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Dec.28.2021

Atherosclerotic Peripheral Artery Disease

Synopsis

Key Points

  • Peripheral artery disease is a condition in which atherosclerosis of the extremities (most commonly the legs) reduces tissue perfusion to varying degrees resulting in manifestations that range from a clinically silent state to critical, limb-threatening ischemia
  • The classically described presenting symptom is intermittent claudication, lower extremity muscle pain with walking that resolves after 10 to 15 minutes of rest; however, symptoms are often more subtle, and some patients with significant disease may be unable to exert themselves sufficiently to trigger claudication r1
  • In advanced disease (eg, critical limb ischemia), pain may be present at rest in the supine position, and improve with leg in a dependent position; when limb ischemia is acute, pain is severe and unremitting with paresthesias
  • Physical findings may include cool extremities with shiny, hairless skin, dystrophic nails, and diminished or absent pulses. Patients with critical limb ischemia often have chronic nonhealing ulcerations, usually on the toes
  • Patients with acute limb ischemia have a cold, pale, pulseless extremity that may be immobile
  • Evaluation of patients with claudication or critical limb ischemia begins with measurement of the ankle-brachial index; levels below 0.9 are indicative of peripheral artery disease r2r3r4
  • Further evaluation with imaging is recommended when revascularization is considered r2r3r4
  • The most effective treatment for claudication is exercise; a structured program, supervised if possible, is ideal r2r3r4r5
  • Risk factor mitigation is an important aspect of management and includes tobacco cessation if applicable, statin therapy (regardless of lipid levels), and treatment of diabetes and hypertension if applicable r2r3r4
  • Antiplatelet therapy (aspirin or clopidogrel) is recommended in all symptomatic patients, and is reasonable in asymptomatic patients with an ankle-brachial index less than or equal to 0.9 r2r3
  • Revascularization is indicated for patients who have persistent claudication despite maximal medical therapy, and for patients with acute or critical limb ischemia; approach is determined by location and extent of disease and overall health status and life expectancy of the patient r2r3r4r6
  • Long-term antiplatelet therapy is indicated after surgical or endovascular intervention r2r7

Urgent Action

  • Patients with acute limb ischemia require immediate anticoagulation and intervention to restore perfusion to affected limb r1

Pitfalls

  • Patients with subclavian artery disease may present with vertebrobasilar symptoms in the absence of localizing upper extremity symptoms

Terminology

Clinical Clarification

  • Peripheral artery disease is a condition in which atherosclerosis of the extremities (most commonly the legs) reduces tissue perfusion to varying degrees
  • Arterial narrowing leads to manifestations that range from a clinically silent state to critical, limb-threatening ischemia

Classification

  • Qualitative (from 2016 American Heart Association/American College of Cardiology guideline) r3r8
    • Asymptomatic (can include patients with atypical symptoms)
    • Intermittent claudication: muscle pain or other localized discomfort that develops during exertion and resolves within 10 minutes of rest
    • Critical limb ischemia: characterized by chronic (2 weeks or longer) ischemic pain at rest, ulcers or nonhealing wounds, or gangrene resulting from peripheral artery disease
      • Also referred to as chronic limb-threatening ischemia r9
    • Acute limb ischemia: severe hypoperfusion characterized by pain, pallor, nonpalpable distal pulses, paresthesias, and paralysis of the limb, which is cold to touch; duration is less than 2 weeks
  • 2 stratification schemes are commonly used: r10
    • Fontaine
      • Stage I: asymptomatic
      • Stage IIa: intermittent claudication after walking more than 200 m
      • Stage IIb: intermittent claudication after walking less than 200 m
      • Stage III: rest pain
      • Stage IV: ulcers or gangrene
    • Rutherford
      • Grade 0, category 0: asymptomatic
      • Grade I, category 1: mild claudication
      • Grade I, category 2: moderate claudication
      • Grade I, category 3: severe claudication
      • Grade II, category 4: ischemic pain at rest
      • Grade III, category 5: minor tissue loss (ischemic ulceration not exceeding ulcers of the digits of the foot)
      • Grade III, category 6: major tissue loss (severe ischemic ulcers or frank gangrene)
  • The Society for Vascular Surgery has proposed the WIfI classification for critical limb ischemia based on the presence and extent of wounds (W), ischemia (I), and infection (fi) r9r11
    • Wounds are graded 0 through 3 on the presence of ulcers and/or gangrene
      • Grade 0: no ulcer, no gangrene
      • Grade 1: small, shallow ulcer; no gangrene
      • Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes
      • Grade 3: extensive, full-thickness ulcer; gangrene extending to forefoot or midfoot
    • Ischemia is graded 0 through 3 based on ankle-brachial index, ankle systolic pressure, and toe pressure
      • Grade 0: ankle-brachial index 0.8 or higher, ankle pressure over 100 mm Hg, toe pressure 60 mm Hg or higher
      • Grade 1: ankle-brachial index 0.6 to 0.79, ankle pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg
      • Grade 2: ankle-brachial index 0.4 to 0.59, ankle pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm Hg
      • Grade 3: ankle-brachial index less than or equal to 0.39, ankle pressure less than 50 mm Hg, toe pressure less than 30 mm Hg
    • Infection is graded 0 through 3 on the basis of presence and depth of local infection and systemic signs
      • Grade 0: no infection
      • Grade 1: mild, superficial infection (skin, subcutaneous layer)
      • Grade 2: local infection involving deep tissues without systemic signs
      • Grade 3: local infection with systemic signs
  • Acute limb ischemia is categorized on the basis of tissue viability r3
    • Category I: viability of the limb not immediately threatened
    • Category II: viability threatened
      • IIa: marginally threatened, salvageable if treated promptly
      • IIb: immediately threatened, possibly salvageable with immediate revascularization
    • Category III: not salvageable
  • Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) r12
    • Anatomic artery lesion classification
    • Provides guidance on decision for endovascular versus open surgical treatment

Diagnosis

Clinical Presentation

History

  • May be asymptomatic (nearly 40% of patients with peripheral artery disease) r6r8c1
  • Classic (but uncommon) presentation is intermittent claudication: lower extremity muscle pain with walking and cessation of pain after 10 to 15 minutes of rest r1c2
    • The location of pain depends on the level at which arterial stenosis occurs; the calf is the most common site, but pain may occur in thigh or buttock with more proximal stenoses
    • More often, symptoms are subtle or atypical, or occur only with exertion beyond the patient's usual level of activity
    • Inquire about distance a patient can walk before onset of pain, recovery time after cessation of activity, and effect of incline on those parameters
  • Atypical claudication, characterized by leg heaviness or tiredness with walking, is common c3c4c5
  • Pain at rest or nocturnal pain that is sometimes relieved by dangling the legs to gravity occurs with more advanced disease (ie, critical limb ischemia); there may be a history of spontaneous ulceration or poor wound healing c6c7c8c9
  • Acute limb ischemia presents with sudden, severe, unremitting pain and paresthesias c10c11c12c13
  • Symptoms may be unilateral or bilateral
  • Patients with upper extremity peripheral vascular disease may experience arm claudication with exercise c14
  • Severe disease in the subclavian artery can result in vertebrobasilar insufficiency and attendant symptoms of dizziness, blurred vision, dysphasia, and syncope (subclavian steal syndrome) c15c16c17c18

Physical examination

  • Patients with peripheral artery disease should undergo noninvasive blood pressure measurement in both arms at least once during the initial assessment r3c19
    • An inter-arm systolic blood pressure difference of more than 15 to 20 mm Hg is abnormal and suggestive of subclavian (or innominate) artery stenosis r3
    • This finding is also seen with aortic dissection, which should be considered
  • Palpate major arteries, including brachial, radial, ulnar, femoral, popliteal, dorsalis pedis, and posterior tibialis, noting strength and symmetry
    • Pulse strength r3
      • 0: absent
      • 1: diminished
      • 2: normal
      • 3: bounding
  • Listen for bruits over major pulse points, supraclavicular and infraclavicular fossae, and abdominal aorta c20c21c22c23c24
  • Inspect limbs for signs of poor perfusion: muscle atrophy; hair loss; shiny skin; thickened, brittle nails; dependent rubor; elevation pallor; ulcerations; and dry gangrene c25c26c27c28c29c30c31c32
  • Distal extremities may demonstrate decreased sensation c33
  • In acute limb ischemia, the affected area is cold, immobile, pulseless, and pale; cyanosis or incipient gangrene may be present and sensation may be diminished or absent c34c35c36c37c38c39c40c41
    • Absence of arterial Doppler signal indicates that limb viability is threatened
    • Absence of both arterial and venous Doppler signals indicates that limb may not be salvageable

Causes and Risk Factors

Causes

  • Peripheral atherosclerosis c42

Risk factors and/or associations

Age
  • Risk increases with age, especially after age 65 years r3c43c44c45c46
  • Lower extremity peripheral artery disease affects 12% to 20% of those aged 60 years and older r6
Sex
  • More common in men; male to female ratio is 2 to 1 r13c47c48
Genetics
  • Some risk factors for peripheral artery disease are heritable (eg, dyslipidemia, diabetes mellitus), but no specific genes or gene mutations have been directly associated with peripheral artery disease r14c49c50
Ethnicity/race
  • More common in people of color than White populations r10
    • More common in Black populations; at older ages, rates among Black patients are approximately 2 to 3 times higher than among White populations r15c51c52
Other risk factors/associations
  • 3 to 4 times more common in smokers than nonsmokers r13c53c54
  • Diabetes is associated with increased risk of occurrence and increased rate of progression r13c55
    • Every 1% elevation in hemoglobin A1C is associated with a 30% increase in risk for peripheral artery disease r8
  • Hypertension increases risk by about 3-fold r13c56
  • Dyslipidemia increases risk; fasting total cholesterol above 270 mg/dL is associated with a 2-fold increase in risk, but the proportional roles of various cholesterol fractions or other lipids have not been clearly defined r10c57
  • Hyperhomocysteinemia is associated with a 2-fold risk of peripheral artery disease r8c58
  • Chronic renal insufficiency has been associated with peripheral vascular disease, and may be a contributing factor r10c59

Diagnostic Procedures

Primary diagnostic tools

  • History and physical examination may suggest the diagnosis c60
  • The ankle-brachial index is recommended as the next step in evaluating lower extremity peripheral artery disease r2r3r4c61
    • Abnormal: ankle-brachial index 0.90 or less
    • Borderline: ankle-brachial index 0.91 to 0.99
    • Normal: ankle-brachial index 1.00 to 1.40
    • Noncompressible: ankle-brachial index above 1.40
  • For patients in whom peripheral artery disease is suspected but whose ankle-brachial index cannot be interpreted because of noncompressible arteries (defined as ankle-brachial index above 1.4), measurement of the toe-brachial index is recommended r2r3
  • For patients whose history suggests claudication and whose ankle-brachial index is normal or borderline, treadmill exercise with ankle-brachial index is recommended r2r3
  • Treadmill testing is also recommended to define functional limitation in patients with an abnormal ankle-brachial reflex r3c62
  • Segmental blood pressures may be done at proximal points to localize stenotic areas, which also provide further information on the extent of disease (ie, single or multiple lesions) r2r3
  • Other noninvasive tests that may be appropriate in some circumstances include toe-brachial index with Doppler pulse wave forms and transcutaneous oxygen pressure r2r3c63
    • Provides prognostic information in patients with nonhealing wounds or gangrene
  • Vascular imaging by duplex ultrasonography, CT angiography, MR angiography, or invasive angiography is recommended in patients in whom revascularization is considered (eg, patients with persistent symptoms despite treatment or with limb-threatening conditions) r2r3c64c65c66
    • In patients with immediately limb-threatening conditions (acute limb ischemia), imaging before emergent catheterization is not necessary r3
    • MR angiography can determine directional flow and is of particular value in evaluation for suspected subclavian steal syndrome
  • All patients should have routine blood work to identify contributing factors (eg, dyslipidemia, hyperglycemia) that are treatable and to serve as a baseline for monitoring subsequently treated therapeutic response c67c68
    • Obtain serum chemistry profile including renal and hepatic function tests, lipid profile, CBC, and hemoglobin A1C level in patients with known or newly discovered diabetes c69c70c71

Laboratory

  • Serum chemistry profile c72
    • May detect previously unrecognized or inadequately controlled hyperglycemia
    • Renal insufficiency may contribute to peripheral vascular disease or may be a manifestation of generalized atherosclerosis and renovascular disease
    • Renal or hepatic insufficiency may limit diagnostic (angiographic) and treatment options
  • Hemoglobin A1C c73
    • Higher glycosylated hemoglobin levels are associated with an increased risk for peripheral artery disease r8
  • Lipid profile c74d1
    • Measures total cholesterol, HDL, and triglyceride levels; LDL levels are calculated
    • Hyperlipidemia is a common risk factor and comorbidity in patients with peripheral vascular disease; further, it confers risk for other forms of cardiovascular disease
      • Correction reduces the risk of major adverse cardiovascular events, although it is not yet clear what effect it has on peripheral vascular disease r16
  • CBC r10c75
    • May identify conditions that further impair oxygen delivery to tissues (eg, anemia) or may complicate existing endovascular lesions (eg, hyperviscosity, thrombocytosis)

Imaging

  • Not routinely indicated for diagnostic purposes, but essential in evaluating patients with severe or refractory disease in whom revascularization is being considered r2r3
    • Digital subtraction angiography has been considered the gold standard but is invasive and entails significant radiation and dye exposure c76
    • The American College of Radiology recommends MR angiography with and without contrast enhancement as the test of choice, followed by CT angiography with contrast enhancement for patients in whom MR angiography is contraindicated r17c77c78
    • Duplex ultrasonography with Doppler is recommended for patients with contrast allergy or renal dysfunction; less accurate below the knee than above, and less accurate when there are multiple sequential stenoses r17c79
      • Recommended by European and UK guidelines as test of choice for initial imaging for lower extremity disease r4r18

Functional testing

  • Treadmill testing r19c80
    • Several protocols exist, and speed and incline may be constant or graded
      • Time to claudication should be recorded
      • Can be done in conjunction with ankle-brachial index; a postexercise ratio of under 0.9 or a drop of 15% to 20% from a normal preexercise ratio is consistent with peripheral artery disease r10

Other diagnostic tools

  • Ankle-brachial index to assess vascular perfusion r8c81
    • First test to assess for peripheral artery disease of the lower extremity
    • Accuracy in predicting peripheral artery disease is variable, especially in the presence of neuropathy or arterial calcification, but the advantages are that it is noninvasive, easy to obtain, and requires no special equipment
    • Blood pressure cuff is placed above the ankle and systolic blood pressure is measured in the dorsalis pedis and posterior tibial arteries with the aid of a handheld Doppler device if necessary
      • Divide the higher systolic measurement of the dorsalis pedis or posterior tibial pulse by the higher systolic value of right and left brachial pulses to calculate the ankle-brachial index
        • Values between 0.6 and 0.89 indicate mild perfusion deficit and may be associated with claudication
        • Values of 0.4 to 0.59 indicate moderate obstruction to perfusion
        • Values under 0.4 indicate severely reduced flow and may be associated with rest pain
    • May be performed after treadmill exercise in patients in whom the diagnosis is suspected but who have a normal or borderline ankle-brachial index at rest r10
      • A postexercise measurement of less than 0.9 or a reduction of 15% to 20% from baseline is diagnostic
  • Toe-brachial index r8c82
    • Requires a toe pressure cuff and handheld Doppler device
    • Toe cuff is wrapped around the great toe and systolic pressure is measured using the Doppler device, placed distal and medial to the cuff
    • Divide result by the brachial systolic value to calculate the ankle-brachial index, using the highest systolic measurements of bilateral readings
      • A ratio above 0.7 is considered within reference range
      • Systolic toe pressure of less than 30 mm Hg indicates inadequate perfusion
  • Segmental pressure readings with Doppler recording of pulse wave forms r2r3c83
    • A noninvasive way to evaluate the degree and level of obstruction
    • Blood pressure cuffs are placed at proximal and distal thigh and at calf and ankle; systolic pressures are taken at each level and Doppler pulse volumes recorded
    • A gradient of 20 mm Hg between thigh cuffs and 10 mm Hg or more between calf and ankle cuffs indicates an area of stenosis between the cuffs
  • Transcutaneous oxygen pressure c84
    • Indicated in patients with ulceration or other wounds to assess probability of healing and as an adjunct measure to determine level of amputation
    • Noninvasive measurement of PO₂ in tissue after local heat stimulation
    • A level below 30 mm Hg indicates significant impairment in perfusion and poor prognosis for wound healing r13

Differential Diagnosis

Most common

  • Lower extremity claudication
    • Spinal stenosis c85
      • Degenerative narrowing of the spinal canal
      • May cause pain and weakness in the buttocks and posterior aspect of the legs
      • Pain not worsened by walking uphill due to flexion of spine; with peripheral artery disease, pain worsens with uphill walking
      • Effect of rest is inconsistent; most effective relief maneuver is flexion of the lumbar spine
      • Definitive differentiation is by imaging of the spine, usually requiring MRI
    • Lumbar radiculopathy c86
      • Usually caused by herniated intervertebral disk
      • May cause sharp, lancinating pain that radiates down the posterior aspect of the leg
      • Not clearly related to exertion, nor relieved by rest; exacerbation and relief tend to be positional in nature
      • Diagnosis is based on imaging (typically with MRI) and electromyogram/nerve conduction studies
    • Chronic compartment syndrome c87d2
      • Accumulation of pressure in 1 or several of the muscle compartments in the leg as the result of vigorous exercise (eg, sprint, long-distance run)
      • Characterized by sharp, bursting pain in the calf muscles
      • Like claudication, pain subsides with rest, although may take longer
      • Distinction is usually based on clinical context
    • Venous claudication c88
      • Venous engorgement occurring when exercise-induced perfusion exceeds venous return owing to chronic venous obstruction (eg, postphlebitic syndrome) or other cause of venous insufficiency
      • Causes sharp, pressurelike pain in the calf
      • Relief occurs with elevation of the affected leg
      • Distinction is clinical
    • Baker cyst c89d3
      • Collection of synovial fluid in the popliteal fossa
      • May cause tightness and pain behind the knee that extends into the calf
      • May be worse with walking but does not resolve with rest
      • Fluid collection can be detected by palpation or ultrasonography
    • Osteoarthritis c90d4
      • Degenerative joint changes; hip and knee are commonly affected
      • Pain may be induced by exercise but is not necessarily relieved by rest
      • Often better when not bearing weight
      • Diagnosis can be made by radiography, which may show erosive changes and narrowed joint space
  • Nonhealing wounds
    • Venous ulcers c91
      • Associated with venous stasis disease
      • Characterized by superficial ulceration in the legs
      • Unlike the dry ulcers of peripheral artery disease, which usually occur on the distal aspects of the digits, venous ulcers occur primarily on the lower leg, especially around the medial malleolus, and tend to weep
      • Mixed arterial-venous ulcers may also occur, where the ulcer clinically appears venous, but the patient has other symptoms of peripheral artery disease
      • Differentiation is primarily clinical
    • Microangiopathic ulcers c92
      • Ulcerations due to small vessel disease (eg, diabetes mellitus, vasculitis, sickle cell disease)
      • Like the ulcers of peripheral artery disease, may occur on the toes, but also common on the feet and legs
      • Distinction is made by clinical context (ie, history of or new diagnosis of a known cause)
    • Neuropathic ulcers c93
      • Caused by pressure on bony prominences, including those caused by occult fractures and deformity
      • Usually occur on the plantar surfaces and are often painless
      • Diagnosis is clinical; examination may reveal sensory loss and radiographs may demonstrate the bony changes of Charcot arthropathy

Treatment

Goals

  • Reduce symptoms (eg, claudication, rest pain), improve exercise capacity (eg, walking time) and preserve extremities
    • A corollary goal is prevention of other cardiovascular events

Disposition

Admission criteria

  • Admission is not generally required except in cases of acute limb ischemia, complications such as infection of ischemic ulcers, or for a revascularization procedure

Recommendations for specialist referral

  • Refer stable patients to a vascular specialist to determine extent of disease and direct management (ie, medical or interventional)
  • Refer all patients with chronic limb-threatening ischemia to a vascular specialist for consideration of limb salvage, unless major amputation is medically urgent r9
  • Patients with acute limb ischemia require immediate consultation with a vascular specialist r6
  • Refer patients with refractory dyslipidemia to a lipid specialist to manage pharmacotherapy
  • Refer patients with associated diabetes mellitus to an endocrinologist to optimize glycemic control
  • Consult a plastic or reconstructive surgeon or other wound care specialist for treatment of ischemic ulcers or other nonhealing wounds

Treatment Options

Management is aimed at controlling contributory conditions, maximizing perfusion, and improving function r2r3r4

  • For most patients, this involves mitigation of risk factors such as smoking, hyperglycemia, dyslipidemia, and high blood pressure r20
    • Prescribe antiplatelet therapy and treat claudication with vasoactive drugs
    • Advise engagement in structured exercise program r5
    • Evidence of benefit in vascular outcomes is not as clearly established for asymptomatic patients as for symptomatic patients r20
  • Early revascularization is recommended for patients with symptomatic upper extremity disease; an endovascular approach is usually favored
  • Revascularization is indicated for patients with persistent lifestyle-limiting lower extremity claudication despite at least 6 monthsr2 of optimal medical therapy
    • Procedure may be endovascular or surgical, depending on anatomy; an endovascular approach is usually favored for aortoiliac artery, superficial femoral artery, popliteal artery stenotic lesions, and chronic total occlusion involving aortoiliac vessels r12r21
    • Endovascular treatment and surgical treatment are both considered appropriate in all anatomic types of critical limb ischemia r21
  • In patients with acute or critical limb ischemia, revascularization is required to salvage limb and reduce morbidity and mortality associated with limb loss r21
    • Initiate anticoagulation with heparin immediately for patients with acute limb ischemia unless contraindicated
    • Revascularization for salvageable limbs must be done within 6 hours for patients with Category II disease and within 24 hours for patients with Category I disease r3
    • Endovascular therapy may involve:
      • Thrombolysis with or without thrombectomy, or
      • Embolectomy with or without immediate or subsequent revascularization
    • Fasciotomy may be required to manage compartment syndrome
    • Patients with critical limb ischemia and ischemic ulcers or other nonhealing wounds require aggressive wound management
    • Pain secondary to critical limb ischemia may be treated with acetaminophen or opioids depending on the severity; refer to pain management specialist if pain is difficult to control and revascularization is not possible or if pain persists after revascularization r4

Mitigation of risk factors

  • With the exception of statin therapy, which improves total walking distance and pain-free walking time, there is little evidence that any of these measures has a direct impact on peripheral vascular disease; recommendations are based primarily on observed reductions in other outcome measures (eg, major cardiovascular events) and on the known contributory role of these risk factors r2
    • Smoking cessation is recommended for all patients who smoke r2r3r4d5
    • Lipid management d1
      • American Heart Association/American College of Cardiology guidelines recommend statin therapy in all patients with peripheral artery disease; Society for Vascular Surgery recommends statin therapy in symptomatic patients with peripheral artery disease, regardless of measured lipid levels r2r3r22
        • Neither guideline establishes a target lipid level, but high-intensity statin therapyr23 is recommended
      • European Society of Cardiology recommends statin therapy in patients with peripheral artery disease, with a goal of reducing LDL to less than 70 mg/dL, or at least 50% of baseline if the initial level is between 70 and 135 mg/dL r18
      • Statins have been shown to improve walking distance; some evidence indicates that they delay functional decline and reduce rates of critical limb ischemia and amputation r16
        • Additionally, statins reduce major cardiovascular events in patients with peripheral artery disease
      • PCSK9 inhibitors are generally well tolerated but long-term safety remains to be proven r23
    • Glycemic control d6
      • Aim to achieve a hemoglobin A1C target of less than 7% if hypoglycemia can be avoided (per recommendations of the Society for Vascular Surgeryr2, American Diabetes Associationr24)
    • Blood pressure control d7
      • Provide treatment in accordance with current guidelines on managing hypertension; blood pressure goals specific to peripheral artery disease have not been established r22
      • ACE inhibitors and β-blockers both have beneficial effects in preventing major cardiovascular events in patients with ischemic cardiovascular disease and are appropriate choices for treating hypertension in patients with peripheral artery disease r2r3
        • A Cochrane review found no evidence of adverse effects on symptoms of peripheral vascular disease in patients with peripheral artery disease who were treated with β-blockers for hypertension or other indications r25

Structured exercise therapy

  • Recommended for all patients with claudication, unless otherwise contraindicated because of comorbidities r2r3r4r5
    • May be supervised or unsupervised, home-based or institutional r2r3
      • Supervised programs are more effective, but unsupervised structured home programs also confer benefit r26r27
      • Supervised exercise therapy typically consists of treadmill or track walking; alternative forms of exercise therapy such as cycling, lower-extremity resistance training, upper-arm ergometry, total body recumbent stepping, and Nordic walking may be equally efficacious r28r29
      • Once a program of supervised therapy is completed, patients should transition to a long-term unsupervised exercise program r29
    • Associated with improvement in walking time and distance
      • A Cochrane review found the following improvements in patients with claudication who undertook a structured exercise program: r30
        • Mean increase in walking time of 4.5 minutes, ranging from 50% to 200% increase from baseline
        • Mean increase in pain-free walking distance of 82 meters and in overall walking distance of 120 meters
    • Compared to medical therapy alone, structured exercise improves walking distance, symptoms of claudication, and quality of life
    • Percutaneous angioplasty combined with supervised exercise therapy results in greater improvement in walking distance and quality of life compared to percutaneous angioplasty alone or medical therapy alone r31
    • Supervised exercise therapy may also have beneficial effects on modifiable cardiovascular risk factors such as blood pressure and cholesterol levels r32

Pharmacotherapy

  • Antiplatelet therapy
    • Aspirin or clopidogrel is recommended in all symptomatic patients, and is reasonable in asymptomatic patients with an ankle-brachial index less than or equal to 0.9 r3
    • Aspirin is favored over clopidogrel by the Society for Vascular Surgeryr2
      • Shown to decrease need for revascularization and reduce all-cause cardiovascular mortality r33
    • The American College of Chest Physicians recommends low-dose aspirin in asymptomatic patients with peripheral artery disease and either aspirin or clopidogrel in symptomatic patients r34
    • Vorapaxar has been studied in patients with peripheral artery disease, and while some studies report a reduction in complications of peripheral vascular disease, the benefit was offset by an increase in moderate to severe bleeding episodes; its role remains unclear r35r36
  • Vasoactive drugs
    • Cilostazol may be used for symptomatic treatment of claudication r2r3r34
      • Improves walking distance in patients with peripheral artery disease r37
    • NICE guidelines recommend naftidrofuryl oxalate in patients who have not experienced improvement with exercise therapy and who are not candidates for surgery; not available in the United States r4
  • Anticoagulation
    • Recommended only in the setting of acute limb ischemia; heparin has been the drug of choice r3
    • Emerging evidence suggests that low-dose rivaroxaban taken twice daily plus aspirin once daily reduces limb events (acute limb ischemia and amputation) and cardiovascular events when compared with aspirin alone r38r39
      • Some increase in bleeding risk, but the net clinical benefit was positive in COMPASS trial

Revascularization is indicated for patients with persistent lifestyle-limiting claudication despite optimal medical therapy, and for patients with acute or critical limb ischemia r2r6

  • May be done through endovascular or open surgical approach; selection depends on the location of the lesion, the length and degree of stenosis or occlusion, the anticipated lifespan of the patient, and the patient's fitness to undergo surgery
    • Endovascular r40
      • May involve angioplasty or stent placement
        • A variety of stent designs have been developed to withstand external mechanical stress, decrease risk of restenosis, or both
      • Favored initial approach in patients whose comorbidities confer high risk with open surgical procedures (eg, ischemic heart disease, heart failure, advanced lung disease, renal failure) and in patients with upper extremity disease r3
      • In patients with chronic limb-threatening ischemia
        • Recommend as favored approach for those with less complex anatomy, intermediate-severity limb threat, or high patient risk r9
        • Usually favored for aortoiliac artery, superficial femoral artery, and popliteal artery stenotic lesions, and chronic total occlusion involving aortoiliac vessels r21
      • For acute limb ischemia, catheter-directed thrombolysis or percutaneous thrombectomy is effective in restoring perfusion r3
    • Surgical r1
      • May involve endarterectomy or bypass
        • May be preferable to stent placement in the common femoral and popliteal arteries owing to mechanical stress to the device caused by joint flexion
        • In general, results in more complete reperfusion and longer duration of patency than endovascular approach
        • In patients with chronic limb-threatening ischemia, 2019 global vascular guidelines recommend vein bypass for average-risk patients with advanced limb threat and high complexity disease r9
      • For acute limb ischemia, open thromboembolectomy may be required if an endovascular approach is not feasible r3
  • Hybrid procedures may be performed in some cases (ie, endovascular approach in amenable segments coupled with endarterectomy or bypass in other areas); likewise, a staged approach may be appropriate in some patients (eg, those with rest pain) r1r3
  • A Cochrane review noted that percutaneous angioplasty was associated with fewer complications and shorter hospital stay than surgical bypass, but that bypass achieves better rates of patency at 1 year r41

Wound healing r3

  • Revascularization is the most effective measure to achieve healing
    • Urgent vascular imaging and revascularization should be considered in patients with diabetic foot ulcers and ankle pressure less than 50 mm Hg, ankle-brachial index less than 0.5, toe pressure less than 30 mm Hg, or transcutaneous oxygen pressure less than 25 mm Hg r42
    • Revascularization should be considered in patients with diabetic foot ulcers and peripheral arterial disease when ulcers are not healing within 4 to 6 weeks despite optimal management r42
  • Debridement, aggressive local wound care, treatment of infection if present, and off-loading of pressure are also essential
  • Adjunctive measures such as hyperbaric oxygen and intermittent pneumatic compression are not universally recommended r43
  • Systemic hyperbaric oxygen therapy may be considered as an adjunctive treatment in ischemic ulcers that do not heal despite revascularization r42

Drug therapy

  • Statin
    • Atorvastatin c94
      • Atorvastatin Calcium Oral tablet; Adults: 80 mg PO once daily has been shown to reduce the progression of atherosclerosis in clinical trials.
  • ACE inhibitor
    • Ramipril c95
      • Ramipril Oral tablet; Adults 55 years and older: Initially, 2.5 mg PO once daily. Gradually titrate to 5 mg/day PO, then increase if tolerated to the target dosage of 10 mg/day PO, given in 1 to 2 divided doses.
  • Antiplatelet agents
    • Aspirin c96
      • Aspirin Oral tablet; Adults: 75 to 325 mg/day PO. Aspirin is also recommended following prosthetic infrainguinal bypass surgery.
    • Clopidogrel c97
      • Clopidogrel Bisulfate Oral tablet; Adults: 75 mg PO once daily.
    • Ticagrelor r44c98
      • Ticagrelor Oral tablet; Adults: 180 mg PO loading dose plus aspirin (usually 325 mg PO) then, beginning 12 hours after loading dose, 90 mg PO twice daily plus aspirin 75 to 100 mg (i.e., 81 mg) PO once daily for 1 year. After 1 year, 60 mg PO twice daily and continue aspirin maintenance dose. Avoid maintenance doses of aspirin above 100 mg/day.
  • Vasoactive agents
    • Cilostazol c99
      • Cilostazol Oral tablet; Adults: 100 mg PO twice daily. A dosage of 50 mg PO twice daily should be considered for patients concomitantly receiving inhibitors of CYP3A4 or CYP2C19.
  • Anticoagulants
    • Heparin c100
      • Heparin Sodium (Porcine) Solution for injection; Adults: 80 units/kg IV bolus, then 18 units/kg/hour IV. If the aPTT is less than 35, increase rate by 4 units/kg/hour and rebolus with 80 units/kg IV. If aPTT is 35 to 45, increase rate by 2 units/kg/hour and rebolus with 40 units/kg IV. If aPTT is 46 to 70, maintain infusion. If aPTT is 71 to 90, decrease rate by 2 units/kg/hour. If aPTT is more than 90, hold infusion for 1 hour and decrease rate by 3 units/kg/hour.
    • Rivaroxaban r39c101
      • Rivaroxaban Oral tablet; Adults: 2.5 mg PO twice daily plus aspirin (75 to 100 mg) PO once daily.

Nondrug and supportive care

Exercise rehabilitation r2r3c102

  • Recommended for all patients except those with Fontaine stage IV disease (ulcers or gangrene) or other contraindications r2r3r4
  • Should consist of a structured regimen, but may or may not be directly supervised
  • Exercise sessions last for 30 to 45 minutes and occur at least 3 times/week for a minimum of 12 weeks r5r29
  • Patients are encouraged to walk to the point of moderate to maximum tolerable claudication, to rest until pain subsides, and then repeat
  • Factors associated with most effective outcomes include: r2
    • Structured regimen
    • Supervised sessions
    • Walking instead of other forms of exercise
    • Session duration of at least 30 minutes
    • Frequency 3 or more times per week
    • Program duration more than 26 weeks
  • Patients who are unable to walk or who cannot tolerate walking to the point of claudication may nevertheless benefit from other forms of exercise (ie, low-intensity walking, cycling, lower-extremity resistance training, upper-arm ergometry, total body recumbent stepping) r3r29
Procedures
Angioplasty with or without stent placement c103
General explanation
  • A deflated balloon catheter is placed percutaneously in the peripheral blood vessels and advanced under fluoroscopy to the area of stenosis
  • The balloon is inflated to press open atherosclerotic plaque; a wire stent may be inserted to increase the diameter of the stenotic vessels and to maintain patency
  • Either the balloon or the stent may be coated or impregnated with a pharmacologic agent (eg, everolimus, paclitaxel) to slow restenosis
Indication
  • Indicated in patients with critical or acute limb ischemia or claudication refractory to maximal medical therapy
  • Anatomy of lesions must be amenable to catheter approach and balloon placement
  • May be preferable approach, when anatomically feasible, in patients with life expectancy of less than 2 years and/or substantial anesthesia risk
  • In patients with chronic limb-threatening ischemia, 2019 global vascular guidelines recommend angioplasty as favored approach for those with less complex anatomy, intermediate-severity limb threat, or high patient risk r9
Contraindications
  • Absence of an accepted indication (eg, in an asymptomatic patient) for the purpose of preventing progression r2r3
Complications
  • Embolization of plaque or thrombosis
  • Restenosis
  • Migration of stent
  • Perforation of vessel
Interpretation of results
  • Reperfusion can be demonstrated fluoroscopically before terminating the procedure
Endarterectomy c104
General explanation
  • Under direct visualization, surgical removal of an obstructing atheromatous lesion
  • Arterial incision is closed with a vein or prosthetic patch, resulting in a vessel of larger diameter to compensate for scarring without jeopardizing luminal flow
Indication
  • Indicated in patients with critical or acute limb ischemia or claudication refractory to maximal medical therapy
  • Focal lesion in a vessel of large caliber (eg, aortoiliac, common femoral arteries) r1
Contraindications
  • Absence of an accepted indication (eg, in an asymptomatic patient) for the purpose of preventing progression r3
  • Unacceptably high medical risk
Complications
  • Embolization of plaque or thrombus
  • Luminal thrombosis
  • Restenosis
Interpretation of results
  • Reperfusion can be demonstrated fluoroscopically before terminating the procedure
Surgical bypass c105
General explanation
  • Construction of an alternate conduit for blood flow around an obstructed artery segment
  • 1 end of the vascular graft is inserted proximal to the obstructing lesion and the other distal to it
    • Prosthetic grafts are preferred in aortoiliac procedures
    • Autogenous venous grafts are preferred for infrainguinal procedures, and may be harvested from great saphenous or other veins
      • Ultrasonographic vein mapping is done preprocedure to identify suitable vessels
Indication
  • Indicated in patients with critical or acute limb ischemia or claudication refractory to maximal medical therapy
  • May be preferable to endovascular approach in patients with life expectancy of 2 years or more because of greater durability of results r13
  • In patients with chronic limb-threatening ischemia, 2019 global vascular guidelines recommend vein bypass for average-risk patients with advanced limb threat and high complexity disease r9
Complications
  • Restenosis
  • Thrombosis
  • Pseudoaneurysm formation
Interpretation of results
  • Reperfusion can be demonstrated fluoroscopically before terminating the procedure
Catheter-directed thrombolysis with or without thrombectomy c106
General explanation
  • Percutaneous passage of a thin catheter via a peripheral artery vein to an arterial thrombus to deliver a thrombolytic agent with or without stent placement
  • May also perform mechanical thrombectomy
Indication
  • Peripheral artery thrombus and acute limb ischemia with a salvageable limb
Contraindications
  • Nonsalvageable limb
  • Established stroke
  • Ischemic stroke in preceding 6 months
  • Active bleeding
Complications
  • Bleeding at other sites, including intracranial
  • Embolization
Interpretation of results
  • Reperfusion can be demonstrated fluoroscopically before terminating the procedure

Comorbidities

  • Diabetes mellitus, atherosclerotic coronary disease, and dyslipidemia are common comorbidities; treatment of these is an integral part of the management of peripheral artery disease r8c107c108c109

Special populations

  • Recent coronary stent or acute coronary syndrome
    • Consider dual antiplatelet therapy with aspirin plus clopidogrel or aspirin plus ticagrelor r35
    • Long-term use of dual antiplatelet therapy confers a higher risk of bleeding than aspirin alone, so it is important to weigh ischemic and bleeding risks
    • Risk scoring systems are available to provide guidance in assessing ischemic and bleeding risks in patients who have undergone stent placement and are candidates for dual antiplatelet therapy r45

Monitoring

  • All patients should be followed with periodic clinical evaluation including reassessment of cardiovascular risk factors, interim history of existing symptoms and development of new ones, and review of functional status r3c110c111
  • Patients who have undergone revascularization should also have periodic measurement of ankle-brachial index r3r46c112
  • Periodic follow-up with duplex ultrasonography may be beneficial in patients who have had infrainguinal autogenous vein bypass or an endovascular procedure r3r46c113

Complications and Prognosis

Complications

  • Patients with critical limb ischemia and chronic nonhealing ulcers may develop osteomyelitis in underlying bone c114
  • Amputation is the most significant complication c115
    • May be precipitated by acute limb ischemia
    • In patients with critical limb ischemia, uncontrolled infection or gangrene may necessitate amputation at some level
  • Infection c116
  • Wounds c117

Prognosis

  • Characterized in most patients by slow progression r8
    • 70% to 80% of patients followed for 5 years after diagnosis remain clinically stable
    • 10% to 20% of patients experience progressive intermittent claudication
    • 1% to 3% of patients develop critical limb ischemia
      • Among people with diabetes, 40% to 50% will undergo an amputation and 20% to 25% will die within a year of diagnosis of critical limb ischemia r47
  • Peripheral artery disease is associated with carotid, cerebral, and coronary atherosclerosis; an ankle-brachial index under 0.9 doubles the likelihood of a coronary event, cardiovascular mortality, and all-cause mortality r8

Screening and Prevention

Screening

At-risk populations

  • The US Preventive Services Task Force concluded that current evidence is insufficient to assess the balance of benefits and harms of screening for peripheral artery disease and cardiovascular disease risk using the ankle-brachial index in asymptomatic adults r48
  • The American Heart Association and American College of Cardiology suggest that screening of asymptomatic patients is reasonable when there is an increased likelihood of disease: r3
    • Age 65 years or older
    • Age 50 to 64 years with known risk factors (eg, diabetes, hyperlipidemia, hypertension, smoking history) or family history of peripheral artery disease
    • Age younger than 50 years with diabetes and 1 additional risk factor
    • Known atherosclerotic disease elsewhere (eg, carotid, coronary, aorta, mesenteric, renal)

Screening tests

Prevention

  • Primary prevention r8
    • True primary prevention is difficult if not impossible to achieve because of the complex nature of contributing heritable and physiologic factors
    • Prevention efforts revolve around mitigation of risk factors; measures of efficacy often reflect clinical outcomes rather than presence of disease
      • Abstinence or cessation of smoking c120c121d5
        • Abstinence from smoking is the only risk factor that can be clearly self-determined; never starting is the most effective measure, as sustained abstinence after cessation is very difficult to maintain
      • Attaining optimal glycemic control is advisable in the management of peripheral artery disease, but the impact on macrovascular disease is not clear c122
      • Blood pressure control has been associated with a significant reduction in complications (including death) of peripheral artery disease by 16% for every 10 mm Hg increment of reduction c123
      • Treatment of dyslipidemia is recommended, and the use of statins may play a role in preventing atherosclerosis separate from reduction of lipid levels c124
  • Secondary prevention after interventional therapy
    • Ongoing medical management of all patients includes measures to mitigate risk factors by treating diabetes and hypertension, administering statin therapy, and encouraging smoking cessation through counseling and pharmacologic intervention r2r3
    • All patients who are able should continue regular exercise and antiplatelet therapy (usually low-dose aspirin) r2r7c125c126
      • The Society for Vascular Surgery recommends dual antiplatelet therapy with aspirin and clopidogrel for 30 days for patients who have undergone infrainguinal endovascular intervention for claudication
      • The American College of Chest Physicians recommends against dual antiplatelet therapy except in patients who have undergone below-knee bypass with placement of prosthetic grafts r34
  • Careful foot care is important in preventing ulceration and other foot injuries that can lead to amputation. Educate patients in foot care as for diabetes: r3r49c127
    • Daily foot inspection, including web spaces, by the patient or a caregiver
    • Notify health care provider immediately if there is a new wound of any kind, or if the foot appears red or is unusually warm to touch
    • Do not walk barefoot, wearing only socks, or wearing thin slippers without protective soles; wear shoes inside and outside of home
    • Do not wear shoes that are too tight or that have irregular inside surfaces that rub the skin
    • Inspect shoes and feel the inside with your hand to identify roughness or foreign objects before putting the shoe on
    • Wear seamless socks and change daily to a clean pair
    • Wash feet daily, avoiding water that is higher than body temperature; dry carefully, including between toes
    • Do not use any kind of heating device to warm feet
    • Lubricate dry skin with emollients, but avoid areas between toes
    • Do not attempt to remove calluses yourself; consult your health care provider
    • Cut toenails straight across; if vision is inadequate, get help from a caregiver or a professional
    • Be sure that your health care provider examines your feet regularly
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