44 Peripheral Arterial Disease

807

From: Essential Cardiology: Principles and Practice, 2nd Ed.

Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ

44 Peripheral Arterial Disease

James J. Jang, ^MD

and Jonathan L. Halperin, ^MD

INTRODUCTION

The most widely recognized peripheral vascular disease in adults is obstructive atherosclerosis of the extremities or peripheral arterial disease (PAD). The traditional term “arteriosclerosis obliterans” distinguishes the development of obstructive lesions from normal aging by which the arteries increase in diameter, rigidity, and calcium content (1). The disease was defined in 1958 by the World Health Organization as a “variable combination of changes of the intima or arteries (as distinguished from arterioles) consisting of the focal accumulation of lipids, complex carbo- hydrates, blood and blood products, fibrous tissue and calcium deposits, and associated with medial changes” (2).

EPIDEMIOLOGY

By the time symptoms of obstructive arterial disease develop there is usually at least 50% nar- rowing of the vascular lumen. Based on a 26-yr longitudinal surveillance of the Framingham Heart Study cohort of 5209 subjects, the annual incidence of symptomatic ischemic arterial obstructive disease was 0.26% for men and 0.12% in women (3). The incidence increased with age until age 75 yr, with about a twofold male predominance at all ages (Fig. 1). The peak incidence of symp- tomatic limb arterial obstructive disease occurred in males in the sixth and seventh decades of life.

Fewer than 10% of nondiabetic cases younger than 60 yr were females. The incidence in women beyond menopause rose quickly toward that in men. Lower extremity vascular disease causes con- siderable morbidity among women, particularly in those following menopause. In a cross-sectional study involving 1601 healthy elderly women (mean age 71 yr, range 65–93 yr), the prevalence of lower extremity arterial disease assessed by ankle-brachial index (ABI) ranged from 2.9% in those aged 65 to 69 yr to 15.5% in those aged 80 yr or older (4). Approximately 20% of those with disease had symptoms of claudication.

The prevalence of arterial obstructive disease exceeds that of symptomatic ischemia (5). Since patients often present with atypical limb symptoms or without claudication, the frequency of PAD diagnosis is generally considerably lower than the prevalence of the disease. Based on the ABI, the prevalence of PAD in unselected populations 25 to 65 yr old was 0.7% for females and 1.3%

for males. The prevalence of disease depends, however, on the threshold ABI selected (6). The

national cross-sectional survey of the PAD Awareness, Risk, and Treatment; New Resources for

Survival (PARTNERS) program, in which PAD diagnosis was defined by ABI 0.9, found the dis-

ease was detected in 29% of patients who were either 50 to 69 yr old with risk factors of tobacco

smoking or diabetes mellitus or 70 yr old regardless of risk factors (7). More than 70% of the

primary care physicians who participated were unaware that their patients had PAD before screen-

ing in the PARTNERS study (7).

The prevalence of asymptomatic atherosclerosis is highest in elderly patients, in whom gan- grene is frequently the initial symptom because coexisting conditions limit ambulation (8). In the Rotterdam Study of 7715 subjects aged 55 yr, the prevalence of PAD was 19.1% based on ABI

<0.9 (9). Symptoms of intermittent claudication were reported by only 6.3% (9). In an elderly nurs- ing home population, the prevalence of severe obstructive arterial disease (ABI <0.7) was approx 50%, and this predicted increased mortality compared to patients without signs of disease (10).

Among patients older than 90 yr, the second most common surgical operation is lower extremity amputation for limb arterial disease or gangrene.

RISK FACTORS

Like other manifestations of atherosclerosis, the prevalence of peripheral arterial disease is related to hyperlipidemia, diabetes mellitus, hypertension, and tobacco smoking, which modify the effects of age, gender, and heredity. It is difficult to separate data pertaining to atherosclerotic disease in the peripheral circulation from observations of coronary artery disease, but there is little reason to suspect substantial difference based on the anatomic site of involvement (3). Specific risk factors appear additive and better predict relative risk than absolute risk. Overall, a risk profile made up of the major cardiovascular risk factors correlates better with intermittent claudication than with clinical manifestations of coronary heart disease.

Hyperlipidemia

The prevalence of hyperlipoproteinemia in patients with PAD ranges in various studies from 31 to 57%, while intermittent claudication is more than twice as common in patients with serum cholesterol levels higher than 260 mg/dL than in those without hyperlipidemia (11). The Edinburgh Artery Study demonstrated that PAD was directly associated with elevated serum cholesterol levels and inversely related to high-density lipoprotein (HDL) levels (12). In addition, the development of PAD is independently associated with elevations in lipid peroxides, such as oxidized low-den- sity lipoproteins (LDL) and very-low-density lipoproteins (VLDL) (13,14).

Diabetes Mellitus

Peripheral atherosclerosis develops more commonly in diabetic patients, with a predilection for the tibial and peroneal arteries between the knees and ankles, for which revascularization procedures are more difficult. While the incidence of femoropopliteal arterial obstructive disease is similar to that in the nondiabetic population, aortoiliac occlusive disease may actually occur less

Fig. 1. Age-specific annual incidence: intermittent claudication. (Adapted from ref. 83.)

frequently in diabetics. The risk of developing PAD appears related to the duration of non-insulin- dependent diabetes mellitus (15). Diabetes raises the risk of ischemic gangrene 20-fold and that of surgical amputation fourfold (16). Coexisting sensory and autonomic neuropathy, lack of reflex hyperemia, loss of pain sensation, and arteriovenous shunting contribute to ischemic complications in diabetics.

Hypertension

The frequency and severity of atherosclerotic disease and its coronary and cerebral complications are increased in hypertensive patients. In the Framingham study cohort, hypertension increased the risk of PAD 2.5- to 4-fold in men and women, respectively (3). Autopsy studies have demon- strated more extensive atherosclerosis of the aortoiliac arteries in hypertensive men than in age- matched normotensive controls. In women, this difference is more generalized along the course of the arterial tree. Limb arterial obstructive disease occurs twice as frequently as coronary artery disease among hypertensive individuals.

Tobacco Smoking

The Framingham Heart Study found a relationship between the number of cigarettes smoked and the incidence of intermittent claudication (17). Multivariate analysis found that tobacco smok- ing was the strongest single risk factor for development of symptomatic obstructive arterial dis- ease (17). From the Framingham Offspring Study, for each 10-pack-yr increment of smoking, there was a 1.3-fold increased incidence of PAD (18). The occurrence of intermittent claudication is twice as frequent in smokers as in nonsmokers. In males with symptomatic atherosclerotic disease of the limb vessels, the majority of patients report smoking cigarettes at the onset of the clinical phase of the disease. Smoking is clearly associated with an increase in amputations and bypass graft occlusions (19,20). Seventy-three to 90% of patients with limb arterial disease are smokers, such that it is distinctly rare to encounter a young female with the disease who does not smoke cigarettes. Pathophysiologic mechanisms from tobacco smoking involve vasoconstriction, lipid metabolism, and thrombogenicity (21).

Additional Risk Factors

Hereditary disorders associated with ischemic complications in the limbs include homocystein- uria, oxalosis, inhibitors of von Willebrand factor, and inherited states associated with increased thrombogenicity. The latter is more closely associated with venous than with arterial diseases.

HISTOPATHOLOGY

Histopathologically, peripheral arteriosclerosis obliterans is identical to atherosclerosis that affects the aorta and its branches, including the coronary, visceral, cervical, and cerebral arteries.

The basic lesion is the atherosclerotic plaque that produces localized stenosis of the lumen with or without areas of complete arterial occlusion. Deposition of thrombus and subsequently pro- gressive fibrosis occur in eccentric layers. Fragmentation of the internal elastic lamina typically occurs and areas of intraplaque hemorrhage and calcification characterize the advanced lesion.

Segmental lesions usually produce stenosis or occlusion of large and medium-sized arteries.

After the thoracoabdominal aorta, the coronary arteries are most commonly affected by atheroscler-

osis, followed by the iliofemoral, carotid, renal, mesenteric, vertebrobasilar, tibial-peroneal, sub-

clavian, brachial, radial, and ulnar arteries. Even in advanced cases, smaller arteries of the digits

are generally spared, though these may become obstructed by thrombus when there is proximal

atherosclerotic disease. Patients with intermittent claudication may have disease at multiple arte-

rial levels. In symptomatic patients, approx 80% have femoropopliteal disease, approx 30% have

lesions at the aortoiliac level, and up to 40% have tibial-peroneal obstruction. Involvement of the

distal vessels is most frequent in diabetics and in the elderly.

NATURAL HISTORY AND PROGNOSIS

The clinical courses of patients with PAD vary markedly, with abrupt vascular occlusion in some cases and chronic progression in others. In patients with aortoiliac disease, a copious collateral circulation tends to develop with a generally favorable prognosis in terms of limb outcome. Patients with distal tibial-peroneal disease have a distinctly poorer outcome, encountering amputation at annual rate of 1.4% (22).

Followed without surgical intervention, yearly mortality averages over 5%, with death usually due to coronary or cerebral vascular disease. In the Framingham Heart Study, the relative mor- tality risk imposed by symptomatic PAD without cardiovascular comorbidity was 1.3 for men and 2.1 for women; total mortality ratios were 2.2 and 4.1, respectively. In patients with severely symp- tomatic PAD the rate of coronary heart disease (defined angiographically as >70% stenosis of at least one coronary vessel) was nearly 90%. About 50% of these patients had decreased left ventricular function (23). Symptomatic PAD raises the risk of myocardial infarction, coronary, and cardiovas- cular death five- to sixfold (Fig. 2) (24). In a 15-yr study of 2777 patients with claudication, over 66% of mortality was attributable to cardiovascular disease (25). Angina and history of myocardial infarction were not predictive of increased mortality. Instead, reduced ABI at rest and following exercise, diabetes mellitus, and age were significant predictors (25).

Remission of intermittent claudication is common. Among patients followed 4 or more yr from onset of symptoms in the Framingham study, 45% became asymptomatic (26). In a Mayo Clinic study, 24% of nondiabetic patients with PAD affecting the superficial femoral artery had symp- tomatic improvement, while 69% experienced no progression of symptoms and clinical deteriora- tion developed in only 7% (27,28). According to the TransAtlantic Inter-Society Consensus (TASC) working group, only 5% of patients with intermittent claudication require surgical or endovascular intervention and approx 2% need major amputation over a 5-yr period (29).

CLINICAL PRESENTATION Intermittent Claudication

The cardinal symptom of obstructive arterial disease in the lower extremities is intermittent clau- dication. Typically, patients describe calf pain, since the gastrocnemius musculature has the greatest

Fig. 2. Relative risk of death in patients with peripheral arterial disease (PAD) compared with patients without

PAD: all-cause mortality, cardiovascular and coronary mortality are shown for asymptomatic, symptomatic,

and all patients. (Adapted from ref. 24.)

oxygen consumption of any muscle group in the leg during ambulation. Some patients report aching, heaviness, fatigue, or numbness when walking, but distress is usually relieved within a few minutes of rest. Ischemic claudication must be distinguished from other conditions producing exertional calf pain (Table 1). Among 460 patients with PAD evaluated in the Walking and Leg Circulation study, only 32.6% had intermittent claudication; the remainder had either no exertional leg symptoms, atypical leg pain, or rest pain (30). Diabetic patients with distal tibial or peroneal arterial obstruction may describe ankle or foot pain while walking; this may be difficult to distin- guish from ischemic neuropathy. With proximal aortoiliac disease, thigh, hip, or buttock claudica- tion or low back pain may develop while walking, usually preceded by calf pain. Bilateral “high claudication” accompanying impotency and global atrophy of the lower extremities characterizes the Leriche syndrome, associated with aortoiliac disease.

Multiple factors contribute to leg discomfort during exercise in patients with PAD. Hemodynam- ically significant arterial stenosis may reduce pressure and flow minimally at rest while the pressure gradient across the stenosis increases during exercise. Extravascular compression by exercising muscle and lack of flow-mediated vasodilation in atherosclerotic vessels may further blunt limb blood flow. Discomfort may be related to activation of local chemoreceptors due to accumulation of lactate or other metabolites as a result of ischemia.

Initial and absolute claudication thresholds are best expressed in terms of pace and incline.

Ambient environmental conditions such as temperature and wind, training, and recruitment of mus- cle groups in less ischemic zones all influence walking capacity and have therapeutic implications in maintaining overall cardiovascular conditioning.

Critical Limb Ischemia

When the minimal nutritional requirements of resting skin, muscle, nerves and bone are not met, ischemic rest pain, ulceration, and gangrene ensue, any of which translates to a poor prognosis. Clin- ically, limb ischemia at rest is manifested first in the cutaneous tissues of the foot, where factors regulating perfusion differ from those governing calf muscle circulation. Reflexive sympatheti- cally mediated vasoconstrictor activity may reduce foot blood flow even under conditions of ische- mia. With tissue necrosis there is typically severe pain that is worse at night with limb elevation and improves upon standing. With advanced neuropathy, ulceration and gangrene may occur pain- lessly. Other symptoms of ischemia at rest include hypesthesia, cold sensitivity, muscular weak- ness, joint stiffness, and contracture.

Severe ischemia of this kind usually demands angiographic examination and therapeutic inter- vention by percutaneous angioplasty or surgical revascularization. When these procedures are not feasible, gangrene commonly ensues and leads to amputation, though remission has been described even at this advanced stage of disease. Critical limb ischemia results in some 150,000 amputations annually in the United States, with perioperative mortality rates of 5 to 10% for below-knee and up to 50% for above-knee amputations.

Acute Arterial Occlusion

The major causes of acute arterial occlusion are trauma, arterial thrombosis, and arterial embol- ism. Traumatic occlusion is usually associated with external compression, transection, or lacera- tion. Increasingly, the clinical spectrum of traumatic arterial occlusive disease includes iatrogenic

Table 1

Differential Diagnosis of Exertional Calf Pain Obstructive arterial disease

Neurogenic pseudoclaudication Venous claudication

Muscular disorders

cases, most commonly associated with indwelling intravascular diagnostic or therapeutic cannu- lation. Atraumatic acute arterial occlusion includes systemic embolism, usually cardiogenic, but occasionally derived from mural thrombi within aneurysms of the aorta, and thrombosis super- imposed on chronic atherosclerosis or other intrinsic arterial disease. Systemic disorders of coag- ulation associated with arterial thrombosis include those associated with anticardiolipin antibodies, circulating lupus anticoagulants, and heparin-associated thrombocytopenia.

Arterial Embolism

Nearly 85% of systemic arterial emboli arise from thrombi in the chambers of the left side of the heart. Atrial fibrillation accounts for about half the cases and ventricular thrombi for most of the remainder. Infective (particularly fungal) endocarditis, cardiac tumors, invasive lesions of the pulmonary venous system, mural thrombi within aortic aneurysms, ulcerated proximal atherosclero- tic lesions, vascular grafts, arteritis, and traumatic arterial lesions represent additional sources of embolism.

Microembolism of atherosclerotic debris consisting of lipid and thrombotic material may originate in the aorta or more distal arteries and lead to occlusion of small distal limb arteries. The source may involve either aneurysmal disease or irregular ulceration of diffusely atherosclerotic vessels that are not dilated. Transesophageal echocardiography and magnetic resonance imaging have identified such atherosclerotic lesions (Fig. 3) (31). The syndrome, designated atheroembol- ism, is often labeled “blue toe syndrome” when the feet are affected, and is characterized by uni- lateral or bilateral, painful, cyanotic toes in the presence of palpable pedal pulses (Fig. 4). The lateral and plantar aspects of the feet are frequently involved and manifest as livedo reticularis and petechiae on feet and legs. The violaceous parts generally blanch with pressure, and the surrounding skin may appear normally perfused. Calf pain and gastrocnemius muscle tenderness is often present as a result of embolic occlusion of small intramuscular vessels. Fever, eosinophilia, and accelera- tion of the erythrocyte sedimentation rate may signal an inflammatory reaction to atheroembolism, which may be difficult to distinguish from acute vasculitis.

Atheroembolism implies a physically unstable proximal atherosclerotic lesion that may be at risk for acute thrombotic arterial occlusion depending on the diameter of the arterial segment involved and other factors governing flow. Antithrombotic therapy should be given in the form of platelet inhibitor or anticoagulant medication. Although angioplasty and stent grafting are some- times effective, intravascular catheterization may provoke embolism. The most definitive approach is removal or exclusion of the source from the circulation. When the lower limbs are ischemic, aorto- bifemoral bypass is often required; but an alternative approach is axillobifemoral extraanatomic

Fig. 3. Magnetic resonance, T2-weighted (A) and transesophageal echocardiographic (B) images of a 4.5-mm

fibroatheromatous aortic plaque showing the eccentric lesion with fibrous cap and lipid-laden core. (From

ref. 84.)

bypass with ligation of the external iliac arteries proximal to the point of anastomosis. When renal embolism occurs, more proximal aortic reconstruction may be necessary. The risks of proximal aortic procedures are considerable, particularly when severe atherosclerosis involves the entire length of the aorta accompanied by a malignant syndrome of cerebral, mesenteric, and limb ischemia.

DIFFERENTIAL DIAGNOSIS

Exertional calf pain may be produced by both nonatherosclerotic arterial obstructive diseases and conditions unrelated to the arterial circulation (Table 1). Among the latter are neurogenic pseudo- claudication (a form of lumbosacral radiculopathy), in which ambulation provokes nerve root irritation with pain referred to the posterior aspect of the lower extremity. Characteristic symp- toms include pain upon walking just a few steps without progression to ischemia at rest, relief on bending forward at the waist, and reproduction of symptoms by straight leg-raising.

Venous claudication illustrates the role of venous pressure as a factor in regional circulatory resistance. Exertional leg pain (especially near the medial aspect of the leg above the ankle) results from insufficiency of the musculovenous pumping mechanism that normally reduces distal venous pressure during ambulation. Venous hypertension contributes to increased local vascular resis- tance and this causes exertional ischemia. Venous claudication is uncommon and usually occurs in patients with concomitant arterial insufficiency.

In patients with McArdle’s syndrome, skeletal muscle metabolites accumulate due to phospho- rylase deficiency, evoking exercise intolerance in the absence of an ischemia-inducing substrate.

Similar metabolites, including but not limited to lactic acid, may be responsible for the pain of intermittent claudication due to obstructive arterial disease.

Obstructive arterial diseases other than atherosclerosis that may produce intermittent claudica- tion include fibromuscular dysplasia (FMD), thromboangiitis obliterans (Buerger’s disease) and other arteritides, arterial entrapment syndromes (most commonly caused by the gastrocnemius muscles) and extravascular compressive lesions, adventitial cysts and tumors, and thromboembo- lic lesions (Table 2). The most prevalent of these diseases is fibromuscular dysplasia, a hyperplastic disorder that usually affects medium-sized and small arteries in Caucasian females (32). The renal

Fig. 4. Typical appearance of atheromatous embolism involving the feet. There is livedo reticularis along the

lateral aspect of the foot and cyanosis of several toes. (From ref. 85.)

and carotid arteries are most frequently involved, but the disorder has also been described in the mesenteric, coronary, subclavian, and iliac arteries. Three histologic varieties have been delineated, based on which layer of the arterial wall displays the predominant features of the process. Medial fibroplasias, the most common FMD, are characterized angiographically by a “string of beads”

appearance, representing multiple thickened fibromuscular ridges alternating with thin areas of the arterial wall. The etiology is unknown, but pathogenic concepts include influence of female sex hormones, vascular microtrauma, and genetic factors. The natural history in limb arteries is less well defined than in the renal and carotid arteries, where progression of stenosis occurs over 5 yr in a third of cases. Clinical manifestations such as intermittent claudication, rest pain, coldness, and cyanosis of the limb and even microembolism are similar to atherosclerosis. In addition to surgical reconstruction, percutaneous angioplasty has been employed for management of FMD. Balloon dilation with or without intravascular stenting has been successfully accomplished with relatively low inflation pressures.

Buerger’s disease (thromboangiitis obliterans) is a nonatherosclerotic segmental inflammatory obliterative disease most commonly affecting small- and medium-sized arteries and veins in both the upper and lower extremities (33). Though the disease was once considered confined to young males, in recent clinical series up to a third of the cases occurred in women. Most patients are heavy users of tobacco, usually cigarette smokers, and antigenic cross-reactivity between type III vascu- lar collagen and a component of tobacco smoke has been considered etiologically important (34).

Distinctive pathological findings distinguish this disorder from other arterial occlusive diseases.

Successful therapy requires abstinence from tobacco.

PHYSICAL FINDINGS

Trophic signs of chronic limb ischemia include subcutaneous atrophy, brittle toenails, hair loss, pallor, coolness, or dependent rubor (Table 3). Other visible changes reflect sympathetic denerva- tion and sensorimotor neuropathy. Severe ischemia produces petechiae, regional edema, tenderness, ulceration, or gangrene. The level of arterial obstruction may be judged by palpation of the femoral,

Table 2

Differential Diagnosis of Obstructive Arterial Disease Arteriosclerosis obliterans

Fibromuscular dysplasia Vasculitis

Vascular entrapment or compression Adventitial cysts and tumors Thrombosis and embolism

Table 3

Trophic Signs of Ischemia in Patients With Peripheral Arterial Disease of the Extremities Chronic arterial obstructive disease

Hair loss

Subcutaneous atrophy

Thickened nails

Dependent rubor

Acute ischemia

Ulceration

Petechiae

Calf tenderness

Dependent edema

popliteal, posterior tibial, and dorsalis pedis pulses. Vascular bruits denote turbulent flow but do not indicate the severity of stenosis.

Cutaneous perfusion may be estimated by the color and temperature of the feet during elevation above heart level at rest and following exercise. The rate of hyperemic color return and venous filling in the foot upon dependency reflect collateral perfusion (Table 4). When this does not meet minimal tissue perfusion requirements, cutaneous ulceration is frequent. Arterial ulcers caused by arterial disease are often as small as 3 to 5 mm in diameter, have irregular borders and pale bases, usually involve the tips of the toes or the heel of the foot, are typically painful on elevation, and are most bothersome at night. The clinical course of these ulcers is often one of rapid progression to extensive gangrene. Vasospasm may produce cutaneous ischemia leading to ulceration of the digits in patients with Raynaud’s phenomenon or chronic pernio. Diabetics, who are prone to com- bined peripheral sensory neuropathy and ischemic disease, often develop deep neurotrophic ulcers from trauma or pressure on the plantar surface. In patients with severe hypertension, painful Hines ulcers related to arteriolar obliteration tend to occur near the lateral malleoli. Vasculitic ulcers are characterized by arteriolar thickening, with or without superimposed thrombosis. Hematologic disorders such as the hemoglobinopathies, hereditary spherocytosis, dysproteinemias, and myelo- proliferative diseases may be associated with cutaneous infarction, venous thrombosis, and micro- vascular occlusion. Chronic venous stasis usually produces indolent or recurrent ulceration near the medial malleoli that are more painful during dependency, which helps distinguish them from ulcers due to arterial disease. A host of systemic diseases may also be associated with cutaneous ulceration in the lower extremities, such as tumors (i.e., Kaposi’s sarcoma), syphilitic chancre and gumma, tuberculous lupus vulgaris, and pyoderma gangrenosum. Factitious and traumatic ulcers may also mimic those induced by obstructive arterial disease (35).

NONINVASIVE EVALUATION (TABLE 5) Doppler Sphygmomanometry

Doppler sphygmomanometry has become part of the initial bedside vascular examination for determination of the ABI. Normally, systolic arterial pressure at the ankle exceeds that at the brachial artery. An ABI 0.9 at rest indicates hemodynamically significant arterial obstruction proximal

Table 4

Elevation and Dependency Tests in the Evaluation of Acral Ischemia

Color return (s) Venous filling (s)

Normal 10 10–15

Adequate collaterals 15–25 15–30

Severe ischemia >35 >40

Table 5

Noninvasive Laboratory Evaluation of Peripheral Arterial Disease Doppler sphygmomanometry Segmental pressure measurement Pulse volume recording

Venous-occlusion plethysmography Radionuclide mapping

Duplex ultrasound imaging

Magnetic resonance angiography

Computed tomographic angiography

to the pneumatic leg cuff. In general, ABI may exceed 0.9 in individuals with obstructive disease in the absence of symptoms; values between 0.5 and 0.9 at rest are typical in patients with inter- mittent claudication, and values below 0.5 are frequently associated with ischemic rest pain, ulcer- ation, and gangrene threatening the viability of the limb (Fig. 5).

Advanced calcific atherosclerosis of vessels beneath the cuff resists compression producing overestimation of regional perfusion pressure. This constitutes the major limitation of sphygmo- manometry, and may falsely elevate the ABI in patients with diabetes mellitus or end-stage renal disease. Ankle-brachial indices may be normal at rest despite hemodynamically significant arterial stenosis, yet decline following calf muscle exercise. Postexercise systolic ankle pressure readings below 90 mmHg are typical of patients with intermittent claudication, and values below 60 mmHg are typical of ulcerative ischemia at rest (36).

Segmental Pressure Measurements

To localize segmental arterial lesions, pneumatic cuffs are applied to determine systolic pressure at several levels, based on the principle that pressure drops distal to the level of obstruction. Segmen- tal pressure measurements are subject to the same limitations as Doppler sphygmomanometry.

Segmental compression cuffs combined with the Doppler ultrasound device, photoplethysmograph, or other flow detectors are subject to error related to arterial rigidity.

Pulse volume recordings overcome some of these limitations. The amplitude of the pulse volume wave reflects local arterial pressure, vascular wall compliance, the number of arterial vessels beneath the cuff, and the severity of atherosclerotic disease. The normal pulse is characterized by a sharp sys- tolic upstroke that rises rapidly to a peak, and then drops off slowly toward the baseline. The down- slope curves toward the baseline and usually contains a dicrotic notch and secondary wave that is midway between the peak and the baseline. The pulse recording distal to an arterial obstruction is more rounded, the anacrotic slope is reduced, the crest is delayed, the catacrotic limb descends more gradually, and the dicrotic wave is lost.

The pulse volume recorder has the advantage of revealing distortions in pulse wave contour even in patients with vascular calcification. The pulse waveforms appear depressed and altered even when arteries are noncompressible. The pulsatility index, representing the ratio of pulse amplitude to mean volume obtained by integration of the deflection, is abnormally low even when systolic pressure

Fig. 5. Measurement of ankle-brachial index (ABI).

readings are falsely elevated. The value of these observations is enhanced by exercise testing, which also provides a quantitative estimate of functional capacity. In addition, exercise testing enables the physician to distinguish PAD from disorders producing similar symptoms, since the ABI declines following exercise in those with arterial obstructive disease.

Ultrasound Velocity Spectroscopy and Imaging

Doppler velocity analysis of normal arteries reveals a triphasic signal. Rapid acceleration to peak systolic velocity occurs along a narrow frequency spectrum, end-systolic deceleration culminates in protodiastolic flow reversal, and antegrade flow resumes in mid-diastole. Peak systolic veloci- ties diminish with advancing age. Arterial obstruction proximal to the probe transforms the wave- form by loss of the reversed flow component and attenuation of all parts of the spectrum, with delayed upstroke and decreased amplitude.

Duplex ultrasound scanning combines B-mode and pulsed-Doppler ultrasound analysis to exam- ine arterial configuration and localize velocity information at sites of stenosis. Flow through a stenosis is accelerated, and turbulence is detected as spectral broadening of the velocities, instead of the narrow band seen with normal flow. Microprocessor-based systems for calculation of blood cell velocities allow accurate estimation of instantaneous pressure gradients and degrees of steno- sis (37). Duplex scanning is more sensitive and specific than segmental blood pressure measure- ments for detection of restenosis following vascular interventional procedures.

The clinical vascular noninvasive laboratory is subject to misconceptions that predispose to misuse. Among these are that findings can establish indications for specific therapeutic procedures, since clinical decisions are best based on symptoms and the physical appearance of the limb. Non- invasive vascular measurements reflect the severity of ischemia, the contribution of obstructive arterial factors to symptoms, and the hemodynamic significance of lesions at various points. It is important that in formulating management decisions, noninvasive testing aid rather than replace the medical history, physical examination, and clinical judgment.

Magnetic Resonance Angiography

Magnetic resonance angiography obviates arterial catheterization and exposure to iodinated contrast material and may identify runoff vessels not visualized by conventional angiography (38).

Magnetic resonance (MR) imaging methods are currently emerging to characterize the arterial wall and atherosclerotic lesions. In the magnetic field, water molecules are excited by a radiofrequency (RF) pulse generating a secondary signal that is detected and measured digitally and displayed as images that distinguish fine details of tissue architecture and composition. Plaque dimensions and composition are assessed using T1-weighted, proton density, and T2-weighted images and tech- niques of real-time, cine MR angiography are under development. Currently, MR imaging is limited in assessing restenosis in arteries following angioplasty and stenting.

Contrast Angiography

The diagnosis of arterial obstructive disease does not generally require invasive techniques, and most patients with intermittent claudication should not undergo angiographic examination.

Contrast angiography is indicated for mapping the extent and location of arterial pathology prior

to a revascularization procedure. Such testing should be reserved for patients in whom the diagno-

sis is in doubt or as a prelude to vascular intervention when conservative approaches are not satis-

factory. Aortic injection of contrast material in patients with aortoiliac occlusive disease can be

accomplished either by the retrograde transfemoral, translumbar, or transaxillary approach. Aortic

injection of contrast material provides visualization of the aorta and proximal limb vessels, but

definition of the circulation distal to the popliteal trifurcations may be compromised by dilution

of proximally injected contrast. In patients with femoropopliteal obstructive disease, antegrade

or retrograde transfemoral angiography can be confined to the involved extremity with fine defini-

tion of the distal vasculature.

Computer-enhanced digital subtraction angiography may be useful in patients with localized stenosis either to minimize the volume of contrast material injected or to improve image resolution.

The technique may be employed with either intravenous or intraarterial contrast injection, especi- ally for postoperative examination of anastomotic segments, but is not an effective means of visual- izing large regions of the arterial tree.

MEDICAL THERAPY

The principles of patient management for PAD involve measures directed at protection of affected tissues, preservation of functional capacity, avoidance of disease progression or acute arterial throm- bosis, restoration of blood flow, and prevention of mortality. These principles can be categorized as local measures, treatment of associated risk factors, drug therapy for claudication, and antithrom- botic agents.

Local Measures

Local measures to reduce skin breakdown and infection are particularly important in diabetics and in patients with severely impaired perfusion. The feet should be kept clean. Moisturizing cream applied to prevent fissuring must be selected to avoid irritant effects. Well-fitted shoes reduce the risk of pressure-induced necrosis. Stockings made of absorbent fibers are recommended. The skin of the feet should be inspected frequently so minor abrasions may be promptly tended. Elastic sup- port stockings may restrict cutaneous blood flow and should be avoided. In patients with ischemia at rest, conservative measures such as positioning the affected limb below heart level increases oxygen tension in ischemic tissues. When edema is present, the limb should be kept horizontal to enhance healing. The heels should be protected from pressure against the bedsheets with sheepskin padding. Blankets should be cradled over a foot-board to reduce friction. Separation of the toes with cotton helps protect against intertriginous friction. Unless purulence is present, dryness is pre- ferred to soaks except for intermittent cleansing. Gentle warmth is recommended to minimize vaso- constriction. Antimicrobial treatment of fungal onycholysis reduces skin breakdown and superin- fection. Topical medications should be used cautiously to avoid inflammatory reactions. Open sores should be cultured and roentgenograms performed on affected limbs to detect possible osteomy- elitis. Antibiotic medication is less effective when delivery to ischemic tissue is impaired. Passive physical therapy may proceed to progressive weight-bearing and ambulation, with attention to foot care and properly fitted footwear, using soft, cotton stockings and nonconstrictive shoes.

Risk Factor Modification

Modification of associated risk factors may reduce the likelihood of progression of atheroscle- rotic disease, as discussed earlier in this chapter. Accordingly, attention should be directed toward correction of dyslipidemia, treatment of diabetes mellitus, control of hypertension, cessation of cigarette smoking, and exercise training.

T REATMENT OF D YSLIPIDEMIA

Lipid-lowering therapy with HMG-CoA-reductase inhibitors (“statins”) have favorable effects in patients with intermittent claudication (39). In addition to improving lipid profiles, statin treat- ment improves walking distance in patients with PAD and decrease the risk of developing new or worsening intermittent claudication (40–42).

T REATMENT OF D IABETES M ELLITUS

Aggressive control of blood glucose reduces the incidence of microvascular complications, but

data are insufficient regarding the efficacy of this strategy on the progression and complications

of peripheral atherosclerosis (43). In the UK Prospective Diabetes Study, aggressive blood-glu-

cose control was not associated with statistically significant reduction in myocardial infarction,

amputation, and death associated with PAD (44).

H YPERTENSION T REATMENT

Meta-analysis has shown approx 40% reduction in the risk of stroke and 10 to 15% reduction in the risk of myocardial infarction with antihypertensive treatment, but specific effects of therapy on peripheral manifestations of atherosclerosis have not been quantified (45). Treatment with the angiotensin-converting enzyme inhibitor ramipril was associated with a 27% relative risk reduc- tion in stroke, myocardial infarction, and death in the subgroup of PAD patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) trial (46).

S MOKING C ESSATION

Clinical prognosis for those with arterial obstructive disease of the extremities seems related to tobacco use. Among smokers with intermittent claudication, 11% of those who continued to smoke required amputation, while this fate befell none who quit (47). Patients with intermittent claudi- cation who stopped smoking had twice the survival benefit of those who continued to smoke at 5 and 10 yr (48,49).

E XERCISE T RAINING

Exercise training improves walking capacity and functional capacity among patients with obstruc- tive arterial disease over a period of several months, but most studies have not identified consistent improvement in measured indices of perfusion and data from well-controlled prospective trials are scant (50). Studies involving animals in which arterial obstructions have been created support the view that regular muscular exercise increases collateral development, but in the clinical setting functional improvement may depend on other factors in muscle metabolism or ergonomics.

T REATMENT OF H YPERHOMOCYSTEINEMIA

Hyperhomocysteinemia is strongly associated with peripheral atherosclerosis. Treatment with B-complex vitamins including folic acid, pyridoxine, and cyanocobalamin reduces homocysteine levels, but there are no conclusive data about the efficacy of treatment on the clinical consequences of atherosclerosis.

Drug Therapy to Reduce Ischemia and Claudication V ASODILATOR D RUGS

In contrast to their usefulness for treatment of patients with angina pectoris, vasodilator drugs have been disappointing for relief of intermittent claudication. In patients with limb ischemia, the goal is to increase the work capacity of exercising muscle. An obstructive arterial lesion producing critical stenosis limits blood supply and reduces distal perfusion pressure. Intramuscular arterioles normally dilate in response to the metabolic demands of exercise. In patients with proximal ste- notic arterial disease, flow augmentation is blunted and distal pressure falls during exercise. This process leads to accumulation of the ischemic metabolites that mediate claudication. The distal vasculature virtually collapses under the compressive force of exercising skeletal muscle, and this mechanism cannot be mitigated by arteriolar vasodilator therapy.

The history of limb arterial disease is replete with therapeutic agents that achieve popularity for awhile before falling into disrepute and disuse when adequate studies confirm their ineffec- tiveness. -Adrenergic agonists, a-adrenergic antagonists, nitrates, and other vasodilator drugs have been evaluated in such clinical trials. No vasodilator agent increases blood flow in exercising skeletal muscle subtended by significant arterial obstructive lesions, or improves symptoms of intermittent claudication and objective measures of exercise capacity (51).

P HARMACOLOGICAL E NHANCEMENT OF C OLLATERAL F LOW

An alternative tactic for patients with obstructive arterial disease involving major limb arteries

is augmentation of collateral perfusion. This is the rationale behind the use of the selective serotonin

antagonist, ketanserin, which in one study increased collateral blood flow in patients with obstruc-

tive lesions. In a multicenter trial involving patients with intermittent claudication, however, tread- mill exercise performance was no better 1 yr after treatment with ketanserin than with placebo (52).

H EMORHEOLOGIC A GENTS

Abnormal rheology is present in many patients with atherosclerotic disease. Oral pentoxifylline is in clinical use to improve the walking capacity of patients with intermittent claudication related to obstructive arterial disease, based upon salutary results in several clinical trials (53). In vitro, abnormally reduced erythrocyte flexibility of blood obtained from patients with claudication is partially corrected, and skeletal muscle oxygen tension has been reported to rise at rest following treatment with pentoxifylline. Improved blood fluidity in vivo has not been conclusively demon- strated, however, in patients with intermittent claudication treated with pentoxifylline. Vascular resistance during reactive hyperemia showed no improvement after administration of pentoxifyl- line compared with placebo in a study of patients with stable intermittent claudication. This result suggests that the hemorheologic effects of the drug were not sufficient to reduce the impedance to blood flow. In fact, pentoxifylline has not been shown to have conclusive clinical benefits (54).

M ETABOLIC A GENTS

Cilostazol, an inhibitor of phosphodiesterase-III with vasodilator, antiplatelet, and vascular smooth muscle cell inhibitory actions, was approved by the US Food and Drug Administration in 1999 for treatment of patients with intermittent claudication. The mechanism of its effect is not well understood. Cilostazol has been compared to placebo in eight controlled trials involving more than 2000 patients and in two studies to pentoxifylline (the only other drug approved in the US for treat- ment of patients with intermittent claudication). Primary endpoints were the distances patients could walk on a treadmill before the onset of claudication pain (initial claudication distance, ICD) and before pain became intolerable (absolute claudication distance, ACD). In six of the eight studies, ICD and ACD were significantly improved with cilostazol compared with placebo. In one study, cilostazol was superior to pentoxifylline; in the other comparison with pentoxifylline, neither drug was superior to placebo (55). In general, 100 mg cilostazol twice daily was superior to a lower dose of 50 mg twice daily. There are no data bearing on longer-term aspects of treatment, such as limb preservation, rate of disease progression, and so on. Several other phosphodiesterase inhibitors (such as milrinone and vesnarinone) have been associated with increased mortality when used as inotropic agents in patients with severe (NYHA class III–IV) congestive heart failure, and cilosta- zol is presently contraindicated in patients with a history of cardiac failure (56).

Propionyl

-carnitine reportedly facilitates transfer of acetylated compounds and fatty acids across mitochondrial membranes, leading to enhanced energy storage. Accumulation of acylcarni- tines in ischemic skeletal muscle correlates with impairment of exercise performance and may reflect abnormal oxidative metabolism (57). Increased substrate availability has been suggested as the mechanism by which proprionyl-

-carnitine supplementation may improve walking capac- ity in patients with intermittent claudication, as suggested by results from a European multicenter trial, but results have been inconsistent in different populations and larger studies are needed (58).

The mechanism by which prostaglandin E

(PGE

) and prostacyclin (PGI

), which are potent vasodilators and inhibitors of platelet aggregation, relieve ischemic rest pain and promote healing of ulcers remains controversial. Intravenous or intraarterial infusions of PGE

and PGI

have effects on blood flow and exercise capacity that persist for weeks to months, but intravenous administra- tion has yielded inconsistent results (59). The major drawback to this type of prostaglandin therapy is the short half-lives of these drugs, but oral analogs are under development. Overall, prostacyclins may provide temporary relief of ischemic rest pain in patients with severe arterial insufficiency, best when given intraarterially, but it is unknown whether this therapy will prevent amputation in patients not amenable to revascularization.

Recently, a few novel agents have been studied to improve walking capacity for PAD patients.

L

-arginine, a substrate for nitric oxide, increased pain-free and total walking distances in patients

with intermittent claudication after 2 wk of administration (60). Avasimibe, an inhibitor of acyl

coenzyme A-cholesterol acyltransferase (ACAT), given in a dose of 50 mg daily for 52 wk dem- onstrated a trend toward improved walking distances that did not reach statistical significance (61).

A NGIOGENESIS

Therapeutic angiogenesis involves administration of vascular growth factors, usually as recom- binant protein or DNA to augment the collateral blood supply to ischemic tissues. Recent clinical trials of angiogenic growth factors have given inconclusive results. The Therapeutic Angiogene- sis with Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (TRAFFIC) study demonstrated that intraarterial administration of recombinant fibroblast growth factor-2 (rFGF-2) improved walking distance in patients with intermittent claudication (62). The Regional Angiogen- esis with Vascular Endothelial growth factor (RAVE) trial, however, did not show improvement in peak walking time in patients with PAD treated with intramuscular vascular endothelial growth factor (VEGF) (63). In a recent study, injection of bone marrow-mononuclear cells into the legs of patients with PAD improved ABI, measurements of tissue oxygenation made by transcutaneous oximetry, and peak walking times 24 wk following implantation (64).

I MMUNE M ODULATION T HERAPY

A novel and investigational therapeutic technique known as immune modulation therapy (IMT) has recently been shown in a clinical trial to increase claudication distance in 70 patients with severe walking impairment (less than 100 m) (65). IMT involves the administration of ex vivo processed autologous blood to induce a cascade of events with the intent of reducing in vascular inflammation and progression of atherosclerosis. A larger multicenter trial of this technique, the Study of Immune Modulation Therapy in Peripheral Arterial Disease and Intermittent Claudication Outcomes (SIM- PADICO), is presently in progress.

Antithrombotic Therapy

Antithrombotic therapy should be considered part of the management of patients with PAD.

In those with chronic disease, the goal is to prevent progression of the obliterative process leading to thrombotic occlusion of arteries and to reduce coronary and cerebrovascular events and mortal- ity. Following limb revascularization, the objective is to prevent thrombotic complications and pre- serve the patency of reconstruction. In those with acute arterial occlusion resulting from embolism or thrombosis, therapy is directed toward preventing propagation of thrombus and recurrent embol- ism. Available approaches include anticoagulant medications, platelet inhibitor agents, thrombo- lytic substances, and direct inhibitors of thrombin. A combination of approaches is warranted for high-risk patients.

There is no conclusive evidence that antithrombotic therapy alters the clinical course of vascu- lar insufficiency related to arteriosclerosis obliterans, although some reports have suggested a bene- fit of anticoagulant or platelet inhibitor agents. Only recently have data emerged indicating that antithrombotic therapy delays the progression of atherosclerotic lesions. In double-blind studies involving several hundred patients, serial angiography revealed less pronounced progression of arterial disease in those randomly assigned to platelet inhibitor medication (aspirin or the combi- nation of aspirin plus dipyridamole) than in those given placebo (66). The role of platelet-inhibitor medication in retarding progression of the atherosclerotic plaque has been demonstrated over a longer period in patients with coronary artery disease.

Intermittent claudication carries important prognostic weight in terms of other atherothrombo-

tic cardiovascular events. Aspirin therapy has been convincingly demonstrated to reduce the risks

of myocardial infarction, ischemic stroke, and vascular death in patients with atherosclerosis. The

Antiplatelet Trialists Collaboration (ATC), a meta-analysis of more than 100 randomized clinical

trials involving about 70,000 participants, concluded that aspirin reduces these vascular events by

about 25%, regardless of dose (68). Nonfatal myocardial infarctions and strokes were reduced by

about one third, while vascular deaths by about one sixth (67). From the ATC, 9214 PAD patients

were reassessed and found to have a 23% reduction in vascular events with antiplatelet therapy (68).

The thienopyridine derivatives ticlopidine and clopidogrel antagonize the platelet adenosine diphos- phate receptor. In Clopidogrel versus Aspirin in Patients of Ischaemic Events (CAPRIE) a large, multicenter trial, 75 mg/d clopidogrel was compared with 325 mg/d aspirin over a mean follow-up of 1.5 yr in 19,185 patients with clinical atherosclerosis (69). Participants included survivors of myocardial infarction or nondisabling stroke as well as those with symptomatic peripheral arterial disease; the primary endpoint was a composite of ischemic stroke, myocardial infarction, or vascular death. Patients treated with clopidogrel had a 5.32% annual risk of primary events compared with 5.83% for those treated with aspirin (a statistically significant relative risk reduction of 8.7%). Most benefit was confined to the 6452 patients entered on the basis of peripheral arterial disease, in whom the relative risk reduction for occurrence of primary vascular events was 24% (p = 0.0028) (Fig. 6).

The benefit of combination clopidogrel and aspirin versus aspirin alone is currently under investiga- tion in patients at high cardiovascular risk, including PAD, in the Clopidogrel for High Atherothrom- botic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

Insufficient data have been forthcoming to validate an advantage to long-term anticoagulation for patients with PAD. The incidence of ischemic events was lower, and survival was greater, among selected anticoagulated patients following femoropopliteal bypass surgery than in a control group (70). The ABI declined more gradually in anticoagulated patients, and graft patency was prolonged out to 12 yr, but this falls short of confirming delayed progression of atherosclerotic vascular dis- ease. In fact, oral anticoagulation given to 2690 patients with PAD undergoing infrainguinal grafting did not reduce graft occlusion as compared with aspirin (71).

INTERVENTIONAL ANGIOGRAPHY

Considerable success has attended transluminal dilation for correction of iliac arterial stenoses, but patency rates are lower in the femoral and popliteal arteries. Initial and long-term success is related to the acuity of ischemic symptoms, morphologic features of the atherosclerotic segment (i.e., the length of obstruction, relation to anatomic branch points, and condition of the distal artery), and co- morbid conditions (e.g., diabetes, active smoking). Experience with obstructions distal to the poplit- eal trifurcation has been disappointing, but “steerable” devices drawn from coronary catheterization enhance outcome in selected cases. In view of the limitation of dilation techniques, various alter-

Fig. 6. Relative-risk reduction and 95% CI by disease subgroup in the CAPRIE trial. MI, myocardial infarction;

PAD, peripheral arterial disease. (From ref. 69.)

native recanalization tools have been developed. Currently, endovascular techniques used to treat atherosclerosis obliterans include percutaneous atherectomy, angioplasty, stents, and thrombolysis.

Antithrombotic therapy prior to catheter intervention is advocated in conjunction with balloon angioplasty procedures to reduce thrombus formation and the associated risk of occlusion at the dilated site. Current practice tends toward pre- and postprocedural administration of aspirin plus ticlopidine or clopidigrel, and intraprocedural administration of heparin, followed by maintenance therapy with aspirin or clopidogrel. Despite this widespread practice, the benefits of antiplatelet or anticoagulant therapy in conjunction with percutaneous interventions of peripheral arterial lesions have not been proven. Some reviewers reported no difference in reocclusion rates with antiplatelet or anticoagulant therapy following peripheral angioplasty (72), but a meta-analysis found increased patency and lower amputation rates with antiplatelet therapy (73).

Transcatheter Atherectomy and Endovascular Stents

Extraction of atherothrombotic material using the Simpson rotating blade device or abrasion and pulverization methods intends to remove atheromatous material and leave the remaining surface smooth. Unlike other methods of angioplasty, atherectomy appears well suited to eccentric athero- sclerotic lesions associated with calcification (74). For stenoses at the femoropopliteal level, angio- graphic success has been reported in 87 to 93% of the lesions removed; recurrent symptoms occurred in 31% of patients during 6 mo of clinical follow-up (75). Additionally, atherectomy for infra- popliteal occlusive disease has demonstrated an overwhelming high restenosis rate (91%) at 6 mo postintervention (76). Therefore, atherectomy is not recommended for routine peripheral athero- sclerotic lesions except for possible limb salvage.

Patency rates following angioplasty and endovascular stent deployment in iliac arterial stenosis were 92% at 9 mo and clinical benefit has been reported to extend for 2 yr (77). Results with infrain- guinal endovascular stents have not been as favorable, however, with restenosis or reocclusion rates of approx 50% in the femoropopliteal segment. Infrainguinal endovascular angioplasty with or with- out stents has been an accepted practice for salvage of critically ischemic limbs. The TASC working group recommends that endovascular interventions for iliac and femoropopliteal arterial occlu- sions that are <3 cm in length (type A) (Fig. 7) (30). Percutaneous angioplasty with stenting of long segment superficial femoral arterial disease has had poor restenosis and reocclusion rates (78).

Endovascular brachytherapy and drug-eluting stents have recently been reported to possibly decrease restenosis rates in intervened femoropopliteal and infrapopliteal arterial occlusions (79, 80). However, long-term prospective clinical trials are necessary to determine the utility of these techniques compared to conventional therapy.

Intraarterial Thrombolysis

Catheter-directed, intraarterial thrombolytic therapy has been used as an adjunct to revascular-

ization for management of both acute and chronic critical limb ischemia. Several studies have com-

pared thrombolytic therapy with surgical revascularization in patients with acute peripheral arterial

insufficiency and have shown comparable rates of mortality and limb salvage (81,82). In the Throm-

bolysis or Peripheral Arterial Surgery (TOPAS) trial, administration of urokinase versus surgery had

similar amputation-free survival at 12 mo (81). However the Surgery versus Thrombolysis for Ische-

mia of the Lower Extremity (STILE) trial showed higher reoccurrence for limb ischemia with lysis

compared to surgery (82). In both studies, lysis was equal to or possibly superior to surgery for arte-

rial occlusions <14 d in duration (81,82). Although the rate of successful reperfusion (50–80%) is

higher with local intraarterial than with systemic (intravenous) thrombolytic therapy, local infusions

allow concurrent angiographic definition of effectiveness and define regional vascular disease so

that angioplasty may be incorporated to prevent reocclusion. Bleeding or thromboembolism up

to 20% of cases may complicate protracted periods of indwelling arterial catheterization. Thrombo-

lytic therapy may be particularly useful in cases of thrombotic distal arterial occlusion in the forearm,

hand, ankle, and foot, where surgical access is difficult.

SURGICAL THERAPY

Surgical intervention is not indicated for the majority of patients with stable intermittent clau- dication who have sufficient collateral blood supply to meet the nutritional requirement of resting limb tissue. It is an indicated procedure if patients fail maximum aggressive medical management and have severe functional impairment. The most pressing indication for surgical revascularization is ischemic rest pain, ulceration, or gangrene amenable to arterial reconstruction when more limited measures, including angioplasty, are insufficient, unsafe, or not feasible. Since most patients with intermittent claudication remain stable or improve with time, surgical intervention becomes appro- priate when the disease process becomes severely debilitating or progressive.

Beyond the severity of ischemia and associated symptoms, the anatomic pathology is important in deciding whether surgery should be undertaken. In general, the syndromic approach to disease

Fig. 7. The TransAtlantic Inter-Society Consensus (TASC) recommendations in the interventional management

of iliac lesions. (Adapted from ref. 29.)

classification reflects the success of surgical bypass procedures. The TASC working group recom- mends that diffuse, multiple iliac lesions, and complete common femoral, superficial femoral, pop- liteal, or proximal trifurcation arterial occlusions be treated with surgery (type D) (Fig. 7) (30).

Revascularization for aortoiliac obstructive disease is associated with approx 85% patency rates at 5 to 10 yr; for femoropopliteal reconstruction, around a 70% patency rate at 5 yr; and for distal anastomosis located beyond the popliteal trifurcation, a patency rate in the range of 40 to 60% after 2 yr. This aspect should be interpreted in the context of a patient’s overall functional status and med- ical condition, with particular reference to risk imposed by associated coronary or cerebrovascular disease.

REFERENCES

1. Wilens SL. The nature of diffuse intimal thickening of arteries. Am J Pathol 1951;27:825–839.

2. World Health Organization Study Group. Classification of atherosclerotic lesions: report of a study group. WHO Tech Rep Ser 1958;143:1–20.

3. Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: The Framingham Study. J Am Geriatr Soc 1985;33:13.

4. Vogt MT, Cauley JA, Kuller LH, Hulley SB. Prevalence and correlates of lower extremity arterial disease in elderly women. Am J Epidemiol 1993;137:559–568.

5. Criqui MH, Froner A, Barrett-Connor E, et al. The prevalence of peripheral arterial disease in a defined population.

Circulation 1985;71:510–515.

6. Hiatt WR, Hoag S, Hamman RF. Effect of diagnostic criteria on the prevalence of peripheral arterial disease: the San Luis Valley Diabetes Study. Circulation 1995;91:1472–1479.

7. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286:1317–1324.

8. Mathiesen FR, Mune O. Arterial insufficiency in the lower extremities of elderly patients. Acta Chir Scand P Suppl 1966;357:78.

9. Meijer WT, Hoes AW, Rutgers D, et al. Peripheral arterial disease in the elderly: the Rotterdam Study. Arterioscler Thromb Vasc Biol 1998;18:185–192.

10. Paris BEC, Libow LS, Halperin JL, Mulvihill MN. The prevalence and one-year outcome of limb arterial obstruc- tive disease in a nursing home population. J Am Geriatr Soc 1988;36:607–612.

11. Greenhalgh RM, Rosengarten DS, Mervart I, et al. Serum lipids and lipoproteins in peripheral vascular disease.

Lancet 1971;3:947.

12. Fowkes FG, Housley E, Riemersma RA, et al. Smoking, lipids, glucose intolerance, and blood pressure as risk fac- tors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am J Epi- demiol 1992;135:331–340.

13. Sanderson KJ, van Rij AM, Wade CR, et al. Lipid peroxidation of circulating low density lipoproteins with age, smoking and in peripheral vascular disease. Atherosclerosis 1995;118:45–51.

14. Harris LM, Armstrong D, Browne R, et al. Premature peripheral vascular disease: clinical profile and abnormal lipid peroxidation. Cardiovasc Surg 1998;6:188–193.

15. Katsilambros NL, Tsapogas PC, Arvanitis MP, et al. Risk factors for lower extremity arterial disease in non-insulin- dependent diabetic persons. Diabet Med 1996;13:243–246.

16. Strandness DE Jr, Priest RE, Gibbon GE. Combined clinical and pathologic study of diabetic and nondiabetic periph- eral arterial disease. Diabetes 1964;13:366–372.

17. Kannel WB, McGee D, Gordon T. A general cardiovascular risk profile: The Framingham Study. Am J Cardiol 1976;

38:46.

18. Murabito JM, Evans JC, Nieto K, et al. Prevalence and clinical correlates of peripheral arterial disease in the Fram- ingham Offspring Study. Am Heart J 2002;143:961–965.

19. Stewart CP. The influence of smoking on the level of lower limb amputation. Prosthet Orthot Int 1987;11:113–116.

20. Ameli FM, Stein M, Prosser RJ, et al. Effects of cigarette smoking on outcome of femoral popliteal bypass for limb salvage. J Cardiovasc Surg (Torino) 1989;30:591–596.

21. Coffman JD, Javett SL. Blood flow in the human calf during tobacco smoking. Circulation 1963;28:932.

22. Imparato AM, Kim G, Davidson T, et al. Intermittent claudication: its natural course. Surgery 1975;78:795.

23. Hertzer NR, Young JR, Kramer JR, et al. Routine coronary angiography prior to elective aortic reconstruction. Arch Surg 1979;114:1336.

24. Criqui M, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients ith peripheral arterial disease.

N Engl J Med 1992;328:381–386.

25. Muluk SC, Muluk VS, Kelley ME, et al. Outcome events in patients with claudication: a 15-year study in 2777 patients.

J Vasc Surg 2001;33:251–257.

26. The Framingham Study: an Epidemiologic Investigation of Cardiovascular Disease. US Government Printing Office, Section 25, 1970.

27. Schadt DC, Hines EA Jr, Juergens JL, et al. Chronic atherosclerotic occlusion of the femoral artery. JAMA 1961;

175:937.

28. Coffman JD. Intermittent claudication: be conservative. N Engl J Med 1991;325:577–578.

29. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. Trans- Atlantic Inter-Society Concensus (TASC). J Vasc Surg 2000;31:S1–S296.

30. McDermott MM, Greenland P, Liu K, et al. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med 2002;136:873–883.

31. Montgomery DH, Ververis JJ, McGorisk G, et al. Natural history of severe atheromatous disease of the thoracic aorta: a transesophageal echocardiographic study. J Am Coll Cardiol 1996;27:95–101.

32. Slovut DP, Olin JW. Fibromuscular dysplasia. N Engl J Med 2004;350:1862–1871.

33. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000;343:864–869.

34. Adar R, Papa MZ, Halpern Z, et al. Cellular sensitivity to collagen in thromboangiitis obliterans. N Engl J Med 1983;

308:1113–1116.

35. Thiele B. Evaluation of ulceration of the lower extremities. Vasc Diag Ther 1980;1:33.

36. Karmody A, Wittmore AD, Baker JD, Ernst CB. Suggested standards for reports dealing with lower extremity ische- mia. J Vasc Surg 1986;4:80–94.

37. Halperin JL. Noninvasive vascular laboratory evaluation: applications for laser angioplasty. In: Sanborn TA, ed.

Laser Angioplasty. AR Liss, New York, 1989, pp. 7–14.

38. Owen RS, Carpenter JP, Baum RA, et al. Magnetic resonance imaging of angiographically occult runoff vessels in peripheral arterial occlusive disease. N Engl J Med 1992;326:1577–1581.

39. Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandina- vian Simvastatin Survival Study (4S). Am J Cardiol 1998;81:333–338.

40. Regensteiner JG, Hiatt WR. Current medical therapies for patients with peripheral arterial disease: a critical review.

Am J Med 2002;112:49–57.

41. Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med 2003;114:359–364.

42. Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandina- vian simvastatin survival study (4S). Am J Cardiol 1998;81:333–335.

43. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;

329:977–986.

44. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–853.

45. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.

HOT Study Group. Lancet 1998;351:1755–1762.

46. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascu- lar events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;

342:145–153.

47. Lassila R, Lepantalo M. Cigarette smoking and the outcome after lower limb arterial surgery. Acta Chir Scand 1988;

154:635–640.

48. Faulkner KW, House AK, Castleden WM. The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease. Med J Aust 1983;1:217–219.

49. Jonason T, Bergstrom R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of periph- eral vascular complications, myocardial infarction and mortality. Acta Med Scand 1987;221:253–260.

50. Skinner JS, Strandness DE Jr. Exercise and intermittent claudication: II. Effect of physical training. Circulation 1967;

36:23.

51. Coffman JD, Mannick JA. Failure of vasodilator drugs in arterioclerosis obliterans. Ann Intern Med 1972;76:35–59.

52. PACK Claudication Substudy Investigators. Randomized placebo-controlled, double-blind trial of ketanserin in claudicants: changes in claudication distance and ankle systolic pressure. Circulation 1989;80:1544–1548.

53. Porter JM, Cutler BS, Lee BY, et al. Pentoxifylline efficacy in the treatment of intermittent claudication: multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients. Am Heart J 1982;104:66–72.

54. Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: a meta-analysis. Arch Intern Med 1999;159:337–345.

55. Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent clau- dication. Am J Med 2000;109:523–530.

56. Dawson DL, Cutler BS, Meissner MH, et al. Cilostazol has beneficial effects in treatment of intermittent claudica- tion. Circulation 1998;98:678–686.

57. Hiatt WR, Nawaz D, Brass EP. Carnitine metabolism during exercise in patients with peripheral arterial disease.

J Appl Physiol 1987;74:236–240.

58. Brevetti G, Chiariello M, Ferulano G, et al. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation 1988;77:767–773.

59. The ICAI (Ischemia Cronica degli Arti Inferiore) Study Group. Prostanoids for chronic critical limb ischemia:

a randomized, controlled, open-label trial with prostaglandin E

. Ann Intern Med 1999;130:412–421.