PERIPHERAL ARTERIAL DISEASE

Zhen Lu, MD

 BASICS

DESCRIPTION

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis in which there is partial or total blockage in the arteries, exclusive of the coronary and cerebral vessels. Objectively, PAD is defined as a resting ankle-brachial index (ABI) of <0.90.

EPIDEMIOLOGY

•  Predominant age: >40 years

•  Predominant sex: male > female (2:1), based on the Framingham study

•  Patients with symptomatic PAD have a 5-year mortality rate of 30%.

•  Highly prevalent syndrome that affects 8 to 12 million individuals in the United States

Incidence

Incidence overall: 1 to 3/1,000/year

Prevalence

•  U.S. prevalence: 2.7 to 4.1%

•  Age-adjusted prevalence of PAD is close to 12%.

•  Up to 29% among patients in primary care practices

ETIOLOGY AND PATHOPHYSIOLOGY

•  In patients with PAD, arterial stenoses cause inadequate blood flow in distal limbs, which fails to meet the metabolic demand during exertion:

–  The degree of ischemia is proportional to the size and proximity of the occlusion to the end organ.

–  Acidic products of anaerobic metabolism build up within the muscle and result in claudication clinically.

–  Arterial occlusion also causes significantly diminished distal pressure in patients with PAD due to atherosclerotic lesions.

•  Most common cause of arterial stenoses is atherosclerosis.

Genetics

Current NIH-funded research focuses on single-nucleotide polymorphisms in candidate genes that are regulated in the vasculature in an attempt to explore genetic factors responsible for PAD.

RISK FACTORS

•  Age >40 years

•  Cigarette smoking

•  Diabetes mellitus

•  Obesity

•  Hypertension

•  Hyperlipidemia

•  Hyperhomocysteinemia

GENERAL PREVENTION

Control risk factors.

COMMONLY ASSOCIATED CONDITIONS

•  See “Risk Factors.”

•  Associated with other common complications of atherosclerosis, including myocardial infarction (MI), transient ischemic attack (TIA), stroke, and limb amputation

•  Occurs in ~40% of patients with cardiovascular disease

 DIAGNOSIS

HISTORY

•  Intermittent claudication, with symptoms typically resolving within 2 to 5 minutes of rest (although it is regarded as the classic symptom for PAD, intermittent claudication is present in only 10% of patients with PAD)

•  Rest leg pain (especially in a supine position)

•  Skin ulceration (in advanced PAD)

•  Gangrene (in advanced PAD)

•  Impotence

PHYSICAL EXAM

•  Skin pallor when leg is elevated above the level of the heart (in mild PAD)

•  Dependent rubor

•  Dry and scaly skin

•  Poor nail growth

•  Hair loss

•  Reduced/absent extremity pulses (in advanced PAD)

DIFFERENTIAL DIAGNOSIS

•  Arterial embolism

•  Deep venous thrombosis

•  Thromboangiitis obliterans (Buerger disease)

•  Osteoarthritis

•  Restless legs syndrome

•  Peripheral neuropathy

•  Spinal stenoses (pseudoclaudication)

•  Intervertebral disc prolapse

DIAGNOSTIC TESTS & INTERPRETATION

Serum glucose is recommended screening for diabetes mellitus in suspected or confirmed PAD.

Initial Tests (lab, imaging)

•  Fasting lipid profile is indicated for risk assessment of hyperlipidemia.

•  Duplex ultrasonography and Doppler color-flow imaging, which are useful in detecting stenosed segments and assessing lesion severity, are initial imaging tests of choice.

•  Magnetic resonance angiography, coupled with 3D reconstruction, is highly sensitive and specific for the localization of occluded lesions.

•  CT scanning has a limited role in the evaluation of PAD.

•  Angiography remains the gold standard in the diagnosis of PAD.

Diagnostic Procedures/Other

•  Doppler ABI measures the ratio of the higher systolic BPs between the dorsalis pedis and the posterior tibial artery versus the higher of the systolic BPs in the two brachial arteries: Values for the ABI should be reported as “incompressible” if >1.40, “normal” if 1.00 to 1.40, “borderline” if 0.91 to 0.99, and “abnormal” if ≤0.90. ABI <0.4: severe ischemia

•  Segmental limb pressures: usually obtained if abnormal ABI measurement is identified; a ≤20-mm Hg reduction in pressure is considered significant for PAD.

•  Treadmill exercise test assesses the severity of claudication and the response to treatment.

•  Segmental volume plethysmography: often used in conjunction with segmental limb pressures to measure the volume changes in an organ or limb; the study is indicated for calcified vessel when the ABI cannot be applied diagnostically.

 TREATMENT

GENERAL MEASURES

•  Claudication exercise rehabilitation program: patient to walk until symptoms develop, then rest and start again, for a total of 30 minutes initially; walking then is increased by 5 minutes until 50 minutes of intermittent walking is achieved.

•  Modification of risk factors, including smoking cessation, diabetes mellitus, hypertension, and hyperlipidemia:

–  Weight loss is associated with a decrease in the risk of cardiovascular disease but has not been shown to improve PAD.

–  Antiplatelet therapy (aspirin) is recommended for patients with PAD when there is no other contraindication; however, neither the addition of an anticoagulant nor anticoagulant therapy alone has demonstrated superior outcome in PAD patients.

–  Lipid-lowering therapy with moderate-intensity statin; simvastatin (20 to 40 mg/day) has been shown to reduce the incidence of new intermittent claudication from 3.6% to 2.3% in patients with coronary artery disease (CAD).

–  No statistical significance for overall improvement of exercise performance or reduction in claudication symptoms for patients on niacin extended-release/lovastatin-combined therapy.

–  β-Adrenergic antagonists should be used with caution in individuals with severe PAD.

–  Smoking cessation is likely to reduce the severity of claudication.

MEDICATION

First Line

Antiplatelet therapy has been the mainstay treatment to prevent ischemic events in patients with PAD. However:

•  The effect of aspirin on the risk reduction of overall ischemic events is inconclusive. Some suggest that aspirin delays disease progression and reduces the need for surgical intervention. AHA/ACCF guidelines (1)[A] note that the use of antiplatelet therapy to reduce cardiovascular risks in asymptomatic patients with borderline ABIs is characterized as “not well-established.” Aspirin is recommended to reduce the risk of MI, stroke, and vascular death in symptomatic patients with PAD.

•  Low-dose aspirin (75 to 150 mg/day) is as effective as higher doses of aspirin.

Second Line

•  Clopidogrel (75 mg/day) is approved by the FDA for the secondary prevention of thrombotic events in patients with symptomatic lower extremity PAD and is recommended as an alternative to aspirin.

•  Vorapaxar (Zontivity) 2.08 mg PO daily is a platelet aggregation inhibitor different in mechanism from existing antiplatelet drugs (TRAP inhibitor). It is contraindicated if history of CVA, TIA, or intracranial hemorrhage; concern for bleeding risk; and is expensive

•  Other medications that may improve symptoms of claudication include pentoxifylline (1.2 g/day), cilostazol (100 mg BID), and naftidrofuryl (600 mg/day).

•  Neither vasodilators nor anticoagulant therapy (e.g., heparin, low-molecular-weight heparin, or oral anticoagulant) has shown any clinically proven efficacy for the treatment of claudication and may be harmful.

•  Cilostazol (100 mg BID) improves walking distance in people with intermittent claudication secondary to PAD. There is currently insufficient data on whether taking cilostazol results in a reduction of all-cause mortality and cardiovascular events or an improvement in quality of life (2)[A].

•  Other medications that may reduce claudication include pentoxifylline (1.2 g/day), naftidrofuryl (600 mg/day), and prostaglandins (120 μg/day). Ticlopidine (250 mg BID) reduces the risk of MI, stroke, and death in patients with PAD, but it has a complication of thrombocytopenia in 2–3% of patients.

ADDITIONAL THERAPIES

•  Weight reduction, smoking cessation, and BP control are essential in treating claudication.

•  Exercise programs are of significant benefit compared with placebo or usual care in improving walking time and distance in people with leg pain from intermittent claudication who were considered to be fit for exercise intervention (3)[A]. A walking program should include walking at least 3 times per week for 30 to 60 minutes each time and has been shown to improve quality of life as much as or more so than medication.

•  A healthy diet high in complex carbohydrates (e.g., whole grains and pastas), fruits and vegetables, and low in salt and animal fats

SURGERY/OTHER PROCEDURES

Surgical interventions, such as revascularization, are warranted for individuals who have debilitating intermittent claudication, ischemic rest pain, or tissue loss:

•  Transluminal balloon angioplasty is a percutaneous method of dilating arterial stenoses or recanalizing occluded vessels with or without stents (reserved for short, isolated, and hemodynamically significant lesions of the iliac or proximal superficial femoral artery).

•  Bypass surgery is the standard operative treatment for lower extremity peripheral occlusive disease.

COMPLEMENTARY & ALTERNATIVE MEDICINE

•  Acupuncture, biofeedback, chelation therapy, and supplements such as Ginkgo biloba, omega-3 fatty acids, and vitamin E have been studied.

•  Ginkgo biloba modestly reduces the symptoms of intermittent claudication (120 mg/day for up to 6 months) and can be considered as an adjunct to exercise therapy. Inconclusive evidence exists for the use of vitamin E.

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

•  An exercise training program composed of walking/bicycle riding improves maximal treadmill walking distance and, therefore, enhances functional capacity.

•  However, little added benefit exists from Ginkgo biloba treatment when added to supervised exercise training in patients with PAD as compared with patients in exercise training program alone.

DIET

A low-fat cardiac diet is recommended.

PROGNOSIS

•  Among patients with intermittent claudication, 15–20% will experience worsening claudication; 5–10% will undergo lower extremity bypass surgery; and 2–5% will need primary amputation (rates for smokers and diabetics are much higher).

•  30,000 to 50,000 people in the United States undergo amputations annually because of PAD.

REFERENCES

1.  Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practical Guidelines. J Am Coll Cardiol. 2011;58(19):2020–2045.

2.  Bedenis R, Stewart M, Cleanthis M, et al. Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2014;(10):CD003748.

3.  Lane R, Ellis B, Watson L, et al. Exercise for intermittent claudication. Cochrane Database Syst Rev. 2014;(7):CD000990.

ADDITIONAL READING

•  Duprez DA. Pharmacological interventions for peripheral artery disease. Expert Opin Pharmacother. 2007;8(10):1465–1477.

•  Gey DC, Lesho EP, Manngold J. Management of peripheral arterial disease. Am Fam Physician. 2004;69(3):525–532.

•  Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. JAMA. 2006;295(5):547–553.

•  Hiatt WR, Hirsch AT, Creager MA, et al. Effect of niacin ER/lovastatin on claudication symptoms in patients with peripheral artery disease. Vasc Med. 2010;15(3):171–179.

•  Wang J, Zhou S, Bronks R, et al. Supervised exercise training combined with ginkgo biloba treatment for patients with peripheral arterial disease. Clin Rehabil. 2007;21(7):579–586.

 CODES

ICD10

•  I73.9 Peripheral vascular disease, unspecified

•  I70.209 Unsp athscl native arteries of extremities, unsp extremity

•  I70.219 Athscl native arteries of extrm w intrmt claud, unsp extrm

CLINICAL PEARLS

•  Screening of a general medical population for PAD is not recommended. Studies have indicated that screening for PAD among asymptomatic adults in the general population could lead to false-positive results and unnecessary workups. The prevalence among the general public who are asymptomatic is low.

•  A patient already receiving medical treatment should be referred for further surgical evaluation for any of the following scenarios:

–  Unsatisfactory results despite medical therapy

–  No definitive diagnosis can be made

–  Critical limb ischemia is present, such as rest pain, gangrene, or ulceration.

•  The clopidogrel (75 mg/day) versus aspirin (325 mg/day) study in the patients at risk of ischemic events (CAPRIE) trial found a 23.8% relative risk ratio for MI, stroke, or cardiovascular death in PAD patients treated with clopidogrel compared with aspirin but no statistically significant difference in overall mortality reduction. Clopidogrel is much more expensive than aspirin.