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.
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
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
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.
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
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
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
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
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
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
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
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, 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.
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
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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