Abstract

Peripheral arterial disease (PAD) is characterized by narrowing and, in final stages, occlusion of the peripheral arteries due to atherosclerotic plaques. Smoking is the most important risk factor for developing PAD. PAD is often a silent disease, but patients may present with features of arterial insufficiency (intermittent claudication, reduced temperature and pulse rate in affected limb, skin discoloration, and trophic changes). On occasion, critical limb ischemia is the only presenting complaint. Segmental blood pressures and pulse volume recordings, particularly the ankle-brachial index (ABI), may support the diagnosis. Further imaging may confirm and assess the location and severity of arterial stenosis or occlusion. Treatment focuses on smoking cessation, graduated exercise, avoiding extremely cold temperatures, and modifying other cardiovascular risk factors. If conservative treatment fails, interventional and surgical management is recommended for low-risk patients with potential long-term success.

Epidemiology

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: ♂ = ♀

References:^[1]^[2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Insufficient tissue perfusion due to atherosclerosis in the aorta and peripheral arteries
Often coexists with coronary artery disease (CAD), stroke, atrial fibrillation, and renal disease
See risk factors for atherosclerosis

PAD usually coexists with coronary artery disease. Smoking is the most important risk factor for PAD!
References:^[3]

Classification

Fontaine Classification of PAD
Stage I	Asymptomatic PAD
Stage II	Pain on exertion IIa: claudication at a walking distance > 200 m IIb: claudication walking distance < 200 m
Stage III	Ischemic pain at rest
Stage IV	Necrosis/gangrene/ulcers IVa: dry necrosis, trophic disorders IVb: infection of necrotic tissue, humid gangrene

References:^[4]

Clinical features

Characteristic features	Description
Silent disease	Up to 20–50% of patients with PAD are asymptomatic!
Intermittent claudication (10–35% of patients)	Pain, cramps, or paresthesia distal to arterial occlusion Femoropopliteal disease (most common) → calf claudication Aortoiliac disease (Leriche's 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→ foot claudication Worsens upon exertion , completely relieved by rest or lowering affected limbs Reproducible when the patient is asked to walk the same distance as when he/she was symptomatic
Absent or diminished pulses	Brachial artery Radial artery Femoral artery Popliteal artery Posterior tibial artery Dorsalis pedis artery
Trophic changes	↓ Skin temperature ↓ Perspiration ↓ Hair on legs Brittle nails, ↓ nail growth Atrophied muscles Dry atrophic, shiny skin and/or bluish skin discoloration Skin pallor when limb is elevated and reactive hyperemia of dependency → Buerger test for examination Livedo reticularis (advanced disease) Gangrene, ulcers, necrosis (end-stage disease): see also “Arterial ulcer”
Rest pain	Typically in distal metatarsals Worse at night Improved when hanging feet over bed or standing
Critical limb ischemia	The presence of any one of the following: Resting pain Ulcer Tissue loss (gangrene) Indicative of limb-threatening arterial occlusion

A bruit, suggestive of arterial stenosis, may be heard in > 60–70% of cases with PAD!

References:^[5]^[6]^[7]^[8]

Diagnostics

Ankle-brachial index (ABI)

ABI is the ratio of systolic ankle blood pressure (BP) to systolic brachial BP
- Right ABI = higher right ankle BP/higher brachial BP
- Left ABI = higher left ankle BP/higher brachial pressure
Normally, ankle BP and brachial BP are equal (ABI = 1), or ankle BP is only slightly higher because of gravity (ABI ≥ 0.9)
Differences in systolic BP indicate different pathologies:
- > 1.3 = medial sclerosis with incompressible vascular wall (generally calcified vessels)
- 1.0–1.30 = normal value
- 0.91–0.99 = borderline
- 0.40– 0.90 = mild to moderate PAD → claudification
- < 0.40 = severe PAD → resting pain, gangrene (critical limb ischemia)
Exercise testing may be required if patients have a normal resting ABI ^[9]

Imaging

While vascular imaging is not necessarily required for diagnosis, it is useful to determine the site and severity of arterial stenosis or occlusion (especially preoperatively and postoperatively)

Color-coded duplex ultrasonography
Digital subtraction angiography (DSA): gold standard
CT angiography
MR angiography
Oscillography

Measurements in diabetic or older patients may be inaccurate because of Monckeberg's sclerosis!

References:^[10]^[11]^[12]

Differential diagnoses

Differential diagnosis of claudication
			Patient characteristics	Clinical Features
Causes of arterial occlusion	Vasculitides	Takayasu's disease	Asian females 15–45 years	Fever, malaise, arthralgia Syncope, angina pectoris Impaired vision
	Vasculitides	Obliterating thromboangiitis	20–40 years	Migratory thrombophlebitis Intermittent claudication, often limited to feet, calves and/or hands Raynaud's syndrome
	(Lower-extremity) Fibromuscular dysplasia		Middle-aged women	Gradual onset of symptoms Rarely affects the extremities, leading to intermittent claudication, critical limb ischemia, and blue toe syndrome
	Popliteal aneurysm		Similar risk factors as PAD	Chronic lower limb ischemia may manifest like PAD Acute limb ischemia → 6 Ps Blue toe syndrome: small vessel occlusion caused by embolus
	Arterial embolism		Young patients without atherosclerotic risk factors	Sudden onset of symptoms 6 Ps
	Popliteal entrapment syndrome			Intermittent claudication
	Cystic adventitial disease		Generally affects men between 30–50 years	Foot pulses may be present during rest and absent following exercise
Mimics of arterial occlusion	Deep vein thrombosis		> 60 years old History of immobilization, obesity, hereditary thrombophilia or malignancy	Swelling Warmth Erythema Progressive tenderness Dull pain: worsened by walking, improved by resting
	Spinal stenosis		Middle-aged to older patients	Bilateral neurogenic claudication
	Diabetic neuropathy		Middle-aged to older patients High BMI	Progressive symmetrical loss of or abnormal sensation in the distal lower extremities (glove and stocking sensation) Normal ABI Neuopathic diabetic foot: warm, dry skin, palpable foot pulses

References:^[13]

The differential diagnoses listed here are not exhaustive.

Treatment

Conservative

Smoking cessation!
Supervised graded exercise therapy
Foot care (especially in diabetic patients)
Avoid cold temperatures

Medical therapy

Modify cardiovascular risk factors: see therapy of atherosclerotic disease
- For all patients: long-term antiplatelet therapy with aspirin, clopidogrel, or ticagrelor as it reduces mortality and morbidity
- Lipid-lowering agent (usually statins)
- Antihypertensive treatment
- Hyperglycemia control
PDE inhibitors (i.e., cilostazol): indicated when smoking cessation and exercise are unsuccessful

Revascularization

Indications
- Critical limb ischemia
- Failure of conservative and pharmacologic treatment
- Inability to perform normal work or activities because of claudication
- No limitations to exercise by other disease (e.g., chronic heart failure) if claudication is improved
- Anatomy of the lesion allows low-risk and long-term success of intervention
Minimally invasive interventional radiology: percutaneous transluminal angioplasty (PTA) with or without stenting
Surgical procedures
- Operative vascular reconstruction (bypass surgery): an autologous vein (e.g., great saphenous vein) is used to bypass the stenosis
- Endarterectomy

Amputation

Last resort in the event of gangrene

References:^[10]^[12]^[14]^[15]^[7]^[6]

Complications

Arterial ulcer
- Definition: skin defect due to impaired blood flow to the lower extremities
- Etiology: most often seen in peripheral arterial disease
- Clinical features
  - Punched-out ulcer with well-defined borders
  - Usually involves the foot, particularly pressure points (e.g., lateral malleolus, tips of the toes)
  - Often severe pain
- Differential diagnosis: venous ulcer
Infection of ulcers; sepsis
Acute limb ischemia
Surgical complications: bleeding, infection of vascular prosthesis, relapse

References:^[16]^[17]

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

Prognosis

Intermittent claudication → good prognosis
Rest pain and/or ischemic ulcers → poor prognosis
Increased cardiovascular mortality → high risk for secondary MI or stroke

A low ABI in PAD is also predictive of an increased risk of all-cause and cardiovascular mortality!References:^[5]

Prevention

Primary and secondary prevention of atherosclerosis