Peripheral arterial disease

Peripheral arterial disease (PAD) is a condition characterized by the atherosclerotic narrowing of peripheral arteries, most commonly of the lower extremities. Lower extremity PAD may be asymptomatic or manifest with intermittent claudication, critical limb ischemia (CLI), or acute limb ischemia (ALI), which is a surgical emergency that is described in a separate article. In the absence of acute ischemia, the first-line diagnostic test for PAD is the ankle-brachial index (ABI). Imaging, preferably via MR angiography, is indicated if revascularization is planned or if the diagnosis remains uncertain. Structured exercise therapy and modification of cardiovascular risk factors may improve intermittent claudication significantly; cilostazol, a vasodilator, may be considered for symptomatic relief. Revascularization is indicated in patients with limb ischemia and those with life-limiting claudication despite exercise therapy. Additionally, secondary prevention strategies for ASCVD should be initiated in all patients to minimize the risk of atherosclerotic cardiovascular disease.

Carotid artery stenosis and chronic mesenteric ischemia are less common types of peripheral arterial disease and are covered separately.

• Prevalence: 8.5 million in the US
  • Prevalence increases with age, starting from the age of 40
  • US incidence rates are highest among African Americans, followed by Hispanics, who are at a slightly higher risk than non-hispanic whites.
• Peak incidence: 60–80 years of age
• Sex: ♂ = ♀ ^[1]

Peripheral arterial disease is equally common in women and men. ^[1]

References:^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Atherosclerosis
  • Atherosclerosis; in the aorta and peripheral arteries → insufficient tissue perfusion → PAD
  • Often coexists with coronary artery disease (CAD), stroke, atrial fibrillation, and renal disease
  • See risk factors for atherosclerosis
• Risk factors for PAD: The following patient groups are at increased risk of PAD.
  • Age ≥ 65 years
  • Age 50–64 years with risk factors for atherosclerosis (e.g., smoking) or a family history of PAD
  • Age ≤ 50 years of age with diabetes plus additional risk factors for atherosclerosis.

PAD usually coexists with coronary artery disease. Smoking is one of the most important risk factors for PAD!

Up to 20–50% of patients with PAD are asymptomatic.

Intermittent claudication

• Seen in approx. 10–35% of patients
• Pain, cramps, or paresthesia distal to arterial occlusion
  • Femoropopliteal disease (most common): typically causes calf claudication
  • Aortoiliac disease (Leriche syndrome)
    • Level of the aortic bifurcation or bilateral occlusion of the iliac arteries
    • Triad of bilateral buttock, hip, or thigh claudication, erectile dysfunction, and absent/diminished femoral pulses
  • Tibiofibular disease: typically causes foot claudication
• Worsens upon exertion ,
• Completely relieved by rest or lowering affected limbs
• Reproducible on asking the patient to walk the same distance at which symptoms typically occur

Rest pain

Rest pain occurs as disease progresses and indicates severe ischemia.

• Typically occurs first in the toes and forefoot
• Worsens with reclining (e.g., while sleeping)
• Improves on hanging feet off the bed or on standing

Critical limb ischemia (CLI) ^[3]

• Indicative of limb-threatening arterial occlusion
• Characterized by the presence of any one of the following:
  • Rest pain lasting ≥ 2 weeks
  • Nonhealing ulcers
  • Tissue loss (gangrene)

Examination findings

• Trophic changes
  • ↓ Skin temperature, ↓ perspiration
  • ↓ Hair on legs, ↓ nail growth, brittle nails
  • Atrophied muscles
  • Dry atrophic, shiny skin and/or bluish skin discoloration
  • Livedo reticularis (advanced disease)
  • Gangrene, ulcers, necrosis (end-stage disease): See also “Arterial ulcer.”
• Absent or diminished pulses: examine distal pulses bilaterally, including
  • Upper extremity: brachial artery, radial artery
  • Lower extremity: femoral artery , popliteal artery , posterior tibial artery , and dorsalis pedis artery
• Buerger sign ^[4][5]
  • With the patient in the supine position, elevate the lower limbs to a 45° angle at the hip.
  • Evaluate for pallor of the feet.
  • Ask the patient to sit up with their legs off of the examination table in the dependent position.
  • Evaluate the time taken for the color to return to the feet and for the veins to become distended.
  • Positive Buerger sign
    • Skin pallor on limb elevation
    • Reactive hyperemia on limb dependency
    • A venous filling time of > 20 seconds may indicate advanced ischemia.
• Bruit: over the affected artery may be heard in > 60–70% of cases with PAD

There are several classification systems for peripheral arterial disease, such as, the Rutherford classification, Global Limb Anatomic Staging System (GLASS), and the Trans-Atlantic Inter-Society Consensus (TASC). See “Overview of classification systems in peripheral artery disease” in the “Tips and Links” section below for details. ^[6]

Classification by clinical presentation ^[3][6]

• Asymptomatic (confirmed PAD in an asymptomatic individual)
• Claudication
• Critical limb ischemia (CLI) ^[7]
• Acute limb ischemia (ALI)

Wound, Ischemia, and foot Infection (WIfI) classification ^[7][8]

• Purpose
  • Quantification of disease burden
  • Evaluation of the risks and benefits of revascularization procedures
• Description
  • The following factors are assigned values from 0 (normal) to 3 (severe abnormality):
    • Wound (W): depth and tissue involvement of existing ulcers
    • Ischemia (I): ankle systolic blood pressure and/or tissue oxygenation
    • Foot Infection (fI): local and systemic signs of infection
  • The benefit of revascularization and the risk of amputation can be estimated based on the three derived values.

Fontaine classification ^[6]

• Stage I: asymptomatic
• Stage II: pain on exertion
• Stage III: pain at rest
• Stage IV: necrosis, gangrene

Approach ^[3][7]

• Acutely cold, painful limb: Suspect ALI, consult vascular surgery immediately for urgent revascularization. ^[7][9]
• Claudication, rest pain, or CLI
  • Perform a comprehensive history and physical examination.
  • Measure ABI.
  • Order additional tests as needed (e.g., for inconclusive ABI results, for tissue loss suggestive of CLI).
• PAD confirmed (based on clinical features and ABI) ^[7][9]
  • Obtain imaging if revascularization is planned or if the diagnosis remains uncertain.
  • Consider screening for abdominal aortic aneurysm.

ALI is an imminently limb-threatening emergency and treatment should not be delayed to investigate the underlying etiology. ^[10]

Ankle-brachial index (ABI) ^[7][10]

ABI is the ratio of systolic ankle blood pressure to systolic brachial blood pressure.

Resting ABI

• Indications
  • First-line diagnostic test for nonacute PAD (i.e., intermittent claudication, rest pain, or CLI) ^[11]
  • Screening for PAD in asymptomatic individuals with risk factors for PAD or known atherosclerosis ^[3]
• Technique
  • Ask the patient to rest in the supine position for approx. 10 minutes.
  • Place the blood pressure cuffs on the ankles and the arms.
  • Locate the pulse using the Doppler.
  • Inflate the cuff until the pulse is no longer audible on the Doppler device, and then inflate the cuff by a further 20 mm Hg.
  • Deflate the cuff slowly, and note the pressure at which the pulse is audible again.
    • Ankle pressure
      • Measure systolic pressure of bilateral dorsalis pedis and posterior tibialis arteries.
      • Note the higher systolic pressure of either the dorsalis pedis or the posterior tibial artery of each leg.
    • Brachial pressure
      • Measure systolic pressure of bilateral brachial arteries.
      • Note the higher brachial blood pressure of either arm.
  • Calculate the ABI for each leg: Divide the highest ankle pressure by the highest brachial pressure.

A low ABI (≤ 0.9) and high ABI (> 1.4) are associated with an increased risk of all-cause and cardiovascular mortality! ^[15]

Exercise ABI ^[16]

• Description: ABI testing following extended exercise of the lower extremity
• Indication: suspicion of PAD in a patient with a normal or borderline ABI
• Findings: Either of the following are consistent with PAD.
  • Post-exercise decrease in ABI by > 20%
  • Post-exercise decrease in ankle systolic blood pressure by > 30 mm Hg

Toe-brachial index ^[10][12][17]

• Definition: the ratio of the systolic blood pressure of the first toe to the systolic brachial blood pressure
• Indications
  • Suspicion of PAD in a patient with a normal or elevated ABI (i.e., ABI > 1.4)
  • Lower extremity wound suggestive of CLI
• Findings: Toe-brachial index ≤ 0.70 is consistent with PAD.

Measures of tissue perfusion ^[13]

• Examples: transcutaneous oximetry, fluorescent imaging of indocyanine green dye, skin perfusion pressure
• Indication: nonhealing wounds or tissue loss suggestive of CLI

Imaging ^[7][18][19]

• Indications ^[19]
  • Patients planned for a revascularization procedure
  • Diagnosis of PAD uncertain (in symptomatic patients)
• Angiography: preferred modality for assessment for revascularization
  • Modalities ^[18]
    • First-line: MR angiography (MRA) without and with IV contrast
    • Contraindications for MRI (e.g., prior stent placement): CT angiography with IV contrast (CTA)
    • Digital subtraction angiography: considered the gold standard for PAD; uncommonly used ^[19]
  • Findings: demonstration of site(s) and extent of arterial occlusion or stenosis and collateral blood flow
• Duplex ultrasound ^[19]
  • Indications ^[18]
    • Patients with contraindications for angiography (e.g., contrast allergy)
    • Postoperative surveillance of bypass graft patency
  • Limitations: low sensitivity for multilevel stenoses and aortoiliac disease ^[19]
  • Findings: Elevated peak systolic velocity (PSV) and PSV ratio suggest PAD.

The differential diagnoses listed here are not exhaustive.

Overview ^[7][10][22]

• Intermittent claudication
  • First-line therapy ^[23][24]
    • Structured exercise therapy
      • Patients repeatedly walk or exercise until the onset of claudication and then rest until the pain subsides
      • This cycle is repeated for 30-45 minutes, three times a week, for a minimum of 12 weeks.
      • Structured exercise therapy has been shown to improve patients' functional status and quality of life.
    • Cardiovascular risk factor modification
  • Persistent claudication despite first-line measures: Consider cilostazol (for symptomatic improvement) OR revascularization.
• CLI: Consider revascularization in addition to structured exercise therapy and cardiovascular risk factor modification.
• Management of complications
  • ALI: immediate referral to vascular surgery (see “Treatment” in “Acute limb ischemia.”)
  • Gangrene
    • Wet gangrene or sepsis
      • Initiate broad-spectrum antibiotics.
      • Immediate surgery consult for amputation
    • Dry gangrene: Urgent vascular surgery referral for possible revascularization prior to amputation.
  • Nonhealing ulcers
    • Interdisciplinary care recommended
    • Goal of care: complete wound healing ^[10]

Risk modification ^[3][25]

As patients with PAD are at an increased risk of atherosclerotic cardiovascular disease (ASCVD) events such as MI or stroke, secondary prevention strategies for ASCVD should be initiated in all patients.

• Smoking cessation
  • Counseling on smoking cessation should occur at every visit for all patients with PAD who smoke.
  • Recommend avoiding passive smoke inhalation.
• Treatment of dyslipidemia
  • Consider high-intensity statin therapy in all patients with PAD.
  • Very high-risk patients : Consider adding ezetimibe ± a PCSK9 inhibitor. ^[26]
  • See “Treatment of hypercholesterolemia in adults” for dosages.
• Glycemic control (in patients with type 2 diabetes)
  • Consider metformin as a first-line oral hypoglycemic agent. ^[27]
  • Aim for a target HbA1c of < 7%. ^[7]
  • See “Treatment of diabetes” for detailed recommendations.
• Antihypertensive treatment
  • Initiate antihypertensives in all patients with PAD and hypertension.
  • Aim for a target systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg. ^[7][28]
  • See “Management of hypertension” for detailed recommendations.
• Single-agent antiplatelet therapy ; : aspirin OR clopidogrel (ticagrelor may also be considered) ^[3][7][28]
  • Recommended in all patients with symptomatic PAD (reduces morbidity and mortality from cardiovascular events)
  • Consider in asymptomatic patients with confirmed PAD

Intensive treatment of atherosclerotic disease and its risk factors improves outcomes in PAD and prevents ischemic events in other arterial beds, including the coronary arteries. ^[10]

Structured exercise therapy ^[3][22]

• Recommended first-line therapy for claudication
• Consider prior to revascularization. ^[23][24][29]
• Involves repetitive exercise until the onset of claudication with intervening periods of rest until the pain subsides

Exercise therapy may improve claudication symptoms but not the ABI, as it primarily promotes collateral blood circulation. ^[30]

Vasodilators ^[3][7][28]

• Indications ^[31]
  • Consider in patients with persistent life-limiting claudication despite exercise therapy and risk factor modification.
  • Consider in patients with moderate to severe claudication who are not candidates for revascularization.
• Preferred agent: cilostazol; (a phosphodiesterase III (PDE3) inhibitor with vasodilatory, antiplatelet, and antithrombotic properties) ^[3][32]
• Important considerations
  • Cilostazol is contraindicated in patients with congestive heart failure. ^[3]
  • May take up to 12 weeks for the patient to experience symptomatic improvement
  • Discontinue cilostazol if there is no improvement after 12 weeks.

Cilostazol improves claudication symptoms and walking distance but has not been shown to decrease major cardiovascular events. ^[3][32]

Pentoxifylline is not effective for treating claudication. ^[3]

Revascularization ^[7][10][23]

The primary goal of revascularization is to improve blood flow in at least one artery to the foot to prevent pain and tissue loss.

• Indications
  • CLI, if the limb is viable
  • Lifestyle-limiting claudication despite optimal medical therapy and exercise
• Modalities ^[10][33][34]
  • Endovascular or surgical revascularization
  • The choice of procedure depends on the location and morphology of the arterial disease and the patient's comorbidities.

Supportive care ^[3][7]

• Foot care
  • All patients with PAD should be educated on self-foot examination and healthy foot care.
  • Any sign of foot infection in a patient with PAD should prompt referral to an interdisciplinary care team.
• Analgesia
  • Complex pain is common in patients with limb ischemia.
  • Adequate treatment of pain and/or referral to pain management service helps preserve the patient's quality of life.
• Wound management
  • Provide multidisciplinary wound care to all patients with tissue loss.
  • Consider adjunctive therapies (e.g., intermittent pneumatic compression) in patients unfit for revascularization. ^[3]

Amputation ^[7][10]

• Wet gangrene, unsalvageable limb: Urgent amputation may be required, especially in patients with sepsis.
• Dry gangrene: Consult vascular surgery to evaluate for revascularization prior to amputation.
  • After successful revascularization, amputation of unsalvageable regions may be performed (staged procedure). ^[10]
  • In high-risk patients with CLI or ALI and limited life expectancy, amputation may be considered as the primary treatment modality (i.e., without revascularization).

Apart from ALI, which is described in a separate article, the following complications can occur due to PAD.

Arterial ulcer

• Definition: ulceration caused by impaired blood flow to the lower extremities
• Clinical features
  • Punched-out ulcer with well-defined borders ^[35]
  • Usually involves the foot, particularly pressure points (e.g., lateral malleolus, tips of the toes)
  • Often causes severe pain
  • Infection of ulcers → sepsis
• Differential diagnosis: See “Differential diagnosis of leg ulcers.”

Dry gangrene

• Definition: a type of gangrenous necrosis caused by ischemia that is characterized by coagulative necrosis on histopathologic examination
• Clinical features
  • Areas with gray-black discoloration showing a clear demarcation between necrotic and viable tissue
  • Autoamputation is possible.
• Diagnosis: based on clinical features
• Management
  • Limb salvage
    • Wrap the wound with bulky dry gauze.
    • Revascularization
  • In case of unsuccessful limb salvage: surgical amputation
• Complications: wet gangrene

Wet gangrene

• Definition: a type of gangrenous necrosis caused by superinfection that is characterized by coagulative and liquefactive necrosis on histopathologic examination
• Clinical features
  • Edema
  • Blistering
  • Discharge or a moist appearance
  • Rapid spread of infection
• Diagnosis: based on clinical features
• Management
  • Analgesia
  • Surgical debridement, drainage, and/or amputation of infected and necrotic tissue
  • Broad-spectrum antibiotics
  • Revascularization (after managing local infection)
  • In case of unsuccessful limb salvage: surgical amputation
• Complications: sepsis

We list the most important complications. The selection is not exhaustive.

See “Prevention of atherosclerotic cardiovascular disease.”

• One-Minute Telegram 6-2020-3/3: Statins underprescribed in patients with PAD

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