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(Circulation. 1996;94:3026-3049.)
© 1996 American Heart Association, Inc.

Articles

Diagnosis and Treatment of Chronic Arterial Insufficiency of the Lower Extremities: A Critical Review

Jeffrey I. Weitz, MD, Chair; John Byrne, MD; G. Patrick Clagett, MD; Michael E. Farkouh, MD; John M. Porter, MD; David L. Sackett, MD; D. Eugene Strandness, Jr, MD; Lloyd M. Taylor, MD

Key Words: AHA Medical/Scientific Statements • peripheral vascular disease • ischemia • claudication • aging

	Introduction

Top Introduction Epidemiology Rules of Evidence Used... Noninvasive Evaluation of Lower... Medical Treatment of... Radiological Interventional... Surgical Treatment Recommendations References

 
Atherosclerosis is the most common cause of chronic arterial occlusive disease of the lower extremities. The arterial narrowing or obstruction that occurs as a result of the atherosclerotic process reduces blood flow to the lower limb during exercise or at rest. A spectrum of symptoms results, the severity of which depends on the extent of the involvement and the available collateral circulation. Thus, symptoms may range from intermittent claudication to pain at rest. Intermittent claudication denotes pain that develops in the affected limb with exercise and is relieved with rest. This pain usually occurs distal to the arterial narrowing or obstruction. Since the superficial femoral and popliteal arteries are the vessels most commonly affected by the atherosclerotic process, the pain of intermittent claudication is most often localized to the calf. The distal aorta and its bifurcation into the two iliac arteries are the next most frequent sites of involvement. Narrowing of these arteries may produce pain in the buttocks or the thighs as well as the legs.

Epidemiological studies indicate that up to 5% of men and 2.5% of women 60 years of age or older have symptoms of intermittent claudication.^{1 2} The prevalence is at least threefold higher when sensitive noninvasive tests are used to make the diagnosis of arterial insufficiency in asymptomatic and symptomatic individuals.³ The symptoms of chronic arterial insufficiency of the lower extremities progress rather slowly over time. Thus, after 5 to 10 years, more than 70% of patients report either no change or improvement in their symptoms, while 20% to 30% have progressive symptoms and require intervention, and less than 10% need amputation.^{4 5} Despite the relatively benign prognosis for the affected limb, however, symptoms of intermittent claudication should be viewed as a sign of systemic atherosclerosis. This explains why, compared with age-matched controls, patients with intermittent claudication have a threefold increase in cardiovascular mortality.^{1 2}

The goals of therapy in patients with chronic arterial insufficiency of the lower extremities are twofold. First, with respect to the affected limb or limbs, the goal is to eliminate ischemic symptoms and prevent progression to vascular occlusion. Accepted treatments are listed in Table 1 and include nonsurgical measures such as exercise, risk factor modification, and pharmacological therapy, as well as surgical treatment, which includes interventional radiological procedures such as angioplasty or stent insertion and surgical treatment such as endarterectomy, bypass grafting, and amputation. The second goal of therapy in patients with intermittent claudication is to prevent cardiovascular complications (ie, stroke, myocardial infarction, and death), which may result from widespread atherosclerosis. At present the best treatment for this indication appears to be aspirin, 75 to 325 mg daily.⁶ Ticlopidine is a reasonable alternative for patients who are intolerant of aspirin.^{7 8 9 10}

View this table: [in this window] [in a new window]   Table 1. Accepted Treatments for Symptomatic Lower Extremity Atherosclerotic Occlusive Disease

The purpose of this paper was to develop guidelines for the treatment of patients with lower extremity arterial disease. The committee first reviewed the epidemiology of the disorder to determine the scope of the problem. Using predefined criteria to grade the quality of the scientific data, the committee then critically evaluated the literature concerning the noninvasive diagnosis and the pharmacological, radiological, and surgical management of atherosclerotic disease of the lower extremities.

	Epidemiology

Top Introduction Epidemiology Rules of Evidence Used... Noninvasive Evaluation of Lower... Medical Treatment of... Radiological Interventional... Surgical Treatment Recommendations References

 
Atherosclerotic vascular disease affecting the lower extremities is the most common form of peripheral vascular disease and can lead to clinical conditions ranging from intermittent claudication or pain at rest to ulceration and gangrene. With a greater percentage of the North American population older than 65, the incidence of lower extremity arterial disease has progressively increased over the past few decades.

Depending on its severity, lower extremity arterial disease can present in different ways, including (1) asymptomatic arterial insufficiency, (2) symptomatic disease presenting as intermittent claudication with positive noninvasive tests, and (3) critical leg ischemia, which defines the subgroup of patients with symptomatic lower extremity arterial disease in which the ischemic process endangers part or all of the lower extremity.¹¹

Prevalence
The prevalence of lower extremity arterial disease is highly dependent on the definition of the condition. Using the classification outlined above, the prevalence of this disorder can be gleaned from the literature.

Asymptomatic Arterial Insufficiency
These patients are identified by a low ankle-brachial index (ABI), which is determined by dividing the systolic blood pressure measured at the ankle by that obtained in the brachial artery. Lower extremity arterial disease is defined by a low ABI, usually 0.9 but ranging in the literature from <0.80 to <0.97.^{3 12 13 14 15 16} The incidence of asymptomatic lower extremity arterial disease in the 55- to 74-year-old age group is about 10% when an ABI <0.9 is used as a reference standard.¹⁷

Symptomatic Lower Extremity Arterial Disease: Diagnosis by Questionnaire or Interview
Several epidemiological studies have used a questionnaire or interview approach to determine the prevalence of intermittent claudication. It is estimated that 1 million Americans become symptomatic each year.¹⁸ The most robust questionnaire developed to date appears to be the Edinburgh Claudication Questionnaire (ECQ), which is a modification of the World Health Organization/Rose Questionnaire. The ECQ has been validated in a study of approximately 300 patients older than 55 who saw their physician for any complaint. When compared with the independent assessment of two blinded clinicians, the ECQ showed a sensitivity of 91% and a specificity of 99% for the diagnosis of intermittent claudication.¹⁹

Using the ECQ to screen 1592 men and women aged 55 to 74 in the Edinburgh Artery Study, Fowkes and colleagues¹⁷ found a 4.6% prevalence of lower extremity arterial disease. In the Framingham study, in which a biannual validated questionnaire was used to screen for symptomatic lower extremity arterial disease, the average rate of development of intermittent claudication over a 2-year period in subjects older than 50 was 0.7% and 0.4% for men and women, respectively.²⁰

Many other population-based studies have shown that the prevalence of intermittent claudication is highly dependent on age, sex, and geographic location of the subjects. Consistent among these studies are the findings that the prevalence of lower extremity arterial disease increases with age and that its predominance in males diminishes after age 70.^{1 3 13 17 21}

Lower Extremity Arterial Disease: Diagnosis by Noninvasive Techniques
Two population-based studies have evaluated the prevalence of lower extremity arterial disease in patients older than 55 when an ABI 0.9 was used as the reference standard.^{17 21} In the Edinburgh Artery Study the prevalence of lower extremity arterial disease was 17% for patients aged 55 to 74.¹⁷ Similar results were found in a study in Denmark that included almost 700 patients aged 60 years. In this study the prevalence of lower extremity arterial disease was 16% for men and 13% for women.¹ Based on these results, it appears that the prevalence of lower extremity arterial disease is about threefold higher when an ABI 0.9 is used as the reference standard instead of the ECQ. Thus, the ABI seems to be a more sensitive index of disease than the ECQ because a large group of asymptomatic or mildly symptomatic patients have a negative ECQ despite an ABI 0.9.

Critical Leg Ischemia
The patients most seriously affected with lower extremity arterial disease have critical leg ischemia that endangers the viability of the lower extremity and includes patients undergoing surgical revascularization procedures or limb amputation.¹¹ It is estimated that approximately 15% to 20% of patients with lower extremity arterial disease will progress from intermittent claudication to critical leg ischemia over the course of their disease. ^{2 22} If the prevalence of intermittent claudication is about 15% for patients older than 50,^{17 21} then about 1% of this population suffers from critical limb ischemia.

Risk Factors
The risk factors for atherosclerosis of the vessels of the lower extremities are the same as those for other vascular beds and include advanced age, male sex, diabetes mellitus, cigarette smoking, hypertension, and increased lipid levels. The influence of each of these risk factors on lower extremity arterial disease is discussed below.

Age
The incidence of lower extremity arterial disease increases with age. For a man younger than 50, the prevalence of intermittent claudication is about 1% to 2%, whereas for those older than 50, prevalence increases to about 5%.^{22 23} A similar trend is seen in women. Given these findings, it is likely that lower extremity arterial disease will become more common as life expectancy increases.

Male Gender
The prevalence of intermittent claudication in women over 50 is approximately 2.5%.²⁴ After age 70, however, prevalence rates for men and women are almost identical.²³

Diabetes Mellitus and Impaired Glucose Tolerance
Numerous studies have demonstrated an association between diabetes mellitus and the development of lower extremity arterial disease.^{25 26 27} In one geographically defined population, almost 25% of patients undergoing lower extremity revascularization surgery were diabetic.²⁸ Furthermore, persons with diabetes have a sevenfold higher rate of lower extremity amputation than persons without diabetes.^{29 30} However, the increased risk of amputation is likely multifactorial in origin and may be related to more distal and diffuse atherosclerosis among persons with diabetes, as well as concomitant peripheral sensory neuropathy that can lead to traumatic ulceration. Finally, impaired glucose tolerance has also been associated with a twofold or fourfold increase in the risk of developing intermittent claudication for men and women, respectively.³¹

Smoking
Cigarette smoking has long been identified as an important risk factor for cardiovascular disease. The association between smoking and lower extremity arterial disease may, in fact, be even stronger than between smoking and coronary heart disease.²⁷ All epidemiological studies of lower extremity arterial disease have confirmed cigarette smoking as a strong risk factor for development of lower extremity arterial disease, with relative risk ratios ranging from 1.7 to 7.5.^{1 13 21 30 31} Furthermore, a diagnosis of lower extremity arterial disease is made up to a decade earlier in smokers than in nonsmokers.^{32 33 34} Based on these observations, interventions to decrease or eliminate cigarette smoking have long been advocated for patients with lower extremity arterial disease.

Hypertension
The Framingham Study provides the most convincing epidemiological evidence linking hypertension with lower extremity arterial disease. In the hypertensive population, there appears to be a gender difference for development of intermittent claudication, with females experiencing a relative risk ratio near 4 and males having a relative risk ratio of about 2.³⁰ Somewhat different results were found in a more recent study in which hypertensive men had an increased risk of developing lower extremity arterial disease but women did not.³²

Hyperlipidemia
Almost 50% of patients with lower extremity arterial disease have hyperlipidemia. In the Framingham Study a fasting cholesterol level >270 mg/dL (7 mmol/L) was associated with a doubling of the incidence of intermittent claudication.³⁵ Although other studies have failed to confirm an association between lower extremity arterial disease and elevated cholesterol levels,^{30 31 36} there is evidence that treatment of hyperlipidemia reduces both progression of atherosclerosis in the peripheral arteries and incidence of intermittent claudication.^{37 38} Finally, an association between lower extremity arterial disease and hypertriglyceridemia has also been reported, but the strength of this association is unclear.^{1 13 20 21 30 31}

Natural History
A knowledge of the natural history of lower extremity arterial disease is necessary when planning management strategies. When patients with intermittent claudication are followed for 5 years, about 50% either have no change in symptoms or may show improvement in functional status presumably due to development of collateral flow. Symptoms progress in about 16% of these patients, and a full 25% will require surgery or experience tissue loss. Less than 4% of patients require a major amputation.³⁹ In the Framingham Study only about 30% of patients with intermittent claudication had persistent symptoms for a minimum of 4 years.⁴⁰

The long-term amputation rate for patients with intermittent claudication is consistently less than 4%. For example, in two large population studies only 1.8% to 2.5% of patients diagnosed with intermittent claudication ever required a major amputation.^{25 40} More recently the estimated major amputation rate has been tabulated on the basis of the results of two independent studies.^{41 42} The major amputation rate in persons without diabetes ranged from 200 to 280 per million per year, whereas in persons with diabetes the rate was markedly higher at 3000 to 3900 per million per year.

In one population-based study of patients with lower extremity arterial disease undergoing initial revascularization surgery, about 20% of patients eventually required an ipsilateral amputation, and 26% required at least one repeat ipsilateral revascularization procedure.²⁸ Patients undergoing aortoiliac or aortofemoral surgery were less likely to require amputation than patients with a more distal revascularization procedure (26% versus 16%; P=.03).

Risk of Cardiovascular Morbidity and Mortality
Because patients with either asymptomatic or symptomatic lower extremity arterial disease have widespread arterial disease, they have a significantly increased risk of stroke, myocardial infarction, and cardiovascular death. At least 10% of patients with lower extremity arterial disease have cerebrovascular disease, and 28% have coronary heart disease.²³

The mortality rate in patients with intermittent claudication is two to three times higher than that in age- and sex-matched controls.²⁰ In one study all-cause mortality 5 and 15 years after the diagnosis of lower extremity arterial disease was 30% and 70%, respectively, compared with 10% and 30% in the appropriate control groups.²² The 5-year mortality rate was 40% in those patients with concomitant symptomatic coronary artery or cerebrovascular disease.²² Thus, in patients with lower extremity arterial disease, 75% will die of a coronary or cerebrovascular event.²⁰

Recently, two epidemiological studies have shown that a low ABI is an independent predictor of both all-cause and cardiovascular mortality.^{43 44} In a substudy of the Systolic Hypertension in the Elderly Program (SHEP) trial, an ABI 0.9 predicted all-cause mortality with a relative risk ratio of 3.8. Similarly, in a study of women over 65, an ABI 0.9 predicted all-cause mortality with a relative risk of 3.1. These findings have prompted the suggestion that measurements of ABI be included as an integral part of the screening physical examination in patients over 55.

In addition to the effects of lower extremity arterial disease on cardiovascular mortality, risk of cardiovascular morbidity is also increased. For example, in one study 20% of patients with intermittent claudication suffered a nonfatal cardiovascular event (eg, myocardial infarction or stroke) over a 5-year period.²⁴ Therefore, the importance of identifying patients with lower extremity arterial disease extends beyond its impact on the lower extremity vascular system. Instead, as illustrated in Fig 1, lower extremity arterial disease should be viewed as a sign of potentially diffuse and significant arterial disease.

View larger version (1K): [in this window] [in a new window]   Figure 1. Epidemiology of lower extremity arterial disease in the population over the age of 55. ABI indicates ankle-brachial index; MI, myocardial infarction.

	Rules of Evidence Used to Develop Clinical Recommendations for the Treatment of Lower Extremity Arterial Disease

Top Introduction Epidemiology Rules of Evidence Used... Noninvasive Evaluation of Lower... Medical Treatment of... Radiological Interventional... Surgical Treatment Recommendations References

 
When summarizing what is known about the causes, clinical course, and management of lower extremity arterial disease, the committee specified the level of evidence used in each case, according to the following classification.

Level I: Randomized trials with low false-positive () and/or low false-negative (ß) errors (high power)
"Low false-positive () error" means a "positive" trial that demonstrated a statistically significant benefit from experimental treatment, whereas "low false-negative (ß) error (high power)" means a "negative" trial that demonstrated either no effect of therapy or no difference between therapies yet was large enough to exclude the possibility of a clinically important benefit of active treatment over placebo or of one active treatment over another (ie, very narrow 95% confidence limits that excluded any clinically important difference between treatment groups).

Level II: Randomized trials with high false-positive () and/or high false-negative (ß) errors (low power)
"High false-positive () error" means a trial with an interesting positive trend that was not statistically significant, whereas "high false-negative (ß) error (low power)" means a "negative" trial that concluded that therapy was not efficacious or that two treatments had similar efficacy, yet because of small numbers of patients could not exclude the real possibility of a clinically important benefit or difference between agents (ie, very wide 95% confidence limits on the difference between treatment groups). The advent of meta-analysis has a major impact in this instance, because it can convert two or more high-quality, homogeneous but small (and therefore level II) trials into a single level I overview.

Level III: Nonrandomized concurrent cohort comparisons
In this case the outcomes of patients who received and complied with a treatment were compared with those of contemporaneous patients who did not (eg, refusal, noncompliance, contraindication, local practice, or oversight) receive these same drugs.

Level IV: Nonrandomized historical cohort comparisons
In this case the outcomes of patients who received therapy (as a result of a local treatment policy) were compared with those of patients treated in an earlier era or at another institution (when and where different treatment policies prevailed).

Level V: Case-series without controls
In this case the reader is simply informed about the fate of a group of patients. Such series may contain extremely useful information about clinical course and prognosis but can only hint at efficacy.

Grading of Recommendations
Ultimate recommendations on the use of therapy are classified into three grades, depending on the level of evidence used to generate them. These three grades of recommendations are illustrated in Table 2 and include grade A, supported by at least one and preferably more level I randomized trial(s); grade B, supported by at least one level II randomized trial; and grade C, supported only by level III, IV, or V evidence.

View this table: [in this window] [in a new window]   Table 2. Relation Between Levels of Evidence and Grades of Recommendations

It is hoped that in time advances in understanding of both the treatment of lower extremity arterial disease and the mechanisms responsible for its pathogenesis will be matched by more level I evidence; such advances will be reflected in an ever-greater proportion of grade A recommendations in the future.

	Noninvasive Evaluation of Lower Extremity Arterial Disease

Top Introduction Epidemiology Rules of Evidence Used... Noninvasive Evaluation of Lower... Medical Treatment of... Radiological Interventional... Surgical Treatment Recommendations References

 
The noninvasive laboratory has come to occupy an important place in the evaluation of patients with peripheral arterial disease of the lower extremities.⁴⁵ While a wide variety of diseases affect the peripheral arteries, the most common is atherosclerosis. The disease is largely one of large- and medium-sized arteries and most frequently involves branch points and bifurcations.

A well-performed physical examination can often determine the proximal site or sites of involvement by obvious pulse deficits and the presence of a bruit at sites of narrowing. For example, absent foot and popliteal pulses indicate an occlusion proximal to the popliteal artery but tell the examiner nothing about the extent of disease below the knee. Before the availability of noninvasive testing, nothing more was usually done unless there was some indication for intervention to increase peripheral blood flow and relieve symptoms. However, with time and experience, it is now known that noninvasive testing can provide the physician with valuable information that can be used for both diagnostic and follow-up purposes.

Whenever arterial occlusive disease is suspected, it is important to determine whether or not the patient has diabetes mellitus, because persons with diabetes have a different distribution of arterial disease with greater involvement of the more distal (ie, tibial) arteries.^{46 47 48 49} In addition, the frequent presence of medial calcification of the tibial and peroneal arteries may create problems when the usual noninvasive tests are used. The most commonly used diagnostic tests are reviewed in this section.

Diagnostic Tests
Pressure Measurements: Ankle-Brachial Index
With increasing degrees of arterial narrowing, there is a progressive fall in systolic blood pressure distal to the sites of involvement.^{50 51} The extent to which pressure falls is dependent on the extent of involvement. This fact has lead to development of methods of indirectly measuring this pressure drop. By the use of sensors, such as continuous-wave (CW) Doppler and a variety of plethysmographic methods, it is possible to measure systolic pressures at all levels of the limb, ie, from the toes to the upper thigh.^{50 52} To accomplish this, a pneumatic cuff is applied to measure the pressure, and the sensing unit is placed distal to the cuff. The cuff is then rapidly inflated above systolic pressures, thereby obliterating flow to the part under study. As the pressure in the cuff is gradually deflated, the point at which flow is resumed is taken as the opening or systolic pressure at that level.

Normally, there is amplification of systolic pressure farther down the limb, ie, systolic pressure at the ankle level should be higher than that recorded from the upper arm.⁵⁰ This means that the systolic pressures recorded from both tibial arteries at the ankle should be at least equal to or higher than that recorded from the arm. Thus, the normal ABI should be 1.0. To account for variability in the measurement, it is generally agreed that a value of 0.95 is normal. For follow-up purposes, changes in the ABI within the range of ±0.15 are considered within the experimental error of the test, whereas changes outside this range are considered indicative of the disease process.⁴⁹ A higher value signifies improvement in arterial perfusion via collaterals, whereas a lower value indicates a decrease in perfusion either because of disease progression or as a result of problems with a reconstructive procedure.

The absolute pressures should also be recorded because they provide a rough index of perfusion at that level. This is particularly important in patients with acute arterial ischemia or in those with critical ischemia. In general, a pressure >50 mm Hg is consistent with good collateral circulation, whereas lower levels often indicate marginal perfusion to the foot.

Assessment of the ABI helps to establish the diagnosis and also serves as a baseline measure for follow-up purposes. ABI determinations may be of limited value in persons with diabetes, however, because calcification of the tibial and peroneal arteries may render them noncompressible. This is an important distinction because there is no relation between calcification and the extent of atherosclerotic disease within these arteries.⁴⁹

Exercise Testing
Measurements of ankle blood pressure can be made both before and after exercise to assess the dynamics of intermittent claudication. At modest workloads a healthy subject can maintain ankle systolic pressures at normal levels. If the exercise is strenuous, there may be a transient fall in systolic pressure that rapidly returns to baseline levels. In patients with intermittent claudication, however, a different response is seen, even at a low workload. Thus, if the patient walks to the point of claudication, ankle systolic pressure falls precipitously, often to unrecordable levels, and will not return to baseline levels for several minutes.^{53 54 55}

Current practice is to use a treadmill preset at a speed of 2 mph with a 12-degree grade.⁵¹ These settings tend to be well tolerated by most patients with intermittent claudication. As the patient walks on the treadmill, time to pain and maximal walking time are recorded. In practice, however, walking time is limited to 5 minutes, because this is sufficient to identify patients with claudication.

The patient walks on the treadmill with the ankle pressure cuffs in place. Once the walk is completed or pain develops, the patient is rapidly placed in the supine position and the ankle pressures are once again measured. Although it is a common practice to also measure arm systolic pressures after exercise, not only is this unnecessary, but it may actually be misleading because (1) arm systolic pressure normally increases after exercise by an amount related to workload and (2) the most important variable is the extent to which ankle pressure falls and the time it takes to recover, ie, the period of postexercise ischemia.^{56 57} In general, if ankle pressure falls by more than 20% of the baseline value and requires more than 3 minutes for recovery, the test is considered abnormal.

Toe Systolic Pressure Index
Because the prevalence of peripheral arterial disease is about 20-fold higher in patients with diabetes mellitus than in age- and sex-matched controls, it is important to consider these patients separately.⁵⁸ Arterial disease in persons with diabetes tends to be more severe and widespread. In addition, calcification of the media is common in these patients, making it difficult to measure ankle pressures. However, because medial calcification does not extend into the digital arteries, it is possible to assess perfusion pressure by measuring toe systolic pressure using either a strain-gauge sensor or a photoplethysmograph.^{59 60} Toe systolic pressure can then be expressed as a ratio of pressure recorded from the arm to obtain the toe systolic pressure index (TSPI).

In measuring toe pressure, it is important to record both the absolute pressure and the index. Normally, the TSPI should be >0.60.⁶¹ Variability of the measurement is ±17%. The absolute levels of systolic pressure may be of value in estimating the healing potential when an ulcer is present. If the absolute pressure is 30 mm Hg, healing is unlikely to occur without some form of intervention.⁶⁰

Segmental Pressures and Pulse Volume Recordings
The level of arterial disease can be estimated by measuring pressures at multiple levels, ie, ankle, calf, above the knee, and upper thigh.⁵⁰ This is done using specially designed cuffs with bladders that encircle the entire limb. Four cuffs of uniform width are used, one for each level of the limb. Although pressures above the knee are artifactually elevated, they can help to localize the site or sites of occlusion. The pulse volume recorder provides similar information but uses the recorded contour of the transmitted pulse as the index of normalcy, since a pulse of normal volume has a sharp systolic peak and a dicrotic wave on the downslope.⁶¹

Flow Velocity Determination
Arterial disease not only changes the normal pressure relations in the limb but also affects the patterns of flow velocity distal to sites of disease. Normally, the arterial velocity patterns in the lower limb at rest have a triphasic pattern, ie, forward flow, reverse flow, and late forward flow.⁵⁵ All of these occur within one pulse cycle and can be observed from the aortoiliac area to the distal tibial and peroneal arteries. The presence of a triphasic velocity pattern excludes a pressure- and flow-reducing lesion proximal to the recording site. With pressure- and flow-reducing lesions, the following may be noted: (1) an increase in peak systolic velocity at the site of narrowing, (2) turbulence distal to the lesion, (3) loss of the reverse flow component, and (4) a reduction in the peak systolic velocity distal to the site of involvement.⁶²

With experience, all of these changes can be assessed with a CW Doppler simply by using the audio output of the system.⁵² With a fast Fourier transform system with directional capabilities, it is possible to record the patterns observed. One disadvantage of the CW system is that it does not provide precise information on the artery being studied. For example, if listening over the superficial femoral artery, it is impossible to be certain that the detected signal came from that artery. This problem is eliminated by using ultrasonic duplex scanning.

Even with the shortcomings of CW systems, they can provide useful indirect information at the bedside at the same time the ABI is being measured. These systems can also be of value when studying diabetic patients with noncompressible arteries. Finally, the nature of the velocity signal obtained with CW systems helps to establish a diagnosis of arterial disease. For example, a monophasic velocity signal from the tibial arteries at the ankle is indicative of more proximal disease.

Ultrasonic Duplex Scanning
Ultrasonic duplex scanning was initially developed to evaluate the extent of atherosclerosis at the carotid bifurcation^{62 63 64} because of the relation between atherosclerosis at this site and stroke. The proximity of the carotid artery to the skin surface makes it readily accessible to ultrasonic energy. In contrast, because the arteries in the lower limbs are at differing depths (abdominal aorta to tibial and peroneal arteries), technological improvements were necessary before they could be successfully examined with this method.^{65 66 67}

The first study of the peripheral arterial circulation by duplex scanning was published in 1985.⁶⁵ This study clearly showed that the method was as accurate in defining the location and severity of arterial lesions as were two radiologists reading arteriograms done in the same patients. Similar results have been obtained when the technique has been applied prospectively,⁶⁷ as summarized in Table 3.

View this table: [in this window] [in a new window]   Table 3. Comparison of Duplex Scanning With Arteriography for Detection of a Stenosis 50% in 20 Patients

To properly use duplex scanning, certain facts must be understood. First, in the arterial supply to the lower limbs, a lesion that reduces pressure and flow under resting circumstances is considered a "critical" stenosis.⁶⁸ Although a reduction in arterial diameter 50% is usually required to produce this problem, lesions that produce less of a decrease in vessel diameter can also produce symptoms of exercise if the flow distal to the stenotic segment is disturbed.⁶⁹ When this occurs, there is loss of potential energy (pressure) that can lead to a flow reduction to the active muscle groups. This is most commonly observed with lesions in the iliac arteries.

Second, estimation of the degree of stenosis by duplex scanning^{65 70} depends on changes in peak systolic velocity that occur from one segment to another. For documentation of the sites and extent of involvement, it is necessary to study the arterial system from the abdominal aorta to the arteries of the distal limb. The B-mode image does not provide sufficient resolution to determine the degree of narrowing. Thus, even though atherosclerotic plaques and areas of calcification can be identified, the degree of stenosis cannot be accurately measured with this technique.

On the basis of a study of 55 healthy subjects,⁶² the normal ranges of peak systolic velocities are 100±20 cm/s in the abdominal aorta; 119±22 cm/s in the common external iliac arteries; 114±25 cm/s in the common femoral artery; 91±14 cm/s in the proximal superficial femoral artery; 94±14 cm/s in the distal superficial femoral artery; and 69±14 cm/s in the popliteal artery. The most reliable method for determining the degree of arterial narrowing is to compare peak systolic velocity changes from one segment of the artery to the next. To accomplish this, the entire length of the artery in question should be scanned using color-flow Doppler. The following criteria are used: normal is a triphasic waveform; a minimal wall lesion (1% to 19% narrowing) is defined as spectral broadening alone; and a 20% to 49% stenosis is indicated by an increase in peak systolic velocity >30% but <100% from the preceding segment with preserved reverse flow even though spectral broadening may be present. A critical stenosis (50% to 99%) is indicated by an increase in peak systolic velocity >100% from one segment to the next, although some investigators have found a 150% increase to be more reliable. Finally, no flow indicates total occlusion.⁶²

Color alone can be used to estimate the degree of narrowing, and although not as precise, it does provide a rough index of disease severity. Normally there is a triphasic color response. Poststenotic turbulence and the presence of a bruit at the site of narrowing are indicative of >50% stenosis, whereas the complete absence of color and evidence of collateral arteries proximal to the site of obstruction suggest total occlusion.^{71 72}

The use of color can also shorten the examination time by aiding in the identification of arteries to the level of the ankle. However, color should not be used without the simultaneous application of real-time spectral analysis of the detected velocity changes. Best results are obtained when the arteries of interest are first identified by color and spectral analysis is then used to quantify the velocity changes across the detected lesion. As illustrated in Table 4, when compared with arteriography, color-Doppler scanning is useful for detecting total occlusion of arteries down to the level of the ankle.^{71 72}

View this table: [in this window] [in a new window]   Table 4. Comparison of Color Doppler Scanning With Arteriography for Detection of Areas of Complete Occlusion in 29 Males

Applications of Duplex Scanning
Although duplex scanning can provide detailed information concerning the status of the arterial system, it should only be used when the patient is scheduled for some form of intervention such as balloon angioplasty or direct arterial surgery. In this setting the stenotic segments are localized, which is helpful in planning treatment.⁷³

Duplex scanning also is useful in follow-up studies of patients who have undergone some form of intervention. In particular, patients who have undergone femoropopliteal or distal saphenous vein grafts^{74 75 76} benefit from close follow-up because 20% to 30% develop myointimal hyperplastic lesions that can be detected by duplex scanning before graft failure occurs. Although surveillance protocols vary, most surgeons follow these patients every 6 weeks to 3 months during the first year and every 6 months thereafter.

Data from several sources suggest that a surveillance program can extend the life of vein grafts. In a level II study, Lundell et al⁷⁷ obtained a 3-year vein graft patency rate of 78% in the group randomly assigned to serial surveillance compared with a patency rate of only 53% in those followed at yearly intervals. In both groups, interventions were performed on all lesions, which reduced graft diameter by >50% or produced a fall in the ABI >0.15.

There is little doubt that these noninvasive testing procedures can be used to follow the natural history of disease with and without treatment. However, short of monitoring vein grafts to detect problems before failure has occurred, there is little consensus about the frequency of repeat studies in patients who have undergone angioplasty or are simply being treated for risk factors associated with progression of atherosclerosis. Since measurements of ABI are simple, they can easily be repeated at an office visit and provide objective evidence of disease progression at little additional cost. Certainly, for any patient with progressive symptoms or a fall in ABI, repeat studies are indicated.⁷⁸

Another advantage of measuring ABI in elderly patients is that it is a surrogate measure of atherosclerosis throughout the body. Thus, an abnormal ABI is one of the best predictors of subsequent cardiovascular events. Because it is so simple to perform, it could well become a standard part of the physical examination of elderly patients and those who appear at risk for development of atherosclerosis.^{43 79 80}

	Medical Treatment of Intermittent Claudication

Top Introduction Epidemiology Rules of Evidence Used... Noninvasive Evaluation of Lower... Medical Treatment of... Radiological Interventional... Surgical Treatment Recommendations References

 
Exercise Therapy
Physical training and exercise therapy for patients with intermittent claudication have been uniformly endorsed by experts in vascular disease.^{81 82 83} Regular exercise therapy coupled with risk factor modification, especially smoking cessation, is the mainstay of conservative therapy for intermittent claudication. In fact, critical review of the available literature suggests that exercise therapy is the most consistently effective medical treatment for this condition.^{84 85} Virtually all prospective studies of patients treated with exercise therapy for at least 3 months document substantial increases in pain-free and maximum walking distances as assessed by treadmill exercise performance. Twenty-eight trials of exercise conditioning have been reported; nine were controlled, sometimes randomized,^{86 87 88 89 90 91 92 93 94} and 19 were uncontrolled.^{95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113} The randomized, controlled trials were generally small and unblinded (level II data), while the remaining reports were level III studies. The majority of the studies evaluated changes in walking ability with a constant-load treadmill protocol. The improvement in pain-free walking time and distance ranged from 44% to 290%, with an average increase of 134%. Maximum walking time and distance increased from 25% to 183%, with an average increase of 96%. Methods of physical conditioning and exercise therapy have included simple walking regimens, dynamic and static leg exercise, and, most commonly, individualized treadmill exercise programs three to four times weekly for several months.

Conditions excluding patients from exercise therapy include unstable angina pectoris, debilitating chronic obstructive pulmonary disease, symptomatic congestive heart failure, and severe manifestations of limb ischemia, such as gangrene or ulceration requiring vascular reconstruction. The main factor limiting success of exercise therapy is lack of patient motivation. For this reason, the most successful programs combine regular, supervised outpatient sessions combined with home exercise programs; regularity rather than intensity should be stressed. Other than unstable cardiopulmonary conditions, comorbid diseases such as coronary artery disease, diabetes mellitus, and severity and location of arterial occlusive disease do not preclude successful response to exercise therapy.¹¹⁴

The precise mechanism accounting for the improvement in pain-free walking capacity with exercise therapy remains unknown. Earlier studies suggested that physical training increased collateral development⁹⁷ ; however, many subsequent reports document no significant increases in ankle pressure measurements or total limb flow measured by plethysmographic, radioisotopic, and thermal dilution techniques.^{98 105 115} Even in studies demonstrating improvements in hemodynamic parameters, these improvements were modest and poorly correlated with enhanced walking capacity.⁸⁹ Other suggested mechanisms include improved oxidative metabolic capacity in involved muscles,^{90 91} altered walking techniques,¹¹⁶ spontaneous fluctuations in pain tolerance,¹¹⁷ changes in perception of claudication pain,¹¹⁸ improved blood hemorheology,⁹³ changes in distribution of blood flow,¹¹⁵ and an increase in capillary density.¹¹⁹

Smoking Cessation
Smoking cessation is frequently combined with exercise therapy in patients with intermittent claudication. Cigarette smoking is the most significant independent risk factor for development of chronic peripheral arterial occlusive disease and is associated with progression of established disease and a higher likelihood of disabling claudication, limb-threatening ischemia, amputation, and the need for intervention.^{5 34 120 121 122} In addition, many observational studies report poorer patency of lower extremity vascular reconstructions among smokers.^{123 124 125 126 127 128} Data are limited on the specific effects of smoking cessation on intermittent claudication.¹²⁹ One controlled, but nonrandomized trial assessed the results of smoking cessation on intermittent claudication and found a statistically significant improvement in maximum walking distance in patients with intermittent claudication who stopped smoking.¹³⁰ Because of the adverse general health effects of cigarette smoking and the marked increase in morbidity and mortality from cardiopulmonary causes among smokers, patients with intermittent claudication should be vigorously counseled to stop smoking.

Drug Therapy
In contrast to the uniform improvement with exercise therapy, drug treatment of intermittent claudication is much more variable. Many types of drugs have been used, and the results are summarized below.

Vasodilators
Although commonly used in the past, controlled trials documented that vasodilators failed to increase blood flow and did not relieve symptoms.¹³¹ Although Poiseuille's law [flow=Pxr⁴/VxL (where P=pressure, r=vessel radius, V=viscosity, and L=vessel length)] describes the relation between a Newtonian fluid and vessel diameter, it also emphasizes the importance of viscosity in determining flow. This relationship is important in understanding the shift of interest from vasodilators to drugs that improve flow by altering viscosity. Vasodilators are ineffective because large vessel dimensions are fixed by the atherosclerotic process and collaterals are maximally dilated in patients with intermittent claudication. Decreased erythrocyte deformability¹³² and abnormal whole blood viscosity¹³³ are present in patients with peripheral arterial disease and offer potential therapeutic targets for agents that affect viscosity.

Rheologic Agents
Pentoxifylline, a methylxanthine derivative, is the only hemorheologically active agent currently approved by the Food and Drug Administration (FDA) for treatment of intermittent claudication. In patients with peripheral arterial disease, pentoxifylline has been reported to improve abnormal erythrocyte deformability,^{134 135} reduce blood viscosity,¹³⁶ and decrease platelet reactivity and plasma hypercoagulability.¹³⁷ Pentoxifylline has been evaluated in a large number of level I and II clinical trials. Although several studies demonstrated that pentoxifylline was statistically significantly more effective than placebo in improving treadmill walking distances,^{138 139 140 141 142 143} no consistent benefit was found in six trials.^{144 145 146 147 148 149} In most studies, patients treated with placebo also had significant improvement, and this tended to obscure benefits attributable to active drug treatment. A critical review of these trials concluded that the actual improvement in walking distance attributable to pentoxifylline is often unpredictable, may not be clinically important compared with the effects of placebo, and does not justify the added expense for most patients.⁸⁵ The drug may have a role in rare patients with markedly reduced walking distances who cannot engage in exercise therapy or who do not respond to exercise treatment. A small increase in claudication distance may permit these subjects to undertake activities that were previously impossible.

Other Agents
Other agents found to be ineffective in the treatment of intermittent claudication on the basis of results of randomized clinical trials (level I and II studies) include ketanserin (a scrotinin antagonist),¹⁵⁰ suloctidil,¹⁵¹ nifedipine,¹⁵² fish oil supplementation,¹⁵³ naftidrofuryl,^{154 155} and EDTA chelation therapy.^{156 157} Another promising drug is L-carnitine, an agent that appears to facilitate the transfer of acylated fatty acids and acetate across mitochondrial membranes, thereby enhancing available energy stores and improving oxidative muscle metabolism. A small, randomized trial (level II) demonstrated significant improvements in walking in comparison to placebo.¹⁵⁸ A large, multicenter trial is currently under way in the United States.

Hemodilution
Hemodilution with removal of red cells and infusions of hydroxyethyl starch¹⁵⁹ has been shown to improve walking distance in a small, randomized, double-blind trial (level II). Clinical improvement was highly correlated with decreased blood viscosity. Although the trial convincingly documents the adverse effects of increased blood viscosity in patients with peripheral vascular disease, hemodilution therapy is clinically impractical.

Antithrombotic Therapy
Aspirin therapy may modify the natural history of chronic lower extremity arterial insufficiency. Data from two level I studies suggest that aspirin, alone or combined with dipyridamole, will delay the progression of established arterial occlusive disease as assessed by serial angiography¹⁶⁰ and decrease the need for arterial reconstruction when used for primary prevention in males.¹⁶¹ The beneficial effect of aspirin is most likely due to prevention or retardation of platelet thrombogenesis on the surface of atherosclerotic plaque; experimental and clinical trial evidence suggests that aspirin has no effect on the progression of atherosclerosis.¹⁶² The protective effect of aspirin in preventing arterial occlusion is also apparent from multiple clinical trials showing improved patency in patients undergoing coronary bypass and infrainguinal bypass grafting.¹⁶³ In general, these trials show that antiplatelet therapy with aspirin prevents thrombotic occlusion of grafts but has little, if any, effect on vein and synthetic graft neointimal hyperplasia.^{164 165} Aspirin appears superior to other currently available antithrombotic drugs. Although a few reports (levels II to IV) suggest beneficial effects from warfarin and other antiplatelet agents in patients with peripheral arterial disease,^{8 166 167 168} there is no convincing evidence from properly designed large trials demonstrating that these drugs will delay or prevent progression of atherosclerosis and peripheral arterial occlusion.¹⁶³

A more compelling rationale to administer aspirin to patients with peripheral arterial disease is to prevent death and disability from stroke and myocardial infarction. Despite the rather benign prognosis for the limb, intermittent claudication may be viewed as an ominous sign of underlying disseminated atherosclerosis that carries a twofold to threefold increase in cardiovascular mortality in comparison to age-matched controls.¹⁶³ In the original meta-analysis from the Antiplatelet Trialists, 31 randomized trials involving more than 29 000 patients with vascular disease were analyzed, and the data convincingly showed that long-term aspirin therapy significantly reduced overall vascular mortality as well as nonfatal stroke and myocardial infarction.¹⁶⁹ An update of this meta-analysis reviewed 174 randomized trials of antiplatelet therapy involving more than 100 000 patients.⁶ Among high-risk patients, aspirin therapy was protective, reducing nonfatal myocardial infarction by one third, nonfatal stroke by about one third, and death from all vascular causes by about one sixth. Gender, advanced age, hypertension, and diabetes had no effect on this benefit. Specific subgroup analysis of patients with peripheral arterial insufficiency and infrainguinal arterial reconstructions was considered, and both groups benefited from aspirin therapy. For all conditions, aspirin 75 to 325 mg daily was at least as effective as any other regimen, including higher-dose aspirin therapy, which is more likely to cause side effects and gastrointestinal complications.⁶

The antiplatelet agent ticlopidine has also been evaluated, and reports from Europe (level II trials) suggest beneficial effects in relieving symptoms, increasing walking distances, and improving ankle pressure indexes.^{9 10} In addition, a meta-analysis of these trials demonstrated that patients with intermittent claudication treated with ticlopidine had a significant reduction in fatal and nonfatal cardiovascular events in comparison to patients treated with placebo.⁷ Although promising, there is a need for confirmatory studies in North America before ticlopidine can be recommended for this use.

Prostaglandins (PGE₁ and PGI₂) with antiplatelet and vasodilatory effects have been administered intravenously or intra-arterially to patients with advanced chronic arterial insufficiency in hopes of relieving rest pain and healing ischemic ulcers.¹⁷⁰ PGE₁ was found to be ineffective in a randomized, double-blind, multicenter trial (level II).¹⁷¹ Selective intra-arterial PGI₂ (5 ng·kg^-1·min^-1 for 72 hours) was found to relieve rest pain and promote healing of ulcers to a significantly greater degree than did placebo treatment in 30 nondiabetic patients, half of whom had thromboangiitis obliterans (level II trial).¹⁷² However, this route of administration is impractical and may cause complications, and these results have not been confirmed in patients suffering from pure atherosclerotic arterial insufficiency. In another double-blind trial, PGI₂, given intravenously to nondiabetic patients with severe arterial insufficiency, produced significantly greater relief of rest pain than did placebo (level II trial).¹⁷³ Relief lasted up to 1 month, was not correlated with changes in Doppler ankle pressure measurements, and was not associated with ulcer healing. More recently, intravenously administered PGI₂ was evaluated in a double-blind trial that contained a high proportion of persons with diabetes (level II trial).¹⁷⁴ The results were disappointing in that PGI₂ had no beneficial effect on ulcer healing or rest pain. Thus, it appears that PGI₂ may provide temporary relief of rest pain in nondiabetic patients with severe arterial insufficiency and may promote healing of ischemic ulcerations when given intra-arterially. However, it is doubtful that such therapy will ultimately prevent amputation in patients with end-stage, nonreconstructible vascular disease.

Lipid-Lowering Agents
There is evidence from two level I studies that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors significantly reduce coronary events in patients with hypercholesterolemia. HMG-CoA reductase inhibitors block the endogenous synthesis of cholesterol and lower LDL levels. One study demonstrated that simvastatin decreased cardiovascular mortality in patients with hypercholesterolemia and evidence of ischemic heart disease.¹⁷⁵ The other study showed that treatment with pravastatin produced a significant reduction in the incidence of myocardial infarction and cardiovascular death in hypercholesterolemic males without overt evidence of ischemic heart disease.¹⁷⁶ A level II study demonstrated that cholesterol-lowering drug treatment in normocholesterolemic patients who sustained myocardial infarction had no effect on coronary disease progression as determined by angiograms and did not reduce clinical events.¹⁷⁷ None of these studies examined whether treatment had an impact on symptoms of peripheral arterial insufficiency of the lower limbs.

Given that intermittent claudication is often a sign of generalized atherosclerosis and may be a marker for occult coronary artery disease, it is reasonable to measure serum cholesterol, particularly LDL cholesterol, in patients with peripheral vascular disease. If the cholesterol level is elevated, treatment with an HMG-CoA reductase inhibitor is reasonable. There is no evidence that these agents will alter the course of the peripheral arterial disease, but they may reduce cardiovascular mortality.

	Radiological Interventional Procedures

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In recent years there has been a dramatic increase in the use of interventional radiological procedures for the treatment of acute and chronic lower extremity arterial disease. This reflects advances in vascular imaging that have made percutaneous transluminal angioplasty (PTA) more feasible, the development of intravascular stents, and the more widespread use of intra-arterial thrombolysis for the treatment of peripheral arterial thrombosis. The data supporting the usefulness of each of these approaches are reviewed below.

Percutaneous Transluminal Angioplasty
Although the majority of patients with symptomatic aortoiliac disease do not require an invasive intervention, for those with incapacitating claudication or limb-threatening ischemia, angioplasty and lower extremity bypass surgery are the two major therapeutic options. Currently, the primary indications for an interventional procedure in patients with lower extremity arterial disease include (1) incapacitating claudication interfering with work or lifestyle; (2) limb salvage in patients with limb-threatening ischemia as manifested by pain at rest, nonhealing ulcers, and/or infection or gangrene; and (3) vasculogenic impotence.

PTA is an appropriate choice only when two important criteria are met. These include arterial disease localized to a vessel segment <10 cm in length and the availability of a skilled vascular interventionalist.¹⁷⁸ Although data comparing surgery with PTA in patients with lower extremity arterial disease are limited, in a randomized trial (level II) that included 252 patients, there was no difference in clinical outcomes during a mean follow-up of 4 years.¹⁷⁹ Even when the influence of site (iliac versus femoropopliteal) and indication (limb salvage versus claudication) were examined, there still was no difference in outcome. However, about one third of patients randomly assigned to PTA required at least one additional vascular procedure during the study period.

When considering PTA, the peripheral vascular tree can be conveniently divided into three regions: iliac, femoropopliteal, and infrapopliteal. Each of these is discussed separately.

Iliac PTA
There is level V evidence suggesting that PTA of the iliac arteries is associated with better long-term success rates than more distal angioplasty.¹⁸⁰ Iliac PTA is useful not only for dilatation of primary lesions but also as an adjunct to definitive femoropopliteal surgery where success rates are high when the procedure is carefully performed. For example, in a level V case-series study of 667 consecutive iliac PTA procedures done at the University of Toronto, initial success rates were as high as 90%.¹⁸¹ However, at 5 years the overall patency rate fell to 53%. The extent of disease at presentation influenced the long-term patency rate. Thus, in patients with isolated lesions in the common iliac arteries and good distal arteriographic run-off, the 5-year patency rate was 63%, whereas in those with poor run-off, it was only 51%. The complication rate was relatively low at 4%.

In another level V study, Tegtmeyer and colleagues¹⁸² reported on their PTA experience in 200 patients with 340 aortoiliac lesions who were followed for a mean of 30 months. Like the University of Toronto study,¹⁷⁸ the initial PTA success rate was about 90%.¹⁸² However, in this study, a 5-year patency rate of 88% was reported. This is likely to be an overestimate, however, because the threshold used to define success was much lower than that used in the University of Toronto study.¹⁷⁸ Based on a level V study in persons with diabetes, the long-term patency rate for iliac PTA appears to be dependent on the indication for the procedure. Thus, when PTA was done for claudication, a 5-year patency rate of 76% was reported, whereas when used for limb salvage, the 5-year rate was only 29%.¹⁸³

Femoropopliteal PTA
Level V evidence suggests that PTA in the femoropopliteal region is associated with a higher risk of failure than iliac PTA. Thus, in a case series of 217 PTA procedures for femoropopliteal disease, initial success was achieved in 90%, and 5-year patency rates were 58%.¹⁸⁴ Factors that adversely affected long-term patency included diabetes mellitus, diffuse atherosclerosis, limb-threatening ischemia, long or eccentric lesions, and poor initial post-PTA appearance.

A recent decision analysis evaluating the cost-effectiveness of revascularization procedures for femoropopliteal disease suggests that PTA is the preferred initial treatment in patients with disabling claudication. In those with critical leg ischemia, PTA is better for the treatment of femoropopliteal stenosis, whereas femoropopliteal occlusion is best managed with bypass grafting.¹⁸⁵

The influence of limb-threatening ischemia on outcome is highlighted by a level V report of 51 patients with severe limb ischemia who underwent femoropopliteal PTA. In this group, the 2-year survival rate was 40%, and the primary limb salvage rate was only 42% at 2 years.¹⁸⁶ Diabetes also is a risk factor. Thus, in one level V study of persons with diabetes undergoing femoral PTA, the 5-year patency rate was 60% in those with claudication but only 7% in those who underwent PTAs because of limb-threatening ischemia.

Infrapopliteal PTA
Only limited level V information is available regarding the effectiveness of infrapopliteal PTA. In one case-series of 146 lesions, the 2-year limb salvage rate was 83%.¹⁸⁷ At the same institution 320 femorodistal surgical revascularization procedures were done over the identical time period with similar limb salvage rates. What was apparent, however, was that only 20% to 30% of patients with infrapopliteal disease were candidates for PTA.

Outcome After PTA
In a level III epidemiological study comparing revascularization rates in Maryland from 1979 to 1989, there was no improvement in the limb salvage rate despite a 24-fold increase in the use of PTA and a twofold increase in the peripheral bypass rate.¹⁸⁸ Over a similar time period in Switzerland, the major amputation rate doubled despite a 13% increase in surgical interventions, ie, PTA or bypass.¹⁸⁹ Comparable results were also reported in a study conducted in Scotland.¹⁹⁰

Based on these three level III studies and the fact that only about one third of patients who require a revascularization procedure are candidates for PTA, it is likely that isolated case-series overestimate the impact of balloon angioplasty on limb salvage. These considerations have led to the recommendation that, for the most part, PTA should be restricted to patients with debilitating claudication, since the failure rate is so high when the procedure is done in subjects with limb-threatening ischemia.¹⁹¹ Because the success rate of PTA is highly operator-dependent, PTA is used more aggressively in clinical centers that manage a larger volume of patients.

Factors Predicting Outcome of Percutaneous Transluminal Angioplasty
The level V Toronto study evaluated the predictors of successful PTA using a Cox stepwise multiple regression model.¹⁸¹ Factors predictive of a favorable outcome included claudication as the indication for the procedure, a stenotic rather than occlusive lesion, good distal run-off, and a more proximally situated lesion. Using this analysis, surgery produced better results than PTA in persons with diabetes and in patients with diffuse vascular disease.¹⁸⁶ In a case-series (level V) at a vascular unit in England, of 101 consecutive limbs with critical ischemia, only 22% were suitable for PTA alone.¹⁹² Of those suitable for PTA, only half showed an improvement. Thus, it appears that PTA may be of only limited benefit in patients with limb-threatening ischemia, although randomized studies are needed to address this issue.

Intravascular Stents
It has been suggested that vascular stenting provides more durable vascular dilatation than simple PTA, particularly when the patient is at high risk for restenosis.¹⁹³ Currently available intravascular stents are either balloon expandable (eg, the Palmaz and Strecker stents) or self-expandable (eg, the Wallsten and Gianturco stents). In 1990 the first large trial (level V) evaluating the Palmaz stent showed only a 2% stent thrombosis rate at 6 months, with almost 90% of patients experiencing some clinical benefit.¹⁹³ However, these encouraging results require confirmation in a larger cohort of patients with lower extremity arterial disease.

Based on the results of two level V studies, it appears that stents are useful for management of PTA-induced dissections.^{179 194} When self-expandable and balloon-expandable stents were compared in a level V study, there was little difference in their performance.¹⁹⁵

At present the role of stents in treatment of lower extremity arterial disease is unclear. Although stent placement is a reasonable adjunct to PTA when a dissection occurs or when the lesion is particularly complex, the role of stents in primary PTA has yet to be established.

Intra-arterial Thrombolysis
Traditionally, balloon embolectomy has been the treatment of choice for patients with acute arterial embolism. However, because surgical thrombectomy is less successful in patients with acute or chronic arterial thrombosis, intra-arterial thrombolysis is an attractive alternative. The results of an early level V study in which systemic infusions of streptokinase were used to recanalize occluded peripheral arteries were disappointing.¹⁹⁶ Thus, successful thrombolysis was achieved in only 30% of patients, and 20% of the subjects had hemorrhagic complications. More encouraging results were obtained when streptokinase was given intra-arterially in lower doses.^{197 198} With recent improvements in catheter technology that simplify drug delivery, intra-arterial thrombolysis has gained widespread acceptance.

Issues that need to be addressed when considering intra-arterial thrombolysis for peripheral artery occlusions include indications, contraindications, and complications of lytic therapy; the choice of lytic agent; the best methods for drug administration; and the results of clinical trials of intra-arterial thrombolysis for the treatment of acute and chronic peripheral artery occlusion. Each of these will be discussed in turn.

Indications for Thrombolytic Therapy
Thrombolytic therapy should be considered (1) in an attempt to, time permitting, convert an emergent surgical procedure into an elective one; (2) to convert a major surgical procedure into a less extensive one; (3) to restore the patency of any acutely occluded vessel that is inaccessible to mechanical thrombectomy; (4) to identify the underlying cause of thrombosis so that it can be corrected with salvage of native artery or bypass graft; (5) to prevent arterial intimal damage from balloon thrombectomy; and (6) to reduce the level of amputation when clot retrieval is incomplete. Based on their experience at Temple University Hospital, Comerota and Cohen¹⁹⁹ have suggested that candidates for intra-arterial thrombolytic therapy should include those with (1) acute thrombosis of a previously patent saphenous vein bypass graft or native artery, (2) acute arterial embolus not accessible to embolectomy, (3) thrombosis of a popliteal artery aneurysm resulting in severe ischemia, provided that all run-off vessels are also thrombosed; and (4) thromboembolic occlusion in situations in which surgery carries a high potential mortality. Settings in which thrombolytic therapy is unlikely to be effective include irreversible limb ischemia, mild to moderate ischemia with tolerable claudication, early postoperative bypass graft thrombosis, and large vessel thrombi easily accessible to surgery.

Contraindications to Thrombolytic Therapy
In certain situations use of thrombolytic agents may be absolutely contraindicated and surgery the preferred option. Martin and Fiebach²⁰⁰ listed a series of absolute and relative contraindications to thrombolysis (Table 5). Another critical consideration is the maximal ischemic time that the affected limb can endure before development of myonecrosis. Patients with an acutely ischemic limb and no evidence of collateral circulation (particularly those with a sensory or motor deficit) and who cannot tolerate 10 to 12 hours of ischemia are not candidates for thrombolysis. Instead, these patients should undergo immediate surgical thrombectomy, with a reconstructive procedure if necessary.

View this table: [in this window] [in a new window]   Table 5. Contraindications to Thrombolysis

Choice of Lytic Agent
A variety of plasminogen activators have been used to recanalize occluded peripheral arteries, including streptokinase, urokinase, and tissue-type plasminogen activator (TPA). Although streptokinase was the first agent used for intra-arterial thrombolysis,^{196 197} there is evidence based on level III and V studies that urokinase is at least as effective as streptokinase but causes fewer bleeding complications.^{201 202} More recent level III and IV studies have shown that TPA is also effective in this setting, and its use is associated with bleeding rates similar to those found with streptokinase.^{203 204}

Meyerovitz et al²⁰⁵ conducted one of the few randomized controlled trials comparing TPA with urokinase. However, this level II study included only 32 patients, which limits