Persons with peripheral arterial disease (PAD) are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from coronary artery disease (CAD). Modifiable risk factors such as cessation of cigarette smoking and control of dyslipidemia, hypertension, and diabetes should be treated. Statins decrease the incidence of intermittent claudication and improve exercise duration, as well as reduce cardiovascular events and mortality in persons with PAD and hypercholesterolemia. Antiplatelet drugs and angiotensin-converting enzyme inhibitors should be administered to all persons with PAD. Beta-blockers should be given if CAD is present. Exercise rehabilitation programs and cilostazol improve exercise time until intermittent claudication. Indications for lower-extremity angioplasty or bypass surgery include incapacitating claudication, limb salvage in persons with limb-threatening ischemia, and impotence of vascular origin. Amputation should be performed if tissue loss has progressed beyond the point of salvage, if surgery is too risky, if life expectancy is very short, or if functional limitations reduce the benefit of limb salvage. (Annals of Long-Term Care: Clinical Care and Aging 2005;13[9]: 35-40)

Peripheral arterial disease (PAD) is a chronic arterial, occlusive disease of the lower extremities caused by atherosclerosis. PAD may cause intermittent claudication, which is pain or weakness with walking that is relieved with rest.

Only one-half of elderly persons with documented PAD are symptomatic. Persons with PAD may not walk far enough or fast enough to induce muscle ischemic symptoms because of comorbidities such as pulmonary disease or arthritis, they may have atypical symptoms unrecognized as intermittent claudication, they may fail to mention their symptoms to their physicians, or they may have sufficient collateral arterial channels to tolerate their arterial obstruction.

If the arterial flow to the lower extremities cannot meet the needs of resting tissue metabolism, critical lower-extremity ischemia occurs with pain at rest or tissue loss. Critical ischemia causes pain at rest in the toes or foot with progression to ulceration or gangrene.

NONINVASIVE DIAGNOSIS
Persons with PAD of the lower extremities may have decreased or absent arterial pulses. Noninvasive tests used to assess lower-extremity arterial blood flow include measurement of ankle and brachial artery systolic blood pressures, characterization of velocity wave form, and duplex ultrasonography. Measurement of ankle and brachial artery systolic blood pressures, using a Doppler stethoscope and blood pressure cuffs, allows calculation of the ankle-brachial index (ABI), which is normally 0.9-1.2. An ABI of less than 0.90 is 95% sensitive and 99% specific for the diagnosis of PAD. The lower the ABI, the more severe the restriction of arterial blood flow, and the more serious the ischemia. Patients with calcified arteries from diabetes mellitus or renal failure occasionally have relatively noncompressible arteries leading to falsely elevated ABI values in the normal range.

Duplex ultrasonography combines Doppler frequency measurements with two-dimensional images of blood vessels. The severity of flow restriction caused by an arterial stenosis can be accurately assessed by this comprehensive, noninvasive method.

PREVALENCE
The prevalence of PAD increases with age. One study showed that 20% of 467 men (mean age, 80 years) and 13% of 1444 women (mean age, 81 years) who are living in the community and are seen in geriatrics clinics have symptomatic PAD.1 The prevalence of symptomatic PAD for individuals living in nursing homes is 32% in 1160 men (mean age, 80 years) and 26% in 2464 women (mean age, 81 years).2

RISK FACTORS
Modifiable risk factors that predispose an individual to PAD include cigarette smoking,1,3-6 diabetes mellitus,1,3-6 hypertension,1,3-6 dyslipidemia,1,3-6 increased plasma homocysteine levels,7 and hypothyroidism.8 Significant independent risk factors for PAD in 467 men (mean age, 80 years) and 1444 women (mean age, 81 years) who are living in the community and seen in academic geriatrics practices were age (odds ratio [OR] = 1.05 for each 1-year increase in age in men, and 1.03 for each 1-year increase in age in women); current cigarette smoking (OR = 2.6 for men and 4.6 for women); systolic or diastolic hypertension (OR = 2.2 for men and 2.8 for women); diabetes mellitus (OR = 6.1 for men and 3.6 for women); serum high-density lipoprotein (HDL) cholesterol (OR = 0.95 for each 1-mg/dL increase in men, and 0.97 for each 1-mg/dL increase in women); and serum low-density lipoprotein (LDL) cholesterol (OR = 1.02 for each 1-mg/dL increase in men and women).1

COEXISTENCE OF OTHER ATHEROSCLEROTIC DISORDERS
Peripheral arterial disease coexists with other atherosclerotic disorders.5,9-11 In a study of 1886 men and women (mean age, 81 years), 270 of 468 persons (58%) with PAD had coexistent coronary artery disease (CAD), and 159 of 468 persons (34%) with PAD had prior ischemic stroke.9 In a study of 1802 men and women (mean age, 80 years) who were living in the community and seen in academic geriatrics practices, 161 of 236 persons (68%) with PAD had coexistent CAD, and 100 of 236 persons (42%) with PAD had coexistent prior ischemic stroke.10 The severity of CAD in patients with obstructive CAD, documented by coronary angiography, is greater in persons with PAD than in persons without PAD,6 and in persons with PAD with a lower ABI.12

CARDIOVASCULAR MORBIDITY AND MORTALITY
Persons with PAD are at increased risk for all-cause mortality, cardiovascular mortality, and cardiovascular events.13-16 At 10-year follow-up of 565 men and women (mean age, 66 years), the presence of PAD significantly increased the risk of all-cause mortality (relative risk [RR] = 3.1), mortality from cardiovascular disease (RR = 5.9), and mortality from CAD (RR = 6.6).13 At 4-year follow-up of 1492 women (mean age, 71 years), an ABI of 0.9 or less was associated with a relative risk of 3.1 for all-cause mortality after adjustment for age, smoking, and other risk factors.14

TREATMENT
Risk Factor Modification
Continuing smoking increases the risk of amputation in patients with intermittent claudication. Patency in lower-extremity bypass grafts is also worse in smokers than in nonsmokers. Smoking cessation decreases the progression of PAD to critical leg ischemia and decreases the risk of myocardial infarction and death from vascular causes.17 Smoking cessation programs should be strongly encouraged in persons with PAD.

Hypertension should be adequately controlled to reduce cardiovascular mortality and morbidity in persons with PAD.18 Although the effect of blood sugar control on PAD is unknown, diabetes mellitus should also be controlled with the hemoglobin A1c level reduced to less than 7% to decrease the incidence of myocardial infarction.19

Treatment of dyslipidemia with statins has been demonstrated to decrease the incidence of mortality, cardiovascular events, and stroke in persons with PAD with and without CAD.20-23 At 5-year follow-up of 4444 men and women with CAD and hypercholesterolemia in the Scandinavian Simvastatin Survival Study, simvastatin significantly reduced the incidence of intermittent claudication by 38%, as compared to placebo.20

The major cause of death in patients with PAD is coronary events. In a study of 264 men and 396 women (mean age, 80 years) with symptomatic PAD and a serum LDL cholesterol of 125 mg/dL or higher, 318 of 660 persons (48%) were treated with a statin, and 342 of 660 persons (52%) were treated with no lipid-lowering drug.22 At 39-month follow-up, treatment with statins caused a significant independent reduction of 58% in the incidence of new coronary events, of 52% in persons with prior myocardial infarction, and of 59% in persons with no prior myocardial infarction.22

In a prospective study of 69 patients (mean age, 75 years) with intermittent claudication, a mean ABI of 0.63, and a serum LDL cholesterol of 125 mg/dL or higher, 34 persons were randomized to simvastatin 40 mg daily and 35 persons to placebo after baseline treadmill exercise tests until the onset of intermittent claudication.24 Compared with placebo, simvastatin significantly increased the treadmill exercise time until the onset of intermittent claudication by 24% at 6 months and by 42% at 1 year after therapy.24 Similar data were reported with the use of atorvastatin 80 mg daily.25

On the basis of the available data, persons with PAD and hypercholesterolemia should be treated with statins to reduce cardiovascular mortality and morbidity and progression of PAD, and to improve exercise time until intermittent claudication in persons with PAD. Since lipid-lowering therapy is underutilized in persons with PAD,26 intensive educational programs are needed to educate physicians to use lipid-lowering therapy in elderly persons with cardiovascular disease and dyslipidemia. Based on data from the Heart Protection Study, persons with PAD should be treated with statins regardless of age, gender, or initial serum lipid levels.21

Antiplatelet Drugs
If one combines the 42 randomized studies of 9706 patients with intermittent claudication, peripheral arterial grafting, or peripheral angioplasty, the incidence of vascular death, nonfatal myocardial infarction, and nonfatal stroke at follow-up was significantly decreased 23% by anti-platelet drugs, with similar benefits among all three groups of patients.27 These data favor the use of aspirin 160-325 mg daily in men and women with PAD.27

Clopidogrel is a thienopyridine derivative that inhibits platelet aggregation by inhibiting the binding of adenosine 5´ diphosphate to its platelet receptor. In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, 5795 persons with PAD were randomized to clopidogrel 75 mg daily, and 5797 persons with PAD were randomized to aspirin 325 mg daily.28 At 1.9-year follow-up, the annual incidence of vascular death, nonfatal myocardial infarction, and nonfatal stroke was 3.7% in persons randomized to clopidogrel versus 4.9% in persons randomized to aspirin, a 24% significant decrease with the use of clopidogrel.28

The utilization of antiplatelet drugs for PAD is common in academic settings. In a vascular surgery clinic, 501 of 506 persons (99%) with PAD were treated with aspirin or clopidogrel.29 In a university general medicine clinic, 85% of patients with PAD were treated with antiplatelet drugs.5

Angiotensin-Converting Enzyme Inhibitors
The American College of Cardiology/American Heart Association guidelines recommend that physicians should consider treating all persons with atherosclerotic vascular disease with angiotensin-converting enzyme inhibitors, unless there are contraindications to the use of these drugs to decrease cardiovascular mortality and morbidity.30

Beta-Blockers
Persons with PAD are at increased risk for developing new coronary events.13-16 Many physicians have been reluctant to use beta-blockers in persons with PAD because of concerns that these agents will aggravate intermittent claudication. However, a meta-analysis of 11 randomized, controlled studies found that beta-blockers do not adversely affect walking capacity or the symptoms of intermittent claudication in persons with mild-to-moderate PAD.31

An observational study was performed in 575 men and women (mean age, 80 years) with symptomatic PAD and prior myocardial infarction.32 Of the 575 individuals, 85 persons (15%) had contraindications to the use of beta-blockers. Of the 490 persons without contraindications, 257 persons (52%) were treated with beta-blockers. Adverse effects causing cessation of beta-blockers occurred in 31 of the 257 persons (12%). At 32-month follow-up, use of beta-blockers caused a 53% significant independent reduction in the incidence of new coronary events in elderly persons with PAD and prior myocardial infarction.32 In a vascular surgery clinic, 301 of 364 persons (83%) with PAD and CAD were treated with beta-blockers.29

Agents Used to Decrease the Frequency and Severity of Intermittent Claudication
Chelation therapy has been shown to be ineffective in the treatment of PAD.33 Numerous drugs have been found to be ineffective in improving walking distance in persons with intermittent claudication.34-36

Two drugs, pentoxifylline and cilostazol, have been approved by the United States Food and Drug Administration for symptomatic treatment of intermittent claudication. However, other studies have found no consistent improvement with pentoxifylline in patients with intermittent claudication in comparison with placebo.37-39 In a vascular surgery clinic, 301 of 301 persons (100%) with intermittent claudication were treated with cilostazol or pentoxifylline.29

Cilostazol inhibits phosphodiesterase type 3, increasing intracellular concentration of cyclic adenosine monophosphate. Cilostazol suppresses platelet aggregation and also acts as a direct arterial vasodilator. Cilostazol has been shown in numerous studies to improve exercise capacity in patients with intermittent claudication,39-41 and in a dose of 100 mg twice daily, was shown to be superior to both placebo and pentoxifylline.41 However, cilostazol should not be given to persons with PAD who also have congestive heart failure.

Exercise Rehabilitation
Exercise rehabilitation programs have been shown to increase walking distance in persons with intermittent claudication through improvements in peripheral circulation, walking economy, and cardiopulmonary function.42 The optimal exercise program for improving claudication pain distance in persons with PAD uses intermittent walking to near-maximal pain during a program of at least 6 months.43 Strength training is less effective than treadmill walking.44

Foot Care
Persons with PAD must wear properly fitted shoes. Careless nail clipping or injury from walking barefoot must be avoided. Feet should be washed daily and the skin kept moist with topical emollients to prevent cracks and fissures, which may have portals for bacterial infection. Fungal infection of the feet must be treated. Socks should be wool or other thick fabrics, and padding or shoe inserts may be used to prevent pressure sores. When a wound of the foot develops, specialized foot gear, including casts, boots, and ankle-foot orthoses, may be helpful in unweighting the affected area.

Lower-Extremity Angioplasty and Bypass Surgery
Revascularization for PAD is favored in patients with proximal disease and with indications for revascularization. A medical approach is favored in patients with distal disease and who are not suitable candidates for revascularization.

Indications for lower-extremity percutaneous transluminal angioplasty or bypass surgery are: (1) incapacitating claudication that interferes with work or lifestyle; (2) limb salvage in persons with limb-threatening ischemia as manifested by pain at rest, nonhealing ulcers, and/or infection or gangrene; and (3) vasculogenic impotence.45 Percutaneous transluminal angioplasty can be performed if there is a skilled vascular interventionalist and the arterial disease is localized to a vessel segment less than 10 cm in length.45 Compared to percutaneous transluminal angioplasty alone, stenting improves 3-year patency by 26%.46 After infrainguinal bypass surgery, oral anticoagulant therapy is preferable in persons with venous grafts, whereas aspirin is preferable in persons with nonvenous grafts.47

Amputation
Nonrandomized studies have shown that both immediate and long-term survival are higher in patients having revascularization rather than amputation for limb-threatening ischemia.48,49 However, amputation of lower extremities should be performed if tissue loss has progressed beyond the point of salvage, if surgery is too risky, if life expectancy is very low, or if functional limitations decrease the benefit of limb salvage.50

CONCLUSION
Patients with PAD should have intensive treatment of modifiable risk factors, and should be treated with statins, antiplatelet drugs, and angiotensin-converting enzyme inhibitors. Beta-blockers should be used if CAD is present. Exercise programs, cilostazol, and statins improve exercise time in patients with intermittent claudication. Revascularization should be performed in patients with proximal disease and appropriate indications.