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Atherosclerotic peripheral artery disease

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Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Nov.29.2023

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
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 less than 0.9 are indicative of peripheral artery disease ^r2^r3^r4
Further evaluation with imaging is recommended when revascularization is considered ^r2^r3^r4
The most effective treatment of claudication is exercise; a structured program, supervised if possible, is ideal ^r2^r3^r4^r5
Cilostazol is recommended for treatment of symptomatic claudication in setting of lower-extremity peripheral artery disease ^r3
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 ^r2^r3^r4
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^r4
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 ^r2^r3^r4^r6
Long-term antiplatelet therapy is indicated after surgical or endovascular intervention ^r4^r7

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
Peripheral artery disease affects more than 230 million people worldwide and is the third leading cause of atherosclerotic morbidity, after coronary artery disease and stroke ^r8

Classification

Qualitative (from 2016 American Heart Association and American College of Cardiology guideline) ^r3^r9
- 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^r10
- 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 ^r11
- 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)
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) ^r10^r12
- 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 greater, ankle pressure greater than 100 mm Hg, toe pressure 60 mm Hg or greater
  - 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) ^r13
- 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) ^r6^r9
Classic (but uncommon) presentation is intermittent claudication: lower-extremity muscle pain with walking and cessation of pain after 10 to 15 minutes of rest ^r1
- 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
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
Acute limb ischemia presents with sudden, severe, unremitting pain and paresthesias
Symptoms may be unilateral or bilateral
Patients with upper-extremity peripheral vascular disease may experience arm claudication with exercise
Severe disease in the subclavian artery can result in vertebrobasilar insufficiency and attendant symptoms of dizziness, blurred vision, dysphasia, and syncope (subclavian steal syndrome)

Physical examination

Patients with peripheral artery disease should undergo noninvasive blood pressure measurement in both arms at least once during the initial assessment ^r3
- 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
Inspect limbs for signs of poor perfusion: muscle atrophy; hair loss; shiny skin; thickened, brittle nails; dependent rubor; elevation pallor; ulcerations; and dry gangrene
Distal extremities may show decreased sensation
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
- 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

Risk factors and/or associations

Age

Risk increases with age, especially after age 65 years ^r3
Lower-extremity peripheral artery disease affects 12% to 20% of those aged 60 years and older ^r6

Sex

More common in males; male to female ratio is 2 to 1 ^r14

Genetics

Some risk factors for peripheral artery disease are heritable (eg, dyslipidemia, diabetes), but no specific genes or gene variants have been directly associated with peripheral artery disease ^r15

Ethnicity/race

More common in people of color than White populations ^r11
- More common in Black populations; at older ages, rates among Black patients are approximately 2 to 3 times higher than among White populations ^r16

Other risk factors/associations

3 to 4 times more common in smokers than nonsmokers ^r14
Diabetes is associated with increased risk of occurrence and increased rate of progression ^r14
- Every 1% elevation in hemoglobin A1C is associated with a 30% increase in risk for peripheral artery disease ^r9
Hypertension increases risk by approximately 3-fold ^r14
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 ^r11
Hyperhomocysteinemia is associated with a 2-fold risk of peripheral artery disease ^r9
Chronic renal insufficiency has been associated with peripheral vascular disease and may be a contributing factor ^r11
Dietary factors including higher intake of saturated fat, cholesterol, and processed meat appear to be associated with increased rate of progression and overall worsened outcomes in persons with peripheral artery disease ^r17
Sedentary lifestyle; risk of peripheral artery disease is inversely related to physical activity ^r8

Diagnostic Procedures

Primary diagnostic tools

History and physical examination may suggest the diagnosis
The ankle-brachial index is recommended as the next step in evaluating lower-extremity peripheral artery disease ^r2^r3^r4
- Abnormal: ankle-brachial index 0.90 or less; considered diagnostic of peripheral artery disease
- 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 ^r3^r4
For patients whose history suggests claudication and whose ankle-brachial index is normal or borderline, treadmill exercise with ankle-brachial index is recommended ^r3^r4
- Treadmill testing is also recommended to define functional limitation in patients with an abnormal ankle-brachial reflex ^r3
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) ^r3^r4
Other noninvasive tests that may be appropriate in some circumstances include toe-brachial index with Doppler pulse wave forms and transcutaneous oxygen pressure ^r3^r4
- Provides prognostic information in patients with nonhealing wounds or gangrene
Vascular imaging by duplex ultrasonography, CT angiography, magnetic resonance 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) ^r3^r4^r18
- In patients with immediately limb-threatening conditions (acute limb ischemia), imaging before emergent catheterization is not necessary ^r3
- Magnetic resonance angiography can determine directional flow and is of particular value in evaluation for suspected subclavian steal syndrome
Perform routine blood work in all patients to identify contributing factors (eg, coronary artery disease, dyslipidemia, hyperglycemia) that are treatable and to serve as a baseline for monitoring subsequently treated therapeutic response
- 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
- For patients admitted with symptomatic peripheral artery disease, a troponin level may have some prognostic value ^r19

Laboratory

Serum chemistry profile
- 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
- Higher glycosylated hemoglobin levels are associated with an increased risk for peripheral artery disease ^r9
Lipid profile
- 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 both major adverse cardiovascular events and major adverse limb events ^r20^r21
CBC ^r11
- May identify conditions that further impair oxygen delivery to tissues (eg, anemia) or may complicate existing endovascular lesions (eg, hyperviscosity, thrombocytosis)
Troponin
- Elevated troponin levels at time of admission for symptomatic peripheral artery disease (eg, critical limb ischemia or claudication) appear to be associated with higher mortality and increased risk of adverse long-term cardiovascular outcomes ^r19

Imaging

Not routinely indicated for diagnostic purposes but essential in evaluating patients with severe or refractory disease in whom revascularization is being considered ^r3^r4
- Digital subtraction angiography has been considered the gold standard but is invasive and entails significant radiation and dye exposure
- Initial imaging modalities to assess revascularization include any of the following: duplex ultrasonography, CT angiography with contrast, magnetic resonance angiography, and invasive angiography
  - American College of Radiology guidelines state that any of these modalities are appropriate, depending on the clinical situation ^r18
  - European and UK guidelines recommend duplex ultrasonography as first line imaging for patients in whom revascularization is being considered ^r2^r22
    - Magnetic resonance angiography can be recommended if further imaging is needed, and CT angiography can be offered if magnetic resonance angiography is contraindicated or not tolerated ^r2

Functional testing

Treadmill testing ^r23
- Several protocols exist, and speed and incline may be constant or graded
  - Record time to claudication
  - Can be done in conjunction with ankle-brachial index; a postexercise ratio less than 0.9 or a drop of 15% to 20% from a normal preexercise ratio is consistent with peripheral artery disease ^r11

Other diagnostic tools

Ankle-brachial index to assess vascular perfusion ^r9
- 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
- With the patient supine, place blood pressure cuff above the ankle and measure systolic blood pressure in the dorsalis pedis and posterior tibial arteries with a handheld Doppler device
  - 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 ^r6^r14
    - Values of 0.90 or lower are abnormal and considered diagnostic of peripheral artery disease
    - Values of 0.7 to 0.89 indicate mild obstruction
    - Values of 0.4 to 0.69 indicate moderate obstruction
    - Values lower than 0.4 indicate severe obstruction
- 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 ^r11
  - A postexercise measurement of less than 0.9 or a reduction of 15% to 20% from baseline is diagnostic
Toe-brachial index ^r9
- Requires a toe pressure cuff and handheld Doppler device
- Wrap toe cuff around the great toe and measure systolic pressure using the Doppler device placed distal and medial to the cuff
- Divide toe systolic pressure by the brachial systolic value to calculate the toe-brachial index, using the highest systolic measurements of bilateral readings
  - A ratio greater than 0.7 is considered within reference range
  - A ratio of 0.7 or lower is considered peripheral artery disease
Segmental pressure readings with Doppler recording of pulse wave forms ^r3^r4
- A noninvasive way to evaluate the degree and level of obstruction
- Place blood pressure cuffs at proximal and distal thigh and at calf and ankle; measure systolic pressures at each level and record Doppler pulse volumes
- 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
- 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 lower than 30 mm Hg indicates significant impairment in perfusion and poor prognosis for wound healing ^r14

Differential Diagnosis

Most common

Lower-extremity claudication
- Spinal stenosis
  - 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
  - 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 ^d1
  - 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 made on the basis of clinical context
- Venous claudication
  - 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 ^d2
  - 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
  - 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 radiographic findings, which may show erosive changes and narrowed joint space
Nonhealing wounds
- Venous ulcers
  - 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
  - Ulcerations due to small vessel disease (eg, diabetes, 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
  - 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 show sensory loss, and radiographs may show 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 ^r10
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 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 ^r2^r3^r4

For most patients, this involves mitigation of risk factors such as smoking, hyperglycemia, dyslipidemia, and high blood pressure ^r24
- 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 ^r24
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 months 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 ^r13^r25
- Endovascular treatment and surgical treatment are both considered appropriate in all anatomic types of critical limb ischemia ^r25
In patients with acute or critical limb ischemia, revascularization to salvage limb and reduce high rates of morbidity and mortality associated with limb loss is standard of care if feasible ^r25
- Start anticoagulation with heparin immediately for patients with acute limb ischemia unless contraindicated ^r26
- 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 the following:
  - 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
- Certain patients with critical limb ischemia and significant comorbidities may be deemed poor candidates for first line therapy with endovascular or surgical revascularization or have unfavorable vascular anatomy for intervention; for these patients, consider conservative treatment ^r27
  - A meta-analysis of conservative treatment in patients with critical limb ischemia found that pooled 12-month all-cause mortality rate was 18% and pooled major amputation rate was 27%, suggesting that though mortality and amputation rates are high in this population, loss of life or limb is not an inevitable outcome ^r27
- 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 ^r2

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 ^r4
- Smoking cessation is recommended for all patients who smoke ^r2^r3^r4^d3
- Lipid management
  - American Heart Association and 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 ^r4^r25^r28
    - Neither guideline establishes a target lipid level, but high-intensity statin therapy is recommended ^r29
  - 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 ^r22
  - 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 ^r20^r21
    - Additionally, statins reduce major cardiovascular events in patients with peripheral artery disease
  - PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are generally well tolerated, but long-term safety remains to be proven ^r29
- Glycemic control
  - For patients with diabetes, aim to achieve a hemoglobin A1C target of less than 7% if hypoglycemia can be avoided (per recommendations of the Society for Vascular Surgery^r4, American Diabetes Association^r30)
- Blood pressure control
  - Provide treatment in accordance with current guidelines on managing hypertension; blood pressure goals specific to peripheral artery disease have not been established ^r28
  - 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 ^r3^r4
    - 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 ^r31

Structured exercise therapy

Recommended for all patients with claudication, unless otherwise contraindicated because of comorbidities ^r2^r3^r4^r5
- May be supervised or unsupervised, home based, or institutional ^r3^r4
  - Supervised programs are more effective, but unsupervised structured home programs also confer benefit ^r32^r33
  - 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 ^r34^r35
  - Once a program of supervised therapy is completed, patients should transition to a long-term unsupervised exercise program ^r35
- 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: ^r36
    - 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 m and in overall walking distance of 120 m
- 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 ^r37
- Supervised exercise therapy may also have beneficial effects on modifiable cardiovascular risk factors such as blood pressure and cholesterol levels ^r38

Pharmacotherapy

Antiplatelet therapy
- Aspirin or clopidogrel is recommended in all symptomatic patients and is reasonable in asymptomatic patients with an ankle-brachial index of 0.9 or more ^r3
- Aspirin is favored more than clopidogrel by the Society for Vascular Surgery ^r4
  - Shown to decrease need for revascularization and reduce all-cause cardiovascular mortality ^r39
- American College of Chest Physicians recommends low-dose aspirin in asymptomatic patients with peripheral artery disease and either aspirin or clopidogrel in symptomatic patients ^r40
- For asymptomatic carotid artery disease, the European Society for Vascular Surgery recommends (from most to least preferred) the following: ^r26
  - Aspirin or clopidogrel or dipyridamole
- For symptomatic carotid artery disease, the European Society for Vascular Surgery recommends various dual antiplatelet combinations, depending on whether endarterectomy, stenting, or no intervention is planned ^r26
- For symptomatic lower-extremity peripheral arterial disease, the European Society for Vascular Surgery recommends the following: ^r26
  - Clopidogrel as first choice
  - Combination aspirin and rivaroxaban as second choice, but not in patients at high risk of bleeding; should be considered preferentially for higher ischemia risk patients
- Dual antiplatelet therapy (with aspirin and clopidogrel) to reduce rates of cardiovascular ischemic events in patients with symptomatic peripheral artery disease has yet to show clear efficacy ^r3^r26
  - Current American Heart Association and American College of Cardiology guidelines state that it may be considered for patients with peripheral artery disease at particularly high risk of cardiovascular ischemic events but without high risk of bleeding ^r3
- Vorapaxar (thrombin receptor antagonist) has been studied in patients with peripheral artery disease, and although some studies report a reduction in complications of peripheral vascular disease, the benefit was offset by an increase in moderate to severe bleeding episodes ^r3^r41^r42
  - Current American Heart Association and American College of Cardiology guidelines state that its overall clinical benefit when added to existing antiplatelet therapy in patients with peripheral artery disease is unclear and do not outline specific recommendations for its use ^r3
Vasoactive drugs
- Cilostazol may be used for symptomatic treatment of claudication ^r3^r4^r40
  - Improves walking distance in patients with peripheral artery disease and intermittent claudication ^r43
  - Contraindicated in patients with any level of heart failure ^r4
- Pentoxifylline may be used for patients who cannot tolerate or have contraindications to cilostazol ^r4
- National Institute for Health and Care Excellence 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 ^r2
Anticoagulation
- 2016 American Heart Association and American College of Cardiology guidelines recommend systemic anticoagulation only in the setting of acute limb ischemia; heparin is the drug of choice ^r3
- Several landmark trials published subsequent to the 2016 guidelines have shown that direct oral anticoagulation in combination with antiplatelet therapy can reduce re-intervention rates, limb events (acute limb ischemia and amputation), and major adverse cardiovascular events compared with antiplatelet therapy alone
  - The COMPASS trial found that for patients with stable peripheral artery disease, low-dose rivaroxaban taken twice daily plus aspirin once daily was associated with reduced major adverse cardiovascular events and limb events compared with aspirin alone; major bleeding was increased but fatal or critical organ bleeding was not ^r44
  - The VOYAGER PAD trial found that in patients with peripheral artery disease who had undergone lower-extremity revascularization, low-dose rivaroxaban taken twice daily plus aspirin once daily was associated with reduced major adverse cardiovascular events and limb events compared with aspirin alone; increased bleeding risk was noted with rivaroxaban plus aspirin ^r45^r46
  - Several meta-analyses have reinforced these findings, but American guidelines have yet to define the appropriate role of direct oral anticoagulation therapy in management of peripheral artery disease ^r47^r48^r49
- 2023 European Society for Vascular Surgery guidelines recommend the following: ^r26
  - Endovascular intervention for lower limb arterial disease
    - Aspirin plus rivaroxaban
  - Lower limb surgical bypass of arterial disease
    - Low risk of bleeding: aspirin plus rivaroxaban
      - Alternatives include vitamin K antagonist (with vein graft) or single antiplatelet agent (with prosthetic graft)
    - High risk of bleeding: single antiplatelet agent
Factors associated with a high risk of bleeding ^r50
- History of cerebral hemorrhage, ischemic stroke, other intracranial pathology
- Recent gastrointestinal bleeding or anemia possibly secondary to gastrointestinal blood loss
- Liver failure or bleeding diathesis
- Extreme old age or frailty
- Renal failure requiring dialysis or with estimated GFR less than 15 mL/minute/1.73 m²
Other investigational therapies
- Many agents have been investigated for management of symptomatic peripheral arterial disease; evidence of efficacy has generally been lacking
- Some evidence suggests that propionyl-L-carnitine, an over-the-counter supplement with metabolic effects, improves walking time and tolerance in patients with intermittent claudication ^r51^r52
  - A 2022 Cochrane systematic review concluded that compared to placebo, propionyl-L-carnitine was associated with mild to moderate improvement in walking distances and similar safety profiles, with moderate certainty evidence ^r51
  - Propionyl-L-carnitine may have a role as an adjunct or alternative to standard medical therapies when standard therapies are contraindicated or ineffective ^r51^r53
- In patients with "no-option" chronic limb-threatening ischemia, the International Union of Angiology recommends consideration of hyperbaric oxygen therapy, transcatheter arterialization of deep veins, and peripheral blood mononuclear cells therapy ^r53

Revascularization is indicated for patients with persistent lifestyle-limiting claudication despite optimal medical therapy and for patients with acute or critical limb ischemia ^r4^r6

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 ^r54
  - 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
    - Recommended as favored approach for those with less complex anatomy, intermediate-severity limb threat, or high patient risk ^r10
    - Usually favored for aortoiliac artery, superficial femoral artery, and popliteal artery stenotic lesions and for chronic total occlusion involving aortoiliac vessels ^r25
  - 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 ^r10
  - 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) ^r1^r3
A Cochrane review noted that percutaneous angioplasty was associated with fewer complications and shorter hospital stay than surgical bypass but that bypass achieved better rates of patency at 1 year ^r55
Long-term platelet therapy is indicated after endovascular or surgical revascularization; dual antiplatelet therapy may be reasonable after revascularization to reduce risk of limb-related adverse events ^r3^r4^r7

Wound healing ^r3

Revascularization is the most effective measure to achieve healing
- Consider urgent vascular imaging and revascularization 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 ^r56
- Consider revascularization in patients with diabetic foot ulcers and peripheral arterial disease when ulcers are not healing within 4 to 6 weeks despite optimal management ^r56
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 ^r57
Systemic hyperbaric oxygen therapy may be considered as an adjunctive treatment in ischemic ulcers that do not heal despite revascularization ^r56

Drug therapy

Statin
- Atorvastatin
  - 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
  - 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
  - Aspirin Oral tablet; Adults: 75 to 162 mg PO once daily.
- Clopidogrel
  - Clopidogrel Bisulfate Oral tablet; Adults: 75 mg PO once daily.
- Ticagrelor ^r58
  - Ticagrelor Oral tablet; Adults: 180 mg PO loading dose, then 90 mg PO twice daily in combination with low-dose aspirin. Reduce dose to 60 mg PO twice daily in combination with low-dose aspirin after 1 year.
Vasoactive agents
- Cilostazol
  - 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.
- Pentoxifylline
  - Pentoxifylline Oral tablet, extended-release; Adults: 400 mg PO 3 times daily; decrease to 400 mg PO 2 times daily if CNS or GI adverse effects occur; if not tolerated despite reduction, discontinue drug.
  - Pentoxifylline Oral tablet, extended-release; Geriatric: See adult dosage.
Anticoagulants
- Heparin
  - Heparin Sodium (Porcine) Solution for injection; Adults: 80 units/kg IV bolus, then 18 units/kg/hour IV continuous infusion, initially. Adjust dose to maintain anti-factor Xa concentration of 0.3 to 0.7 units/mL or an aPTT range that correlates to this anti-factor Xa range.
- Rivaroxaban ^r44
  - Rivaroxaban Oral tablet; Adults: 2.5 mg PO twice daily in combination with low-dose aspirin.

Nondrug and supportive care

Exercise rehabilitation ^r3^r4

Recommended for all patients except those with Fontaine stage IV disease (ulcers or gangrene) or other contraindications ^r2^r3^r4
Should consist of a structured regimen but may or may not be directly supervised
When supervised exercise programs are unavailable, structured home-based exercise programs are recommended ^r59
Exercise sessions last for 30 to 45 minutes and occur at least 3 times/week for a minimum of 12 weeks ^r5^r35
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: ^r4
- 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) ^r3^r35

Procedures

Angioplasty with or without stent placement

General explanation

A deflated balloon catheter is placed percutaneously in the peripheral blood vessels and advanced under fluoroscopy to the area of stenosis
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 ^r10

Contraindications

Absence of an accepted indication (eg, in an asymptomatic patient) for the purpose of preventing progression ^r3^r4

Complications

Embolization of plaque or thrombosis
Restenosis
Migration of stent
Perforation of vessel

Interpretation of results

Reperfusion can be shown fluoroscopically before terminating the procedure

Endarterectomy

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 shown fluoroscopically before terminating the procedure

Surgical bypass

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 ^r14
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 ^r10

Complications

Restenosis
Thrombosis
Pseudoaneurysm formation

Interpretation of results

Reperfusion can be shown fluoroscopically before terminating the procedure

Catheter-directed thrombolysis with or without thrombectomy

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 shown fluoroscopically before terminating the procedure

Comorbidities

Diabetes, atherosclerotic coronary disease, and dyslipidemia are common comorbidities; treatment of these is an integral part of the management of peripheral artery disease ^r9
Prevalence of peripheral artery disease is higher among persons with chronic kidney disease; risk for severe disease, including amputation, is markedly increased ^r60

Special populations

Recent coronary stent or acute coronary syndrome
- Consider dual antiplatelet therapy with aspirin plus clopidogrel or aspirin plus ticagrelor ^r61
- 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 ^r62

Monitoring

Follow all patients 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 ^r3
Patients who have undergone revascularization should also have periodic measurement of ankle-brachial index ^r3^r63
Periodic follow-up with duplex ultrasonography may be beneficial in patients who have had infrainguinal autogenous vein bypass or an endovascular procedure ^r3^r63^r64

Complications and Prognosis

Complications

Patients with critical limb ischemia and chronic nonhealing ulcers may develop osteomyelitis in underlying bone ^d4
Leg symptoms such as claudication affect physical function and quality of life ^r8
Major adverse limb events include acute limb ischemia and lower-extremity major amputations (at the ankle or above) ^r8
- Amputation is the most significant complication
  - May be precipitated by acute limb ischemia
  - In patients with critical limb ischemia, uncontrolled infection or gangrene may necessitate amputation at some level
Infection
Wounds

Prognosis

Characterized in most patients by slow progression ^r9
- 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 ^r65
Peripheral artery disease is associated with carotid, cerebral, and coronary atherosclerosis; an ankle-brachial index less than 0.9 doubles the likelihood of a coronary event, cardiovascular mortality, and all-cause mortality ^r9

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 ^r66
The American Heart Association and American College of Cardiology state that screening of asymptomatic patients is reasonable when there is an increased likelihood of disease ^r3^r8
- Aged 65 years or older
- Aged 50 to 64 years with known risk factors (eg, diabetes, hyperlipidemia, hypertension, smoking history) or family history of peripheral artery disease
- Aged younger than 50 years with diabetes and 1 additional risk factor
- Known atherosclerotic disease elsewhere (eg, carotid, coronary, aorta, mesenteric, renal)

Screening tests

Ankle-brachial index

Prevention

Primary prevention ^r9
- 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
    - 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
  - 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
  - Treatment of dyslipidemia is recommended, and the use of statins may play a role in preventing atherosclerosis separate from reduction of lipid levels
  - Some data indicate that Mediterranean diet (ie, emphasizing whole grains, fruits, vegetables, beans, nuts and seeds), fiber, and vitamin supplementation may reduce the incidence of peripheral artery disease for primary prevention ^r17
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 ^r3^r4
- All patients who are able should continue regular exercise and antiplatelet therapy (usually low-dose aspirin) ^r4^r7
  - 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 ^r4
  - American College of Chest Physicians recommends against dual antiplatelet therapy except in patients who have undergone below-knee bypass with placement of prosthetic grafts ^r40
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 ^r3^r67
- Daily foot inspection, including web spaces, by the patient or a caregiver
- Notify health care practitioner 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 practitioner
- Cut toenails straight across; if vision is inadequate, get help from a caregiver or a professional
- Be sure that your health care practitioner examines your feet regularly

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