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, chronic limb-threatening ischemia (CLTI), 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 resting ankle-brachial index (ABI). Imaging (e.g., MR angiography, CT angiography, duplex ultrasonography) 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, management of atherosclerotic cardiovascular disease should be initiated in all patients.

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

• Prevalence: 10–12 million in the US ^[1]
  • Prevalence increases with age, starting from the age of 40
  • Incidence is highest among African American individuals, followed by Hispanic and non-Hispanic White individuals.
• Peak incidence: : 60–80 years of age
• Sex: ♂ = ♀ ^[2]

Peripheral arterial disease is equally common in women and men. ^[2]

Epidemiological data refers to the US, unless otherwise specified.

PAD is caused by atherosclerosis.

• Risk factors for PAD
  • Smoking is one of the most important risk factors.
  • See “Risk factors for atherosclerosis.”
• Risk amplifiers for PAD: increase the risk of severe cardiovascular events and/or amputation in patients with PAD ^[1]
  • Age ≥ 75 years
  • Diabetes mellitus
  • End-stage renal disease
  • Ongoing use of tobacco products
  • Depression
  • ASCVD in ≥ 2 vascular areas (i.e., peripheral, coronary, and/or cerebrovascular arterial beds)
  • Microvascular disease (e.g., retinopathy, neuropathy)

PAD usually coexists with coronary artery disease.

Atherosclerosis in the aorta and peripheral arteries →; narrowing of the arterial lumen → insufficient tissue perfusion ; distal to the occlusion → PAD

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

Symptoms

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
    • Typically causes a triad of bilateral buttock, hip, or thigh claudication; erectile dysfunction; and absent or diminished femoral pulses
  • Infrapopliteal disease: typically causes foot claudication
• Worsens upon exertion
• Completely relieved by rest or lowering affected limbs (typically within 10 minutes) ^[1]
• 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

Other symptoms ^[1]

• Difficulty walking due to symptoms other than claudication, e.g.:
  • Lower extremity muscular discomfort requiring > 10 minutes of rest to resolve
  • Painless leg weakness, numbness, or fatigue
• Erectile dysfunction

Examination findings

• Lower extremity lesions, e.g.:
  • Nonhealing or slow-healing wounds (see “Arterial ulcers”)
  • Gangrenous necrosis (e.g., wet gangrene and/or dry gangrene)
• 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)
• Absent or diminished pulses (i.e., brachial artery, radial artery, popliteal artery, and dorsalis pedis artery)
• Buerger sign ; ^[3][4]
  • 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

Clinical subsets of PAD ^[1]

The following subsets apply to patients with confirmed PAD.

• Asymptomatic PAD
• Chronic symptomatic PAD (includes intermittent claudication)
• Chronic limb-threatening ischemia: characterized by rest pain, nonhealing lower extremity wounds, and/or gangrene for > 2 weeks ^[1]
• Acute limb ischemia

Classification systems

See also: “Overview of classification systems in peripheral artery disease” in “Tips and Links.” ^[5]

Wound, Ischemia, and foot Infection (WIfI) classification ^[6][7]

• 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 ^[5]

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

Other classification systems ^[5]

• Rutherford classification
• Global Limb Anatomic Staging System
• TransAtlantic Inter-Society Consensus
• Angiosome classification

General principles ^[1]

• Consider screening asymptomatic patients at increased risk for PAD. ^[1][8][9]
• Screening modality: resting ABI
• Screening individuals without risk factors for PAD is not recommended.

Patients at increased risk for PAD ^[1]

• ≥ 65 years of age ^[1]
• 50–64 years of age with risk factors for atherosclerosis (e.g., smoking), CKD, or family history of PAD ^[1]
• < 50 years of age with diabetes mellitus and ≥ 1 additional risk factors for atherosclerosis ^[1]
• Any individual with another type of ASCVD (e.g., CAD, abdominal aortic aneurysm)

Diagnosis of acute limb ischemia is discussed separately.

Approach

• Perform a comprehensive history and physical examination in patients with risk factors for PAD; examination should include:
  • Lower extremity pulses
  • Skin (e.g., wounds, trophic changes, pallor, rubor)
  • Assessment for peripheral neuropathy
  • Capillary refill time
• In patients with clinical features of PAD, measure resting ABI.
  • PAD is confirmed if ABI is ≤ 0.9.
  • If ABI is > 0.9: Confirm PAD with additional testing (e.g., exercise ABI, toe-brachial index) based on clinical presentation.
• Obtain imaging if:
  • The diagnosis remains uncertain
  • Revascularization is planned

ALI is an imminently limb-threatening emergency. Treatment should not be delayed to investigate the underlying cause (see “Treatment of ALI”). ^[10];

Ankle-brachial index (ABI) ^[1][6][10]

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

Resting ABI

• Indications
  • First-line diagnostic test for suspected nonacute PAD (i.e., intermittent claudication, rest pain, or nonhealing ulcers or gangrene in the lower limbs) ^[11]
  • Screening for patients at increased risk for PAD ^[1]
• Technique
  • Ask the patient to rest in the supine position for approx. 10 minutes.
  • Place blood pressure cuffs on the ankles and arms.
  • Locate the pulse using a Doppler.
  • Inflate the cuff until the pulse is no longer audible on the Doppler device, 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 the systolic pressure of the dorsalis pedis and posterior tibialis arteries bilaterally.
      • Note the higher systolic pressure of either the dorsalis pedis or the posterior tibial artery of each leg.
    • Brachial pressure
      • Measure the systolic pressure of the brachial arteries bilaterally.
      • 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.
• Ancillary studies: Either or both may be used with resting ABI to support the diagnosis. ^[1]
  • Pulse volume recording
  • Doppler waveforms

A low ABI (≤ 0.9) and a high ABI (> 1.4) are associated with an increased risk of all-cause and cardiovascular mortality. ^[14]

Exercise ABI ^[15]

• Description: ABI testing after extended exercise of the lower extremity
• Indications
  • Suspicion of PAD in patients with a normal or borderline resting ABI
  • Confirmed PAD with ABI ≤ 0.9 (to evaluate functional status) ^[1]
• Findings: Either of the following is consistent with PAD.
  • Postexercise decrease in ABI of > 20%
  • Postexercise decrease in ankle systolic blood pressure of > 30 mm Hg

Toe-brachial index with waveforms ^[1][12][16]

• Definition: the ratio of systolic blood pressure in the first toe to systolic brachial blood pressure
• Indications
  • Resting ABI > 1.4 and suspected PAD
  • Suspicion of CLTI
  • CLTI with nonhealing wounds: to assess the need for revascularization
• Findings: Toe-brachial index ≤ 0.7 is consistent with PAD.

Measures of tissue perfusion ^[1]

• Indications
  • Suspicion of CLTI
  • CLTI with nonhealing wounds: to assess the need for revascularization
• Modalities
  • Transcutaneous oximetry
  • Skin perfusion pressure

Imaging ^[1][17]

• Indications ^[18]
  • Patients with a planned revascularization procedure ^[1]
  • May be considered in symptomatic patients if the diagnosis of PAD is uncertain
• Modalities ^[19]
  • MR angiography with IV contrast
  • CT angiography with IV contrast
  • Duplex ultrasound: Elevated peak systolic velocity (PSV) and PSV ratio suggest PAD.
  • Catheter angiography

Chronic exertional compartment syndrome ^[22][23][24]

• Definition: recurrent reversible increase in pressure within a fascial compartment that results in pain and/or neurological symptoms due to compromised perfusion
• Etiology: repetitive physical activity (e.g., athletes, military trainees)
• Clinical features
  • Location: lower legs (most common), forearms, feet
  • Muscle pain, tightness, weakness, and swelling exacerbated by exercise and relieved with rest
  • Paresthesia, numbness, and/or transient nerve palsy (e.g., foot drop) may occur.
• Diagnostics
  • Symptoms reliably provoked by repetitive activity
  • Invasive compartment pressure measurements before and after exercise
  • Noninvasive testing: used mainly to evaluate for differential diagnoses ^[23]
    • Radiography
    • Bone scintigraphy
    • MRI
• Treatment
  • Conservative management: avoidance of provocative activities, gait retraining
  • Elective fasciotomy if conservative management fails

The differential diagnoses listed here are not exhaustive.

Treatment of ALI and complications of PAD (i.e., arterial ulcers, wet gangrene, and dry gangrene) are discussed separately.

General principles ^[1][6][25]

• All patients
  • Start preventive measures (e.g., management of ASCVD).
  • Offer supportive care (e.g., preventive foot care).
• Patients with chronic symptomatic PAD
  • Start structured exercise therapy.
  • Prescribe antithrombotic therapy.
  • If symptoms persist, consider cilostazol (for intermittent claudication) and/or revascularization.
  • Provide multidisciplinary wound care for nonhealing wounds or gangrene.
  • For patients with CLTI:
    • Refer for revascularization if the limb is viable.
    • Provide wound care as needed (e.g., for arterial ulcers).
    • Consider amputation in patients with life-threatening complications (e.g., sepsis). ^[1]

Structured exercise therapy ^[1][25]

• Indication: : recommended for all patients with chronic symptomatic PAD (e.g., intermittent claudication)
• Key elements
  • A qualified health care professional designs and supervises an individualized exercise routine.
  • The patient exercises (e.g., walks or bikes) until pain becomes moderate or severe.
  • They then rest until the pain subsides and resume exercise.
  • 60-minute sessions are repeated 3 times a week for a minimum of 12 weeks. ^[1]
• Setting: a medical setting (e.g., for cardiac rehabilitation) or standalone facility with medical supervision

Exercise therapy may improve claudication but not the ABI, as therapy primarily promotes collateral blood circulation. ^[26]

Prevention of progression and complications ^[1][27]

Start management of ASCVD in all patients, as patients with PAD have an increased risk of further ASCVD events (e.g., MI or stroke).

• Lifestyle modifications for ASCVD prevention: (e.g., smoking cessation)
  • Counseling on smoking cessation should occur at every visit for all patients with PAD who smoke.
  • Recommend avoiding passive smoke inhalation.
• Antithrombotic therapy: recommended for symptomatic PAD ^[1];
  • Preferred options
    • Single antiplatelet therapy: aspirin; (off-label) or clopidogrel or ticagrelor ^[1][6][28]
    • OR low-dose rivaroxaban PLUS low-dose aspirin ^[1]
  • Dual antiplatelet therapy (e.g., aspirin PLUS clopidogrel) may be considered after revascularization.
• Lipid-lowering therapy
  • Start high-intensity statin therapy in all patients with PAD.
  • Consider adding ezetimibe ± a PCSK9 inhibitor (e.g., in patients with very high-risk ASCVD or inadequate response to statin monotherapy). ^[1][29]
  • See also “Lipid-lowering therapy for ASCVD.”
• Management of comorbidities
  • Management of hypertension
    • Initiate antihypertensives in all patients with PAD and hypertension; ACE inhibitors or ARBs are preferred. ^[1]
    • Aim for a target systolic blood pressure of < 130 mm Hg and diastolic blood pressure of < 80 mm Hg. ^[1]
  • Management of diabetes mellitus
    • Provide lifestyle recommendations for patients with diabetes mellitus. ^[1]
    • Recommended antihyperglycemic treatment: GLP-1 agonists and/or SGLT-2 inhibitors ^[1][9]
    • Glycemic goals should be individualized. ^[9]
• Routine vaccinations: SARS-CoV-2 and annual influenza vaccinations are recommended for all patients with PAD.

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

Vasodilator therapy ^[1][6]

• Indications
  • Intermittent claudication to improve symptoms and functional status
  • May be considered after revascularization of femoropopliteal disease to reduce the risk of re-stenosis
• Agent: cilostazol (a phosphodiesterase type 3 inhibitor with vasodilatory, antiplatelet, and antithrombotic properties) ^[1][30]
• Absolute contraindication: congestive heart failure of any severity

Cilostazol improves claudication symptoms and walking distance but has not been shown to decrease major cardiovascular events. ^[1]

Revascularization ^[1][6][31]

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 ^[1]
  • CLTI (if the limb is viable)
  • Chronic symptomatic PAD with lifestyle-limiting claudication despite optimal medical therapy and structured exercise therapy
• Modalities ^[1][32][33]
  • 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 ^[1][6]

• Foot care^[1]
  • All patients with PAD should be educated on how to examine their feet and foot care.
  • Inspection is recommended at every visit (at least annually). ^[1]
  • Recommend therapeutic footwear for patients with a high risk for ulcers.
  • Hyperbaric oxygen therapy may be an option for patients with CTLI and nonhealing diabetic foot ulcers.
  • Refer to a specialist if possible, especially for patients with any sign of a foot infection.
• 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
  • 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 to attempt complete wound healing
  • Consider adjunctive therapies (e.g., intermittent pneumatic compression) in patients unfit for revascularization. ^[1]

Amputation ^[1][6]

• 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 CLTI 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 ^[34]
  • 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 107-2024-3/3: Rivaroxaban plus aspirin in PAD: the combo that walks the walk
• One-Minute Telegram 6-2020-3/3: Statins underprescribed in patients with PAD

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