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


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.7-10

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.


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


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, 12-16 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.


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.25-27 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


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.32-34 Based on these observations, interventions to decrease or eliminate cigarette smoking have long been advocated for patients with lower extremity arterial disease.


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


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.

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

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 () errors (high power). "Low false-positive () error" means a "positive" trial that demonstrated a statistically significant benefit from experimental treatment, whereas "low false-negative () 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 () errors (low power). "High false-positive () error" means a trial with an interesting positive trend that was not statistically significant, whereas "high false-negative () 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.

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

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.46-49 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.53-55

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 bifurcation62-64 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.65-67

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.

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 scanning65,70 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

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 grafts74-76 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

Exercise Therapy

Physical training and exercise therapy for patients with intermittent claudication have been uniformly endorsed by experts in vascular disease.81-83 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,86-94 and 19 were uncontrolled.95-113 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.5,34,120-122 In addition, many observational studies report poorer patency of lower extremity vascular reconstructions among smokers.123-128 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.


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=P×r4/V×L (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,138-143 no consistent benefit was found in six trials.144-149 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 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,8,166-168 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 29000 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 100000 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

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.

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 the reliability of the conclusions. TPA tended to cause more rapid thrombolysis than urokinase, but by 24 hours the lysis rates were similar. Although bleeding complications tended to be more frequent with TPA, clinical outcomes were the same in both groups. A small randomized trial (level II) comparing urokinase with streptokinase suggested that urokinase is superior to streptokinase.206 Based largely on this evidence, urokinase currently is the most widely used agent for intra-arterial thrombolysis.207,208

Techniques for Intra-arterial Thrombolysis

The technique most often practiced today is that described by McNamara and Fischer201 in 1985. In patients with femoral and iliac thromboses, the preferred access site is the contralateral femoral artery. Access through the ipsilateral femoral is favored for thrombi in the superficial femoral, popliteal, or tibial arteries. By using the ipsilateral limb, potential catheter-related complications in the intact limb are avoided. If neither femoral artery can be used, a low brachial artery access may be considered.

Once the access site is identified, a small Teflon (polytetrafluoroethylene [PTFE])-coated guidewire is inserted after direct puncture and is manipulated into the thrombus. A review of the literature209 suggests that successful passage of the guidewire through the thrombus predicts a >95% likelihood of successful lysis, whereas inability to pass the thrombus reduces the chance of success. Shortell and Ouriel210 obtained similar results when they performed multivariate analysis on data from a level V study in 80 patients. Thrombolysis was successful in 85% of patients with clots penetrated by the guidewire and in none of those with impenetrable clots. Successful outcome was more frequent in prosthetic grafts (78%) and native arterial occlusions (72%) than in vein graft thromboses (53%). Persons without diabetes had higher success rates than persons with diabetes (80% and 52%, respectively).

Once the guidewire is placed in the clot, a coaxial catheter wire is passed over it, and the thrombolytic agent is infused for 2 to 4 hours to determine the susceptibility of the thrombus to lysis. If there is angiographic evidence of lysis, thrombolytic therapy is continued for up to 48 hours or until there is no angiographic evidence of further thrombolysis.

A more recent modification is the pulse-spray technique,211,212 in which a multi-sidehole catheter is used to deliver high-pressure pulsed injections of fibrinolytic agent throughout the clot. Despite the theoretical advantages of this new delivery system, a small level II randomized controlled trial failed to show an advantage of the pulse-spray technique over slow infusion techniques in terms of rapidity of lysis, initial success rates, complication rates, or 30-day clinical outcome.213


The complications of this approach can be related to intra-arterial catheter insertion or can be a result of thrombolytic therapy. Catheter-related complications include pericatheter thrombosis, which, based on level V studies, occurs in 2.9% to 16.7% of patients,214,215 and pseudoaneurysm formation, which is seen in 1.2% to 1.4% of patients.216,217 The major complication of thrombolytic therapy, however, is bleeding, and level V studies report overall mortality ranging from 0.6% to 2.8%, which is largely due to hemorrhage.214,218 The frequency of complications varies widely, depending on the definition and reporting of hemorrhagic complications. When only those studies that defined bleeding in terms of need for transfusion or surgical evacuation are considered, streptokinase was reported to cause bleeding in 3.9% to 60%, whereas urokinase caused bleeding in 2.8% to 25% of cases.219 Intracranial hemorrhage was reported in 0.5% to 8% of patients given streptokinase and in 3.7% of those treated with urokinase.219 As the experience with intra-arterial thrombolysis has increased, the rate of intracranial hemorrhage has decreased and is now cited at <1%. Other reported complications include renal failure (4% to 9% with streptokinase and 4.5% with urokinase), distal embolization (1.9% to 16% with streptokinase and 2% to 15% with urokinase), and aneurysm/graft rupture (4.5% with streptokinase and 1.8% with urokinase).214,215,220-222 Additional problems in patients treated with streptokinase include serious gastrointestinal bleeding and retroperitoneal hematomas, which occur in 1% to 2.8% and 7.6% to 8.5%, respectively.223,224 Level II studies comparing TPA with urokinase have failed to demonstrate any consistent difference in complication rates.204,225

Results of Thrombolytic Therapy for Acute and Chronic Arterial Thromboses

The overall success rates in most reported studies vary widely due to (1) small numbers of patients, (2) variation in disease severity, and (3) heterogeneity of indications. Results also vary with indication (embolic versus thrombotic, native artery versus bypass graft, vein versus prosthetic graft, and acute versus chronic thrombosis). In a number of level V studies, thrombolytic therapy was associated with limb salvage rates varying from 60% to 70%.225-228 The effectiveness of thrombolytic therapy for the treatment of acute and chronic occlusions of native arteries and of bypass grafts is discussed below.

Acute native arterial occlusions. In level V studies the success rate of thrombolysis for the initial recanalization of thrombosed native arteries has ranged from 58% to 100%.217,218,229-232 Although widely used for the treatment of arterial thrombosis, thrombolytic therapy has also been studied in the setting of acute arterial embolism. Thus, in a level II randomized, controlled study comparing immediate surgical thrombectomy with intra-arterial thrombolysis,231 revascularization rates and the need for adjunctive revascularization procedures (either bypass grafting or percutaneous angioplasty) were similar in both groups. Based on these findings, the authors concluded that the management of the acutely ischemic limb should include a judicious combination of both modalities. In 1994 Ouriel et al232 reported the results of a level II study in 57 patients with acute peripheral arterial ischemia who were randomly assigned to either thrombolysis or surgical revascularization. Although limb salvage rates were similar in both groups (82% at 12 months), patients given thrombolytic therapy had a significantly improved 1-year cumulative survival rate, which appeared to be the result of fewer in-hospital cardiopulmonary complications.

Chronic native arterial thrombosis. Level V evidence suggests that primary recanalization rates depend to a large extent on duration of occlusion. In a case-series successful lysis was achieved in 72% of patients with an occlusion <7 days in duration and in only 24% of those with an occlusion >6 months' duration.231 Based on a review of the literature, Hess228 has suggested that local thrombolytic therapy can be used for all arterial thromboses existing for 6 to 8 months and all embolic occlusions present for 6 to 8 weeks.

Thrombosed bypass grafts. In a level V study of 35 patients, Whittemore et al235 reported an overall autogenous vein graft patency of 37% 1 year after thrombolysis. Another level V study by Sullivan and colleagues236 reported an overall patency rate of 56% at 1 year for 40 occluded grafts. Gardiner et al237 found a 20% patency in 22 grafts at 1 year (level V). In a report on the experience in Vienna for failed femorodistal grafts (level V), Bull and coworkers238 found a cumulative patency rate of 36% at 3 years. In a level II study in which surgery was compared with TPA for the treatment of graft thrombosis, Graor et al239 found significantly higher patency rates at 30 days with thrombolysis than with thrombectomy. Overall experience suggests that prosthetic grafts are more amenable to successful thrombolysis than autogenous vein grafts and that vein graft thrombosis occurring within 1 year after reconstruction responds better than thrombosis that occurs later. However, the role of surgery in patients with vein graft thrombosis should not be overlooked. In a review, Van Breda240 points out that if surgical revision can be easily performed with autogenous vein, surgical reconstruction is preferred because cumulative, secondary 5-year patency rates of autogenous infrainguinal vein graft approach 85%. However, in patients with insufficient vein or with a history of repeated thromboses, thrombolysis is a reasonable alternative.

The Surgery versus Thrombolysis for Ischemia of the Lower Extremity (STILE) trial included 393 patients from 31 centers in North America.225 In this level II study designed to compare intra-arterial thrombolytic therapy with surgery in patients with lower limb ischemia due to nonembolic arterial and graft occlusion, patients were randomly assigned to surgery or lytic therapy with either TPA or urokinase. The study was stopped prematurely because interim analysis at 6 months suggested that a significant difference in the primary end points had already occurred. Thus, at 30 days, patients randomly assigned to surgery had significantly less ongoing or recurrent ischemia than those given thrombolytic therapy. However, the incidence of death, major amputation, and major morbidity at 30 days was similar in both treatment groups. At 6 months of follow-up there was improved amputation-free survival in patients with acute ischemia who were treated with thrombolytic agents, whereas those with chronic ischemia had lower amputation rates with surgery. Based on these results, the authors recommended thrombolytic therapy for patients with acutely ischemic limbs (<14 days) and surgical revascularization for patients with chronic ischemia (>14 days). No significant differences in either efficacy or safety were found between TPA and urokinase.

Surgical Treatment

Indications for Surgery

To date, indications for surgical treatment of lower extremity ischemia have been defined in terms of severity of symptoms, with hemodynamic data serving to confirm the diagnosis but not as the primary indication for surgery. There is general agreement that surgical treatment is indicated to relieve symptoms of limb-threatening ischemia, including ischemic pain at rest, ischemic ulcers, and gangrene. There also is general agreement that surgery is indicated to remove or bypass and exclude sources of atheroemboli.241 In contrast, intermittent claudication is considered only a relative indication for surgical treatment and then only after an adequate trial of nonsurgical therapy. Presently there is no consensus regarding disease severity, whether assessed by symptoms or hemodynamic parameters, for which operative treatment of claudication is appropriate.

The evidence that supports these commonly accepted indications for surgery as well as the choice of one type of surgical therapy over another are critically examined in the sections below. The results of treatment of lower extremity ischemia are typically evaluated by multiple parameters that have been summarized in the recommended reporting standards of the Joint Vascular Societies.242 These include the operative morbidity and mortality associated with the treatment and the patency of the surgical repair. Patency is best defined in hemodynamic terms as a sustained improvement in ABI 15% as well as by other objective means such as postoperative angiography or duplex scanning. Patency is classified as primary or secondary. Primary patency means uninterrupted patency of the original treatment without any revision such as thrombectomy, thrombolytic infusion, or angioplasty. Secondary patency refers to patency of the repair as maintained by these measures. It is widely accepted that primary patency describes the success of the procedure itself, whereas secondary patency describes the success of the procedure and its postoperative follow-up as well as the detection and treatment of complications. Clearly, comparison of various surgical procedures requires the use of primary patency figures. In addition to patency, surgical procedures on the lower extremity to relieve symptoms of limb-threatening ischemia (ischemic pain at rest, ischemic ulcer, or gangrene) are evaluated by calculation of limb salvage, defined as retention of the limb without the need for amputation above the metatarsal level (ie, without the need for a prosthesis to permit ambulation), and by long-term patient survival. Patency, limb salvage, and patient survival are calculated by the life-table method.

Obviously the objective parameters described above are well suited for quantitative outcome evaluation of surgical treatment, yet many other parameters may be as, or more, appropriate than patency, limb salvage, and survival. Adequate relief of symptoms, including relief of pain, healing of ischemic lesions, return to unimpeded ambulation, maintenance of independent living (freedom from nursing home), and general level of patient satisfaction or quality of life are all valid parameters for assessment of lower extremity revascularization, especially from the patient's point of view. Although few, if any, of these parameters are addressed in most modern reports, they are likely to become increasingly important in future investigations.

Surgery Compared With Other Treatments

Level I Evidence

There have been no prospective randomized studies of sufficient size and adequate design comparing surgical treatment of lower extremity ischemia with other therapies. Some reasons for this are obvious. For example, few would be willing to randomly assign patients with limb-threatening ischemia to surgery or nonoperative therapy. However, there is no apparent difference in outcome when various methods for the treatment of claudication are compared, yet few randomized clinical trials have been performed.

Level II Evidence

Surgical treatment of intermittent claudication was compared with exercise therapy by Lundgren and coauthors95 in 1989. These authors randomly assigned 75 patients with intermittent claudication verified by vascular laboratory testing to either surgery alone, surgery combined with exercise training, or exercise training alone. Comparable patients were included in the different groups as assessed by the usual risk factors and initial severity of disease. End points included ABI, toe blood pressure, calf muscle blood flow, and walking performance. After treatment, there were significant increases in ABI and toe blood pressure in the two groups that underwent surgery but not in the group that received exercise alone. All three groups showed significant improvement in calf muscle blood flow and in walking performance. The magnitude of the improvement was significantly greater in the operation plus exercise group than in those who underwent surgery alone, and the group that underwent surgery had greater improvement than the exercise-alone group. As expected, there were more complications in the surgical groups.

A comparison of surgical reconstruction with PTA for treatment of lower extremity ischemia was the subject of Veterans Administration Cooperative Study No. 199, the results of which were reported by Wilson and coauthors243 in 1989. In this study 263 male patients from seven VA hospitals were randomly assigned to treatment by surgery or balloon angioplasty. To be eligible for the study, patients had to have angiographic lesions that both surgical and radiological investigators agreed were amenable to angioplasty. Although the severity of symptoms was not a limiting factor because only patients with lesions amenable to angioplasty were included in the study, most had disease that was less severe than that usually treated by surgery, with 73% having claudication only and the remainder having ischemic pain at rest. None had ischemic ulcers or gangrene. The groups were well matched with respect to symptoms, risk factors, and severity and location of disease as assessed both by angiography and hemodynamics. The parameters evaluated included failure (defined as a loss of patency or failure to achieve initial improvement as determined by objective criteria) and patient survival. The results are illustrated in Table 6. The surgical group maintained slightly higher success rates in each category (P=.037), with the differences being explained almost entirely by the lower initial success rate of angioplasty. Successful angioplasty in this study was as durable as successful surgery. However, this trial has been criticized because the surgical results may have been compromised by the use of prosthetic grafts for infrainguinal bypass.

Levels III to V Evidence: Results of Surgery

Although numerous publications have described the overall results of lower extremity surgical revascularization, aggregate description of results is relatively meaningless because many of the factors that influence the outcome of surgical procedures were largely ignored. These include indication for operation (claudication or limb-threatening ischemia), surgical site (aortoiliac, infrainguinal, or multilevel), and whether the operation was for primary revascularization or reoperation. For infrainguinal bypass operations, the bypass conduit material (greater saphenous vein, alternate veins, or prosthetic) and the site of the distal anastomosis (popliteal, tibial, or pedal) also are important. In patients with aortoiliac disease, the presence or absence of simultaneous femoropopliteal disease influences results, as does the procedure performed (anatomic bypass, extra-anatomic bypass, or endarterectomy). Thus, unless patients have been stratified for each of these factors, it is impossible to draw meaningful conclusions from the results of studies of the surgical treatment of lower extremity ischemia.

Table 6 lists examples of the reported results of various procedures with respect to graft patency and limb salvage. It is apparent that the range of anticipated results is wide, depending on the variables described above. Understanding these relationships is critical for meaningful comparison of results of various techniques. It is obviously inappropriate to compare the results of PTA performed to treat claudication with aggregate surgical results that include many patients operated on for limb salvage. Similarly, it is inappropriate to compare the results of prosthetic bypass performed preferentially in patients with claudication in whom venous bypass would have been possible if chosen with the results of prosthetic bypass performed when all possible sources of autogenous vein have been exhausted. These considerations emphasize the importance of randomized trials for meaningful comparison of surgical and nonsurgical techniques. They also emphasize the importance of rigid adherence to recommended standards for all reports describing treatment of lower extremity ischemia, regardless of whether treatment is surgical or nonsurgical.

Survival of patients after lower extremity revascularization varies widely, depending on the specific patient population being described. A uniform feature of all reports, however, is markedly reduced survival when compared with the anticipated survival for the general population without specific manifestations of atherosclerosis. Interestingly, several reports have suggested that long-term survival is directly correlated with the severity of the presenting lower extremity ischemia, whether assessed by symptoms, physiological tests, or the extent of anatomic lesions.243-246 For example, the 5-year survival rate of patients with claudication treated nonoperatively has been reported to be as high as 87%,1 compared with 80% for patients with claudication treated by surgery,247 38% for patients undergoing surgery for limb-threatening ischemia,248 and only 12% for patients undergoing reoperative surgery for limb-threatening ischemia.249

Despite these considerations, conclusions can be drawn regarding the safety and efficacy of surgical treatment of lower extremity ischemia, especially ischemia sufficiently severe to produce limb-threatening symptoms. Several series have documented the ability of surgical revascularization to provide durable salvage of unselected limbs threatened by ischemia in 85% to 90% of cases.248,250,251 Important principles in achieving these results include use of detailed arteriography in all patients with threatened limbs, use of autogenous conduits for infrainguinal bypass whenever possible, and aggressive lifetime follow-up (including vascular laboratory surveillance of reconstruction) to detect recurrent lesions. Aggressive reoperation for recurrent lesions and/or recurrent symptoms is necessary in 10% to 15% of patients during follow-up. Surgical mortality is < 5%. Five-year survival in the group of patients with limb-threatening ischemia is approximately 50%, emphasizing the advanced age and severe coronary and cerebral atherosclerosis present in these patients. The fact that survival is lower than limb salvage in this patient group means that the majority of patients (approximately 85% in most series) operated on for limb salvage symptoms undergo a single surgical procedure that results in salvage of the threatened limb for the remainder of their life.

Limb-threatening ischemia typically occurs in elderly patients with multiple severe coexisting medical conditions. There is appropriate concern by many physicians regarding the advisability of revascularization surgery, especially because patients undergoing these major procedures often require multiple transfusions, prolonged hospitalization, intensive care, and, frequently, subsequent procedures to achieve foot healing. Unfortunately, a decision not to perform revascularization in the setting of limb-threatening ischemia makes amputation virtually inevitable. This is a problem because amputation is in itself a surgical procedure involving risks and length of hospitalization at least equivalent to those of revascularization and with a far less desirable outcome from the patient's point of view. Although there has never been a randomized study comparing revascularization with amputation for limb-threatening ischemia, this issue has been addressed, at least in part, by the study of Ouriel and colleagues.251 These investigators compared mortality and morbidity results of nonrandomized, but concurrently performed, amputation and revascularization procedures from the same hospital in which patients in each group were stratified for operative risk. Operative mortality, hospital stay, and long-term survival were all superior in the revascularization group, and the advantage over the amputation group was greatest in the patient subgroups with the highest predicted operative risk. Other studies of mortality associated with amputation confirm that both immediate and long-term survival are considerably inferior to those achieved with revascularization.252 Based on these studies, most vas-cular surgeons recognize few contraindications to revascularization for limb-threatening ischemia. An exception is made in the case of chronically institutionalized, neurologically impaired, permanently nonambulatory patients for whom there is no advantage to revascularization over amputation.

The cost of amputation versus revascularization has not been addressed in a randomized study. Several nonrandomized comparison studies have concluded that successful revascularization is consistently less expensive than amputation, with the difference being explained largely by the increased need for long-term care for amputees.253,54 Although failure of revascularization followed by amputation is obviously the most expensive sequence, this scenario is of relatively minor importance since failure of revascularization is infrequent in most series.

In addition to increased operative risk, some patients present for consideration of revascularization with far advanced ischemia, including extensive gangrenous lesions of the foot. In the past some surgeons have recommended primary amputation in these patients to avoid a situation in which a patent revascularization procedure fails to produce foot healing, making amputation necessary. However, more recent studies have demonstrated healing of even extensive ischemic foot lesions using a combination of revascularization, minor foot amputations, and reconstructive surgical techniques.255-257 The problems of achieving healing of ischemic foot lesions are magnified in patients with end-stage renal disease, identified by multiple groups as the most difficult patient category. Although the limb salvage rates achieved in these patients are lower than in other categories, they remain sufficiently high to justify an aggressive approach to revascularization.258,259

Choice of Surgical Procedure

Level I Evidence

It is possible to perform infrainguinal bypass procedures using autogenous vein or prosthetic material. Since veins contain valves, the grafts must be reversed or the valves must be rendered incompetent if nonreversed or left in situ. Prosthetics currently available for clinical use in the United States include Dacron, PTFE, and, by convention, glutaraldehyde-treated human umbilical veins (HUV). Use of autogenous vein versus prosthetic, in situ versus reversed vein grafts, and various prosthetics versus others has been addressed by randomized trials. The largest of these addressed the issue of autogenous vein versus prosthetic for infrainguinal bypass.

In a 6-year prospective multicenter randomized trial, Veith and associates260 compared the use of autogenous greater saphenous vein to PTFE in 845 infrainguinal bypass operations that were nearly equally divided between popliteal (485 grafts) and infrapopliteal (360) sites of distal anastomosis. At 5 years the primary patency rate for autogenous vein grafts to the popliteal artery was 68% compared with a 38% patency rate for PTFE (P<.025). These differences were even more dramatic in grafts to the infrapopliteal vein, in which the 5-year primary patency rate for autogenous veins was 49% compared with a 12% patency rate for PTFE (P<.001). The data from this study are shown in Figs 2 and 3. There were no differences between the groups with respect to operative morbidity and mortality. Interestingly there were no significant differences in limb salvage between the two groups, reflecting the success of secondary procedures in maintaining limb salvage when primary procedures failed.

In a second large prospective multicenter randomized trial of graft material for infrainguinal bypass, investigators in 18 Veterans Affairs Medical Centers studied 596 subjects.261 Patients requiring primary (no previous ipsilateral bypass) popliteal and infrapopliteal grafts had autogenous saphenous vein bypass (in situ or reversed, according to the surgeon's preference) if this conduit was available. If veins were not available or were inadequate, patients were randomly assigned to receive PTFE, Dacron, or HUV grafts. Two hundred twelve reversed saphenous grafts were performed; there were 249 in situ grafts. One hundred thirty-five prosthetic grafts were performed, equally divided between the three prostheses. Vein graft patencies were superior to prosthetic for popliteal (76% versus 64% at 2 years, P=.08) and for infrapopliteal grafts (73% versus 30% at 2 years, P<.001). The numbers of patients in the individual prosthetic groups were too small to permit valid comparison among them.

Level II Evidence

Several small prospective randomized studies have compared the various conduits for infrainguinal bypass. Two trials comparing saphenous vein femoropopliteal grafts performed by reversal with the in situ technique showed no differences.262,263 A third multicenter randomized trial that included 125 patients compared reversal with in situ technique for infrapopliteal bypass also found no difference.264

Two small randomized trials have compared HUV prosthetic grafts to PTFE grafts for femoropopliteal grafting.265,266 In both trials the primary patency of HUV grafts was significantly superior to that achieved with PTFE (75% versus 40% at 1 year, P=.014; and 71% versus 39% at 6 years, P<.001). Despite the documented superior patency when HUV grafts have been compared with PTFE, most surgeons prefer PTFE grafts over HUV. This is because of the high frequency with which aneurysms occur in HUV grafts during long-term follow-up.267 Finally, a small randomized trial comparing externally supported PTFE to nonsupported PTFE for femoropopliteal bypass found no difference in patency.268

With regard to aortofemoral bypass to treat aortoiliac disease, several randomized trials have compared the different prostheses. Polterauer et al269 compared Dacron with PTFE bifurcation grafts and found no significant differences. Another trial randomly assigned patients to standard knitted Dacron or collagen-impregnated knitted Dacron and compared operative blood loss. The blood loss was similar in both groups.270 In an interesting variation on randomized trial design, Robicsek and colleagues271 placed specially manufactured bifurcation prostheses in which one limb was woven and one limb was knitted Dacron fabric into 158 patients. After 7 1/2 years of follow-up there were no differences between the two limbs of the prostheses.

Levels III to V Evidence

For aortoiliac disease the results of aortofemoral bypass and aortoiliac endarterectomy are equivalent with respect to patency (Table 6). Most surgeons prefer bypass because endarterectomy operations are longer, more technically demanding, and associated with greater blood loss. For elderly patients and those with increased operative risk, satisfactory results have been reported with extra-anatomic bypass grafting procedures (axillofemoral, femorofemoral) that avoid the physiological stress of aortic clamping and abdominal cavity surgery. Patency rates of extra-anatomic bypass grafting have historically been lower than those of aortofemoral grafting (Table 6). A recent comparison of aortofemoral and axillofemoral grafting found that patencies were not different when use of the latter was confined to elderly patients with a limited life expectancy.272

For infrainguinal bypass, the superiority of saphenous vein over prosthetic conduit is well established by large randomized trials.260 This is clearly true when the distal anastomosis is below the knee. In the largest trial comparing saphenous vein with prosthetic conduits,260 there was a trend for improved patency of saphenous veins over PTFE conduit for above-knee femoropopliteal bypass (61% and 38% patency at 4 years, respectively), but this difference was not statistically significant (P>.25). The lack of a significant difference between saphenous vein and prosthetic conduit has led some to advocate preferential use of prosthetic conduit, specifically PTFE, for bypass to the above-knee popliteal artery.273 Arguments in favor of this practice include preservation of the vein for later coronary bypass or secondary bypass after failure of the initial PTFE procedure. Despite these arguments, preferential use of PTFE over saphenous vein for above-knee bypass is not supported by most authorities.274,275 Careful studies have shown that the saphenous vein, when saved, is rarely needed for subsequent bypass, whether lower extremity or coronary.276,277 In addition, studies purporting to show similar patency for saphenous vein and PTFE for above-knee bypass must be viewed with caution. Invariably, PTFE patency in previously unoperated patients has been compared with aggregate saphenous vein experiences in which patients undergoing reoperation were included in the patency results. A valid comparison is with saphenous vein bypass patients who are previously unoperated and have good-quality, usable veins. Five-year patency figures in this category for above-knee bypass grafting exceed 85% in uncontrolled series.278 The lack of a significant difference in randomized trials must be viewed with caution. The specific patient group of above-knee bypass was small, follow-up was short, and the patency curves rapidly diverged in favor of vein at the time the study was stopped.260

The superiority of greater saphenous vein over prosthetic for infrainguinal bypass seems well established. However, in modern practice, many patients require infrainguinal bypass, and the ipsilateral greater saphenous vein is not available or is not suitable for use as a bypass conduit. This occurs because of previous use of the vein for lower extremity or coronary bypass, previous vein stripping, and intrinsic vein disease (eg, previous superficial venous thrombosis). Use of alternate autogenous veins (including arm veins, lesser saphenous veins, and superficial femoral veins) to achieve autogenous bypass grafting has been reported by several authors.279-283 As shown in Table 6, the results achieved with these procedures are generally inferior to those achieved with intact ipsilateral greater saphenous vein. The patency results of alternate vein bypass to infrapopliteal arteries are superior to those achieved with prosthetic grafting. For grafts to the popliteal arteries, the results of alternate autogenous vein bypass are not clearly superior to those achieved with prosthetic grafting, especially in view of recently reported improved results of prosthetic grafting, using modified anastomotic techniques and long-term anticoagulation with warfarin.284,285 Comparison of prosthetic to alternate autogenous vein grafts for patients requiring femoropopliteal grafting in the absence of intact greater saphenous vein is an ideal subject for a multicenter randomized trial.

Occlusive failure of infrainguinal bypass grafts most frequently results from localized stenotic lesions, either within the graft or from progression of stenotic disease in the native arteries proximal or distal to the graft.286,287 Several studies have shown that careful long-term follow-up of autogenous vein grafts using objective vascular laboratory techniques, especially duplex scanning, can reliably detect such stenotic lesions, permitting correction before the occurrence of recurrent symptoms and graft thrombosis. The ability of graft surveillance programs to improve the overall results of both reversed and in situ autogenous grafting has been well described.77-79,288,289 However, this approach has not yet been shown to improve the results of prosthetic grafting.


1. Examination of the pedal pulses should be part of the routine physical examination for all patients older than 55 years. Measurement of the ABI is recommended for patients who have diminished or nonpalpable pedal pulses. The TSPI is a reasonable alternative to ABI determination in patients with diabetes mellitus. These grade C recommendations are based on level III studies43,44 indicating that an ABI <0.9 is predictive of cardiovascular mortality. Although level I and II data are lacking, these recommendations reflect level I evidence that the risk of cardiovascular mortality in patients with atherosclerosis, as documented by an abnormal ABI, is lowered by aspirin.6,168

2. Exercise therapy along with risk factor modification, especially smoking cessation, should be the initial management of all patients with nondisabling intermittent claudication. This is a grade B recommendation based on level II studies.86-94 Despite the lack of level I data, this recommendation is strongly backed by the fact that studies have consistently shown that these maneuvers produce clinical improvement. In addition, the low expense and the general cardiovascular health benefits of regular exercise and risk factor modification also support their widespread use in this patient population.

3. Aspirin, 75 to 325 mg daily, may improve the natural history of patients with intermittent claudication by preventing progressive arterial occlusion. In addition, because these patients are at high risk of future cardiovascular events (ie, stroke, myocardial infarction, and vascular death), they should be treated with lifelong aspirin therapy unless there are contraindications. This grade A recommendation is based on level I studies,160,161 as well as meta-analyses of multiple level I and level II studies.6,169

4. Lipid lowering with an HMG-CoA reductase inhibitor is recommended for patients with intermittent claudication who have an elevated level of serum cholesterol. This grade A recommendation is based on two level I studies175,176 demonstrating that these agents reduce cardiovascular mortality in hypercholesterolemic patients with175 or without176 overt evidence of ischemic heart disease. At present there is no evidence that lipid-lowering agents alter the course of peripheral arterial disease.

5. Pentoxifylline is not recommended for most patients with intermittent claudication. This is a grade A recommendation based on level I and II data138-149 that show inconsistent and only modest benefit with treatment. Pentoxifylline may be helpful in rare patients who do not respond to exercise therapy or who cannot exercise; however, definitive supportive evidence for this recommendation is lacking.

6. Exercise,86-94 PTA,179 and surgery95,243 are effective treatments for claudication. This grade B recommendation is based on level II evidence. Surgery is associated with a higher initial success rate than other treatments, and this benefit is maintained in follow-up. However, because the complication rate of operative therapy is slightly higher than that of nonsurgical treatment, surgery should not be performed without an adequate trial of nonoperative therapy.

7. Selective or intra-arterial thrombolytic therapy can be considered in patients with acute thrombotic or embolic occlusion of a native artery or a prosthetic graft, provided that there is a low risk of myonecrosis developing during the time needed to achieve revascularization by this method. This grade B recommendation is based on two level II studies231,232 and considerable level III data.224-227

8. Both revascularization surgery and amputation are effective treatments for limb-threatening ischemia. This grade C recommendation is based on levels III to V evidence.251-259 Revascularization has the obvious advantage of preserving the limb. Since there are no advantages to amputation with regard to operative risk251,252 or overall cost,253,254 revascularization may be the preferred alternative in nearly all patients, regardless of coexisting conditions. Primary amputation is preferred only in chronically institutionalized, neurologically impaired patients who are permanently nonambulatory.

9. The choice of surgical procedure depends on the level of arterial disease.

Aortoiliac disease. It is concluded that there is no convincing evidence that any currently available aortic bifurcation prosthesis (knitted Dacron, woven Dacron, protein-impregnated Dacron, PTFE) is superior to any other for aortofemoral bypass. This grade B recommendation is based on level II data.269-271 The following grade C recommendations are made on the basis of levels III to V evidence: (1) Aortofemoral bypass is preferred by most surgeons to endarterectomy, but the results of endarterectomy in skilled hands are equivalent to bypass290-292; (2) the results of multilevel bypass (simultaneous aortofemoral and infrainguinal bypass) are satisfactory when this procedure is performed in selected patients293; and (3) extra-anatomic bypass procedures (axillofemoral, femorofemoral) are satisfactory alternatives to aortofemoral bypass in patients with increased operative risk or other contraindications to aortic surgery.272

Infrainguinal bypass. Intact greater saphenous vein is the conduit of choice for infrainguinal bypass. This is a grade A recommendation based on level I evidence.260 Grade B recommendations based on level II evidence include (1) there is no difference in the results of saphenous vein bypass performed by either reversed or in situ techniques262-264; (2) HUV has higher long-term patency but a higher incidence of graft-related complications (aneurysm) than does PTFE265-267; (3) the overall superiority of one prosthetic over another (PTFE versus HUV versus Dacron) for infrainguinal bypass has not been established294; and (4) infrainguinal graft patency, limb salvage, and long-term relief of symptoms are maximized by frequent objective follow-up of operated patients with aggressive graft surveillance and repeat operation for detected lesions that threaten graft patency.77-79,288,289

10. Grade C recommendations based on levels III to V evidence include (1) long-term patency of prosthetic bypass may be enhanced by anastomotic techniques using autogenous patches and by long-term warfarin anticoagulation284,285; (2) for patients requiring infrapopliteal bypass in whom the greater saphenous vein is not available, the use of alternate autogenous vein with splicing of segments from multiple sources (if necessary) is superior to prosthetic grafts279-283; and (3) for patients requiring bypass to the popliteal artery in whom the greater saphenous vein is not available, the superiority of alternate autogenous vein over prosthetic has not been established.294


The authors thank S. Crnic for her help with the preparation of this manuscript. Dr Weitz is a Career Investigator of the Heart and Stroke Foundation of Ontario.


  1. Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Med Scand. 1982;211:249-256.
  2. Jelnes R, Gaardsting O, Hougaard Jensen K, Baekgaard N, Tonnesen KH, Schroeder T. Fate in intermittent claudication: outcome and risk factors. Br Med J (Clin Res Ed). 1986;293:1137-1140.
  3. Criqui MH, Fronek A, Barrett-Conner E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71:510-515.
  4. Imparato AM, Kim GE, Davidson T, Crowley JG. Intermittent claudication: its natural course. Surgery. 1975;78:795-799.
  5. Cronenwett JL, Warner KG, Zelenock GB, Whitehouse WM Jr, Graham LM, Lindenauer M, Stanley JC. Intermittent claudication: current results of nonoperative management. Arch Surg. 1984;119:430-436.
  6. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106.
  7. Boissel JP, Peyrieux JC, Destors JM. Is it possible to reduce the risk of cardiovascular events in subjects suffering from intermittent claudication of the lower limbs? Thromb Haemost. 1989;62:681-685.
  8. Katsumura T, Mishima Y, Kamiya K, Sakaguchi S, Tanabe T, Sakuma A. Therapeutic effect of ticlopidine, a new inhibitor of platelet aggregation on chronic arterial occlusive diseases: a double-blind study versus placebo. Angiology. 1982;33:357-367.
  9. Arcan JC, Panak E. Ticlopidine in the treatment of peripheral occlusive arterial disease. Semin Thromb Hemost. 1989;15:167-170.
  10. Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, Grasselli S, Violi F, Hellemans H, Vanhove P. Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial. J Lab Clin Med. 1989;114:84-91.
  11. Second European Consensus Document on chronic critical leg ischemia. Eur J Vasc Surg. 1992;6(suppl A):1-32.
  12. Criqui MH, Fronek A, Klauber MR, Barrett-Connor E, Gabriel S. The sensitivity, specificity, and predictive value of traditional clinical evaluation of peripheral disease: results from noninvasive testing in a defined population. Circulation. 1985;71:516-522.
  13. Gofin R, Kark JD, Friedlander Y, Lewis BS, Witt H, Stein Y, Gotsman MS. Peripheral vascular disease in a middle-aged population sample: the Jerusalem Lipid Research Clinic Prevalence Study. Isr J Med Sci. 1987;23:157-167.
  14. Beach KW, Strandness DE Jr. Arteriosclerosis obliterans and associated risk factors in insulin-dependent and non-insulin-dependent diabetes. Diabetes. 1980;29:882-888.
  15. Ouriel K, McDonnell AE, Metz CE, Zarins CK. A critical evaluation of stress testing in the diagnosis of peripheral vascular disease. Surgery. 1982;91:686-693.
  16. Carter SA. Clinical measurement of systolic pressures in limbs with arterial occlusive disease. JAMA. 1969;207:1869-1874.
  17. Fowkes FGR, Housley E, Cawood EH, Macintyre CC, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1991;20:384-392.
  18. Wilt TJ. Current strategies in the diagnosis and management of lower extremity peripheral vascular disease. J Gen Intern Med. 1992;7:87-101.
  19. Leng GC, Fowkes FGE. The Edinburgh Claudication Questionnaire: an improved version of the WHO/Rose Questionnaire for use in epidemiological surveys. J Clin Epidemiol. 1992;45:1101-1109.
  20. Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: the Framingham Study. J Am Geriatr Soc. 1985;33:13-18.
  21. Schroll M, Munck O. Estimation of peripheral arteriosclerotic disease by ankle blood pressure measurements in a population study of 60-year-old men and women. J Chronic Dis. 1981;34:261-269.
  22. Dormandy J, Mahir M, Ascady G, Balsano F, De Leeuw P, Blomberg P, Bousser MG, Clement D, Coffman J, Deutshinoff A, et al. Fate of the patient with chronic leg ischaemia: a review article. J Cardiovasc Surg (Torino). 1989;30:50-57.
  23. Vogt MT, Wolfson SK, Kuller LH. Lower extremity arterial disease and the aging process: a review. J Clin Epidemiol. 1992;45:529-542.
  24. Dormandy J. Peripheral vascular disease. Med North Am. 1994; 353-360.
  25. Widmer LK, Biland L, DaSilva A. Risk profile and occlusive periphery artery disease (OPAD). In: Proceedings of the 13th International Congress of Angiology; June 1985; Athens, Greece; 28.
  26. Stout RW. Diabetes, atherosclerosis and aging. Diabetes Care. 1990;13(suppl 2):20-23.
  27. Gordon T, Kannel WB. Predisposition to atherosclerosis in the head, heart, and legs: the Framingham study. JAMA. 1972;221:661-666.
  28. Farkouh ME, Rihal CS, Gersh BJ, Rooke TW, Hallett JW Jr, O'Fallon WM, Ballard DJ. Influence of coronary heart disease on morbidity and mortality after lower extremity revascularization surgery: a population-based study in Olmsted County, Minnesota (1970-1987). J Am Coll Cardiol. 1994;24:1290-1296.
  29. Jonason T, Ringqvist I. Factors of prognostic importance for subsequent rest pain in patients with intermittent claudication. Acta Med Scand. 1985;218:27-33.
  30. Hughson WG, Mann JI, Garrod A. Intermittent claudication: prevalence and risk factors. Br Med J. 1978;1:1379-1381.
  31. Criqui MH, Browner D, Fronek A, Klauber MR, Coughlin SS, Barrett-Connor E, Gabriel S. Peripheral arterial disease in large vessels is epidemiologically distinct from small vessel disease: an analysis of risk factors. Am J Epidemiol. 1989;129:1110-1119.
  32. Gown AM, Tsukada T, Ross R. Human atherosclerosis, II: immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986;125:191-207.
  33. Kannel WB, Shurtleff D. The Framingham Study: cigarettes and the development of intermittent claudication. Geriatrics. 1973;28:61-68.
  34. DePalma RG. Patterns of peripheral atherosclerosis: implications for treatment. In: Shepherd JT, Morgan HG, Packard CJ, Brownlie SM, eds. Atherosclerosis: Developments, Complications and Treatment: Proceedings of the International Symposium, Gleneagles Hotel, Perthshire, Scotland, April 23-26, 1987. New York, NY: Elsevier Science Publishing Co; 1987:161-174.
  35. Kannel WB, Skinner JJ Jr, Schwartz MJ, Shurtleff D. Intermittent claudication: incidence in the Framingham Study. Circulation. 1970;41:875-883.
  36. Zimmerman BR, Palumbo PJ, O'Fallon WM, Ellefson RD, Osmundson PJ, Kazmier FJ. A prospective study of peripheral occlusive arterial disease in diabetes, III: initial lipid and lipoprotein findings. Mayo Clinic Proc. 1981;56:233-242.
  37. Duffield RGM, Lewis B, Miller NE, Jamieson CW, Brunt JN, Colchester AC. Treatment of hyperlipidaemia retards progression of symptomatic femoral atherosclerosis: a randomised controlled trial. Lancet. 1983;2:639-642.
  38. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.
  39. McDaniel MD, Cronenwett JL. Basic data related to the natural history of intermittent claudication. Ann Vasc Surg. 1989;3:273-277.
  40. Peabody CN, Kannel WB, McNamara PM. Intermittent claudication: surgical significance. Arch Surg. 1974;109:693-697.
  41. Danish Amputation Register, Herlev Hospital, Copenhagen, 1989.
  42. Most RS, Sinnock P. The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care. 1983;6:87-91.
  43. Vogt MT, Cauley JA, Newman AB, Kuller LH, Hulley SB. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA. 1993;270:465-469.
  44. Newman AB, Sutton-Tyrrell K, Vogt MT, Kuller LH. Morbidity and mortality in hypertensive adults with a low ankle/arm blood pressure index. JAMA. 1993;270:487-489.
  45. Marinelli MR, Beach KW, Glass MJ, Primozich JF, Strandness DE Jr. Noninvasive testing vs clinical evaluation of arterial disease: a prospective study. JAMA. 1979;241:2031-2034.
  46. Strandness DE Jr, Priest RR, Gibbons GE. A combined clinical and pathological study of nondiabetic and diabetic vascular disease. Diabetes. 1964;13:366-372.
  47. Gensler SW, Haimovici H, Hoffert P, Steinman C, Beneventano TC. Study of vascular lesions in diabetic, non-diabetic patients. Arch Surg. 1965;91:617-622.
  48. Wheelock FC Jr. Transmetatarsal amputation and arterial surgery in diabetic patients. N Engl J Med. 1961;264:316-320.
  49. Lindbom A. Arteriosclerosis and arterial thrombosis in the lower limb: a roentgenological study. Acta Radiol Scand. 1950;80(suppl):38-48.
  50. Strandness DE Jr, Bell JW. Peripheral vascular disease: diagnosis and objective evaluation using a mercury strain gauge. Ann Surg. 1965;161(suppl):1-35.
  51. Sumner DS, Strandness DE Jr. The relationship between calf blood flow and ankle blood pressure in patients with intermittent claudication. Surgery. 1969;65:763-771.
  52. Strandness DE Jr, Schultz RD, Sumner DS, Rushmer RF. Ultrasonic flow detection: a useful technic in the evaluation of peripheral vascular disease. Am J Surg. 1967;113:311-320.
  53. Strandness DE Jr. Exercise testing in the evaluation of patients undergoing direct arterial surgery. J Cardiovasc Surg (Torino). 1970;11:192-200.
  54. Strandness DE Jr, Bell JW. Ankle pressure responses after reconstructive arterial surgery. Surgery. 1966;59:514-516.
  55. Strandness DE Jr. Hemodynamics of the normal arterial and venous system. In: Strandness DE Jr, ed. Duplex Scanning in Vascular Disorders. New York, NY: Raven Press; 1993:45-79.
  56. Stahler C, Strandness DE Jr. Ankle blood pressure response to graded treadmill exercise. Angiology. 1967;18:237-241.
  57. Skinner JS, Strandness DE Jr. Exercise and intermittent claudication, I: effect of repetition and intensity of exercise. Circulation. 1967;36:15-22.
  58. Beach KW, Brunzell JD, Strandness DE Jr. Prevalence of severe arteriosclerosis obliterans in patients with diabetes mellitus: relation to smoking and form of therapy. Arteriosclerosis. 1982;2:275-280.
  59. Holstein P, Lassen NA. Healing of ulcers on the feet correlated with distal blood pressure measurements in occlusive arterial disease. Acta Orthop Scand. 1980;51:995-1006.
  60. Orchard TJ, Strandness DE Jr. Assessment of peripheral vascular disease in diabetes: report and recommendations of an international workshop sponsored by the American Diabetes Association and the American Heart Association, September 18-20, 1992, New Orleans, Louisiana. Circulation. 1993;88:819-828.
  61. Raines JK. The pulse volume recorder in peripheral arterial disease. In: Berstein EF, ed. Vascular Diagnosis. 4th ed. St Louis, Mo: CV Mosby Co; 1993:534-543.
  62. Strandness DE Jr. Peripheral arterial system. In: Duplex Scanning in Vascular Disorders. 2nd ed. New York, NY: Raven Press; 1993:159-195.
  63. Barber FE, Baker DW, Strandness DE Jr. Duplex scanner II for simultaneous imaging of artery tissues and flow. In: Proceedings of Ultrasonics Symposium, IEEE, 1974. Publication No. 74CH0896-ISU.
  64. Phillips DJ, Powers JE, Eyer MK, Blackshear WM Jr, Bodily KC, Strandness DE Jr, Baker DW. Detection of peripheral vascular disease using the Duplex Scanner III. Ultrasound Med Biol. 1980;6:205-218.
  65. Jager KA, Phillips DJ, Martin RL, Hanson C, Roederer GO, Langlois YE, Ricketts HJ, Strandness DE Jr. Noninvasive mapping of lower limb arterial lesions. Ultrasound Med Biol. 1985;11:515-521.
  66. Kohler TR, Andros G, Porter JM, Clowes A, Goldstone J, Johansen K, Raker E, Nance DR, Strandness DE Jr. Can duplex scanning replace arteriography for lower extremity arterial disease? Ann Vasc Surg. 1990;4:280-287.
  67. Kohler TR, Nance DR, Cramer MM, Vandenburghe N, Strandness DE Jr. Duplex scanning for diagnosis of aortoiliac and femoropopliteal disease: a prospective study. Circulation. 1987;76:1074-1080.
  68. May AG, Vandeberg L, DeWeese JA, Rob DG. Critical arterial stenosis. Surgery. 1963;54:250-259.
  69. Carter SA. Response of ankle systolic pressure to leg exercise in mild or questionable arterial disease. N Engl J Med. 1972;287:578-582.
  70. Legemate DA, Teeuwen C, Hoeneveld H, Ackerstaff RGA, Eikelboom BC. The potential for duplex scanning to replace aorto-iliac and femoro-popliteal angiography. Eur J Vasc Surg. 1989;3:49-54.
  71. Hatsukami TS, Primozich J, Zierler RE, Strandness DE Jr. Color Doppler characteristics in normal lower extremity arteries. Ultrasound Med Biol. 1992;18:167-171.
  72. Hatsukami TS, Primozich JF, Zierler RE, Harley JD, Strandness DE Jr. Color Doppler imaging of infrainguinal arterial occlusive disease. J Vasc Surg. 1992;16:527-533.
  73. Edwards JM, Coldwell DM, Goldman ML, Strandness DE Jr. The role of duplex scanning in the selection of patients for transluminal angioplasty. J Vasc Surg. 1991;13:69-74.
  74. Bandyk DF, Schmitt DD, Seabrook GR, Adams MB, Towne JB. Monitoring functional patency of in situ saphenous vein bypasses: the impact of a surveillance protocol and elective revision. J Vasc Surg. 1989;9:286-296.
  75. Bandyk DF. Postoperative surveillance of infrainguinal bypass. Surg Clin North Am. 1990;70:71-85.
  76. Mattos MA, van Bemmelen PS, Hodgson KJ, Ramsey DE, Barkmeier LD, Sumner DS. Does correction of stenoses identified with color duplex scanning improve infrainguinal graft patency? J Vasc Surg. 1993;17:54-66.
  77. Lundell A, Lindblad B, Bergqvist D, Hansen F. Femoropopliteal-crural graft patency is improved by an intensive surveillance program: a prospective randomized study. J Vasc Surg. 1995;21:26-33.
  78. Strandness DE Jr, Andros G, Baker JD, Bernstein EF. Vascular laboratory utilization and payment: report of the Ad Hoc Committee of the Western Vascular Society. J Vasc Surg. 1992;16:163-170.
  79. Applegate WB. Ankle/arm blood pressure index: a useful test for clinical practice? JAMA. 1993;270:497-498. Editorial.
  80. Vogt MT, McKenna M, Anderson SJ, Wolfson SK, Kuller LH. The relationship between ankle-arm index and mortality in older men and women. J Am Geriatr Soc. 1993;41:523-530.
  81. Taylor LM Jr, Porter JM. Natural history and non-operative treatment of chronic lower extremity ischemia. In: Rutherford RB, ed. Vascular Surgery. 3rd ed. Philadelphia, Pa: WB Saunders; 1989:653-667.
  82. Joyce JW. Non-operative, non-pharmacologic management of lower extremity occlusive disease. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery. 2nd ed. Philadelphia, PA: BC Decker; 1991:550-552.
  83. Verhaeghe R, Bounameaux H. Peripheral arterial occlusion: thromboembolism and antithrombotic therapy. In: Fuster V, Verstraete M, eds. Thrombosis in Cardiovascular Disorders. Philadelphia, Pa: WB Saunders; 1992:423-449.
  84. Ernst E, Fialka V. A review of the clinical effectiveness of exercise therapy for intermittent claudication. Arch Intern Med. 1993;153:2357-2360.
  85. Radack K, Wyderski RJ. Conservative management of intermittent claudication. Ann Intern Med. 1990;113:135-146.
  86. Larsen OA, Lassen NA. Effect of daily muscular exercise in patients with intermittent claudication. Lancet. 1966;2:1093-1096.
  87. Ericsson B, Haeger K, Lindell SE. Effect of physical training on intermittent claudication. Angiology. 1970;21:188-192.
  88. Dahllof AG, Holm J, Schersten T, Sivertsson R. Peripheral arterial insufficiency: effect of physical training on walking tolerance, calf blood flow, and blood flow resistance. Scand J Rehabil Med. 1976;8:19-26.
  89. Hiatt WR, Regensteiner JG, Hargarten ME, Wolfel EE, Brass EP. Benefit of exercise conditioning for patients with peripheral arterial disease. Circulation. 1990;81:602-609.
  90. Holm J, Dahllof AG, Bjorntorp P, Schersten T. Enzyme studies in muscles of patients with intermittent claudication: effect of training. Scand J Clin Lab Invest Suppl. 1973;128:201-205.
  91. Dahllof AG, Bjorntorp P, Holm J, Schersten T. Metabolic activity of skeletal muscle in patients with peripheral arterial insufficiency. Eur J Clin Invest. 1974;4:9-15.
  92. Mannarino E, Pasqualini L, Menna M, Maragoni G, Orlandi U. Effects of physical training on peripheral vascular disease: a controlled study. Angiology. 1989;40:5-10.
  93. Ernst EE, Matrai A. Intermittent claudication, exercise, and blood rheology. Circulation. 1987;76:1110-1114.
  94. Lundgren F, Dahllof AG, Lundholm K, Schersten T, Volkmann R. Intermittent claudication: surgical reconstruction or physical training? A prospective randomized trial of treatment efficiency. Ann Surg. 1989;209:346-355.
  95. Jonason T, Jonzon B, Ringqvist I, Oman-Rydberg A. Effect of physical training on different categories of patients with intermittent claudication. Acta Med Scand. 1979;206:253-258.
  96. Rosfors S, Bygdeman S, Arnetz BB, Lahnborg G, Skoldo L, Eneroth P, Kallner A. Longterm neuroendocrine and metabolic effects of physical training in intermittent claudication. Scand J Rehabil Med. 1989;21:7-11.
  97. Skinner JS, Strandness DE Jr. Exercise and intermittent claudication, II: effect of physical training. Circulation. 1967;36:23-29.
  98. Alpert SJ, Larsen OA, Lassen NA. Exercise and intermittent claudication: blood flow in the calf muscle during walking studied by the xenon-133 clearance method. Circulation. 1969;39:353-359.
  99. Lepantalo M, Sundberg S, Gordin A. The effects of physical training and flunarizine on walking capacity in intermittent claudication. Scand J Rehabil Med. 1984;16:159-162.
  100. Blumchen G, Landry F, Kiefer H, Schlosser V. Hemodynamic responses of claudicating extremities: evaluation of a long range exercise program. Cardiology. 1970;55:114-127.
  101. Jonason T, Ringqvist I. Effect of training on the post-exercise ankle blood pressure reaction in patients with intermittent claudication. Clin Physiol. 1987;7:63-69.
  102. Jonason T, Ringqvist I. Prediction of the effect of training on the walking tolerance in patients with intermittent claudication. Scand J Rehabil Med. 1987;19:47-50.
  103. Jonason T, Ringqvist I, Oman-Rydberg A. Home-training of patients with intermittent claudication. Scand J Rehabil Med. 1981;13:137-141.
  104. Folley WT. Treatment of gangrene of the feet and legs by walking. Circulation. 1957;15:670-689.
  105. Sorlie D, Myhre K. Effects of physical training in intermittent claudication. Scand J Clin Lab Invest. 1978;38:217-222.
  106. Clifford PC, Davies PW, Hayne JA, Baird RN. Intermittent claudication: is a supervised exercise class worthwhile? Br Med J. 1980;280:1503-1505.
  107. Hall J, Barnard R. The effects of an intensive 26-day program of diet and exercise on patients with peripheral vascular disease. J Cardiac Rehabil. 1982;2:569-574.
  108. Hedberg B, Langstrom M, Angquist KA, Fugl-Meyer AR. Isokinetic plantar flexor performance and fatiguability in peripheral arterial insufficiency. Acta Chir Scand. 1988;154:363-369.
  109. Andriessen MPHM, Barendsen GJ, Wouda AA, de Pater L. Changes of walking distance in patients with intermittent claudication during six months intensive physical training. Vasa. 1989;18:63-68.
  110. Ruell PA, Imperial ES, Bonar FJ, Thursby PF, Gass GC. Intermittent claudication: the effect of physical training on walking tolerance and venous lactate concentration. Eur J Appl Physiol. 1984;52:420-425.
  111. Carter SA, Hamel ER, Paterson JM, Snow CJ, Mymin D. Walking ability and ankle systolic pressures: observations in patients with intermittent claudication in a short-term walking exercise program. J Vasc Surg. 1989;10:642-649.
  112. Williams LR, Ekers MA, Collins PS, Lee JF. Vascular rehabilitation: benefits of a structured exercise/risk modification program. J Vasc Surg. 1991;14:320-326.
  113. Feinberg RL, Gregory RT, Wheeler JR, Snyder SO Jr, Gayle RG, Parent FN III, Patterson RB. The ischemic window: a method for the objective quantitation of the training effect in exercise therapy for intermittent claudication. J Vasc Surg. 1992;16:244-250.
  114. Hiatt WR, Regensteiner JG. Exercise rehabilitation in the treatment of patients with peripheral arterial disease. J Vasc Med Biol. 1990;2:163-170.
  115. Johnson EC, Voyles WF, Atterbom HA, Pathak D, Sutton MF, Greene ER. Effects of exercise training on common femoral artery blood flow in patients with intermittent claudication. Circulation. 1989;80(suppl 3, pt 2):III-59-III-72.
  116. Schoop W. Mechanism of beneficial action of daily walking training of patients with intermittent claudication. Scand J Clin Lab Invest Suppl. 1973;128:197-199.
  117. Zetterquist S. The effect of active training on the nutritive blood flow in exercising ischemic legs. Scand J Clin Lab Invest. 1970;25:101-111.
  118. Greenspan K, Lawrence PF, Esposito DB, Voorhees AB. The role of biofeedback and relaxation therapy in arterial occlusive disease. J Surg Res. 1980;29:387-394.
  119. Henriksson J, Nygaard E, Andersson J, Eklof B. Enzyme activities, fibre types and capillarization in calf muscles of patients with intermittent claudication. Scand J Clin Lab Invest. 1980;40:361-369.
  120. Hughson WG, Mann JI, Tibbs DJ, Woods HF, Walton I. Intermittent claudication: factors determining outcome. Br Med J. 1978;1:1377-1379.
  121. Juergens J, Barker H, Hines E. Atherosclerosis obliterans: review of 520 cases with special reference to pathogenic and prognostic factors. Circulation. 1960;21:188-195.
  122. Jonason T, Ringqvist I. Factors of prognostic importance for subsequent rest pain in patients with intermittent claudication. Acta Med Scand. 1985;218:27-33.
  123. Myers KA, King RB, Scott DF, Johnson N, Morris PJ. The effect of smoking on the late patency of arterial reconstructions in the legs. Br J Surg. 1978;65:267-271.
  124. Robicsek F, Daugherty HK, Mullen DC, Masters TN, Narbay D, Sanger PW. The effect of continued cigarette smoking on the patency of synthetic vascular grafts in Leriche syndrome. J Thorac Cardiovasc Surg. 1975;70:107-113.
  125. Ameli FM, Stein M, Provan JL, Prosser R. The effect of postoperative smoking on femoropopliteal bypass grafts. Ann Vasc Surg. 1989;3:20-25.
  126. Lassila R, Lepantalo M. Cigarette smoking and the outcome after lower limb arterial surgery. Acta Chir Scand. 1988;154:635-640.
  127. Greenhalgh RM, Laing SP, Cole PV, Taylor GW. Smoking and arterial reconstruction. Br J Surg. 1981;68:605-607.
  128. Herring M, Gardner A, Glover J. Seeding human arterial prostheses with mechanically derived endothelium: the detrimental effect of smoking. J Vasc Surg. 1984;1:279-289.
  129. Birkenstock WE, Louw JH, Terblanche J, Immelman EJ, Dent DM, Baker PM. Smoking and other factors affecting the conservative management of peripheral vascular disease. S Afr Med J. 1975;49:1129-1132.
  130. Quick CRG, Cotton LT. The measured effect of stopping smoking on intermittent claudication. Br J Surg. 1982;69(suppl):S24-S26.
  131. Coffman JD. Vasodilator drugs in peripheral vascular disease. N Engl J Med. 1979;301:159-160. Letter.
  132. Reid HL, Dormandy JA, Barnes AJ, Lock PJ, Dormandy TL. Impaired red cell deformability in peripheral vascular disease. Lancet. 1976;1:666-668.
  133. Dormandy JA, Hoare E, Colley J, Arrowsmith DE, Dormandy TL. Clinical, haemodynamic, rheological, and biochemical findings in 126 patients with intermittent claudication. Br Med J. 1973;4:576-581.
  134. Ehrly AM. Improvement of the flow properties of blood: a new therapeutical approach in occlusive arterial disease. Angiology. 1976;27:188-196.
  135. Angelkort B, Maurin N, Boateng K. Influence of pentoxifylline on erythrocyte deformability in peripheral occlusive arterial disease. Curr Med Res Opin. 1979;6:255-258.
  136. Johnson WC, Sentissi JM, Baldwin D, Hamilton J, Dion J. Treatment of claudication with pentoxifylline: are benefits related to improvement in viscosity? J Vasc Surg. 1987;6:211-216.
  137. Angelkort B, Kiesewetter H. Influence of risk factors and coagulation phenomena on the fluidity of blood in chronic arterial occlusive disease. Scand J Clin Lab Invest Suppl. 1981;156:185-188.
  138. Accetto B. Beneficial hemorheologic therapy of chronic peripheral arterial disorders with pentoxifylline: results of double-blind study versus vasodilator-nylidrin. Am Heart J. 1982;103:864-869.
  139. Bollinger A, Frei C. Double blind study of pentoxifylline against placebo in patients with intermittent claudication. Pharmatherapeutica. 1977;1:557-562.
  140. Di Perri T, Guerrini M. Placebo controlled double blind study with pentoxifylline of walking performance in patients with intermittent claudication. Angiology. 1983;34:40-45.
  141. Roekaerts F, Deleers L. Trental 400 in the treatment of intermittent claudication: results of long-term, placebo-controlled administration. Angiology. 1984;35:396-406.
  142. Strano A, Davi G, Avellone G, Novo S, Pinto A. Double-blind, crossover study of the clinical efficacy and the hemorheological effects of pentoxifylline in patients with occlusive arterial disease of the lower limbs. Angiology. 1984;35:459-466.
  143. Lindgarde F, Jelnes R, Bjorkman H, Adielsson G, Kjellstrom T, Palmquist I, Stavenow L. Conservative drug treatment in patients with moderately severe chronic occlusive peripheral arterial disease: Scandinavian Study Group. Circulation. 1989;80:1549-1556.
  144. Porter JM, Cutler BS, Lee BY, Reich T, Reichle FA, Scogin JT, Strandness DE. 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.
  145. Dettori AG, Pini M, Moratti A, Paolicelli M, Basevi P, Quintavalla R, Manotti C, Di Lecce C. Acenocoumarol and pentoxifylline in intermittent claudication: a controlled clinical study: the APIC study group. Angiology. 1989;40(pt 1):237-248.
  146. Gallus AS, Gleadow F, Dupont P, Walsh J, Morley AA, Wenzel A, Alderman M, Chivers D. Intermittent claudication: a double-blind crossover trial of pentoxifylline. Aust NZ J Med. 1985;15:402-409.
  147. Perhoniemi V, Salmenkivi K, Sundberg S, Johnsson R, Gordin A. Effects of flunarizine and pentoxifylline on walking distance and blood rheology in claudication. Angiology. 1984;35:366-372.
  148. Reilly DT, Quinton DN, Barrie WW. A controlled trial of pentoxifylline (Trental 400) in intermittent claudication: clinical, haemostatic and rheological effects. NZ Med J. 1987;100:445-447.
  149. Tonak J, Knecht H, Groitl H. Treatment of circulatory disturbances with pentoxifylline: a double blind study with Trental. Pharmatherapeutica. 1983;3(suppl 1):126-135.
  150. PACK Claudication Substudy. Randomized placebo-controlled, double-blind trial of ketanserin in claudicants: changes in claudication distance and ankle systolic pressure. Circulation. 1989;80:1544-1548.
  151. Verhaeghe R, Van Hoof A, Beyens G. Controlled trial of suloctidil in intermittent claudication. J Cardiovasc Pharmacol. 1981;3:279-286.
  152. Creager MA, Roddy MA. The effect of nifedipine on calf blood flow and exercise capacity in patients with intermittent claudication. J Vasc Med Biol. 1990;2:94-99.
  153. Gans ROB, Bilo HJG, Weersink EGL, Rauwerda JA, Fonk T, Popp-Snijders C, Donker AJM. Fish oil supplementation in patients with stable claudication. Am J Surg. 1990;160:490-495.
  154. Clyne CA, Galland RB, Fox MJ, Gustave R, Jantet GH, Jamieson CW. A controlled trial of naftidrofuryl (Praxilene) in the treatment of intermittent claudication. Br J Surg. 1980;67:347-348.
  155. Greenhalgh RM. Naftidrofuryl for ischemic rest pain: a controlled trial. Br J Surg. 1981;68:265-266.
  156. Guldager B, Jelnes R, Jorgensen SJ, Nielsen JS, Klaerke A, Mogensen K, Larsen KE, Reimer E, Holm J, Ottesen S. EDTA treatment of intermittent claudication: a double-blind, placebo-controlled study. J Intern Med. 1992;231:261-267.
  157. van Rij AM, Solomon C, Packer SGK, Hopkins WG. Chelation therapy for intermittent claudication: a double-blind, randomized, controlled trial. Circulation. 1994;90:1194-1199.
  158. Brevetti G, Chiariello M, Ferulano G, Policicchio A, Nevola E, Rossini A, Attisano T, Ambrosio G, Siliprandi N, Angelini C. 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.
  159. Ernst E, Matrai A, Kollar L. Placebo-controlled, double-blind study of haemodilution in peripheral arterial disease. Lancet. 1987;1:1449-1451.
  160. Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease: a prospective double-blind arteriographically controlled trial. Lancet. 1985;1:415-419.
  161. Goldhaber SZ, Manson JE, Stampfer MJ, LaMotte F, Rosner B, Buring JE, Hennekens CH. Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians' Health Study. Lancet. 1992;340:143-145.
  162. Hirsh J, Dalen JE, Fuster V, Harker LB, Salzman EW. Aspirin and other platelet-active drugs: the relationship between dose, effectiveness, and side effects. Chest. 1992;102(suppl 4):327S-336S.
  163. Clagett GP, Graor RA, Salzman EW. Antithrombotic therapy in peripheral arterial occlusive disease. Chest. 1992;102(suppl 4):516S-528S.
  164. Fuster V, Chesebro JH. Role of platelets and platelet inhibitors in aortocoronary artery vein-graft disease. Circulation. 1986;73:227-232.
  165. Boobis LH, Bell PR. Can drugs help patients with lower limb ischaemia? Br J Surg. 1982;69(suppl):S17-S23.
  166. Coffman JD. Intermittent claudication and rest pain: physiologic concepts and therapeutic approaches. Prog Cardiovasc Dis. 1979;22:53-72.
  167. Tillgren C. Obliterative arterial disease of the lower limbs, IV: evaluation of long-term anticoagulant therapy. Acta Med Scand. 1965;178:203.
  168. Jones NAG, De Haas H, Zahavi J, Kakkar VV. A double-blind trial of suloctidil v placebo in intermittent claudication. Br J Surg. 1982;69:38-40.
  169. Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J (Clin Res Ed). 1988;296:320-331.
  170. Balzer K, Rogatti W, Ruttgerodt K. Efficacy and tolerability of intra-arterial and intravenous prostaglandin E1 infusions in occlusive arterial disease stage III/IV. Vasa Suppl. 1989;28:31-38.
  171. Schuler JJ, Flanigan DP, Holcroft JW, Ursprung JJ, Mohrland JS, Pyke J. Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease: results of a prospective randomized, double-blind, multicenter clinical trial. J Vasc Surg. 1984;1:160-170.
  172. Nizankowski R, Krolikowski W, Bielatowicz J, Szczeklik A. Prostacyclin for ischemic ulcers in peripheral arterial disease: a random assignment, placebo controlled study. Thromb Res. 1985;37:21-28.
  173. Belch JJF, McKay A, McArdle B, Leiberman P, Pollock JG, Lowe GD, Forbes CD, Prentice CR. Epoprostenol (prostacyclin) and severe arterial disease: a double-blind trial. Lancet. 1983;1:315-317.
  174. Cronenwett JL, Zelenock GB, Whitehouse WM Jr, Lindenauer SM, Graham LM, Stanley JC. Prostacyclin treatment of ischemic ulcers and rest pain in unreconstructible peripheral arterial occlusive disease. Surgery. 1986;100:369-375.
  175. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
  176. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-1307.
  177. Sacks FM, Pasternak RC, Gibson CM, Rosner B, Stone PH. Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemic patients: Harvard Atherosclerosis Reversibility Project (HARP) Group. Lancet. 1994;334:1182-1186.
  178. Johnston KW. Aortoiliac disease treatment: a surgical comment. Circulation. 1991;83(suppl I):I-61-I-62.
  179. Wolf GL, Wilson SE, Cross AP, Deupree RH, Stason WB, for the principal investigators and their associates of Veterans Administration Cooperative Study Number 199. Surgery or balloon angioplasty for peripheral vascular disease: a randomized clinical trial. J Vasc Interv Radiol. 1993;4:639-648.
  180. Casarella WJ. Noncoronary angioplasty. Curr Probl Cardiol. 1986;11:141-174.
  181. Johnston KW, Rae M, Hogg-Johnston SA, Colapinto RF, Walker PM, Baird RJ, Sniderman KW, Kalman P. Five-year results of a prospective study of percutaneous transluminal angioplasty. Ann Surg. 1987;206:403-413.
  182. Tegtmeyer CJ, Hartwell GD, Selby JB, Robertson R Jr, Kron IL, Tribble CG. Results and complications of angioplasty in aortoiliac disease. Circulation. 1991;83(suppl I):I-53-I-60.
  183. Stokes KR, Strunk HM, Campbell DR, Gibbons GW, Wheeler HG, Clouse ME. Five-year results of iliac and femoropopliteal angioplasty in diabetic patients. Radiology. 1990;174(pt 2):977-982.
  184. Capek P, McLean GK, Berkowitz HD. Femoropopliteal angioplasty: factors influencing long-term success. Circulation. 1991;83(suppl I):I-70-I-80.
  185. Hunink MGM, Wong JB, Donaldson MC, Meyerovitz MF, de Vries J, Harrington DP. Revascularization for femoropopliteal disease: a decision and cost-effectiveness analysis. JAMA. 1995;274:165-171.
  186. Currie IC, Wakeley CJ, Cole SEA, Wyatt MG, Scott DJA, Baird RN, Horrocks M. Femoropopliteal angioplasty for severe limb ischaemia. Br J Surg. 1994;81:191-193.
  187. Schwarten DE. Clinical and anatomical considerations for nonoperative therapy in tibial disease and the results of angioplasty. Circulation. 1991;83(suppl I):I-86-I-90.
  188. Tunis SR, Bass EB, Steinberg EP. The use of angioplasty, bypass surgery, and amputation in the management of peripheral vascular disease. N Engl J Med. 1991;325:556-562.
  189. Enzler MA. Failure of an increased number of revascularization procedures to decrease the rate of lower-extremity amputations. Radiology. 1994;190:904-905. Letter.
  190. Pell JP, Whyman MR, Fowkes FGR, Gillespie I, Ruckley CV. Trends in vascular surgery since the introduction of percutaneous transluminal angioplasty. Br J Surg. 1994;81:832-835.
  191. Hasson JE, Archer CW, Wojtowycz M, McDermott J, Crummy A, Turnipseed WD. Lower extremity percutaneous transluminal angioplasty: multifactorial analysis of morbidity and mortality. Surgery. 1990;108:748-754.
  192. Cooper JC, Welsh CL. The role of percutaneous transluminal angioplasty in the treatment of critical ischaemia. Eur J Vasc Surg. 1991;5:261-264.
  193. Strecker EP, Hagen B, Liermann D, Schneider B, Wolf HR, Wambsganss J. Iliac and femoropopliteal vascular occlusive disease treated with flexible tantalum stents. Cardiovasc Intervent Radiol. 1993;16:158-164.
  194. Bonn J, Gardiner GA Jr, Palmaz J, Shapiro MJ, Sullivan KL, Levin DC. Improved angioplasty hemodynamics after Palmaz vascular stent placement. Circulation. 1989;80(suppl II):II-411. Abstract.
  195. Becker GJ, Palmaz JC, Rees CR, Ehrman KO, Lalka SG, Dalsing MC, Cikrit DF, McLean GK, Burke DR, Richter GM, et al. Angioplasty-induced dissections in human iliac arteries: management with Palmaz balloon-expandable intraluminal stents. Radiology. 1990;176:31-38.
  196. Amery A, Deloof W, Vermylen J, Verstraete M. Outcome of recent thromboembolic occlusions of limb arteries treated with streptokinase. BMJ. 1970;4:639-644.
  197. Dotter CT, Rosch J, Seaman AJ, Dennis D, Massey WH. Streptokinase treatment of thromboembolic disease. Radiology. 1972;102:283-290.
  198. Dotter CT, Rosch J, Seaman AJ. Selective clot lysis with low-dose streptokinase. Radiology. 1974;111:31-37.
  199. Comerota AJ, Cohen GS. Thrombolytic therapy in peripheral arterial occlusive disease: mechanisms of action and drugs available. Can J Surg. 1993;36:342-348.
  200. Martin M, Fiebach BJ. Short-term ultrahigh streptokinase treatment of chronic arterial occlusions and acute deep vein thromboses. Semin Thromb Hemost. 1991;17:21-38.
  201. McNamara TO, Fischer JR. Thrombolysis of peripheral arterial and graft occlusions: improved results using high-dose urokinase. AJR Am J Roentgenol. 1985;144:769-775.
  202. McNamara TO. Role of thrombolysis in peripheral arterial occlusion. Am J Med. 1987;83:6-10.
  203. Berridge DC, Gregson RH, Makin GS, Hopkinson BR. Tissue plasminogen activator in peripheral arterial thrombolysis. Br J Surg. 1990;77:179-182.
  204. Berridge DC, Gregson RH, Hopkinson BR, Makin GS. Randomized trial of intra-arterial recombinant tissue plasminogen activator, intravenous recombinant tissue plasminogen activator and intra-arterial streptokinase in peripheral arterial thrombolysis. Br J Surg. 1991;78:988-995.
  205. Meyerovitz MF, Goldhaber SZ, Reagan K, Polak JF, Kandarpa K, Grassi CJ, Donovan BC, Bettmann MA, Harrington DP. Recombinant tissue-type plasminogen activator versus urokinase in peripheral arterial and graft occlusions: a randomized trial. Radiology. 1990;175:75-78.
  206. van Breda A, Katzen BT, Deutsch AS. Urokinase versus streptokinase in local thrombolysis. Radiology. 1987;165:109-111.
  207. Bell W. Update on urokinase and streptokinase: a comparison of their efficacy and safety. Hospital Formulary. 1988;23:230-241.
  208. Janosik JE, Bettmann MA, Kaul AF, Souney PF. Therapeutic alternatives for subacute peripheral arterial occlusion: comparison by outcome, length of stay, and hospital charges. Invest Radiol. 1991;26:921-925.
  209. Lawrence PF, Goodman GR. Thrombolytic therapy. Surg Clin North Am. 1992;72:899-918.
  210. Shortell CK, Ouriel K. Thrombolysis in acute peripheral arterial occlusion: predictors of immediate success. Ann Vasc Surg. 1994;8:59-65.
  211. Bookstein JJ, Fellmeth B, Roberts A, Valji K, Davis G, Machado T. Pulsed-spray pharmacomechanical thrombolysis: preliminary clinical results. AJR Am J Roentgenol. 1989;152:1097-1100.
  212. Bookstein JJ, Valji K. Pulse-spray pharmacomechanical thrombolysis. Cardiovasc Intervent Radiol.1992;15:228-233.
  213. Kandarpa K, Chopra PS, Aruny JE, Polak JF, Donaldson MC, Whittemore AD, Mannick JA, Goldhaber SZ, Meyerovitz MF. Intraarterial thrombolysis of lower extremity occlusions: prospective, randomized comparison of forced periodic infusion and conventional slow continuous infusion. Radiology. 1993;188:861-867.
  214. Ferguson LJ, Faris I, Robertson A, Lloyd JV, Miller JH. Intra-arterial streptokinase therapy to relieve acute limb ischemia. J Vasc Surg. 1986;4:205-210.
  215. Belkin M, Donaldson MC, Whittemore AD, Polak JF, Grassi CJ, Harrington DP, Mannick JA. Observations on the use of thrombolytic agents for thrombotic occlusion of infrainguinal vein grafts. J Vasc Surg. 1990;11:289-296.
  216. McNamara TO, Bomberger RA, Merchant RF. Intra-arterial urokinase as the initial therapy for acutely ischemic lower limbs. Circulation. 1991;83(suppl I):I-106-I-119.
  217. Graor RA, Risius B, Denny KM, Young JR, Beven EG, Hertzer NR, Ruschhaupt WF III, O'Hara PJ, Geisinger MA, Zelch MG. Local thrombolysis in the treatment of thrombosed arteries, bypass grafts, and arteriovenous fistulas. J Vasc Surg. 1985;2:406-414.
  218. McNamara TO, Bomberger RA. Factors affecting initial and 6 month patency rates after intraarterial thrombolysis with high dose urokinase. Am J Surg. 1986;152:709-712.
  219. Faggioli GL, Ricotta JJ. Thrombolytic therapy for lower extremity arterial occlusion. Ann Vasc Surg. 1993;7:297-302.
  220. Durham JD, Geller SC, Abbott WM, Shapiro H, Waltman AC, Walker TG, Brewster DC, Athanasoulis CA. Regional infusion of urokinase into occluded lower-extremity bypass grafts: long-term clinical results. Radiology. 1989;172:83-87.
  221. Sullivan KL, Gardiner GA Jr, Shapiro MJ, Bonn J, Levin DC. Acceleration of thrombolysis with a high-dose transthrombus bolus technique. Radiology. 1989;173:805-808.
  222. Gardiner GA Jr, Koltun W, Kandarpa K, Whittemore A, Meyerovitz MF, Bettmann MA, Levin DC, Harrington DP. Thrombolysis of occluded femoropopliteal grafts. AJR Am J Roentgenol. 1986;147:621-626.
  223. Rush DS, Gewertz BL, Lu CT, Neely SM, Ball DG, Beasley M, Zarins CK. Selective infusion of streptokinase for arterial thrombosis. Surgery. 1983;93:828-833.
  224. Kakkasseril JS, Cranley JJ, Arbaugh JJ, Roedersheimer LR, Welling RE. Efficacy of low-dose streptokinase in acute arterial occlusion and graft thrombosis. Arch Surg. 1985;120:427-429.
  225. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity: the STILE trial. Ann Surg. 1994;220:251-266.
  226. Browse DJ, Torrie EP, Galland RB. Early results and 1-year follow-up after intra-arterial thrombolysis. Br J Surg. 1993;80:194-197.
  227. Barr H, Lancashire MJ, Torrie EP, Galland RB. Intra-arterial thrombolytic therapy in the management of acute and chronic limb ischaemia. Br J Surg. 1991;78:284-287.
  228. Hess H, Ingrisch H, Mietaschk A, Rath H. Local low-dose thrombolytic therapy of peripheral arterial occlusions. N Engl J Med. 1982;307:1627-1630.
  229. Italian Cooperative Study Bologna. Endoarterial treatment of acute ischemia of the limbs with urokinase. Int Angiol. 1989;8:53-56.
  230. Sicard GA, Schier JJ, Totty WG, Gilula LA, Walker WB, Etheredge EE, Anderson CB. Thrombolytic therapy for acute arterial occlusion. J Vasc Surg. 1985;2:65-78.
  231. Nilsson L, Albrechtsson U, Jonung T, Ribbe E, Thorvinger B, Thorne J, Astedt B, Norgren L. Surgical treatment versus thrombolysis in acute arterial occlusion: a randomised controlled study. Eur J Vasc Surg. 1992;6:189-193.
  232. Ouriel K, Shortell CK, DeWeese JA, Green RM, Francis CW, Azodo MV, Gutierrez OH, Manzione JV, Cox C, Marder VJ. A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia. J Vasc Surg. 1994;19:1021-1030.
  233. Decrinis M, Pilger E, Stark G, Lafer M, Obernosterer A, Lammer J. A simplified procedure for intra-arterial thrombolysis with tissue-type plasminogen activator in peripheral arterial occlusive disease: primary and long-term results. Eur Heart J. 1993;14:297-305.
  234. Hess H. Thrombolytic therapy in peripheral vascular disease. Br J Surg. 1990;77:1083-1084.
  235. Whittemore AD, Donaldson MC, Polak JF, Mannick JA. Limitations of balloon angioplasty for vein graft stenosis. J Vasc Surg. 1991;14:340-345.
  236. Sullivan KL, Gardiner GA Jr, Kandarpa K, Bonn J, Shapiro MJ, Carabasi RA, Smullens S, Levin DC. Efficacy of thrombolysis in infrainguinal bypass grafts. Circulation. 1991;83(suppl 1):I-99-I-105.
  237. Gardiner GA Jr, Harrington DP, Koltun W, Whittemore A, Mannick JA, Levin DC. Salvage of occluded arterial bypass grafts by means of thrombolysis. J Vasc Surg. 1989;9:426-431.
  238. Bull PG, Guttierez E, Mendel H, Schlegl A, Dellinger C. Thrombolysis combined with angioplasty for failed femorodistal arterial grafts. Acta Chir Belg. 1993;93:276-283.
  239. Graor RA, Risius B, Young JR, Lucas FV, Beven EG, Hertzer NR, Krajewski LP, O'Hara PJ, Olin J, Ruschhaupt WF. Thrombolysis of peripheral arterial bypass grafts: surgical thrombectomy compared with thrombolysis--a preliminary report. J Vasc Surg. 1988;7:347-355.
  240. Van Breda A. Thrombolysis in arterial bypass grafts. Semin Thromb Hemost. 1991;17:7-13.
  241. Karmody AM, Powers SR, Monaco VJ, Leather RP. Blue toe syndrome: an indication for limb salvage surgery. Arch Surg. 1976;111:1263-1268.
  242. The Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery/North American Chapter, International Society for Cardiovascular Surgery. Suggested standards for reports dealing with lower extremity ischemia. J Vasc Surg. 1986;4:80-94.
  243. Wilson SE, Wolf GL, Cross AP. Percutaneous transluminal angioplasty versus operation for peripheral arteriosclerosis: report of a prospective randomized trial in a select group of patients. J Vasc Surg. 1989;9:1-9.
  244. Howell MA, Colgan MP, Seeger RW, Ramsey DE, Sumner DS. Relationship of severity of lower limb peripheral vascular disease to mortality and morbidity: a six-year follow-up study. J Vasc Surg. 1989;9:691-697.
  245. Felix WR Jr, Sigel B, Gunther L. The significance for morbidity and mortality of Doppler-absent pedal pulses. J Vasc Surg. 1987;5:849-855.
  246. Kallero KS, Bergqvist D, Cederholm C, Jonsson K, Olsson PO, Takolander R. Late mortality and morbidity after arterial reconstruction: the influence of arteriosclerosis in the popliteal artery trifurcation. J Vasc Surg. 1985;2:541-546.
  247. Malone JM, Moore WS, Goldstone J. Life expectancy after aortofemoral grafting. Surgery. 1977;81:551-555.
  248. Taylor LM Jr, Hamre D, Dalman RL, Porter JM. Limb salvage vs amputation for critical ischemia: the role of vascular surgery. Arch Surg. 1991;126:1251-1258.
  249. Edwards JE, Taylor LM Jr, Porter JM. Treatment of failed lower extremity bypass grafts with new autogenous vein bypass grafting. J Vasc Surg. 1990;11:136-144.
  250. Veith FJ, Gupta SK, Wengerter KR, Goldsmith J, Rivers SP, Bakal CW, Dietzek AM, Cynamon J, Sprayregen S, Gliedman ML. Changing arteriosclerotic disease patterns and management strategies in lower-limb-threatening ischemia. Ann Surg. 1990;212:402-414.
  251. Ouriel K, Fiore WM, Geary JE. Limb-threatening ischemia in the medically compromised patient: amputation or revascularization? Surgery. 1988;104:667-672.
  252. De Frang RD, Taylor LM Jr, Porter JM. Basic data related to amputations. Ann Vasc Surg. 1991;5:202-207.
  253. Raviola CA, Nichter LS, Baker JD, Busuttil RW, Machleder HI, Moore WS. Cost of treating advanced leg ischemia: bypass graft vs primary amputation. Arch Surg. 1988;123:495-496.
  254. Mackey WC, McCullough JL, Conlon TP, Shepard AD, Deterling RA, Callow AD, O'Donnell TF. The costs of surgery for limb-threatening ischemia. Surgery. 1986;99:26-35.
  255. Veith FJ, Gupta SK, Samson RH, Scher LA, Fell SC, Weiss P, Janko G, Flores SW, Rifkin H, Bernstein G, Haimovici H, Gliedman ML, Sprayregen S. Progress in limb salvage by reconstructive arterial surgery combined with new or improved adjunctive procedures. Ann Surg. 1981;194:386-401.
  256. Cronenwett JL, McDaniel MD, Zwolak RM, Walsh DB, Schneider JR, Reus SF, Colen LB. Limb salvage despite extensive tissue loss: free tissue transfer combined with distal revascularization. Arch Surg. 1989;124:609-615.
  257. Gibbons GW, Marcaccio EJ Jr, Burgess AM, Pomposelli FB Jr, Freeman DV, Campbell DR, Miller A, LoGerfo FW. Improved quality of diabetic foot care, 1984 vs 1990: reduced length of stay and costs, insufficient reimbursement. Arch Surg. 1993;128:576-581.
  258. Edwards JM, Taylor LM Jr, Porter JM. Limb salvage in end-stage renal disease (ESRD): comparison of modern results in patients with and without ESRD. Arch Surg. 1988;123:1164-1168.
  259. Harrington EB, Harrington ME, Schanzer H, Haimov M. End-stage renal disease: is infrainguinal revascularization justified? J Vasc Surg. 1990;12:691-696.
  260. Veith FJ, Gupta SK, Ascer E, White-Flores S, Samson RH, Scher LA, Towne JB, Bernhard VM, Bonier P, Flinn WR. Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J Vasc Surg. 1986;3:104-114.
  261. Veterans Administration Cooperative Study Group 141. Comparative evaluation of prosthetic, reversed, and in situ vein bypass grafts in distal popliteal and tibial-peroneal revascularization. Arch Surg. 1988;123:434-438.
  262. Moody AP, Edwards PR, Harris PL. In situ versus reversed femoropopliteal vein grafts: long-term follow-up of a prospective, randomized trial. Br J Surg. 1992;79:750-752.
  263. Watelet J, Cheysson E, Poels D, Menard JF, Papion H, Saour N, Testart J. In situ versus reversed saphenous vein for femoropopliteal bypass: a prospective randomized study of 100 cases. Ann Vasc Surg. 1987;1:441-452.
  264. Wengerter KR, Veith FJ, Gupta SK, Goldsmith J, Farrell E, Harris PL, Moore D, Shanik G. Prospective randomized multicenter comparison of in situ and reversed vein infrapopliteal bypasses. J Vasc Surg. 1991;13:189-199.
  265. Aalders GJ, van Vroonhoven TJMV. Polytetrafluoroethylene versus human umbilical vein in above-knee femoropopliteal bypass: six-year results of a randomized clinical trial. J Vasc Surg. 1992;16:816-824.
  266. Eickhoff JH, Buchardt Hansen HJ, Bromme A, Ericsson BF, Kordt KF, Mouritzen C, Myhre HO, Norgren L, Rostad H, Trippestad A. A randomized clinical trial of PTFE versus human umbilical vein for femoropopliteal bypass surgery: preliminary results. Br J Surg. 1983;70:85-88.
  267. Miyata T, Tada Y, Takagi A, Sato O, Oshima A, Idezuki Y, Shiga J. A clinicopathologic study of aneurysm formation of glutaraldehyde-tanned human umbilical vein grafts. J Vasc Surg. 1989;10:605-611.
  268. Gupta SK, Veith FJ, Kram HB, Wengerter KR. Prospective, randomized comparison of ringed and nonringed polytetrafluoroethylene femoropopliteal bypass grafts: a preliminary report. J Vasc Surg. 1991;13:163-172.
  269. Polterauer P, Prager M, Holzenbein T, Karner J, Kretschmer G, Schemper M. Dacron versus polytetrafluoroethylene for Y-aortic bifurcation grafts: a six-year prospective, randomized trial. Surgery. 1992;111:626-633.
  270. De Mol van Otterloo JC, Van Bockel JH, Ponfoort ED, Van den Akker PJ, Hermans J, Terpstra JL. Randomized study on the effect of collagen impregnation of knitted Dacron velour aortoiliac prostheses on blood loss during aortic reconstruction. Br J Surg. 1991;78:288-292.
  271. Robicsek F, Duncan GD, Daugherty HK, Cook JW, Selle JG, Hess PJ, Lawhorn R. 'Half and half' woven and knitted Dacron grafts in the aortoiliac and aortofemoral positions: seven and one-half years follow-up. Ann Vasc Surg. 1991;5:315-319.
  272. Passman MA, Taylor LM, Moneta GL, Edwards JM, Yeager RA, McConnell DB, Porter JM. Comparison of axillofemoral and aortofemoral bypass for aortoiliac occlusive disease. J Vasc Surg. 1996;23:263-271.
  273. Quinones-Baldrich WJ, Busuttil RW, Baker JD, Vescera CL, Ahn SS, Machleder HI, Moore WS. Is the preferential use of polytetrafluoroethylene grafts for femoropopliteal bypass justified? J Vasc Surg. 1988;8:219-228.
  274. Whittemore AD, Kent KC, Donaldson MC, Couch NP, Mannick JA. What is the proper role of polytetrafluoroethylene grafts in infrainguinal reconstruction? J Vasc Surg. 1989;10:299-305.
  275. Londrey GL, Ramsey DE, Hodgson KJ, Barkmeier LD, Sumner DS. Infrapopliteal bypass for severe ischemia: comparison of autogenous vein, composite, and prosthetic grafts. J Vasc Surg. 1991;13:631-636.
  276. Berlakovich GA, Herbst F, Mittlbock M, Kretschmer G. The choice of material for above- knee femoropopliteal bypass: a 20-year experience. Arch Surg. 1994;129:297-302.
  277. Sterpetti AV, Schultz RD, Feldhaus RJ, Peetz DJ Jr. Seven-year experience with polytetrafluoroethylene as above-knee femoropopliteal bypass graft. Is it worthwhile to preserve the autologous saphenous vein? J Vasc Surg. 1985;2:907-912.
  278. Taylor LM Jr, Porter JM. Clinical and anatomic considerations for surgery in femoropopliteal disease and the results of surgery. Circulation. 1991;83(suppl I):I-63-I-69.
  279. Kent KC, Whittemore AD, Mannick JA. Short-term and midterm results of an all- autogenous tissue policy for infrainguinal reconstruction. J Vasc Surg. 1989;9:107-114.
  280. Harris RW, Andros G, Dulawa LB, Oblath RW, Salles-Cunha SX, Apyan R. Successful long-term limb salvage using cephalic vein bypass grafts. Ann Surg. 1984;200:785-792.
  281. Chang BB, Paty PSK, Shah DM, Leather RP. The lesser saphenous vein: an underappreciated source of autogenous vein. J Vasc Surg. 1992;15:152-157.
  282. Schulman ML, Badhey MR, Yatco R, Pillari G. An 11-year experience with deep leg veins as femoropopliteal bypass grafts. Arch Surg. 1986;121:1010-1015.
  283. Taylor LM Jr, Edwards JM, Porter JM. Present status of reversed vein bypass grafting: five-year results of a modern series. J Vasc Surg. 1990;11:193-206.
  284. Taylor RS, Loh A, McFarland RJ, Cox M, Chester JF. Improved technique for polytetrafluoroethylene bypass grafting: long-term results using anastomotic vein patches. Br J Surg. 1992;79:348-354.
  285. Bartlett ST, Olinde AJ, Flinn WR, McCarthy WJ III, Fahey VA, Bergan JJ, Yao JS. The reoperative potential of infrainguinal bypass: long-term limb and patient survival. J Vasc Surg. 1987;5:170-179.
  286. Szilagyi DE, Elliott JP, Hageman JH, Smith RF, Dall'olmo CA. Biologic fate of autogenous vein implants as arterial substitutes: clinical, angiographic and histopathologic observations in femoro-popliteal operations for atherosclerosis. Ann Surg. 1973;178:232-246.
  287. Hobson RW. Recurrent symptoms and vein graft stenosis: the failing graft. In: Brewster DC, ed. Common Problems in Vascular Surgery. Chicago, Ill: Year Book Medical Publishers Inc; 1989:289-293.
  288. Mills JL, Harris EJ, Taylor LM Jr, Beckett WC, Porter JM. The importance of routine surveillance of distal bypass grafts with duplex scanning: a study of 379 reversed vein grafts. J Vasc Surg. 1990;12:379-389.
  289. Nehler MR, Moneta GL, Yeager RA, Edwards JM, Taylor LM Jr, Porter JM. Surgical treatment of threatened reversed infrainguinal vein grafts. J Vasc Surg. 1994;20:558-563.
  290. Szilagyi DE, Elliott JP Jr, Smith RF, Reddy DJ, McPharlin M. A thirty-year survey of the reconstructive treatment of aortoiliac occlusive disease. J Vasc Surg. 1986;3:421-436.
  291. Taylor LM Jr, Moneta GL, McConnell D, Yeager RA, Edwards JM, Porter JM. Axillofemoral grafting with externally supported polytetrafluoroethylene. Arch Surg. 1994;129:588-594.
  292. Inahara T. Evaluation of endarterectomy for aortoiliac and aortoiliofemoral occlusive disease. Arch Surg. 1975;110:1458-1464.
  293. Dalman RL, Taylor LM Jr, Moneta GL, Yeager RA, Porter JM. Simultaneous operative repair of multilevel lower extremity occlusive disease. J Vasc Surg. 1991;13:211-221.
  294. Dalman RL, Taylor LM Jr. Basic data related to infrainguinal revascularization procedures. Ann Vasc Surg. 1990;4:309-312.



"Guidelines for the Diagnosis and Treatment of Chronic Arterial Insufficiency of the Lower Extremities: A Critical Review" was approved by the Science Advisory and Coordinating Committee of the American Heart Association in February 1996.

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