Lower Extremity Peripheral Arterial Disease

The American Heart Association defines peripheral vascular disease (PVD) as "diseases of blood vessels outside of the heart and brain."¹ Peripheral arterial disease (PAD) is the most prevalent form of PVD and increases the risk of mortality sixfold over a 10-year period.^1,2 PAD reduces artery diameter secondary to atherosclerosis. The classification of PAD includes an extensive group of arterial syndromes that result from structural and functional abnormalities of arteries supplying the brain, visceral organs, and limbs.³ These syndromes include lower extremity PAD, renal arterial disease, mesenteric arterial disease, and various aneurysms. This article focuses on lower extremity PAD and intermittent claudication.

EPIDEMIOLOGY AND ETIOLOGY
According to the 2000 National Health and Nutrition Examination Survey (NHANES), the incidence of PAD in individuals older than age 39 was 4.3%, which equates to approximately five million people.^2,4 As the population ages, this incidence increases threefold, to approximately 14.5% of people by age 70. The NHANES study showed no gender-based differences in prevalence of PAD. However, non-Hispanic blacks had the highest incidence. ^2,4,5

Lower extremity PAD may result from thromboembolus, inflammation, or trauma; however, the most common cause is atherosclerosis. Thus, the same risk factors associated with atherosclerosis apply to lower extremity PAD. These risk factors include smoking, diabetes, dyslipidemia, hypertension, family history of cardiovascular disease, prior heart or vascular disease, hyperhomocysteinemia, and renal im­ ­ pairment.^1,3,5

Smoking is the most significant predictor of lower extremity PAD. A smoker is two to three times more likely to develop lower extremity PAD than a person with coronary artery disease.^6,7 Diabetes mellitus was found to be present in 12% to 20% of patients with PAD. The risk of diabetic patients developing lower extremity PAD is proportional to the severity and duration of diabetes in these patients.³ The Framingham Heart Study found that diabetes increased the risk of intermittent claudication and critical limb ischemia, which requires immediate surgical amputation.^3,6,7 The study also linked hypertension to an elevated risk of intermittent claudication.^6,7 However, the correlation between hypertension and PAD is not well defined. Epidemiological studies have shown that higher total cholesterol levels are found in lower extremity PAD patients with intermittent claudication. An increased prevalence of PAD is also found in patients with familial hypercholesterolemia.^3,6-8 Homocysteine was recently established as an independent risk factor for atherosclerosis. An estimated 30% to 40% of patients with lower extremity PAD have elevated homocysteine levels. In one study, levels of homocysteine in the PAD group were significantly higher than the levels in the control group: 14.9 versus 11.3 micromoles, respectively (P <.001).^3,9

PATHOPHYSIOLOGY
Systemic atherosclerosis occurs when the lining of the arteries is damaged by high blood pressure, smoking, and other factors that are toxic to the artery lining. Formation of lipid plaques is caused by the accumulation of low-density lipoproteins at the site of arterial damage. Once formed, the plaques are capped by platelets. Over time, these deposits increase in number and size, leading to occlusion of the arterial lumen of large- and medium-sized vessels, thereby narrowing the diameter of the vessels and impeding blood flow. The most commonly affected peripheral arteries are the femoro­ poplitealtibial, aortoiliac, and carotid arteries. Other affected arteries include the vertebral, splenic, renal, and brachiocephalic arteries. ^5,10

CLINICAL PRESENTATION AND DIAGNOSIS
Patients with lower extremity PAD present with cramping, aching, fatigue, weakness, or pain upon movement, or with no symptoms. When pain is experienced during movement but relieved with rest, it is termed intermittent claudication. The symptoms of claudication result from local ischemia. These patients have ample blood flow; thus, the symptoms related to ischemia are not present when the limb is at rest.³ Pain at rest is referred to as critical limb ischemia and is typically experienced by patients with more progressive disease as a result of insufficient blood supply to the extremity.⁵

Leg-related symptoms can provide some clues of the location of the arterial stenosis. For example, stenosis involving the iliac arteries generates pain in the hip, thigh, buttock, and calf. Calf pain is typical of stenosis of the femoral and popliteal arteries, while tibial artery involvement may give rise to calf or foot pain and numbness.³ Patients may also present with Leriche syndrome, comprising claudication, erectile dysfunction, and large-scale atrophy of lower extremities secondary to the presence of aortoiliac obstruction. Other clinical symptoms may include hair loss on ankles and feet and thickened toenails.^5,10,11

Obtaining a thorough patient history is vital in the diagnosis of lower extremity PAD. Patient history should include assessment of risk factors for atherosclerotic disease, such as smoking, diabetes, hypertension, hyperlipidemia, and family history of atherosclerotic disease.³ The physical examination should incorporate blood pressure measurement, auscultation of pulses and bruits, and bilateral palpitation of pulses. Skin should be examined for tone, texture, and color, as well as hair distribution and the presence of ulcers or lacerations. Routine laboratory data for cholesterol levels, basic chemistry, and cell blood count differential should be evaluated.^5,11

Physical examination must be combined with diagnostic tests, such as the ankle-brachial index (ABI), which is a sensitive index used to detect symptomatic and asymptomatic PAD. ABI values less than or equal to 0.9 indicate the presence of PAD; ABI values of 0.69 to 0.41 are considered moderate PAD; and values less that 0.4 suggest more evolved ischemic disease.^8,11 ABI is calculated by dividing the ankle systolic blood pressure by the brachial systolic blood pressure from blood pressure measurements with a blood pressure cuff. ABI can be used as a predictor of cardiovascular events and to monitor the progression of PAD. ¹¹ Other valid diagnostic options include treadmill exercise testing, active pedal plantarflexion, segmental pressures and pulse volume readings, and Doppler wave analysis. As PAD progresses, patients may undergo invasive angiography with contrast dye or revascularization.^3,11

Continued progression of lower extremity PAD can result in critical leg ischemia, manifested as new wounds, pain at rest, or gangrene. At this stage, prognosis is poor without revascularization and depends on the extent of arterial damage, characteristics of limb ischemia, and the ability to restore circulation rapidly. Without prompt attention, irreversible tissue and nerve damage may occur.³ In the treatment of PAD, early detection and atherosclerotic risk reduction to slow disease progression are of primary importance.

PHARMACOLOGIC RISK REDUCTION
Treatment of lower extremity PAD includes modification of the risk factors for atherosclerosis, smoking cessation, exercise, and a low-cholesterol diet. Observational studies suggest that current smokers have an increased risk of death, myocardial infarction, and amputation, compared to patients who quit smoking.³

Hyperlipidemia is associated with increased risk of atherosclerotic disease and cardiovascular events. The goal for patients with PAD is a low-density lipoprotein (LDL) level of less than 100 mg/dL. However, if a patient has multiple risk factors, an LDL target of less than 70 mg/dL may be desired to reduce cardiovascular risk.¹² Statin therapies, such as simvastatin and atorvastatin, have been shown to improve pain-free walking distance and to reduce the onset of intermittent claudication in patients with PAD.^13-15

The treatment of hypertension is important for reducing the risk of cardiovascular events and slowing the progression of PAD. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends the reduction of systolic blood pressure to less than 140 mmHg and of diastolic blood pressure to less than 90 mmHg. However, if the patient has diabetes mellitus or chronic kidney disease, target blood pressure should be 130/80 mmHg.¹⁶

The Heart Outcomes Prevention Evaluation study enrolled more than 9,000 high-risk patients, including approximately 4,000 patients with PAD. In this study, ramipril, an angiotensin-converting enzyme inhibitor, reduced the risk of the composite end point (myocardial infarction, stroke, and/or cardiovascular death), compared to placebo: 14% versus 17.8%, respectively (P <.001).¹⁷  Historically, beta-blockers were thought to be contraindicated in patients with PAD. However, a meta-analysis of 11 studies showed that beta-blockers did not adversely affect walking capacity or symptoms of intermittent claudication in mild to moderate PAD.^18,19 Patients with PAD may benefit from a beta-blocker or angiotensin-converting enzyme inhibitor to help reduce cardiovascular events. 

Treatment of elevated homocysteine levels greater than 14 micromoles per liter is not well established, but prospective trials are in progress.³ There is evidence of effective reduction of homocysteine levels with folic acid and B-complex vitamins, but no correlation with reduction in cardiovascular events has been observed. In a meta-analysis of 12 trials, homo­ ­ ­ cysteine levels lowered by 25% with folic acid (dosage 0.5 to 5 mg/day) and by 7% with the addition of cobalamin (0.5 mg/day).²⁰ Treatment with B-complex vitamins and folic acid is generally safe; however, there is a risk of masking cobalamin deficiency with the use of folic acid alone.

Antiplatelet therapy with aspirin or clopidogrel is indicated to decrease the risk of myocardial infarction, stroke, and vascular death in patients with PAD. Studies showed a 23% odds reduction in risk of cardiovascular events with 75 to 325 mg of aspirin daily. Higher doses of aspirin (>325 mg), however, increased the rates of intracranial and gastrointestinal bleeding. Other antiplatelet medications, particularly the thienopyridine agents--ticlopidine and clopidogrel--have been shown to reduce cardiovascular events. The thienopyridine agents are recommended as an alternative to aspirin therapy when patients are unable to tolerate, or have a contraindication with, aspirin.^12,19,21

INTERMITTENT CLAUDICATION
Nonpharmacologic Therapy
The effect of exercise on claudication has been studied extensively. A supervised exercise-training program consisting of 30- to 45-minute sessions--at least three times per week for a minimum of 12 weeks--improved maximal walking ability. Improvement has been seen as early as four weeks, but patients continue to improve after six months of participation.²² Supervised exercise programs increased maximal exercise ability, compared to medications: 150% versus 40% to 60%, respectively.³ Patients should have a complete medical examination by a physician prior to beginning an exercise program.

Pharmacologic Therapy
Cilostazol: According to the American Heart Association Practice Guidelines, cilostazol is recommended to help PAD patients with intermittent claudication increase their walking distance. In addition, a therapeutic trial of cilostazol is preferred in patients with PAD lifestyle-limiting claudication.³ Cilostazol is a phosphodiesterase III inhibitor that causes platelet aggregation and vasodilation by increasing cyclic adenosine monophosphate in the platelets and vascular dilation. The vascular dilation effect is greater in the femoral vascular beds, with minimal to no effect on the renal arteries.²³ In eight prospective, randomized trials, cilostazol improved maximal walking distance by 44% to 50%, compared to placebo, after 12 to 24 weeks of therapy. In addition, pain-free walking distance was improved by 60% to 67% with cilostazol.²⁴ Patients may experience a benefit at weeks two and four, but treatment for at least 12 weeks is preferred for maximal benefit. Additionally, 100 mg cilostazol twice daily increased high-density lipoprotein by 12% and decreased triglycerides by 15.8%, compared to placebo (P = .0001) at week 24.²⁴ Cilostazol is metabolized by the cytochrome P450 isoenzymes 3A4 and 2C19 into two active metabolites. Due to various drug interactions (Table 1), the dose of cilostazol should be reduced by 50% when coadminstered with cytochrome P450 system inhibitors. Cilostazol is contraindicated in heart failure. The FDA mandates a black box warning stating cilostazol should not be used in patients with heart failure. See Table 1 for dosage, drug interactions, and significant adverse effects of cilostazol.^23,25 Other phosphodiesterase inhibitors, including milrinone, have been associated with increased mortality in patients with heart failure and reduced systolic left ventricular dysfunction.

Pentoxifylline: This is a second-line agent for the treatment of intermittent claudication in patients with PAD. Pentoxifylline increases walking distance by decreasing the viscosity of the blood. Alterations in blood viscosity increase perfusion of the microcirculation and enhance tissue oxygenation. Pentoxifylline also affects erythrocyte flexibility. The effect on blood viscosity is exerted by the parent compound but primarily by the active metabolites of pentoxifylline. Pentoxifylline is primarily metabolized by the liver and excreted by the renal system.²⁶ In a composite of studies, pentoxifylline demonstrated an improvement in pain-free walking and total walking distance when compared with placebo. However, pentoxifylline was inferior to cilostazol in pain-free walking and total walking distance.²⁷

Various adverse events have been reported with pentoxifylline (Table 1). Digestive and central nervous system side effects are directly dose related, and a dosage reduction may alleviate these adverse effects. Patients may see improvement in walking distance at weeks two and four, but for maximal effects, treatment should be continued for at least eight weeks.^26,27 Although pentoxifylline is extensively metabolized by the liver, with the exception of theophylline few major drug interactions exist. Pentoxifylline increases theophylline serum concentrations by approximately 30% when these two agents are coadministered. Drug levels of patients currently on theophylline should be monitored frequently to prevent toxicity.²⁸ In addition, pentoxifylline should be avoided in patients with a history of cerebral or retinal hemorrhage.²⁶

Alternative Therapies: Alternative therapies, such as L-arginine, ginkgo biloba, vitamin E, and chelation therapy, have been studied for the treatment of claudication in patients with PAD. The evidence is marginal for L-arginine and ginkgo biloba in the treatment of PAD, while there is no evidence to support treating PAD with vitamin E and chelation therapy.

L-arginine is a precursor of nitric oxide, which leads to vasodilation and inhibition of platelet aggregation. Two placebo-controlled trials of L-arginine demonstrated some improvement in pain-free walking and maximal walking distance. Ginkgo biloba is an herb with properties related to decreased blood viscosity, decreased erythrocyte aggregation, and inhibited platelet-activating factor. In trials, patients receiving 120 to 160 mg of ginkgo biloba extract showed improvement in pain-free walking, but the results were minimal.³

Vitamin E (alpha-tocopherol) and chelation therapies have not shown any beneficial effects on claudication with PAD. Vitamin E is a lipid-soluble antioxidant. Several studies over the past 50 years have compared vitamin E with placebo for improvement in various outcomes in patients with high cardiovascular risk. None of these studies demonstrated any significant  differences in the use of vitamin E in the treatment of PAD when compared with placebo.²⁹

Chelation is proposed to leach calcium out of the atherosclerotic plaques. It has been used to treat heavy metal poisoning and claudication. Several studies have evaluated the effects of chelation on pain-free walking and maximal walking distance in patients with PAD. However, the results showed no difference when compared placebo. In fact, chelation therapy may be harmful due to potential serious adverse effects, such as hypocalcemia, renal insufficiency, proteinuria, and gastrointestinal distress. ³

Vasodilator Prostaglandins: Vasodilator prostaglandins, e.g., beraprost and iloprost, have been studied in the treatment of claudication but are not FDA approved for the treatment of PAD. Vasodilator prostaglandins cause vasodilation and inhibition of platelet aggregation by activating adenyl cyclase. One study showed improvement in maximal walking distance with oral beraprost at six months. However, two other placebo-controlled trials failed to show improvement in pain-free walking or maximal walking distance with either oral beraprost or iloprost. Based on the evidence, oral vasodilator prostaglandins are not recommended for the treatment of claudication in patients with PAD.³

Surgery
Patients with continued symptomatic claudication even after modification of atherosclerotic risk factors, exercise, and medications, such as cilostazol or pentoxifylline, should be referred for revascularization. Revascularization consists of lower extremity angioplasty, stenting, or bypass surgery. Criteria for revascularization include incapacitating claudication interfering with work or lifestyle; limb salvage in persons with limb-threatening ischemia, manifested by rest pain, nonhealing ulcers, and/or infection; and vasculogenic impotence. Amputation of the extremity is reserved for patients with life-threatening ischemia beyond the point of recovery.^3,19

The Pharmacist's Role
Pharmacists can advise and educate health professionals about significant drug interactions and contraindications with cilostazol and pentoxifylline. Pharmacists can also have an active role in the care of PAD patients by encouraging modification of atherosclerotic risk factors and promoting proper treatment. They can educate patients about modifiable atherosclerotic risk factors, including smoking, hypertension, diabetes, hyperlipidemia, and elevated homocysteine, and explain to them that most risk factors may be minimized with diet, exercise, and use of over-the-counter and prescription medications. In addition, educating patients about the potential side effects of PAD treatment may help to improve patient compliance.

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