most common cause of lower extremity PAD is atherosclerosis; less common etiologies include inflammatory disorders of the arterial wall (vasculitis) and “bland” arteriopathies such as fibromuscular dysplasia and arterial entrapment.

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    The burden of symptomatic PAD in the community is unknown. Based on the prevalence of an abnormal ankle–brachial index (ABI)— the ratio of systolic blood pressure (BP) at the ankle to systolic BP in the arm—in population-based cohorts, it is estimated that at least 5 million people in the United States and more than 200 million people worldwide have PAD. The prevalence of PAD is similar in men and postmenopausal women, but men are more likely to have classical symptoms of claudication. PAD poses a significant health care burden, and total annual costs associated with hospitalization of patients with PAD in the United States are estimated to be in excess of $21 billion, a number projected to rise as the population ages.

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    Risk Factors

    Risk factors for PAD are similar to those for other atherosclerotic vascular diseases, with smoking and diabetes mellitus being the strongest. Markers of inflammation and thrombosis, elevated lipoprotein (a) and homocysteine levels, and chronic kidney disease are also associated with PAD. African Americans have a lower ABI than whites, but this may be the result of physiologic factors rather than true differences in atherosclerotic burden. Women tend to have a lower ABI than men and this may partly result from lower height in women. Twin studies suggest a genetic predisposition to PAD, and in a case-control study, family history of PAD was associated with a doubling of the odds of having PAD.

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    Atherosclerotic plaque results in stenosis or occlusion of lower extremity arteries, leading to exertional leg symptoms. Additional factors that reduce functional capacity include endothelial dysfunction, abnormalities of the microvasculature, abnormal rheology, and poor oxygen extraction. There are two broad subtypes of atherosclerotic PAD affecting the lower extremities: proximal, involving the aortoiliac and femoropopliteal locations, and distal, involving the infrapopliteal location. Distal disease is often accompanied by medial arterial calcification that leads to poorly compressible (“stiff”) arteries and is associated with higher mortality than proximal disease.

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    Preventive measures for PAD are similar to other forms of atherosclerotic vascular disease, with avoidance of smoking being the most important. Early detection of PAD may identify patients at increased risk of adverse cardiovascular events. The U.S. Preventive Services Task Force does not recommend routine screening with ABI because of lack of evidence that early detection results in more effective treatment of risk factors or better outcomes. Targeted screening of individuals who are at increased risk, such as those aged older than 65 years and those aged older than 50 years who are smokers or who have diabetes is recommended by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.

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    Clinical Manifestations

    The classical symptom of PAD is claudication—an aching, cramping, or tightness provoked by exercise, involving one leg or both legs, and occurring at a fairly constant walking distance. Relief is obtained by standing still. However, some patients with PAD may be asymptomatic or have leg discomfort atypical for claudication. A subset of patients may present with acute or chronic critical limb ischemia. Signs of PAD include diminished pulses, arterial bruits, decreased capillary refill, elevation pallor, dependent rubor, and trophic changes. Patients with critical limb ischemia often have pain at rest and ulceration or gangrene of the toes on examination.

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    Diagnosis of Peripheral Artery Disease

    The diagnosis of PAD is based on clinical presentation and noninvasive testing in the lower extremities.

    Noninvasive lower extremity arterial testing typically includes measurement of ABIs at rest, segmental BPs, and continuous wave Doppler (Figure 1, Table 1). To obtain segmental BPs, cuffs are placed at three to four sites in the lower extremities. Generally a drop in BP of more than 12 mm Hg between two locations indicates a hemodynamically significant stenosis between the cuffs. Continuous wave Doppler waveforms can be qualitatively analyzed to assess arterial blood flow. Normally a triphasic or biphasic response is present, whereas a reduced biphasic or monophasic signal indicates a hemodynamically significant stenosis. Additional testing may include treadmill exercise testing to detect mild disease and measure pain-free and maximum walking times, toe–brachial indices in patients with poorly compressible arteries, and transcutaneous oximetry to assess tissue oxygenation in the setting of severe PAD/critical limb ischemia (see Figure 1, Table 1). Ultrasound combined with Doppler (duplex scanning) is a relatively inexpensive, readily available modality for imaging atherosclerotic plaque in peripheral arteries and is commonly used to assess stent or graft patency after revascularization.

    FIGURE 1    Noninvasive evaluation of patients suspected to  have peripheral artery disease.

    Table 1

    Noninvasive Evaluation of Lower Extremity Arterial Disease

    Abbreviations: ABI = ankle–brachial index; BP = blood pressure; ECG =   electrocardiogram; PAD = peripheral arterial disease.

    Angiography is useful in planning for revascularization. Computed tomographic angiography is widely available, requires relatively short scanning time, has low operator dependency, and provides high- resolution images that can be processed for three-dimensional reconstruction. The drawbacks of computed tomography angiography are that it requires a contrast load and may provide suboptimal delineation of heavily calcified or small distal vessels. Magnetic resonance angiography provides good spatial resolution and avoids radiation but is technically more challenging, cannot be used in patients with certain metallic or electronic implants, and carries a risk of nephrogenic systemic fibrosis when gadolinium contrast is administered to patients with chronic kidney disease. Conventional angiography is indicated in symptomatic patients for whom revascularization is being contemplated.

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    Differential Diagnosis

    In older individuals, lumbar spinal stenosis and giant cell arteritis can mimic atherosclerotic PAD, whereas in younger individuals, thromboangiitis obliterans and arterial occlusive disease due to arterial entrapment can cause symptoms of claudication.

    Spinal stenosis can lead to leg discomfort (pseudoclaudication) that may be confused with claudication. Pseudoclaudication is usually a paresthetic discomfort that occurs with standing and walking, usually bilateral and relieved by sitting or leaning forward. Often there is a history of chronic back pain or previous lumbosacral spinal surgery.

    The diagnosis of lumbar spinal stenosis can be confirmed from characteristic findings on computed tomography (CT) or magnetic resonance imaging of the lumbar spine, electromyography, and normal or minimally abnormal ABIs before and after exercise.

    Occasionally patients may have both claudication and pseudoclaudication.

    Giant cell arteritis can involve peripheral arteries, and symptoms of peripheral artery involvement may dominate the clinical picture.

    Therapy is directed mainly at the underlying disease, and only after the inflammatory process is controlled should revascularization of chronically ischemic extremities be contemplated.

    Thromboangiitis obliterans (Buerger disease) is a segmental inflammatory disease involving the small and medium vessels of the arms and legs. The Shionoya diagnostic criteria for thromboangiitis obliterans include history of smoking, onset before age 50, infrapopliteal arterial occlusive disease, upper extremity involvement or phlebitis migrans, and absence of atherosclerotic risk factors other than heavy smoking. Angiography usually shows multiple, bilateral focal segments of stenosis or occlusion with normal proximal vessels. Treatment includes avoidance of all forms of tobacco to reduce the risk of ulcer formation and amputation. Symptoms of claudication may improve with aspirin, clopidogrel (Plavix),1 pentoxifylline (Trental),1 and cilostazol (Pletal).1 In severe digital ischemia with ulceration, sympathectomy may be useful to control pain and to improve cutaneous blood flow. Options for revascularization are generally limited.

    Popliteal artery entrapment (PAE) can occur owing to compression from the medial head of the gastrocnemius muscle, the plantaris muscle, or the popliteal muscle. Repeated compression of the popliteal artery can lead to localized atherosclerosis, poststenotic dilatation, or thrombosis, resulting in ischemia in the distal leg or foot. The diagnosis should be considered in a young man with claudication in the arch of the foot or calf with reduced pedal pulses on sustained active plantar flexion and can be confirmed with duplex ultrasonography or CT/magnetic resonance angiography. If PAE has been diagnosed in one limb, the contralateral limb should be screened because bilateral disease occurs in more than 25% of patients.

    Although the natural history of PAE is not well defined, surgery is advocated to prevent progression of the disease from repetitive arterial trauma.

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    Treatment of Peripheral Artery Disease

    The main goals in managing patients with PAD are to reduce risks of adverse cardiovascular outcomes, improve functional capacity, and preserve limb viability (Table 2). Multiple comorbidities are common in patients with PAD and present additional challenges in management.

    Table 2

    Management of Peripheral Artery Disease

    Treatment of Cardiovascular Risk Factors

    Hyperlipidemia. High-intensity statin therapy is indicated in patients with PAD to lower low-density lipoprotein cholesterol (LDL-C) by 50% or more. A specific target LDL-C level is not mandated by the AHA/ACC, although other expert bodies recommend a target of less than 70 mg/dL for patients with atherosclerotic cardiovascular disease (ASCVD). In the Heart Protection Study, the subgroup of patients with PAD assigned to simvastatin (Zocor) (vs. placebo) had a 25% relative risk reduction in cardiovascular events over 5 years of follow- up (a reduction similar to that in persons without PAD). In a large registry study, statin use was associated with an ~ 18% lower rate of adverse limb outcomes (including worsening of symptoms, peripheral revascularization, and amputation). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors should be considered in patients with PAD who are intolerant of statins or do not achieve the target LDL-C level while on the maximal dose of a statin. In the FOURIER trial, patients with PAD derived as great a benefit, if not a greater benefit, than other subgroups, with PCSK9 inhibition.

    Hypertension. There is controversy related to BP targets, with a recent trial suggesting a systolic BP goal of less than 120 mm Hg in those at higher cardiovascular risk. There are no comparative trials to support use of a particular class of antihypertensive agents over another in patients with PAD. However, angiotensin-converting enzyme inhibitors may be preferred antihypertensive agents to reduce the adverse cardiovascular events associated with PAD. In the Heart Outcomes Prevention Evaluation (HOPE) study of 9297 patients with diabetes or vascular disease (including 4051 with PAD), ramipril (Altace) reduced adverse cardiovascular outcomes compared to placebo over a 5-year follow-up. Beta-blockers are not contraindicated and can be safely used in patients with PAD when indicated.

    Diabetes. Treatment of diabetes does not reduce cardiovascular events but may lower risks of microvascular disease and neuropathy. This is important in patients with PAD and diabetes in whom foot ulceration is a highly morbid adverse outcome. Since intensive blood glucose control may increase mortality in patients with established cardiovascular disease, a target A1C should be chosen based on age, duration of diabetes, and presence of comorbid conditions. In a recent study of patients with diabetes and ASCVD, empagliflozin (Jardiance), an oral hypoglycemic agent, reduced adverse cardiovascular events.

    Smoking cessation. Persons with PAD who quit smoking have a lower risk of death, progression of disease, critical limb ischemia and amputation, myocardial infarction, stroke, and bypass graft failure than patients who continue to smoke. Referral for counseling and/or use of adjunctive pharmacotherapy (varenicline [Chantix], bupropion [Zyban], or nicotine replacement therapy) may increase abstinence rates.

    Antiplatelet agents. Patients with symptomatic PAD should receive antiplatelet therapy in the form of aspirin (75–325 mg daily). A metaanalysis of randomized trials showed that aspirin use in patients with PAD led to a nonsignificant reduction in cardiovascular events and a significant reduction in nonfatal stroke. Aspirin did not improve outcomes among persons with an ABI less than or equal to 0.95 but without symptoms. In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) randomized trial of patients with symptomatic PAD or other manifestations of atherosclerotic disease, clopidogrel (Plavix) (75 mg daily) was slightly more effective than aspirin in reducing risk for a composite outcome of ischemic stroke, myocardial infarction, or vascular death. Dual antiplatelet therapy can be considered in patients with symptomatic PAD who are not at increased risk of bleeding. Vorapaxar (Zontivity), a new antiplatelet agent that blocks the thrombin protease-activated receptor-1, reduced the risk of cardiovascular death or ischemic events in patients with ASCVD but increased the risk of bleeding, including intracranial hemorrhage. In the subgroup with PAD, the drug reduced acute limb ischemia and peripheral revascularization events, leading to its approval for use in patients with PAD without a history of stroke.

    Warfarin (Coumadin)1 is not recommended, as the combination of warfarin and aspirin did not result in greater reduction in cardiovascular events than aspirin alone and was associated with more bleeding. In the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) study, ticagrelor (Brilinta)1 was not superior to clopidogrel in patients with symptomatic PAD. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study, low-dose rivaroxaban (Xarelto)1 alone or in combination with aspirin was superior to aspirin alone in reducing adverse cardiovascular events.

    Improving Functional Capacity

    Poor functional capacity in patients with PAD is often multifactorial, including comorbidities such as coronary heart disease (CHD), pulmonary disease, and degenerative joint disease. The degree of functional limitation varies depending on the degree of arterial stenosis, collateral circulation, exercise capacity, and comorbid conditions. Several strategies may improve functional capacity in PAD.

    Supervised exercise. A program that incorporates walking at least three times per week (30–60 minutes/session) for at least 12 weeks should be the first-line therapy for claudication. In the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) trial comparing supervised exercise and stenting in patients with aortoiliac disease on optimal medical therapy, supervised exercise resulted in significantly greater improvements in mean peak walking time at 6 months (5.8 vs. 3.7 minutes); however, quality-of-life indicators were better in those randomized to stenting. Supervised exercise for PAD is not reimbursed by U.S. insurers. A home-based group-mediated cognitive-behavioral walking intervention that included goal setting, self-monitoring, managing pain during exercise, and walking at least 5 days per week improved 6-minute walking distance by 53 m compared to a control group that received health education alone. Exercise may be a useful adjunct to revascularization. In a trial of 212 patients with PAD and claudication, those randomized to endovascular revascularization and supervised exercise had a greater improvement in maximal walking distance at 12 months than those randomized to exercise alone (1237 vs. 955 m).

    Medications. Pharmacotherapy is only modestly effective for improving symptoms of claudication. Cilostazol (Pletal), a phosphodiesterase inhibitor with antiplatelet and vasodilatory properties, improves maximal treadmill walking distance by ~ 25%. Side effects include tachycardia, diarrhea, and increased bleeding tendency. Because it increases intracellular cyclic adenosine monophosphate (cAMP), it is contraindicated in patients with heart failure or low ejection fraction. The dose is 100 mg orally daily (50 mg orally twice daily in patients taking diltiazem [Cardizem], ketoconazole [Nizoral], or other inhibitors of cytochrome P450 3A4). Naftidrofuryl, a 5 hydroxy-tryptamine receptor blocker2 that inhibits platelet aggregation, may be more effective than cilostazol and is approved in Europe for claudication. Atorvastatin (Lipitor)1 (80 mg daily for 12 months) modestly improved pain-free walking time, but not maximal walking time, compared to placebo.

    Revascularization (Figure 2). Revascularization is indicated when there are limiting symptoms in spite of an exercise program and medical therapy, and there is a reasonable likelihood of symptomatic improvement (including absence of other conditions that might limit functional capacity such as heart failure or lung disease), as well as limb salvage in the setting of critical limb ischemia. The revascularization strategy for each patient should be individualized based on patient preferences, anatomic factors, availability of optimal conduits, and operative risk.

    FIGURE 2    Normal lower limb arterial anatomy and percutaneous  and surgical revascularization for peripheral artery  disease.

    Aortoiliac angioplasty and stenting have high procedural success rates (~ 96%) and a 3-year patency rate of ~ 82%. Stent placement is generally avoided in the common femoral artery owing to the risk of biomechanical stress-related stent fractures and the potential for interference with future arterial access. Endovascular intervention in the superficial femoral artery is associated with high rates of restenosis, and several technologies to limit restenosis including drug- eluting or covered stents, drug-coated balloons, and brachytherapy are being evaluated. Endovascular therapy of isolated infrapopliteal disease is not recommended for claudication. Patients should receive dual antiplatelet therapy for at least 30 days, and longer if a drug- eluting stent is placed.

    Surgical bypass (see Figure 2) should be considered when an endovascular approach has failed or is not feasible from an anatomic standpoint. Aortofemoral bypass is a durable operation for aortoiliac disease, with patency rates up to 90% at 5 years. In patients who are poor surgical candidates, cross-clamping of the aorta can be avoided by an axillary–femoral graft often combined with a femoral–femoral graft. Endarterectomy is the procedure of choice for common femoral artery lesions and is often combined with an endovascular approach. The saphenous vein is the preferred conduit for infrainguinal bypass, but a prosthetic conduit can be used for femoral–popliteal bypass if the above-knee popliteal artery is the target vessel and good runoff is present. Femoral–tibial bypass is an option in patients with critical limb ischemia and infrapopliteal disease. There is no clear guidance on antithrombotic therapy after surgical revascularization; however, in patients undergoing infrainguinal bypass surgery, venous grafts had better patency with warfarin1 than aspirin therapy, whereas prosthetic grafts had better patency on aspirin. For below-knee prosthetic grafts, dual antiplatelet therapy is preferred. A cardiac stress imaging study may be indicated preoperatively to assess the presence and severity of CHD in patients with PAD with poor functional capacity. However, there is no benefit from “prophylactic” coronary revascularization in patients with PAD undergoing surgical revascularization.

    Preserving limb viability. Weight reduction (if obese), avoidance of vasoconstrictor drugs, proper foot care, daily inspection of the feet, and prompt evaluation of any skin lesion/ulceration are of paramount importance in patients with diabetes and PAD. Patients with diabetes are at the highest risk of amputation. The combination of peripheral neuropathy, small-vessel disease, or PAD in patients with diabetes makes foot trauma more likely to be associated with a nonhealing wound or ulcer. The presence of critical limb ischemia significantly increases risk of amputation, and the amputation rate over 1 year is 25%.

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    In patients with claudication, symptoms remain stable in 70% to 80%, worsen in 10% to 20%, and progress to critical limb ischemia in 1% to 2% over 5 years. Independent predictors of a decline in the ABI include advanced age, current tobacco use, hypertension, diabetes mellitus, and increased level of LDL-C. Patients should be followed to assess compliance with lifestyle measures and drug therapy and to assess for changes in functional capacity. Patients who have undergone revascularization should be monitored for stent/graft patency. Postsurgical graft stenosis is treated with open or endovascular intervention to prevent graft occlusion.

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    Adverse cardiovascular events and death. PAD is associated with substantial morbidity; CHD and/or cerebrovascular disease are present in more than half of persons diagnosed with PAD. An ABI of less than or equal to 0.9 is associated with doubling of mortality compared to a normal ABI. In patients with critical limb ischemia (ischemic rest pain, ulceration, and gangrene), 1-year mortality is 25%. Based on registry data, the 1-year incidence of cardiovascular death, myocardial infarction, and ischemic stroke was higher in persons with PAD than in those with CHD (5.35% vs. 4.52%).

    Adverse limb outcomes. The incidence of adverse limb outcomes including worsening of symptoms, peripheral revascularization, and amputation was 26% over 4 years, based on registry data. Smoking and diabetes are associated with high rates of adverse limb outcomes. Continued use of tobacco results in a 10-fold increase in the risk for major amputation and a more than 2-fold increase in mortality.

    Diabetes is a major risk factor for amputation in patients with symptomatic PAD (12-fold increased risk of below-knee amputation and a cumulative risk of major amputation exceeding 11% over 25 years).

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    This chapter is based in part on Kullo IJ, Rooke TW. Peripheral artery disease. N Engl J Med. 2016;374(9):861–871.


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    Arain F.A., Ye Z., Bailey K.R., et al. Survival in patients with poorly compressible leg arteries. J Am Coll Cardiol. 2012;59:400–407.

    CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–1339.

    Fakhry F., Spronk S., van der Laan L., et al. Endovascular revascularization and supervised exercise for peripheral artery disease and intermittent claudication: A randomized clinical trial. JAMA. 2015;314:1936–1944.

    Fowkes F.G., Rudan D., Rudan I., et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: A systematic review and analysis. Lancet. 2013;382:1329–1340.

    Khaleghi M., Isseh I.N., Bailey K.R., et al. Family history as a risk factor for peripheral arterial disease. Am J Cardiol. 2014;114:928–932.

    Kullo I.J., Bailey K.R., Kardia S.L., et al. Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study. Vasc Med. 2003;8:237–242.

    Lin J.S., Olson C.M., Johnson E.S., et al. The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction among asymptomatic adults: A systematic evidence review for the U.S. Preventive Services Task Force.

    Ann Intern Med. 2013;159:333–341.

    McDermott M.M., Liu K., Guralnik J.M., et al. Home-based walking exercise intervention in peripheral artery disease: A randomized clinical trial. JAMA. 2013;310:57–65.

    Murphy T.P., Cutlip D.E., Regensteiner J.G., et al. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: Six-month outcomes from the claudication: Exercise versus endoluminal revascularization (CLEVER) study. Circulation. 2012;125:130– 139.

    Rooke T.W., Hirsch A.T., Misra S., et al. 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58:2020–2045.

    1 Not FDA approved for this indication. 1 Not FDA approved for this indication. 2  Not available in the United  States.

    1  Not FDA approved for this  indication.

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