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© Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 123

Abstract: Along with coronary artery disease and cerebrovascular disease, peripheral artery

disease (PAD) is primarily caused by atherosclerosis. In fact, PAD is a marker of advanced

atherosclerotic disease, as evidenced from several studies that suggest approximately 60% of

patients with PAD have polyvascular disease or manifestations of atherosclerosis in the coronary

or cerebrovascular territories as well. However, despite a PAD prevalence that is � 15% in

patients with cardiovascular risk factors aged 60 to 69 years and � 35% in patients aged 70 to 82

years, there is a lack of disease awareness on the part of both physicians and patients. This lack

of awareness most likely contributes to the high cardiovascular risk associated with a diagnosis

of PAD. For example, in the Reduction of Atherothrombosis for Continued Health (REACH)

Registry, patients with PAD experienced the highest rates of all-cause mortality, cardiovascular

death, myocardial infarction, stroke, or hospitalization for atherothrombotic events. High-risk

patients should be screened for the presence of PAD. If diagnosed, physicians should institute

a comprehensive treatment strategy that includes lifestyle modifi cation and appropriate risk-

reducing therapies. Because PAD is a manifestation of atherosclerosis, antiplatelet therapy should

be a critical component of any PAD treatment plan. This article reviews the epidemiology and

cardiovascular risks associated with PAD, as well as available diagnostic and treatment options.

Keywords: peripheral artery disease; atherosclerosis; cardiovascular risk factors;

ankle-brachial index

IntroductionPeripheral artery disease (PAD) manifests as arterial stenosis, occlusion, or aneurysm

of the aorta or renal, mesenteric, and extremity arterial vasculature. Atherosclerosis

is the most common underlying etiology. Because atherosclerosis is systemic, many

patients with PAD have concomitant coronary artery disease (CAD) and/or cerebrovas-

cular disease (CVD).1 The international Reduction of Atherothrombosis for Continued

Health (REACH) Registry reinforced that PAD is associated with high cardiovascular

event rates.2 This article reviews the burden of PAD and discusses effective ways

of diagnosis and management.

EpidemiologyThe United States National Health and Nutrition Examination Study observed a 4.3%

prevalence of PAD among adults aged � 40 years in the United States,3 which varies

as a function of age (Figure 1).3,4 Prevalence of PAD also varies by race and ethnic-

ity, with the highest rates found in non-Hispanic blacks aged � 60 years (19.5%),

followed by Mexican Americans (15.6%) and non-Hispanic whites (11.7%).3 Only 20%

to 30% of patients with PAD exhibit typical symptoms of intermittent claudication.3,5

The Burden of Peripheral Artery Disease and the Role of Antiplatelet Therapy

Herbert Aronow, MD, MPH1

William R. Hiatt, MD2

1St. Joseph Mercy Hospital, Ann Arbor, MI; 2University of Colorado, Denver, CO

Correspondence: Herbert Aronow,MD, MPH,Michigan Heart and Vascular Institute5325 Elliot Drive, Suite 203,Ann Arbor, MI 48106.Tel: 734-712-8000Fax: 734-712-8010E-mail: [email protected]

Global reprints distributed only by Postgraduate Medicine USA. No part of Postgraduate Medicine may be reproduced or transmitted in any form without written permission from the publisher. All permission requests to reproduce or adapt published material must be directed to the journal office in Berwyn, PA, no other persons or offices are authorized to act on our behalf. Requests should include a statement describing how material will be used, the complete article citation, a copy of the figure or table of interest as it appeared in the journal, and a copy of the “new” (adapted) material if appropriate

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124 © Postgraduate Medicine, Volume 121, Issue 4, July 2009, ISSN – 0032-5481, e-ISSN – 1941-9260

Herbert Aronow and William R. Hiatt

Although men are more likely to have symptomatic PAD

than women,6,7 the overall disease prevalence is similar in

both sexes.3,8

Typical PAD symptoms include intermittent claudication,

described as exertional discomfort or cramping in the calves,

thighs, or buttocks that is relieved by rest. Less frequently,

patients may have erectile dysfunction.9,10 The discomfort

associated with walking often leads to decreased mobility and

thus, decreased quality of life.11,12 In advanced cases, critical

limb ischemia (CLI) (rest pain, skin ulceration, or gangrene)

may develop, which, if left untreated, can result in limb loss.

Asymptomatic or atypical symptomatic patients account

for the majority of PAD cases. These patients still have some

measure of limb dysfunction, including diminished strength,

and are at risk for diminished functional status and ischemic

cardiovascular events.9

The Health Burden of PAD—Atherothrombotic RiskThe dangers of PAD extend well beyond impaired mobility

and function because PAD is also a marker for atherosclerotic

disease in other vascular territories (“polyvascular disease”).

In the REACH Registry, � 60% of patients with PAD had

polyvascular disease: 40% had CAD; 10% had CVD; and

13% had CAD and CVD.1 A retrospective analysis of 1328

women and 474 men aged 60 to 102 (mean 80 ± 9) years at an

academic hospital-based geriatrics practice revealed a similar

distribution, as 68% had CAD and 42% had CVD.13 Data

from A Global Atherothrombosis Assessment (AGATHA)

indicated that of all patients with PAD, 23% had PAD and

CAD, 21% had PAD and CVD, and 24% had all 3.14

The 1-year REACH Registry outcomes show that

compared with CAD or CVD patients, those with PAD

had the highest rates of all-cause mortality; cardiovascular

death; cardiovascular death, myocardial infarction (MI),

stroke, or hospitalization for atherothrombotic events

(15.2% for CAD, 14.5% for CVD, and 21.1% for PAD for

the composite); hospitalization for ischemic arterial events,

bleeding, or claudication; carotid angioplasty, stenting, or

surgery; peripheral artery bypass grafts; PAD angioplasty

and stenting; and amputation.2 The 5-year mortality rate for

symptomatic or advanced PAD is 28%, greater than breast

cancer (11%), and Hodgkin’s lymphoma (14%).15

In one population study, cardiovascular death over a

5-year period was more likely in patients with claudication

(risk ratio [RR], 2.67; 95% confidence interval [CI],

1.34–5.29) and major (RR, 2.08; 95% CI, 1.13–3.83) or

minor asymptomatic PAD (RR, 1.74; 95% CI, 1.09–2.76)

compared with patients without PAD.16 Over a 10-year period,

patients with PAD had a 3-fold greater risk (RR, 3.1; 95% CI,

1.9–4.9) of dying from any cause, a 6-fold greater risk (RR,

5.9; 95% CI, 3.0–11.4) of dying from cardiovascular disease,

and an almost 7-fold greater risk (RR, 6.6; 95% CI, 2.9–14.9)

of dying from CAD compared with patients without PAD.17

The Economic Burden of PADA recent US study of Medicare costs from 1999 to 2005

found that initial treatment and 1-year follow-up of PAD

costs approximately 5% more than similar CAD treat-

ment ($50 110 vs $47 515).18 A recent study conducted

to determine Medicare expenditures for treatment costs

in the nondisabled elderly reported that $4.4 billion was

spent on PAD-related treatment, 88% of which was for

inpatient care.19 Treatment costs increased with age at rates

of 4.5%, 7.5%, and 11.8% for individuals aged 65 to 74, 75

to 84, and � 85 years, respectively. According to a report

published by the research and consulting company SAGE,

which specializes in lower-limb vascular disease, amputa-

tions are associated with a signifi cant cost burden in patients

with PAD.20 SAGE estimates that the 160 000 amputations

performed annually in the United States for PAD incur

approximately $10 billion in additional costs because most

patients can no longer live independently. A 25% reduction

in the number of amputations, primarily through early PAD

detection, could save an estimated $2.9 billion.

Underdiagnosis of PADPeripheral artery disease is underdiagnosed, partly because

of its often asymptomatic nature and lack of patient and

35

25

15

30

20

10

5

038−59 60−69 70−82

Age in years

% P

reva

lenc

e of

PA

DFigure 1. Prevalence of peripheral artery disease (PAD).

Figure created with data from Circulation.4


PAD and Antiplatelet Therapy

physician awareness. In a cross-sectional population survey

of 2501 adults (mean age 67 years) with high risk factor

prevalence, only 26% expressed familiarity with PAD.

Among these, awareness was poor, with half being unaware

that diabetes and smoking increase PAD risk, three-fourths

unaware that PAD is associated with increased heart attack

and stroke risk, and 86% unaware that PAD could lead to

amputation.21 Investigators of the PAD Awareness, Risk

and Treatment: New Resources for Survival (PARTNERS)

program report that 85% to 90% of PAD cases would be

missed if physicians relied solely on patients presenting

with intermittent claudication.22 Unless physicians perform

an extensive examination, including a thorough pulse

assessment or determination of the ankle-brachial index

(ABI), PAD can be missed.10,23 Even patients who have

intermittent claudication do not consistently report it because

they often attribute their symptoms to aging.23 Additionally,

patients with PAD do not always report their diagnosis to

their physician.22

Simple Ways to Diagnose PADSelf-reported questionnaires such as the Edinburgh

Claudication Questionnaire,24 an updated version of the

World Health Organization Rose Questionnaire, the Walking

Impairment Questionnaire,25 and the Peripheral Artery

Questionnaire (Table 1)26 are useful in identifying patients

with symptomatic PAD. However, PAD identifi cation based

on typical leg symptoms will miss a signifi cant number of

diagnoses. Evidence-based guidelines for PAD treatment

recommend a standardized review of vascular symptoms that

include assessment of exertional limitation, lower extremity

rest pain, and poorly healing leg and feet wounds.9,27

Due to the high polyvascular disease risk, its associated

morbidity and mortality, and the large economic and func-

tional burden of late diagnosis, it is imperative that primary

care physicians identify patients at a high risk of developing

PAD (Table 2) and perform a thorough vascular history and

physical examination. According to the American College

of Cardiology (ACC) and the American Heart Association

Table 1. Questionnaires Commonly Used in the Diagnosis of Peripheral Artery Disease (PAD)

Name No. of Questions

Parameters Assessed

Used in Diagnosis of PAD

Edinburgh Claudication Questionnaire (ECQ)24

5 1. Symptom onset2. Symptom duration

San Diego Claudication Questionnaire (SDCQ)4,89

1. Symptom onset2. Symptom duration

Used to Judge Severity of PAD and Response to Therapy

Walking Impairment Questionnaire (WIQ)25

18 1. Diffi culty walking a distance in the past month

2. Diffi culty walking a certain speed in the past month

3. Symptoms associated with walking impairment

Peripheral Artery Questionnaire (PAQ)26

20 1. Physical limitations 2. Symptom frequency, severity, and

change over time 3. Social function 4. Treatment satisfaction 5. Quality of life

Medical Outcomes Study 36-Item Short-Form (SF-36) Health Survey

36 1. Vitality 2. Physical functioning 3. Bodily pain 4. General health perceptions 5. Physical role functioning 6. Emotional role functioning 7. Social role functioning 8. Mental health



(AHA) PAD guidelines, a thorough vascular examination

should include measurement of blood pressure in both arms;

palpation of carotid, brachial, radial, ulnar, femoral, popliteal,

dorsalis pedis, and posterior tibial pulses; assessment of pulse

intensity; auscultation of the abdomen, fl anks, carotid, and

femoral arteries for bruits; and examination of the feet for

color, temperature, and skin integrity.9

Ankle-Brachial IndexA simple ABI measurement is the most sensitive, specifi c,

cost-effective, and noninvasive means of detecting PAD in a

primary care setting. Following blood pressure measurement

using a handheld Doppler device, the ABI is calculated for

each lower extremity by dividing the ankle systolic blood

pressure (higher of the dorsalis pedis and posterior tibial

pressures) by the higher brachial systolic blood pressure. An

ABI of � 0.9, associated with � 50% stenosis in � 1 artery,

is diagnostic for PAD.

The ABI has also been shown to predict mortality in

patients with PAD. One study reported a 3.1% relative mor-

tality risk for every 0.5 incremental decrease in the ABI;28 the

cumulative survival after 5 years was 63% for patients with

an ABI of � 0.5, 71% for patients with an ABI of 0.5 to 0.69,

and 91% for those with an ABI of � 0.7. Investigators in the

Cardiovascular Health Study noted a similar fi nding.29 In a

recent meta-analysis of 16 studies (48 294 patients), the risk

of death assessed by ABI followed a reverse J-shaped curve,

with the lowest-risk ABI being 1.1 to 1.4.30 The 10-year

mortality rates for men and women with an ABI of � 0.9

were 18.7% and 12.6%, respectively. The risk remained high

even after adjusting for the Framingham Risk Score (FRS),

suggesting that adding ABI measurement to the FRS may

improve cardiovascular risk prediction.

Evidence suggests that the ABI should be measured in

high-risk patients. Investigators of A Global Atherothrom-

bosis Assessment (AGATHA) found a signifi cant correlation

between the number of risk factors present and an abnormal

ABI; the frequency of an abnormal ABI increased from 15%

of the population with 2 risk factors to 29% of those with 5

risk factors.14 In the PAD Awareness Risk and Treatment:

New Resources for Survival (PARTNERS) study, patients

aged 50 to 69 years who smoked or had diabetes and those

aged � 70 years were screened with ABIs; 44% of patients

with PAD (alone or with CAD) were newly diagnosed.22

Additional Diagnostic ModalitiesAn ABI-based PAD diagnosis can be confirmed with

additional tests, including Doppler waveform analysis,

pulse volume recording, duplex arterial ultrasound, walking

tolerance testing, magnetic resonance angiography,

and computed tomography angiography. Noninvasive

angiographic techniques are only recommended in cases in

which the diagnosis is uncertain or when revascularization is

being considered.10 Although the ABI is an effective tool, it is

not without limitations. In patients with calcifi ed arteries, such

as those with diabetes or advanced renal disease, vessels may

be noncompressible, resulting in an artifi cially elevated ABI.

When PAD is suspected but the ABI is unusually high, toe

pressure measurement should be performed because they are

much less susceptible to calcifi cation.10 Similarly, when the

ABI is normal but PAD is suspected, exercise testing (walking

tolerance testing or “toe ups”) should be undertaken.

Risk Factors Associated with PADRisk factors for PAD are similar to those associated with other

atherosclerotic vascular diseases, although the strength of their

association may vary (Figure 2; Table 3). Cigarette smoking is a

very powerful predictor of PAD. Current smokers have as much

as a 6-fold greater risk of developing PAD than those who do not

smoke;3,7,8,22,31 although the risk for former smokers is not as high

as that of current smokers, it remains signifi cant. Current smoking

is also a signifi cant predictor of PAD progression32 and increases

the risk of peripheral graft failure 3-fold.33

Diabetes is also a strong predictor of PAD. The risk of

developing PAD in diabetic patients is 2- to 4-fold greater than

in the nondiabetic population.3,7,8,22,34–37 Poor glycemic control is

associated with PAD progression and increased amputation and

mortality.32,35,36,38–40 Hypertension and dyslipidemia are also asso-

ciated with PAD, but to a lesser extent than with CAD and CVD.

Individuals with hypertension (blood pressure � 140/90 mm

Hg) and dyslipidemia have approximately a 2-fold greater risk

of developing PAD than those without these conditions.3,7,8,22

It should be noted that although obesity is a well-established

risk factor for CVD and CAD, it has not been associated with

Table 2. American College of Cardiology/American Heart Association Criteria for Identifying Patients at High Risk for Prevalent Peripheral Artery Disease

- Persons aged � 50 years who have diabetes and at least one other atherosclerotic risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)- Persons aged 50 to 69 years who have a history of smoking or diabetes- All persons aged � 70 years- Persons with leg symptoms upon exertion or ischemic rest pain- Persons with an abnormal lower extremity pulse examination- Persons with known atherosclerotic coronary, carotid, or renal artery disease



an increased risk of PAD.3,8,32 Impaired renal function, as

determined by the glomerular fi ltration rate, increases the

likelihood of developing PAD,3,8,41 is a predictor of poor

outcomes in patients undergoing lower limb revascular-

ization,42 and results in greater rates of CLI, ulceration,

gangrene, and mortality.43

Elevated biomarkers, including homocysteine,

C-reactive protein (CRP), and fi brinogen are associated

with an increased risk of PAD. Hyperhomocysteinemia

has been associated with a near 10-fold increased risk of

mortality.44 Hyperhomocysteinemia has also been shown

to be a marker of polyvascular disease among patients

with PAD45 and to be associated with disease progres-

sion.46 High CRP levels are associated with a 2- to 3-fold

increased risk of developing PAD.3,47–51 The risk of PAD

development and/or progression grows with increasing CRP

levels, as does the revascularization risk.32,47,52 Fibrinogen is

also associated with an increased risk of developing PAD

and cardiovascular events, including death.48,50,51 Patients

with the highest levels of fi brinogen are the most likely to

develop PAD.51,53–55

Management of PADEvidence-based guidelines for the effective management

of PAD have been published by the ACC/AHA,9 the

Scottish Intercollegiate Guidelines Network (SIGN),10 and

the Trans-Atlantic Inter-Society Consensus (TASC) II.27

These guidelines recommend therapeutic lifestyle changes,

risk factor modifi cation, pharmacological intervention to

increase walking distance, and the use of antiplatelet therapy

to reduce cardiovascular risk and increase the success of

revascularization. The ACC/AHA class I recommendations

for patients with PAD are found in Table 3.

Risk Factor Modifi cationDue to the high risk of cardiovascular events in patients with

PAD, both the SIGN and ACC/AHA guidelines recommend

risk factor and lifestyle modifi cations. Cessation of cigarette

smoking through the use of nicotine replacement and behavior

modifi cation therapy is paramount. A daily exercise program,

preferably supervised in the initial stages, and consumption

of a healthy, well-balanced diet including fruits, vegetables,

and low-fat dairy products are also important, particularly

Smoking

Diabetes

Hypertensiona

Dyslipidemia

Renal Diseaseb

Hyperhomocysteinemia

C-Reactive Protein

Fibrinogen

0.5 1.5 2.5 3.5 4.51 2 3 4 5

Figure 2. Risk factors associated with developing lower extremity peripheral artery disease.3,8,9,41,51

aDefi ned as systolic and diastolic blood pressures of � 140 mm Hg and � 90 mm Hg, respectively.bDefi ned as a glomerular fi ltration rate � 90 mL/min.Adapted from the American Heart Association, Inc.9



Table 3. American College of Cardiology/American Heart Association Class I Recommendations for the Management of Peripheral Artery Disease (PAD)a,9

Recommendations Level of Evidenceb

All Patients

Antiplatelet therapy with 75–325-mg aspirin daily is indicated to reduce the risk of adverse cardiovascular ischemic events.

A

Hypertensive patients should be administered antihypertensive therapy to achieve a blood pressure of � 140/90 mm Hg (nondiabetics) or � 130/80 mm Hg (diabetics or persons with chronic kidney disease).

A

β-Blockers are effective antihypertensive agents and are not contraindicated in patients with PAD. A

Diabetic patients should properly care for their feet, and all skin lesions, and ulcerations should be urgently addressed.

B

For patients who smoke, comprehensive smoking cessation, including behavior modifi cation therapy, nicotine replacement, and/or bupropion should be strongly encouraged.

B

Antiplatelet therapy with 75-mg clopidogrel daily is an effective alternate antiplatelet therapy. B

All patients should be treated with a statin to achieve a target LDL-C level of � 100 mg/dL. B

Asymptomatic

High-risk patients should be identifi ed by examination and/or ABI. B

Antiplatelet therapy is indicated to reduce the risk of adverse cardiovascular ischemic events. C

Intermittent Claudication (IC)

Supervised exercise therapy for a minimum of 30 to 45 minutes at least 3 times a week for 12 weeks. A

In the absence of heart failure, 100-mg cilostazol twice daily is indicated to improve symptoms and increase walking distance.

A

Endovascular intervention should only be considered if exercise and pharmacotherapy have not produced appreciable benefi ts and/or there is a very favorable risk/benefi t ratio.

A

Patients with IC should undergo a vascular examination that includes measurement of the ABI. B

Patients with IC and a normal resting ABI should be tested for ABI after exercise. B

All patients should receive comprehensive risk factor modifi cation and antiplatelet therapy. C

Only those patients with a signifi cant disability or those with favorable anatomy should be considered for endovascular or surgical intervention.

C

Critical Limb Ischemia (CLI)

All patients undergoing revascularization should be prescribed antiplatelet therapy indefi nitely. A

Patients scheduled to undergo surgical repair should undergo cardiovascular risk assessment. B

Patients with CLI who have a suggestion of atheroembolism should be evaluated for aneurysmal disease.

B

Systemic antibiotics should be initiated promptly if there is evidence of limb infection or cellulitis and/or infected wounds.

B

Patients with CLI and skin breakdown should be referred for wound care. B

Patients with a history of CLI or who are at high risk should inspect their feet daily and receive written and verbal instructions on self-surveillance.

B, C

Patients with signifi cant necrosis of the weight-bearing portions of the foot, an uncorrectable fl exion contracture, paresis, ischemic rest pain, sepsis, or a limited life expectancy due to comorbid conditions should be evaluated for amputation.

C

All patients with CLI should undergo rapid evaluation for and treatment of factors known to increase the risk of amputation.c

C

Patients with a history of CLI should be evaluated at least biannually due to the high risk of recurrence.

C

aClass I recommendations are those for which there is evidence for and/or general agreement that a given procedure or treatment is benefi cial, useful, and effective; blevel of evidence A = data derived from multiple randomized clinical trials or meta-analyses; level of evidence B = data derived from a single randomized trial or nonrandomized stud-ies; level of evidence C = consensus opinion of experts, case studies, or standard-of-care; crisk factors associated with an increased risk of amputation include diabetes, severe renal failure, severely decreased cardiac output, vasospastic diseases, smoking and tobacco use, infection, skin breakdown, and traumatic injury.Abbreviations: ABI, ankle-brachial index; LDL-C, low-density lipoprotein cholesterol.



in treating symptoms of claudication and modifying some

risk factors.9,10

Based on a number of clinical trials, most notably

the Heart Protection Study, all patients with PAD and a

low-density lipoprotein cholesterol (LDL-C) concentra-

tion of � 100 mg/dL should be treated with a statin if

tolerated.56 Guideline-recommended goals include an

LDL-C of � 100 mg/dL in all patients and � 70 mg/dL

in patients with high-risk PAD. Hypertension should be

controlled using a combination of behavior modifi cation

and pharmacological intervention with any drug class that

effectively lowers blood pressure and is tolerated by the

patient. β-Adrenergic receptor-blocking drugs (β-blockers)

are not contraindicated,57 and angiotensin-converting

enzyme inhibitors (ACE-Is) are highly recommended.58

Although no available clinical trials demonstrate that

glycemic control in patients with diabetes reduces PAD-

associated cardiovascular events, both the SIGN and ACC/

AHA guidelines recommend controlling hemoglobin A1C

(HbA1C

) levels to � 7.0% to lower the risk of microvascular

events such as nephropathy and retinopathy.9,10 Glycemic

control may be especially important for patients undergoing

surgical revascularization.40 It should be noted, however,

that results of the Action to Control Cardiovascular Risk in

Diabetes (ACCORD) trial found that aggressive lowering of

glucose to near-normal levels (HbA1C

� 6.0%) increased the

risk of mortality in adults with type 2 diabetes.59 The intensive

blood sugar treatment cohort was stopped prematurely after

interim data showed a 22% higher risk of death compared

with the standard treatment group.

In both the SIGN and ACC/AHA PAD guidelines,

lowering of homocysteine levels through the use of folic

acid and vitamin B12

supplements carries a low-level recom-

mendation because of the lack of clinical trial-based evidence

supporting its effi cacy. Although a 12-year prospective study

of 51 529 men found that for every 400 μg/day increment of

folate intake, the multivariate-adjusted PAD risk decreased by

21%,60 controlled clinical trials will be necessary to address

more fully whether vitamin supplements and lowering homo-

cysteine levels are benefi cial in patients with PAD.61,62

Antiplatelet TherapyAs platelets are central to the pathophysiology of athero-

sclerosis and atherothrombosis, antiplatelet therapy is an

indispensable treatment for patients with PAD. Aspirin, the

most well-known and well-established antiplatelet agent,

inhibits platelet activation by blocking the synthesis of throm-

boxane A2, a molecule important for platelet aggregation.

The thienopyridines ticlopidine and clopidogrel block the

binding of adenosine diphosphate (ADP) to its receptor on

platelets, thus preventing the ADP-dependent activation

of the glycoprotein IIb/IIIa complex and, subsequently,

fi brinogen accumulation. Due to its proven effi cacy and

safety profi le, clopidogrel is the thienopyridine of choice in

patients who are aspirin-intolerant.63

Based on multiple clinical trials, treatment with antiplatelet

therapy is the standard of care for patients with PAD and

reduces their risk of cardiovascular complications and other

ischemic events. Table 4 summarizes available clinical

evidence for antiplatelet therapy use in patients with PAD.

Currently, aspirin and clopidogrel are the only antiplatelet

agents recommended for PAD.9 This recommendation is

based largely on the Antithrombotic Trialists’ Collaboration

study that demonstrated a 22% reduction in serious vascular

events in patients with PAD treated with antiplatelet therapy

compared with control.64 However, a recent meta-analysis

of 18 randomized trials (N = 5269) that compared aspirin,

either alone or in combination with dipyridamole, with

placebo showed that aspirin did not signifi cantly reduce the

risk of MI, stroke, or cardiovascular death in patients with

PAD (RR, 0.88; 95% CI, 0.76−1.04); further analysis did

show that aspirin therapy signifi cantly reduced the risk of

the secondary endpoint of nonfatal stroke (RR, 0.66; 95%

CI, 0.47−0.94).65 The Clopidogrel Versus Aspirin in Patients

at Risk for Ischemic Events (CAPRIE) trial, conducted

in � 19 000 patients with a history of recent MI, ischemic

stroke, or established PAD, found that clopidogrel compared

with aspirin signifi cantly reduced the risk of MI, stroke, or

vascular death by 8.7% in the overall population and by 23%

in the subgroup with PAD (n = 6452) over approximately

2 years (Figure 3).63 Although the safety and tolerability

profi les of aspirin and clopidogrel were comparable, aspirin

was associated with a signifi cantly greater risk of gastroin-

testinal bleeding, whereas clopidogrel was associated with

greater rates of bruising, rash, and diarrhea.

Because dual antiplatelet therapy with aspirin and

clopidogrel has well-established efficacy in reducing

cardiovascular risk in patients with acute coronary

syndromes (ACS),66,67 it was studied in patients at risk

of atherothrombosis or who had established PAD, CAD,

or CVD. Dual antiplatelet therapy in the Clopidogrel for

High Atherothrombotic Risk and Ischemic Stabilization,

Management, and Avoidance (CHARISMA) trial did

not demonstrate a greater benefi t compared with aspirin

monotherapy.1 However, in the post hoc subgroup analysis

of 9478 patients with a prior MI, stroke, or symptomatic



PAD (the “CAPRIE-like” cohort), the primary event rate was

signifi cantly lower with clopidogrel plus aspirin compared

with aspirin monotherapy (7.3% vs 8.8%; P = 0.01).66 For the

safety endpoints, there was no signifi cant difference in the

rate of severe bleeding, but there was a signifi cant increase

in moderate bleeding with combination therapy compared

with aspirin alone (2.0% vs 1.3%; P = 0.004). In the overall

population, there was a 25% increase in the rate of severe

bleeding with combination therapy compared with aspirin

alone (1.7% vs 1.3%; relative risk, 1.25; P = 0.09). The rate

of moderate bleeding was 2.1% among clopidogrel/aspirin

recipients compared with 1.3% of aspirin recipients (RR,

1.62; P � 0.001).1 Based on the overall negative results

of this trial, current PAD guidelines recommend a single

antiplatelet drug and not dual antiplatelet therapy.

Other agents, including dipyridamole or the combination

of aspirin plus dipyridamole, are not recommended for use

in patients with PAD because of limited evidence of benefi t.

However, some data indicate that dipyridamole might be used

to prevent restenosis/reocclusion after peripheral endovascular

intervention.68 Similarly, preliminary evidence suggests that

the antiplatelet agent cilostazol reduces restenosis following

Table 4. Evidence Supporting the Effi cacy of Antiplatelet Therapy in Patients with Peripheral Artery Disease (PAD)a

Study Population Treatment Key Clinical Findings

Antithrombotic Trialists Collaboration64

All patients with PAD Antiplatelet vs placebo Antiplatelet therapy associated with a 23% odds reduction (SE, 8%; P = 0.004) in the number of vascular events

Patients with PAD with IC Antiplatelet vs placebo Antiplatelet therapy associated with a 23% odds reduction (SE, 9%) in the number of vascular events

Patients with PAD who underwent peripheral grafting

Antiplatelet vs placebo Antiplatelet therapy associated with a 22% odds reduction (SE, 16%) in the number of vascular events

Patients with PAD who underwent peripheral angioplasty

Antiplatelet vs placebo Antiplatelet therapy associated with a 29% odds reduction (SE, 35%) in the number of vascular events

Berger et al65 Patients with PAD ASA ± dipyridamole vs control ASA ± dipyridamole associated with a nonsignifi cant 12% reduction in the risk of vascular events (RR, 0.88; 95% CI, 0.76–1.04), with sensitivity analyses failing to identify any responsive subgroups

CAPRIE Steering Committee63 Patients with symptomatic PAD ASA vs clopidogrel Compared with ASA, clopidogrel sig-nifi cantly reduced the annual relative risk of vascular events by 23.8% (95% CI, 8.9–36.2; P = 0.0028)

CHARISMA Investigatorsb65 Patients with symptomatic PAD ASA + placebo vs ASA + clopidogrel

Compared with ASA alone, dual therapy with ASA and clopidogrel did not reduce the odds of having a seri-ous vascular event (HR, 0.87; 95% CI, 0.67–1.12; P = 0.285) over a mean treatment period of 27.6 months

Patients with polyvascular disease (subgroup analysis)

ASA + placebo vs ASA + clopidogrel

Compared with ASA alone, dual therapy with ASA and clopidogrel signifi cantly reduced the odds of having a serious vascular event (HR, 0.55; 95% CI, 0.33–0.91; P = 0.018) over a mean treatment period of 27.6 months

aFor all trials, vascular events are either cardiovascular death, nonfatal MI, or nonfatal stroke. bTrial results were negative in the overall population of patients with established atherothrombotic disease and those with at least 3 cardiovascular risk factors.Abbreviations: ASA, aspirin; CAPRIE, Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CI, confi dence interval; HR, hazard ratio; IC, intermittent claudication; MI, myocardial infarction; RR, risk ratio; SE, standard error.



coronary artery stenting69 and reduces atherosclerotic

progression of symptomatic intracranial arterial stenosis.70

Anticoagulant therapy is not recommended for use in

patients with PAD.71 Results of the Warfarin Antiplatelet

Vascular Evaluation (WAVE) trial found that use of both

an antiplatelet agent and an oral anticoagulant was not

more effective than antiplatelet therapy alone in reducing

cardiovascular risk and was associated with an increase in

life-threatening bleeding.72 A number of ongoing clinical

trials (Table 5) should increase our understanding of the role

of antiplatelet therapy in PAD treatment.

Treatment of Claudication SymptomsA number of studies73 have demonstrated the benefi t of

regular exercise in improving walking ability and routine daily

activities. Revascularization (bypass surgery or angioplasty)

is also effective in relieving claudication.74 Patients with clau-

dication can also benefi t from pharmacological intervention.

Cilostazol, a phosphodiesterase type 3 inhibitor with both

vasodilator and antiplatelet properties that is used to treat

patients with PAD with claudication inhibits the expression

of vascular cell adhesion molecules and smooth muscle cell

proliferation. In 2 separate meta-analyses of trials that exam-

ined the effects of cilostazol in patients with symptomatic

PAD, cilostazol was associated with signifi cant improvements

in the maximal walking distance and the maximal pain-free

walking distance.75,76 In addition, patients who were prescribed

cilostazol reported an increased quality of life. Of note, cilo-

stazol carries a US Food and Drug Administration-mandated

black-box warning that it should not be used by patients with

heart failure.9 An earlier drug in this class, pentoxyphylline,

is used infrequently because of reports indicating that it was

no better than placebo in improving pain-free walking or

walking distance in patients with PAD.77,78

Undertreatment of PADDespite its associated increased morbidity and mortality, PAD

remains underdiagnosed and undertreated. The PARTNERS

study reported that patients with PAD were less likely than

patients with CAD to be prescribed antihypertensive (77%

40 30 20 10 10 20 30 400Aspirin better Clopidogrel better

Relative-risk reduction (%)

MI

Stroke

PAD

All patients

Figure 3. Relative risk reduction and 95% confi dence interval by disease subgroup in the Clopidogrel Versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) study. The CAPRIE study included 6452 patients with peripheral artery disease (PAD).

Reprinted from The Lancet, Vol. 348, the CAPRIE Steering Committee, “A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE),” pages 1329-1339, Copyright (1996), with permission from Elsevier. 63

Abbreviations: MI, myocardial infarction.



vs 95%), lipid-lowering (56% vs 73%), and antiplatelet

(54% vs 71%) therapies.22 Patients with PAD enrolled in

the REACH Registry were also less likely than patients with

CAD to be prescribed antihypertensive (92.4% vs 97.4%),

antiplatelet (81.7% vs 85.6%), and lipid-lowering (70.0% vs

80.9%) therapies at baseline.1 Underutilization of evidence-

based medication may have contributed to the elevated

1-year cardiovascular event rates reported for patients with

PAD compared with patients with CAD (5.35% vs 4.52%

for the combined endpoint of cardiovascular death, MI, or

stroke and 21.14% vs 15.20% for the combined endpoint

of cardiovascular death, MI, stroke, or hospitalization for

atherothrombotic events).

Publication of the ACC/AHA guidelines has not yet

improved the rate of medication usage among patients with

PAD.79 In a population-based study, only 69% of patients

reported antiplatelet use, 29% of patients with diagnosed

hypertension did not meet blood pressure targets, 20% of

patients with diabetes had poor glycemic control, and 19% of

patients with hyperlipidemia were not managed appropriately.

A survey of patients referred to a vascular clinic after a PAD

diagnosis revealed that only 70% and 44% of patients were

prescribed antiplatelet and statin therapy, respectively.80

Furthermore, they found that patients with CAD were more

likely to be prescribed guideline-recommended medications

than those with PAD alone.

Although patients with PAD with polyvascular disease

may be more likely to receive guideline-recommended

treatment than patients with PAD alone, patients hospitalized

for ACS in the Global Registry of Acute Coronary Events

(GRACE) were less likely to receive ACE-Is, aspirin,

β-blockers, and lipid-lowering agents if they had PAD than

if they did not.81 Even patients with severe PAD manifested

as CLI and requiring surgical revascularization or amputation

were found to be undertreated with antiplatelet, lipid-

lowering, and antihypertensive medications.82,83 The underuse

of recommended PAD treatments is a worldwide problem

and has been well documented in the United Kingdom,80

China,84 the United States,79 and France.85

Potential SolutionsA program similar to the AHA’s Get With the Guidelines

initiatives for CAD and CVD86 may be appropriate for patients

with PAD. In addition, the involvement of pharmacists in out-

patient management of patients with PAD with dyslipidemia

has been shown to increase the use of guideline-recommended

therapies87 and warrants consideration as a technique to

improve the broader medical management of PAD. Data

from various population-based studies reveal that special-

ists are more likely to prescribe guideline-recommended

medical therapies than general practitioners,1,80 but general

practitioners are in a better position to diagnose and treat PAD

early in the disease process. The creation and use of a PAD

patient database, akin to that employed for a number of dis-

eases in the United Kingdom, may be benefi cial in increasing

awareness among primary care physicians. Registry data such

as REACH may also contribute to a broader understanding

of treatment and outcomes in patients with PAD in the pri-

Table 5. Ongoing Clinical Trials Designed to Study the Effects of Antiplatelet Therapy in Treating Patients with PADa

Trial Name Status Dates of Interest Population Outcome Measures Treatments

CASPAR (NCT00174759)

Complete, pending publication

– Patients undergoing below-the-knee bypass grafting

Graft patency, limb salvage, and survival

ASA + placebo vs ASA + clopi

MIRROR (NCT00163267)

Recruitingb Completion expected October 2008

Patients undergoing peripheral vascular intervention

Platelet activation, clinical symptoms, occlusions, microcirculation, safety

Clopi vs placebo

(NCT00262561) Recruiting Enrollment initiated January 2006

Patients with lower-limb atherosclerosis

Platelet activity, MI, UA, stroke, TIA, vascular intervention, sudden worsening of symptoms, amputation, death

ASA vs clopi vs ASA + clopi

ACCELA (NCT00443287)

Complete, pending publication

Enrollment initiated March 2007

Patients with IC Walking capacity, safety Clopi + Cilos + HMR1766 vs clopi + cilos + placebo

aInformation was obtained from ClinicalTrials.gov; the ClinicalTrials.gov identifi er for each trial is indicated in parentheses. bRecord last updated April 18, 2007.Abbreviations: ASA, aspirin; Cilos, cilostazol; Clopi, clopidogrel; IC, intermittent claudication; MI, myocardial infarction; PAD, peripheral artery disease; TIA, transient ischemic attack; UA, unstable angina.



mary care and specialist communities. Finally, participants

in the Blue Shield of Michigan Cardiovascular Consortium

(BMC2) registry, which was designed to improve quality of

care in patients undergoing peripheral vascular intervention

and to measure the effectiveness and appropriateness of

using peripheral vascular intervention to improve outcomes

in patients with PAD88 have witnessed improved utilization

of evidence-based medical therapies over time. Expansion

of regional registries such as the QI2 to a national scale may

broaden their potential reach.

SummaryPeripheral artery disease poses serious health risks

and is associated with substantial health and economic

burdens. Antiplatelet therapy remains a cornerstone of

PAD treatment, with well-established effi cacy and safety

in preventing vascular events. Despite the signifi cant health

and economic burden, clear evidence for effective treatment,

and the availability of treatment guidelines, PAD remains

underdiagnosed and undertreated. Comprehensive efforts

are needed to increase patient and physician awareness of

PAD, establish national PAD registries, and more broadly

disseminate published treatment guidelines in the United

States and abroad.

AcknowledgmentsThis manuscript was written and edited by the authors, who

take full responsibility for its content. Editorial assistance

in coordinating revisions and creating fi gures and tables in

the preparation of this manuscript was provided by Susan

Abulhawa and was funded by the Bristol-Myers Squibb/

Sanofi Pharmaceuticals Partnership.

Confl ict of Interest StatementHerbert Aronow, MD, MPH discloses confl icts of interest

with Bristol-Myers Squibb/sanofi -aventis and Pfi zer. William

R. Hiatt, MD discloses confl icts of interest with Bristol-

Myers Squibb and sanofi -aventis.

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