Peripheral arterial disease (PAD) is a debilitating chronic illness that is most prevalent in the elderly. Patients with PAD experience substantial walking impairment and diminished quality of life due to symptoms of limb ischemia (claudication) as well as increased cardiovascular disease (CVD) morbidity and mortality. Peripheral arterial disease is typically due to aggressive atherosclerosis resulting from untreated CVD risk factors.

Peripheral arterial disease is defined as obstruction of blood flow to areas except the coronary and cerebral vessels. This article will focus on the detection of PAD and medical management, especially lifestyle modification of chronic obstructive atherosclerotic occlusion of arteries in the lower limb.1

The hallmark of PAD is intermittent claudication, defined as exercise-induced lower limb ischemia distal to the site of arterial occlusion that is relieved within 10 minutes of rest.2 Claudication symptoms are often described as pain, fatigue, numbness, or weakness in the hips, buttocks, thigh, or calf that is alleviated with rest.3 Although most clinicians associate PAD with claudication, provocative findings from recent studies suggest that there is a wide range of leg symptoms associated with PAD. In fact, only 30% to 50% of older adults with documented PAD report these classic or typical claudication symptoms.2 One study suggests that among patients with PAD, individuals who are older, male, diabetic, or screened with ankle-brachial index (ABI) in primary care settings are more likely to be asymptomatic or have exertional leg symptoms other than intermittent claudication.4

Although not well understood, the diversity of leg symptoms associated with PAD may be due to a number of factors such as comorbid conditions in this older age group, including arthritis or pulmonary disease and physical activity levels insufficient to induce ischemic symptoms.4 Further, some individuals may have adequate collateral arterial channels to tolerate increased demand during exercise.5

Based on the limited number of trials, there appears to be a difference between men and women in the manifestation or experience of PAD symptoms. Women report a higher prevalence of leg pain at rest or with exertion, lower functional capacity, impaired walking ability, worse self-reported quality of life and physical functioning compared with men with PAD.6-8 Mood state or depression may also affect a patient's awareness of or description of leg pain.2 We recently found that women reported lower physical functioning and impaired mood state compared with men of similar age and with equivalent severity of PAD.7

The results of these studies demonstrate the importance of increasing awareness of the full spectrum of symptoms associated with a broad range of patients with PAD. Additionally, these findings suggest that clinicians who depend solely on a classic history of claudication may miss an opportunity to accurately diagnose PAD.9 If PAD goes undetected and risk factors untreated, atherosclerosis progresses, leading to critical limb ischemia with pain at rest, tissue loss, and eventual loss of limb.10

Prevalence of PAD and Associated Risk Factors

The prevalence of PAD is higher than other vascular diseases, including myocardial infarction and stroke. Peripheral arterial disease affects 4.5 to 7.6 million Americans and prevalence is age-dependent, increasing from 9% in the 55-65 age group to as high as 47-57% in those older than 70 years.11 By 2050, approximately 9.6 to 16 million adults 65 years and older will be diagnosed with PAD.12 Peripheral arterial disease has a 3-fold higher CVD morbidity and a 40% greater mortality rate if associated with symptomatic cerebrovascular disease.13 Most (68%) PAD patients have concomitant coronary artery disease (CAD)14 that contributes to the high rate of nonfatal cardiovascular events.15

A majority of patients with PAD have multiple modifiable CVD risk factors, including cigarette smoking,16,17 type 2 diabetes,17 hypertension,17 dyslipidemia,17 obesity,18 and a sedentary lifestyle.19 Additionally, 57% of patients with PAD have at least 3 of 5 factors that classify them with metabolic syndrome, according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). This syndrome places them at even greater risk for future CVD events and mortality.20,21 The significance of multiple risk factors in PAD is their additive effect on overall risk.22 Despite the known detrimental effects of CVD risk factors and the proven efficacy of individual risk factor modification in other patient populations, data are rapidly accumulating that patients with PAD are untreated or receive inadequate treatment of CVD risk factors in a variety of practice settings ranging from general primary care clinics to specialty clinics in vascular surgery.17,23-27 Undertreatment of atherothrombotic risk factors in PAD patients has been attributed to deficiencies in provider knowledge and attitudes,28 glucocentric treatment goals,29 and lack of public awareness that CVD risks are associated with PAD.

Diagnosis and Screening for PAD

The most effective, accurate, and practical means to detect PAD is the ABI. The ABI is 95% sensitive and 99% specific for diagnosing PAD.30 The ABI is a noninvasive test that is performed using a Doppler ultrasound probe and conventional blood pressure cuffs. The ABI is determined by dividing the higher of the 2 systolic blood pressures at each ankle (dorsalis pedis or posterior tibial) by the higher of the 2 systolic blood pressures in each arm.10 An ABI >=1.0 is considered normal.31 An ABI <=0.90 indicates PAD.10 An ABI >=1.30 may reflect medial calcification, often seen in patients with diabetes or persons with chronic renal failure. Often, in these individuals, ankle pressures are spuriously elevated because of noncompressible vessels.31 When vessels are noncompressible, toe pressures are recommended using photoplethysmography or pulse-volume recordings to assess severity of PAD.31

Because of the increased morbidity and mortality associated with PAD, aggressive screening is needed. Currently, screening is recommended for the following patients at risk for PAD:32,33

* Any patients with exertional leg pain

* Patients older than 50 years with associated risk factors (smoking, diabetes)

* Diabetic persons with >20 years' duration of disease

* All patients over the age of 70 years

A diagnostic challenge is the individual who presents with typical symptoms of claudication, has normal resting pedal pulses, and a normal resting ABI (>=1.0). For these patients, exercise testing has been performed to elicit symptoms of claudication using a graded exercise test such as the Skinner Gardner exercise protocol.34 Patients with typical claudication symptoms will exhibit a >20 mm Hg decrease in ankle pressure within 1 minute postexercise.34 In lieu of treadmill testing, active pedal plantar flexion (repeated standing up on the toes) may be performed.31

Evidence for Cardiovascular Risk Factor Management in Patients With PAD

Pharmacotherapy

As described earlier, PAD is most common in older adults particularly men over the age of 70 years. Because of the increased incidence of CVD morbidity and mortality in addition to the increased disease burden, aggressive risk factor modification is recommended to reduce adverse events. Treatment goals for PAD include symptom relief with exercise and medical therapy, and secondary prevention to prolong life by medical management, smoking cessation, and lifestyle modification with diet and exercise.33 Peripheral arterial disease is considered a coronary artery disease equivalent by the NCEP ATP III guidelines and warrants aggressive management of risk factors. Risk factor management is incorporates are described in detail in the AHA/ACC PAD guidelines that integrate current treatment guidelines for individual risk factors.33

Secondary analyses of large longitudinal prospective randomized clinical trials (RCT), including the Heart Protection Outcomes Evaluation (HOPE) study and the Scandinavian Simvastatin Survival Study (4S), have demonstrated the efficacy of pharmacotherapy in reducing nonfatal cardiovascular events (including myocardial infarction and death) and microvascular events (such as neuropathy and retinopathy) in persons with PAD. These studies found that treatment of hyperlipidemia with HMG Co-a reductase inhibitors or statins and niacin35,36; hypertension with angiotensin-converting enzyme inhibitors (ACE-I)37; type 2 diabetes with sulfonylure as and insulin38; smoking cessation39 and antiplatelet therapy with aspirin40 effectively reduced adverse CVD events. Further investigation is needed to examine the provocative recent finding that statins, independent of its lipid-lowering effects, improved symptoms and pain-free walking distance in patients with PAD.41

Antiplatelet therapy is a highly effective means of altering the natural history of PAD and coronary artery disease by interfering with platelet function and thrombus formation, and reducing subsequent ischemic events.10 Therefore, treatment of PAD necessitates lifelong antiplatelet therapy; aspirin (75-150 mg/d) is currently recommended for these individuals. This recommendation is based on the Antithrombotic Trialists' Collaboration that demonstrated a 23% relative risk reduction in favor of antiplatelet therapy.42 The Clopidogrel (75 mg/d) versus Aspirin (325 mg/d) in Patients at Risk for Ischemic Events (CAPRIE) trial suggests that clopidogrel may be superior to aspirin in improving walking distance and reducing mortality.43 However, because of higher cost and nonformulary status, aspirin is still the most widely prescribed antiplatelet agent.44 The efficacy of combining the agents clopidogrel and aspirin has not been substantiated and studies are currently underway to examine the safety and efficacy of this antiplatelet regimen.

To date, pharmacotherapy for treatment of intermittent claudication is very limited. Currently, pentoxifylline, a xanthine derivative with rheologic properties causing red blood cell deformability is available. However, its efficacy has not been fully demonstrated in patients with PAD.45 Another alternative for claudication is cilostazol, a type 3 phosphodiesterase inhibitor that acts to inhibit platelet aggregation and also induces vasodilation. Although a meta-analysis of 8 randomized clinical trials demonstrated the benefit of cilostazol in improving pain-free and maximal walking distance, it is contraindicated in patients with PAD and heart failure because of the increased cardiac mortality seen with other drugs in this class.46

Due to the limited medical treatments available to patients with PAD for the management of claudication symptoms, research has been directed to alternative therapies including oral l-arginine and gingko biloba. l-Arginine is a semiessential amino acid that is the precursor to nitric oxide, a potent vasodilator with anti-atherogenic properties.47 Administration of l-arginine may slow the progression of atherosclerosis and increase blood flow by increasing bioavailability of nitric oxide.47 Although studies using intravenous l-arginine have demonstrated its efficacy in improving blood flow and endothelial function, its long-term efficacy on functional capacity is inconclusive.48 Currently, studies are being conducted to examine whether long-term oral l-arginine improves functional capacity in patients with intermittent claudication.

Gingko biloba has long been used in Europe to treat PAD but is under current investigation in the United States.49,50 The efficacy of this agent has primarily been attributed to its antioxidant effects, endothelium-dependent relaxing effects, and inhibition of platelet-activating factors.51,52 While promising, the mechanism of action and efficacy have yet to be determined in this population.

Exercise

The cornerstone of treatment of PAD is exercise to improve peripheral circulation, walking economy, cardiopulmonary function, and functional capacity.53 The data to support the efficacy of supervised exercise in improving claudication are robust with the length of the program influencing the magnitude of increase in maximal walking distance of up to 150% (range 74% to 230%).54 Functional benefits (increased walking speed, distance, duration, and decreased symptoms) accrue gradually and can occur in as early as 4 to 8 weeks,5,55 but greater benefit is conferred with programs of 6 months or longer.56,57 Typical improvements in walking distance include more than 100% increase in peak exercise performance and self-reported physical function. Longer walking interventions achieve greater benefit. However, most studies have been of short duration, 3 to 6 months,55 with few longer than 12 months.5,56,58

To date, exercise studies of patients with PAD have primarily been conducted in a laboratory setting, and thus, current recommendations include referral to an exercise program. Although a CPT code (93668) is now available for this referral, overall effectiveness is limited by the lack of insurance reimbursement for exercise programs. Exercise recommendations have been extrapolated from clinical trials in patients with PAD. Based on these studies, walking is the most effective mode of exercise. Although resistance training does confer some benefit, it has been shown to be less effective than walking in improving walking distance in patients with PAD.5 Recently, pole striding exercise has been demonstrated to increase cardiovascular fitness, improve symptoms and quality of life in a small group of PAD patients.59

Exercise intensity is based on the workload achieved during a treadmill test that elicited claudication pain within 3 to 5 minutes of walking. Once this workload has been determined, the patient is asked to walk at this set workload until claudication of moderate intensity. Once this point is reached the patient is allowed to rest (standing or sitting) until pain subsides. The exercise-rest-exercise pattern is repeated for the duration of the exercise session. The goal for exercise duration is 30 to 50 minutes of pain-free walking and is accomplished by increasing the exercise interval by 5 minutes each session. Sessions are recommended at least 3 to 5 times per week.5

Diet

Evidence is lacking to address specific dietary recommendations for patients with PAD. Accordingly, recommendations are similar to those with established CVD.60 Of considerable interest are the findings from recent studies that have demonstrated that diets high in fruits, vegetables, whole grains, limited dairy and salt intake plus reduced saturated fat, total fat, and cholesterol improve CVD risk factors (cholesterol, blood pressure, and weight),61,62 and fatal and nonfatal CVD events.63 Most notable of these diets are the Dietary Approaches to Stop Hypertension (DASH)64 and the Mediterranean diet.65 Clearly, research is needed to determine underlying mechanisms responsible for improvement from adherence to various types of diet as well as the extent of improvement resulting from multiple risk factor reduction programs that integrate dietary modification.

Conclusion

Peripheral arterial disease is a chronic, debilitating illness that is common in older adults, particularly men over the age of 70 years. Peripheral arterial disease is a significant health problem because of its devastating effects on functional capacity that may eventually lead to disability and a poor quality of life. Additionally, persons with PAD are at increased risk for myocardial infarction, stroke, and death. Although PAD is a common clinical condition and signals systemic atherosclerosis requiring aggressive risk factor management, PAD is frequently not detected. Groups at high risk for PAD requiring screening include individuals with exertional leg pain, older adults with CVD risk factors, persons with diabetes of more than 20 years' duration, and all patients over the age of 70 years.

Beyond poor detection in this population, evidence also suggests that management of CVD risk factors requires greater attention by providers. Evidence-based practice guidelines are currently available for the detection, diagnosis, and management of PAD.33 Even when patients are diagnosed with PAD, their risk factors are not managed to the level specified in the ATP III guidelines for a coronary artery disease equivalent. The challenge that currently exists is to increase public and provider awareness of PAD to improve screening and detection of PAD. Once diagnosed, an integrated, preventive approach is needed that combines pharmacotherapy and lifestyle modification to address the multiple CVD risk factors commonly found in this older patient population.

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