ACCREDITATION
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1.0 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Valid June 1 - August 31, 2005. Estimated time: 1 hour

FULL DISCLOSURE POLICY AFFECTING CME ACTIVITIES
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The presenting faculty reported the following: Dr. Gunderson and Dr. Federman have indicated that they have not received financial support for consultation, research or evaluation or have a financial interest relevant to this article. No faculty member has indicated that their presentation will include information on off-label products.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

Educational Objectives
1. To understand the epidemiology and risk factors for the development of peripheral arterial disease
2. To recognize the clinical signs and symptoms of peripheral arterial disease
3. To be able to treat the symptoms of peripheral arterial disease
4. To be able to prevent the cardiovascular morbidity and mortality associated with peripheral arterial disease

The term peripheral arterial disease (PAD) refers to atherosclerotic disease of the lower extremities and is important for several reasons. First, its presence has been found to be an independent risk factor for vascular disease in other
regions, resulting in increased rates of cardiovascular events and mortality. Second, PAD can itself be symptomatic, causing claudication and potentially limb-threatening ischemia. Last, there is a growing appreciation of the more subtle ways PAD may be manifested symptomatically, either by atypical leg pain or by adversely affecting functional status. Peripheral arterial disease is important for the older adult for all of these reasons, especially because its prevalence increases markedly with age.

EPIDEMIOLOGY
Peripheral arterial is common. A recent population-based survey in the United States found the overall prevalence of PAD to be 4.3% in participants over 40 years of age and 14.5% in those over age 70 years.1 Indeed, age is a major risk factor for PAD. One population-based study from the Netherlands, for example, found that 19% of participants over the age of 55 had evidence of PAD, and this increased to 55% of the group over age 85 years.2 Similarly, another population-based study from the United States found that 13% of all participants over age 65 years had PAD, but this figure increased to 17% for the group ages 75-79 years, 26% in those ages 80-84 years, and 35% in those ages 85 years or older.3

Risk factors for PAD seem to be the same as for atherosclerosis elsewhere, and include age, smoking, diabetes, hypertension, elevated low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol. In the study from the Netherlands, for example, 64% of the incidence of PAD was explained by the presence of current smoking (18% of the incidence), past smoking (4%), hypertension (17%), age greater than 75 years (11%), total cholesterol (7%), diabetes (5%), and low HDL cholesterol (2%).2 Additional risk factors that have been more variably reported include male gender, elevated homocysteine levels, and inflammatory markers such as fibrinogen, d-dimer, and C-reactive protein (CRP).

NATURAL HISTORY
Traditionally, the natural history of PAD itself has been considered to be benign because of the low rate of the development of limb-threatening ischemia and amputation. For example, one study found that of 104 patients with claudication followed nonoperatively, only 5.8% required amputation after 2.5 years.4 Additionally, the severity of claudication generally has been reported to be stable over time. This relatively sanguine course for claudication has been questioned by recent studies. First, it was found that among a group of individuals with apparently asymptomatic PAD, over half developed leg pain during a six-minute walk, suggesting that leg symptoms alone may not be a reliable means of following the course of PAD.5 Second, recent studies have shown that the presence of PAD has deleterious effects on individuals’ functioning, independent of leg symptoms.6 Last, patients with PAD seem to be at risk not just for decreased functional performance, but for a progressive decline in this performance, independent of known confounders.7

Regardless of the complex role PAD may have on individuals’ quality of life and functioning, patients with PAD clearly have an increased rate of cardiovascular events and mortality, independent of preexisting disease and other risk factors. For example, one study found that compared with matched controls, patients with PAD had a threefold risk of death over 10 years, mostly from coronary artery disease.8 Furthermore, both symptomatic and asymptomatic individuals with PAD share this increased risk. Other studies have demonstrated similar findings, although most have generally studied individuals between ages 60 and 70 years. Two studies have looked primarily at groups with average ages over 75 years old. In the first, a sub-study of the Systolic Hypertension in the Elderly Program (SHEP), individuals with a mean age of 76 with PAD were found to have a two- to threefold increased rate of mortality and cardiovascular disease compared to individuals without PAD or other cardiovascular diseases.9 In the second study, derived from the Framingham Study, elderly patients with PAD and a mean age of 80 years were followed for up to four years for mortality and cardiovascular events. Unlike all other major studies, this study failed to show an increased risk of mortality in patients with PAD, although there was an increased risk of stroke or transient ischemic attack.10 In summary, the bulk of the data clearly shows an increased risk for cardiovascular events and death in patients with PAD, independent of preexisting disease and traditional risk factors. It is less clear, however, how much this risk persists as patients age, especially in those over age 80 years.

CLINICAL CHARACTERISTICS
Symptoms
Studies have shown that PAD is commonly asymptomatic.11 When symptomatic, the classic complaint is intermittent claudication, which is typically manifested as leg pain occurring with exertion and relieved by rest. Disease affecting different arterial segments to the legs generally results in pain in the particular vascular territory affected. Femoro-popliteal disease is the most common and causes calf claudication. Aortoiliac disease, on the other hand, may result in claudication affecting the buttock, thigh, and calf, and if the internal iliac artery is affected, may result in erectile dysfunction, a syndrome termed Leriche’s syndrome. If vascular occlusion becomes severe enough, blood flow may not be sufficient to meet the metabolic requirements of resting tissue, resulting in rest pain, ischemic leg ulcers, and gangrene. This is generally known as critical limb ischemia.

More recently, it has been shown that patients with PAD may suffer from a broad range of symptoms other than typical claudication. One study classified patients with PAD into six different presentations: those with classic claudication; those with claudication and occasional rest pain; those with atypical exertional leg pain that does not cause the patient to stop and rest; those with atypical exertional leg pain that does cause the patient to stop; and two additional groups of asymptomatic patients—those who are sedentary and those who are active. They found that as classified, only 32% of referred patients had classic claudication, and the remainder were either asymptomatic or had atypical symptoms. The authors concluded that there was a broad range of leg symptoms associated with PAD, that associated conditions such as diabetic neuropathy and spinal stenosis may influence an individual’s complaints, and that a significant percentage of apparently asymptomatic patients are without symptoms due to their inactivity.5

These same authors have also shown that not only can PAD cause pain but also that it is associated with poor performance on functional tests such as the six-minute walk test, accelerometer-measured physical activity, repeated chair rises, standing balance, and four-meter walking velocity.6 Additionally, individuals with PAD are at risk for accelerated functional decline independent of other factors,7 have increased rates of depression,12 and have weaker legs than matched controls.13

Physical exam
Patients with PAD are frequently asymptomatic or have atypical complaints, so the physical exam is frequently the first step in diagnosis. A review of published studies on the subject found that the peripheral pulse exam was the most useful test for PAD. Although 8% of normal individuals lack a dorsalis pedis pulse and 3% lack a posterior tibialis, only 0.7% lack both. Therefore, the absence of both pedal pulses had a high specificity for PAD. Surprisingly, their absence has a low sensitivity, as one of these pedal pulses may be present in up to one-third of individuals with PAD. Other signs that were found to be helpful if present were a femoral bruit, a venous filling time of greater than five seconds, and a unilaterally cool extremity. Contrary to traditional teaching, capillary refill, foot discoloration, atrophic skin, and hairless extremities were not found to be helpful. Also, inter-rater reliability for diminished pulses (as opposed to present or absent pulses) has been found to be low and therefore seemingly unhelpful.14

Diagnosis
The traditional gold standard for the diagnosis of PAD has been contrast angiography. Fortunately, a number of useful noninvasive tests are also available, some of which can be easily performed in the primary care office (Table I). The most frequently used diagnostic test is the simple ankle-brachial index (ABI). The test is performed by measuring the systolic blood pressure in the brachial, posterior tibial, and dorsalis pedis arteries using a portable Doppler machine with the patient supine and rested. The higher of the two foot pressures on each side is then divided by the higher of the arm pressures. A normal ABI is between 1.0 and 1.3, because normally the blood pressure is higher in the feet than arms. An ABI less than 0.9 has a high sensitivity and specificity for detecting angiographically significant stenosis in one of the major leg arteries. An ABI between 0.81 and 0.9 is suggestive of mild disease, between 0.51 and 0.8 of moderate disease, and less than 0.5 of severe disease and potentially limb-threatening ischemia. Repeating the ABI after the patient has exercised on a treadmill may increase the sensitivity of an ABI.

Additionally, an ABI greater than 1.3 suggests abnormally calcified, stiff vessels, and in one study was found to be associated with increased mortality.15 Other testing modalities are required to document PAD if the ABI is greater than 1.3.

Several other noninvasive tests are available for the diagnosis of PAD. Segmental leg pressures can be used to help localize sites of atherosclerotic occlusions simply by obtaining serial blood pressures along the length of the leg. A drop of 20 mm Hg from one site to a more distal site is generally considered evidence of a significant intervening obstruction. Additionally, segmental volume plethysmography can be used in conjunction with segmental limb pressures to assess the location of disease. Ultrasound is another method of confirming diagnosis and obtaining anatomic information about sites of obstruction. Magnetic resonance angiography (MRA) can give detailed anatomic information and, in some institutions, has largely replaced conventional angiography prior to vascular procedures, thus obviating the need for arterial puncture and contrast injection.

MANAGEMENT
Management of PAD can be divided into measures to prevent cardiovascular morbidity and measures to reduce symptoms. In practice, clinicians should pursue both avenues.

Treatments with cardiovascular benefit
A number of interventions have been reported to prevent cardiovascular events in patients with PAD, including initiation of antiplatelet agents, lipid-lowering medications, smoking cessation, angiotensin-converting enzyme inhibitors, tight glycemic control in persons with diabetes, beta blockers, and control of hypertension (Table II).16-19

Antiplatelet agents. The strongest evidence supporting any intervention to prevent morbidity and mortality in individuals with PAD probably is with antiplatelet medications. A recent meta-analysis of antiplatelet trials, primarily with aspirin, for secondary prevention in patients with established vascular disease found a 22% relative risk reduction for major vascular events. A sub-analysis including 42 trials that looked at 9214 patients with PAD found a near identical 23% relative risk reduction.16 Most authorities agree with the authors who recommend prophylactic aspirin in doses between 75 and 325 mg daily for patients with PAD.

Clopidogrel, another antiplatelet medication, which exerts its antiplatelet effect by inhibiting platelet activation via the ADP receptor, has also been studied in PAD. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study17 followed 19,185 patients with recent myocardial infarction, stroke, or symptomatic PAD who were randomized to either clopidogrel 75 mg daily or aspirin 325 mg daily. This study found a statistically significant 8.7% relative risk reduction for major vascular events or vascular death for those subjects randomized to clopidogrel. The study also found that in the subgroup of patients with symptomatic PAD there was an even larger 23% relative risk reduction.17 Despite this study, clopidogrel generally has not been universally favored over aspirin for patients with symptomatic PAD because of concerns over cost. A recent study nevertheless concluded that based on CAPRIE, the use of clopidogrel for patients with symptomatic PAD would increase cost by only $25,100 per quality-adjusted life-years, a cost that is within traditional societal limits.20

Cholesterol-lowering agents. The National Cholesterol Education Program (NCEP) includes PAD as a coronary heart disease equivalent, and therefore recommends an LDL goal of less than 100 mg/dL for affected individuals.21 In the large Heart Protection Study,18 the subgroup of patients with PAD and no known coronary artery disease who were treated with simvastatin had an approximate 25% reduction in cardiovascular events when compared to those given placebo, a reduction very similar to that derived by groups with other vascular disease, including coronary heart disease.

Angiotensin-converting enzyme inhibitors. In a sub-study of the Heart Outcomes Prevention Evaluations (HOPE) study,19 patients randomized to the angiotensin-converting enzyme inhibitor ramipril, who had either symptomatic or asymptomatic PAD, had statistically significant decreased cardiovascular outcomes (combined stroke, myocardial infarction, or cardiovascular mortality) when compared to those given placebo, despite minimal blood pressure effects. The average age of patients in the study was approximately 66 years, and the dose of ramipril was titrated to a goal of 10 mg daily. The risk reduction for the primary outcome of combined vascular events was 19% after a mean of 4.5 years.

Smoking cessation. Smoking cessation may be the most significant intervention to prevent cardiovascular events in patients with PAD, but this has not been extensively studied. One study followed 343 patients with claudication for up to 10 years and compared cardiovascular events and mortality in the 11% who were able to quit with the remainder who continued to smoke. Despite the small sample size, the group who quit smoking was found to have significantly fewer myocardial infarctions, cardiac death, and lower one-year mortality.22

Glycemic control in persons with diabetes. In general, the large United Kingdom Prospective Diabetes Study23 (UKPDS) of glycemic control in persons with type 2 diabetes did not find a statistically significant benefit for tight glycemic control in preventing macrovascular complications or mortality. In a sub-study of the UKPDS, however, the risk of newly diagnosed PAD was independently affected by glycemic control, with a 22% decrease in incident PAD after six years for each 1% decrement in HbA1c.24 The implication is that glycemic control can affect the pathogenesis, and potentially the natural course of PAD itself, but has not been shown to prevent cardiovascular events and mortality.

Blood pressure control. Few studies have looked at the effect of strict blood pressure control in PAD, although hypertension is believed to be a significant factor in its pathogenesis. A recent meta-analysis of randomized controlled studies of the treatment of hypertension in those with PAD concluded that there was insufficient evidence to make a conclusion. The authors also concluded that there was insufficient evidence to avoid the use of beta blockers in patients with PAD for fear of worsening peripheral blood flow.25

Symptomatic treatments
Exercise therapy. A mainstay of symptomatic therapy for patients with claudication is exercise therapy. One meta-analysis concluded that exercise therapies improved pain-free walking time by an average of 180% and maximal walking time by 120%.26 A recent review recommended that all patients with claudication should be considered for referral to a claudication exercise-rehabilitation program and that the ideal program would involve intermittent treadmill or track walking until the point of moderate claudication, followed by a brief rest before the resumption of activity. The initial session should include 35 minutes of intermittent walking, which should be lengthened gradually to 50 minutes of walking. Sessions should occur at least three times per week for six months.27 Whether more informal exercise programs would show a similar benefit has not been extensively studied, although a small pilot study showed that a home-based exercise prescription significantly improved initial pain-free and maximal walking distances.28

Drugs for claudication. Pentoxifylline and cilostazol are available in the United States for symptomatic treatment of claudication. Pentoxifylline improves the deformability of red blood cells and has antiplatelet effects, although its mechanism for claudication is not known. However, its clinical benefits are not dramatic. Cilostazol, a phosphodiesterase inhibitor, is a vasodilator, inhibitor of platelet aggregation, and inhibitor of vascular smooth muscle proliferation. Studies of cilostazol have found a moderate benefit in maximal treadmill walking distance of approximately 30-80%.29 Exuberance for cilostazol has been somewhat tempered by its cost and contraindication in patients with congestive heart failure.

Revascularization. Because of the perception of a generally benign course for PAD in terms of leg outcomes such as amputation and the need for urgent revascularization, most patients are conservatively managed to prevent cardiovascular comorbidity and improve functioning and quality of life. Patients with rest pain, nonhealing leg ulcers associated with a low ABI, and those with severe debilitating claudication, however, should be referred for possible revascularization by either surgical or nonsurgical intervention.

CONCLUSION
Peripheral arterial disease is a common disorder, especially in the older adult, and is associated with a high rate of vascular comorbidity, claudication, and declining functional status. The main danger with PAD is its association with cardiovascular morbidity and mortality, and affected individuals need to be aggressively managed for cardiovascular risk reduction. Additionally, PAD may affect quality of life by causing classic claudication or a surprising variety of atypical leg complaints. Last, PAD is a strong independent risk factor for declining functional status. Increasing provider awareness of PAD can lessen the impact of this major public health burden.