Peripheral arterial disease

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.

• 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.

• 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]

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, ulcers or gangrene (can be dry or humid)

References:^[4]

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 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 Worsens with reclining (e.g., while sleeping) 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]

Ankle-brachial index (ABI)

• First-line diagnostic test (high specificity and sensitivity) ^[9]
• Defined as the ratio of systolic ankle blood pressure (BP) to systolic brachial BP
• The ABI is calculated for each leg by dividing the higher systolic pressure of either the dorsalis pedis or posterior tibialis of the respective leg by the higher blood pressure of either the right or left arm
  • Right ABI = highest systolic BP in the right ankle/brachial BP in the arm with the highest systolic pressure
  • Left ABI = highest systolic BP in the left ankle/brachial BP in the arm with the highest systolic pressure
• Normally, ankle BP and brachial BP are equal (ABI = 1), or ankle BP is only slightly higher because of gravity (ABI > 1)
• 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 → claudication
  • < 0.40 = severe PAD → resting pain, gangrene (critical limb ischemia)
• Exercise testing may be required if patients have a normal resting ABI ^[10]

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

ABI measurements in diabetic or older patients may be inaccurate because of Monckeberg sclerosis!

References:^[11][12][13]

Differential diagnosis of claudication
			Patient characteristics	Clinical features
Causes of arterial occlusion	Vasculitides	Takayasu arteritis	Asian females 15–45 years	Fever, malaise, arthralgia Syncope, angina pectoris Impaired vision
		Obliterative endarteritis	20–40 years	Migratory thrombophlebitis Intermittent claudication, often limited to feet, calves and/or hands Raynaud 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		Most commonly affects young men < 30 years	Intermittent claudication
	Cystic adventitial disease		Generally affects men between 30–50 years	Foot pulses may be present during rest and absent following exercise [14]
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	Neurogenic claudication Accompanied by weakness or numbness Bilateral or unilateral leg and back pain Improved with lumbar flexion
	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 Neuropathic diabetic foot: warm, dry skin, palpable foot pulses

The differential diagnoses listed here are not exhaustive.

Conservative ^[13]

• 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
  • Antiplatelet therapy reduces morbidity and mortality
    • Aspirin: irreversible cyclooxygenase inhibition → decreased thromboxane A2 synthesis → decreased platelet aggregation
    • ADP receptor inhibitors
      • Clopidogrel: inhibition of the P2Y₁₂ ADP receptor → decreased platelet activation and platelet-fibrin crosslinking
      • Ticagrelor; : reversible inhibition of the P2Y₁₂ ADP receptor (otherwise identical downstream effects as clopidogrel)
  • Lipid-lowering agent (usually statins)
  • Antihypertensive treatment
  • Hyperglycemia control
• PDE inhibitors
  • Cilostazol (the single most effective medication)
    • It is indicated in patients with lifestyle-limiting intermittent claudication; only after 3 months of supervised graded exercise therapy.
    • It is administered as a therapeutic trial for 3–6 months.
    • If no or minimal improvement occurs, consider advanced vascular imaging (see “Imaging” above).
    • Mechanisms
      • Phosphodiesterase 3 (PDE3) inhibition → increased cAMP → increased activity of protein kinase A → reduced platelet aggregation
      • Myosin light chain kinase inhibiton → vascular smooth muscle relaxation → arterial vasodilation

Revascularization^[15]

• Indications ^[11]
  • 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:^{[11][13][15][16][7][6]}

• 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 ^[17]
    • Usually involves the foot, particularly pressure points (e.g., lateral malleolus, tips of the toes)
    • Often severe pain ^[18]
  • Differential diagnosis: venous ulcer
• Infection of ulcers; sepsis
• Acute limb ischemia
• Complications of endovascular intervention: see “Complications at the site of vascular access”
• Surgical complications: bleeding, infection of vascular prosthesis, relapse

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

• 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! ^[5]

See primary and secondary prevention of atherosclerosis.