Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease

Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease

Author
Emile R Mohler, III, MD
Section Editor
Denis L Clement, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC



Last literature review version 16.2: May 2008 | This topic last updated: January 18, 2008 (More)


INTRODUCTION — Patients with compromise of blood flow to the extremities as a consequence of peripheral arterial disease may present with typical ischemic pain of one or more muscle groups, atypical pain or no symptoms. Intermittent claudication (derived from the Latin word for limp) is defined as a reproducible discomfort of a defined group of muscles that is induced by exercise and relieved with rest. This disorder results from an imbalance between supply and demand of blood flow that fails to satisfy ongoing metabolic requirements.

The etiology, risk factors, and clinical manifestations of claudication are reviewed here, with emphasis upon the presentation of peripheral arterial disease (PAD) due to atherosclerosis. The frequency of asymptomatic disease will also be discussed. The noninvasive evaluation and management of this disorder by medical therapy, percutaneous intervention, and surgery are presented separately. (See "Noninvasive diagnosis of peripheral arterial disease" and see "Medical management of claudication" and see "Indications for surgery in the patient with claudication").

The majority of patients with PAD have atherosclerotic disease of the lower extremity. Atherosclerotic PAD of the upper extremity is much less common and is discussed elsewhere. (See "Upper extremity peripheral arterial disease").

ETIOLOGY — Although numerous diseases can cause intermittent claudication (show figure 1), the vast majority of patients with claudication suffer from peripheral atherosclerosis. The clinical history can help distinguish among some of the less common causes of this disorder. As examples, a history of limb trauma, radiation exposure, vasculitis, or ergot use for migraines represent some important clues to the etiology of claudication. In endurance athletes, especially cyclists, a common cause is kinking of the iliac artery which may result in endofibrosis [1] .

Nonarterial pathologic conditions should also be considered in the differential diagnosis of limb discomfort. These include:

• Deep venous thrombosis
• Musculoskeletal disorders
• Peripheral neuropathy
• Spinal stenosis (pseudoclaudication)


PREVALENCE — The prevalence of PAD increases progressively with age, beginning after age 40 [2-7] . As a result, PAD is growing as a clinical problem due to the increasingly aged population in the United States and other developed countries.

The relationship between PAD prevalence and age was illustrated in an analysis of 2174 participants ≥40 years of age in the 1999 to 2000 National Health and Nutrition Examination Survey (NHANES) [7] . The prevalence of PAD, defined as an ankle-brachial index (ABI) <0.90 in either leg, was 0.9 percent between the ages of 40 and 49, 2.5 percent between the ages of 50 and 59, 4.7 percent between the ages of 60 and 69, and 14.5 percent age 70 and older. (See "Noninvasive diagnosis of peripheral arterial disease", section on Ankle-brachial index).

A higher prevalence was noted in the PARTNERS program of primary care practices across the United States in which almost 7000 patients age ≥70 years or 50 to 69 years with a history of cigarette smoking (more than 10 pack-years) or diabetes were evaluated by history and by ABI (with a value ≤0.90 considered diagnostic of PAD) [8] . PAD was present in 29 percent overall: 13 percent had PAD alone (55 percent newly diagnosed) and 16 percent had PAD and cardiovascular disease (35 percent newly diagnosed). A classic history of claudication, as described below, was present in only 11 percent of patients with PAD.

The 2007 TASC II consensus document on the management of PAD made the following estimates for the prevalence of PAD in Europe and North America [9] :

• 27 million affected individuals
• 413,000 hospital discharges of paitents with chronic PAD per year with 88,000 hospitalizations involving lower extremity arteriography and 28,000 discharges for embolectomy or thrombectomy of lower limb arteries


RISK FACTORS — The risk factors that favor the development of peripheral arterial atherosclerosis are similar to those that promote the development of coronary atherosclerosis [7,8,10-14] . These include:

• Diabetes mellitus
• Hyperlipidemia
• Cigarette smoking
• Hypertension

Data from the Framingham Heart Study of 381 men and women who were followed for 38 years revealed that the odds ratio for developing intermittent claudication was 2.6 for diabetes mellitus, 1.2 for each 40 mg/dL (1 mmol/L) elevation in the serum cholesterol concentration, 1.4 for each 10 cigarettes smoked per day, and 1.5 for mild and 2.2 for moderate hypertension [11] . In addition, diabetic patients have worse arterial disease and a poorer outcome than nondiabetics [15] .

Similar findings were noted in NHANES analysis cited above of 2174 patients aged 40 and older [7] . The risk of PAD was significantly increased in current smokers (odds ratio [OR] 4.46) and for patients with diabetes (OR 2.71), hypertension (OR 1.75), or hypercholesterolemia (OR 1.68). Other significant risk factors were black race (OR 2.83) and decreased renal function (OR 2.00).

Patients with PAD are more likely to have increased levels of triglycerides and/or cholesterol, apolipoprotein B, and very low density lipoprotein [16-18] . Conversely, high density lipoprotein cholesterol and apolipoprotein A-I and A-II values, the "protective" lipoproteins, are reduced in these patients [19] . The risk of intermittent claudication may also be increased in patients with elevated plasma lipoprotein(a) and fibrinogen levels [20-22] . (See "Lipoprotein classification; metabolism; and role in atherosclerosis").

In addition to atherosclerotic risk factors being associated with an increased prevalence of PAD, these risk factors are also associated with the earlier onset of PAD. Patients who are 50 to 69 years with a history of cigarette smoking (more than 10 pack-years) or diabetes may have a similar incidence of asymptomatic PAD as patients ≥70 years of age [8] .

The importance of ethnicity in the risk for PAD was evaluated in a population-based epidemiologic survey of 2343 randomly selected participants in San Diego [23] . PAD was defined as an ankle-to-brachial index ≤0.90, an abnormal Doppler waveform, or prior revascularization for PAD. Blacks had a significantly higher prevalence of PAD than non-Hispanic whites (7.8 versus 4.9 percent, odds ratio 2.30). Although blacks had significantly higher rates of diabetes and hypertension and a significant increase in body mass index, the increase in risk for PAD was similar after adjustment for these and other variables. Hispanics and Asians had somewhat lower rates of PAD than non-Hispanic whites, but the number of affected patients was small and the difference was not significant.

Patients at risk — Based in part upon the above observations, the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD, which were produced in collaboration with major vascular medicine, vascular surgery, and interventional radiology societies, identified the following groups at risk for lower extremity PAD [24] :

• Age ≥70 years
• Age 50 to 69 years with a history of smoking and.or diabetes
• Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis


• Leg symptoms suggestive of claudication with exertion or ischemic pain at rest
• Abnormal lower extremity pulse examination
• Known atherosclerosis at other sites (eg, coronary, carotid, or renal arterial disease)


Predictors of progression — The risk factors that predict progression of PAD were evaluated in a longitudinal study of 403 patients at baseline and at a mean follow-up of 4.6 years using a standard questionnaire, clinical examination, and noninvasive testing assessing the ankle-to-brachial index (ABI) for large vessel (LV) disease and the toe-to brachial index (TBI) for small vessel (SV) disease [25] . The following findings were noted:

• Among patients with the largest fall in ABI (the LV cohort), current cigarette smoking, the ratio of total to HDL cholesterol, hs-CRP, and Lp(a) were statistically important predictors.
• Among patients with the largest fall in the TBI (SV cohort), diabetes was the only significant predictor of progression.


CLINICAL PRESENTATION — Patients with PAD often present with symptoms of leg ischemia. However, many patients are asymptomatic, particularly those first detected by ABI screening, and, among symptomatic patients, atypical symptoms are more common than classic claudication [8,26] . The 2005 ACC/AHA guidelines on PAD suggested the following distribution of clinical presentation of PAD in patients ≥50 years of age [24] :

• Asymptomatic — 20 to 50 percent
• Atypical leg pain — 40 to 50 percent
• Classic claudication — 10 to 35 percent
• Critical limb ischemia — 1 to 2 percent


The clinical manifestations of critical limb ischemia (also called limb-threatening ischemia) are discussed separately. (See "Clinical manifestations and evaluation of chronic critical limb ischemia").

Classification — Two classification systems have been used for lower extremity PAD: the Fontaine system and the Rutherford system. Both are based upon the severity of symptoms and markers or severe disease such as ulceration and gangrene (show table 1) [9] .

Symptomatic disease — Among symptomatic patients, the perception of claudication can vary from severe debilitating discomfort at rest to a bothersome pain of seemingly little consequence. The severity of symptoms of claudication depends upon the amount of stenosis, the collateral circulation, and the vigor of exercise.

Patients with claudication can present with buttock and hip, thigh, calf, or foot claudication, either singly or in combination. The usual relationship between the site of pain and site of arterial disease can be summarized as follows:

• Buttock and hip — aortoiliac disease
• Thigh — common femoral artery or aortoiliac
• Upper two-thirds of the calf — superficial femoral artery
• Lower one-third of the calf — popliteal artery
• Foot claudication — tibial or peroneal artery


Physical examination in the patient with claudication can be normal, but commonly reveals diminished or absent pulses below the level of stenosis with occasional bruits over stenotic lesions and evidence of poor wound healing over the area of diminished perfusion [27] . Other physical findings may include a unilaterally cool extremity, a prolonged venous filling time, shiny colored skin, hair loss, skin atrophy and nail changes [27] .

Physical signs can also help determine the extent and distribution of vascular disease [27] . These include an abnormal femoral pulse, lower extremity bruits, and the Buerger test (foot pallor with elevation of the leg and, in the dependent position, a dusky red flush spreading proximally from the toes).

Buttock and hip claudication — Patients with aortoiliac occlusive disease (Leriche's syndrome) may complain of buttock, hip, and, in some cases, thigh claudication. The pain is often described as aching in nature and may be associated with weakness of the hip or thigh with walking. Bilateral aortoiliac disease that is severe enough to cause symptoms almost always causes impotence in men; another diagnosis should therefore be entertained if impotence is absent.

Physical examination reveals diminished or absent pulses beginning in the groin area are found bilaterally, with occasional bruits over the iliac and femoral arteries. Other findings include muscle atrophy and slow wound healing in the legs.

Conditions that resemble Leriche's syndrome are:

• Osteoarthritis of the hip or knee joints — Osteoarthritis can be distinguished clinically from aortoiliac disease because osteoarthritic pain may not disappear promptly after exercise, may be associated with weather changes, and may vary in intensity from day to day.

• Neurogenic claudication — Neurogenic claudication, also called pseudoclaudication, describes a pain syndrome due to lumbar neurospinal canal compression, which is usually due to osteophytic narrowing of the neurospinal canal. The clinical presentation often helps to distinguish true claudication from pseudoclaudication. Unlike true claudication which occurs with walking and is relieved by stopping, pseudoclaudication causes pain with erect posture (lumbar lordosis) and is relieved by sitting or lying down. Patients with pseudoclaudication may also find symptomatic relief by leaning forward and straightening the spine (usually done with pushing a shopping cart or leaning against a wall). (See "Lumbar spinal stenosis").


Thigh claudication — Atherosclerotic occlusion of the common femoral artery may induce claudication in the thigh, calf, or both. Patients with occlusive disease of the femoral or popliteal arteries have normal groin pulses but decreased pulses distally.

Calf claudication — Calf claudication is the most common complaint. It is usually described as a cramping pain that is consistently reproduced with exercise and relieved with rest. Cramping in the upper two-thirds of the calf is usually due to superficial femoral artery stenosis, whereas cramping in the lower third of the calf is due to popliteal disease. This type of cramping pain in the calf can be confused with two other conditions:

• Nocturnal leg cramps — Nocturnal leg cramps occur among older and infirmed patients. This complaint is thought to be neuromuscular rather than vascular in origin. (See "Nocturnal leg cramps, night starts, and nocturnal myoclonus").
• Calf pressure and tightness. — This symptom is primarily seen in athletes, and is usually associated with chronic exercise. It is thought to be due to increased compartment pressure and may persist even after rest.


Foot claudication — Claudication of the foot is usually accompanied by occlusive disease of the tibial and peroneal vessels. Isolated foot claudication is rarely seen with atherosclerotic occlusive disease but is commonly seen with thromboangiitis obliterans (Buerger's disease).

Vasospastic claudication — Vasospastic claudication refers to a condition characterized by normal pulses and no bruits at rest, but symptoms of claudication with stress. These symptoms were originally thought to be due to vasospasm. However, a subcritical atherosclerotic lesion is now felt to underlay these symptoms in most patients. Rarely, extrinsic compression can also cause this condition, as occurs with popliteal-artery entrapment syndrome.

Ischemic rest pain — A progressive decrease in limb perfusion can result in ischemic rest pain. Such discomfort typically occurs at night and involves the digits and forefoot. The pain may be more localized in patients who develop an ischemic ulcer or gangrenous toe.

The precipitating cause of ischemic rest pain may be trauma superimposed on an area of borderline perfusion or less often microembolization or local thrombus formation. Affected patients frequently find that the pain is relieved by hanging their feet over the edge of the bed or, paradoxically, by walking around the room. Chronic tissue ischemia may also result in ischemic neuropathic pain that is frequently described as throbbing or burning with a superimposed severe shooting pain up the limb.

Atypical symptoms — Some patients with PAD have atypical symptoms as a result of comorbidities, physical inactivity, and alterations in pain perception. This issue was addressed in a study of 460 men and women with known PAD [26] . Symptoms were classified as follows:

• Classic claudication — Exertional calf pain that does not begin at rest, causes the patient to stop walking, and resolves within 10 minutes of rest — 150 patients (33 percent)
• Atypical exertional leg pain type I — Pain similar to that of classic claudication, but does not cause the patient to stop walking — 41 patients (9 percent)
• Atypical exertional leg pain type II — Pain similar to that of classic claudication, but does not involve the calves or does not resolve within 10 minutes of rest — 90 patients (20 percent)
• Leg pain on both exertion and rest — 88 patients (19 percent)
• No exertional leg pain, physically active (walked more than six blocks in previous week) — 63 patients (14 percent)
• No exertional leg pain, physically inactive — 28 patients (6 percent)


Compared to patients with classic claudication, those with leg pain on both exertion and rest were more likely to have diabetes, neuropathy, or spinal stenosis in addition to PAD. Functional capacity varied among groups, being best among those with type I atypical exertional leg pain and worst among those with pain on both exertion and rest.

A much lower rate of classic claudication was noted in the report from the PARTNERS program cited above in which 6417 patients were at risk for PAD (either age ≥70 or age 50 to 69 with a history of diabetes or more than 10 pack-years of cigarette smoking) in a primary care setting [8] . PAD, identified by the ABI or by history, was present in 29 percent:

• Among the patients with a new diagnosis of PAD, approximately 47 percent had no history of leg symptoms, 47 percent had atypical leg symptoms, and only 6 percent had classic claudication.
• Among the patients with known prior PAD, approximately 25 percent had no leg symptoms, 61 percent had atypical leg symptoms, and 14 percent had classic claudication.


Popliteal aneurysm — The popliteal artery is the most common site of a peripheral artery aneurysm [28] . A popliteal aneurysm in one leg should prompt evaluation for other aneurysms as they are bilateral in approximately half of cases and are associated with an abdominal aortic aneurysm in approximately one-third of cases [29] .

The etiology is unclear, but risk factors include hypertension, diabetes, smoking, and ischemic heart disease. The pathophysiology of the aneurysm involves inflammatory infiltration with associated mediators, such as matrix metaloproteinases, that result in degradation of the medial layer of the vessel wall [30] .

The initial presentation of a popliteal aneurysm may be distal lower extremity ischemia due to embolization from the aneurysmal sac. It is estimated that 60 percent of patients are symptomatic at time of presentation and approximately 30 percent have limb-threatening ischemia [31,32] . Rupture is another mode of presentation and is thought to occur in 2 to 4 percent of patients [33] . Popliteal aneurysms can also compress the adjacent vein causing distal edema and a prominent venous pattern on the lower leg. Nerve compression may also cause symptoms.

Intervention is indicated in aneurysms greater than 2 centimeters in diameter or in aneurysms that contain mural thrombus. The standard surgical approach is open surgical ligation and bypass with saphenous vein. One surgical case series reported a five-year patency of 69 percent, a secondary patency of 87 percent, and limb salvage rate of 87 percent [34] . An adjunctive approach is use of intraoperative intra-arterial thrombolysis [35] .

An endovascular approach to repair of popliteal aneurysms involves placement of a fabric-lined metal stent within the vessel known as a "stent graft" [33] . There are more than 20 reports of endovascular repair of popliteal aneurysms, but most are small case series. In one randomized study patients received either conventional open repair or endovascular repair using a stent graft [36] . One patient had early stent graft thrombosis on the day after the procedure that was treated with thrombolysis and angioplasty. The 12 month and 48 month follow-up showed a primary patency rate for the conventional group and of the endovascular repair group to be 100 and 86.7 percent and 81.6 and 80 percent, respectively.

Asymptomatic disease — Many patients with PAD have unrecognized disease as illustrated by the following observations:

• The PARTNERS program cited above evaluated 6417 patients at risk for PAD (either age ≥70 or age 50 to 69 with a history of diabetes or more than 10 pack-years of cigarette smoking) in a primary care setting [8] . PAD, identified by the ABI or by history, was present in 29 percent. Among the patients with a new diagnosis of PAD, approximately 45 percent had no history of leg symptoms and only 5.5 percent had classic claudication.

• Another study included 239 men and women ages 55 and older with no history of PAD who were recruited from a general internal medicine practice [37] . The ABI was abnormal (<0.90) in 14 percent. Most of these patients did not report exertional leg symptoms. However, they were not able to walk as far in six minutes as a group of patients without PAD (1,362 versus 1,539 feet).


The physical examination is also unreliable. As an example, an abnormal femoral pulse has a high specificity and positive predictive value but low sensitivity for large vessel disease [38] . The best single discriminator is an abnormal posterior tibial pulse. This part of the physical examination should only be performed after the patient has warmed up after coming indoors from cold weather.

Detection of asymptomatic PAD has value because it identifies patients at increased risk of atherosclerosis at other sites. As an example, as many as 50 percent of patients with PVD have at least a 50 percent stenosis in one renal artery [39] . Thus, patients with asymptomatic PAD, most often detected by ABI, should be aggressively treated with risk factor reduction (eg, aspirin, lipid lowering, blood pressure control). In addition to protecting against coronary disease and stroke, lipid lowering may also slow progression of the PAD (as measured by angiography) [40] . (See "Medical management of claudication", section on Risk factor reduction, and see "Secondary prevention of cardiovascular disease: Risk factor reduction").

Activity level — As noted in some of the studies described above, functional capacity is diminished in some patients with PAD even in the absence of claudication [37,41] . In addition, a gradual decline in activity level may mask the symptoms and lead to an underestimation of disease severity.

This issue was addressed in a study of 417 patients with PAD and 259 without disease who underwent measurement of ABI and assessment of functional capacity at baseline and one and two years later [41] . Patients with an ABI <0.50 had a significantly greater annual decline in six-minute walk distance than those with an ABI of 0.50 to <0.90 or those with an ABI of 0.90 to 1.50 (73 versus 59 and 13 feet, respectively). In addition, patients with PAD who reported no exertional pain had a greater annual decline in six-minute walk distance than those with typical intermittent claudication (77 versus 36 feet).

These findings suggest that activity level is an important factor in the evaluation of patients with PAD. Patients with evidence of PAD who report no or few symptoms should be asked about functional capacity and decline in activity over time.

Correlation of ABI with symptoms and site of PAD — There is a general but not absolute correlation between symptoms and the site and severity of PAD, with severity being estimated from the ankle-brachial index (ABI, abnormal less than 0.90). (See "Noninvasive diagnosis of peripheral arterial disease", section on Ankle-brachial index).

This was illustrated in a study using a claudication questionnaire for exertional leg pain in 3658 subjects, 24 percent of whom had PAD (defined as an ABI ≤0.90) in one or both legs [42] . The following findings were noted:

• At ABIs of 1.00-1.09 (normal), 0.80 to 0.89 (just abnormal), and 0.40 to 0.49 (markedly reduced), the proportion of legs with any leg pain increased progressively from 18 percent to 61 percent to 83 percent. Pain was also more common in legs with ABIs ≥1.40, a presumed marker of vascular stiffness

• At the same ABIs, the proportion of legs with classic claudication increased progressively from 2 percent to 22 percent to 46 percent. In contrast, typical pain and noncalf pain did not show much correlation with the ABI. Pain occurring at rest was the most common pain symptom in patients without PAD.

• Discordance was noted in some patients between the site of PAD and the site of pain. Patients with unilateral PAD were more likely to report bilateral than unilateral pain (42 versus 29 percent). Furthermore, among 80 patients with unilateral PAD and unilateral pain, the pain was in the other leg in 11 (14 percent).


Not surprisingly, since PAD is a manifestation of systemic atherosclerosis, a low ABI is also predictive of an increased risk of all-cause and cardiovascular mortality [43,44] and of the development of coronary artery calcification [45] . (See "Diagnostic and prognostic implications of coronary artery calcification detected by computed tomography").

DIAGNOSIS — As noted above, there is a high prevalence of lower extremity PAD in patients over age 70 and in patients between the ages of 50 and 69 with atherosclerotic risk factors, particularly smoking and/or diabetes [7-9] . (See "Prevalence" above and see "Risk factors" above).

Based upon these observations, the 2005 ACC/AHA guidelines on PAD and the 2007 TASC II consensus document on the management of PAD recommended that the standard review of symptoms should include questions related to a history of walking impairment, symptoms of claudication, ischemic rest pain, or nonhealing wounds in patients ≥70 years of age, those ≥50 years of age with a history of smoking and/or diabetes, or, in TASC II, those with a Framingham risk score of 10 to 20 percent at ten years [9,24] .

Measurement of the resting ankle-brachial systolic pressure index (ABI) should be performed in patients with one or more of the above findings on the review of symptoms. An ABI of ≤0.90 has a high degree of sensitivity and specificity for the diagnosis, using arteriography as the gold standard [9] . (See "Noninvasive diagnosis of peripheral arterial disease", section on Ankle-brachial index).

DIFFERENTIAL DIAGNOSIS — Classic claudication is characterized by cramping pain that is consistently reproduced with exercise and relieved with rest. However, many patients have atypical symptoms that may be confused with a number of other disorders [8,9,26] . These include nerve root compression, spinal stenosis, and hip arthritis (show table 2). (See "Atypical symptoms" above).

NATURAL HISTORY — 2005 ACC/AHA guidelines on PAD estimated the following rates of limb and cardiovascular outcomes at five years in patients with noncritical claudication [24] :

• For limb morbidity — stable claudication in 70 to 80 percent, worsening claudication in 10 to 20 percent, and critical limb ischemia in 1 to 2 percent

• For cardiovascular morbidity and mortality — nonfatal myocardial infarction or stroke in 20 percent, and death in 15 to 30 percent (three-quarters due to cardiovascular causes); an association between cardiovascular disease and PAD has been noted in multiple studies [43,44,46] . The importance of PAD as a marker for coexistent coronary artery disease cannot be understated.


Among the 1 to 2 percent of patients with critical limb ischemia, the guidelines estimated the following outcomes at one year:

• Alive with two limbs — 50 percent
• Amputation — 25 percent
• Cardiovascular mortality — 25 percent

These general estimates do not apply equally to all patients. The risk factors for progressive PAD are described above [25] . The prognosis for both limb loss and survival is significantly worse in diabetic patients and those who continue to smoke [47] . (See "Predictors of progression" above).

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Claudication"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.