risk of incident PAD.7 Other atherosclerotic risk factors associated with PAD include cigarette smoking, hypertension, and

dyslipidemia.8 Hypertriglyceridemia is a more significant risk factor for PAD than for coronary artery disease, and this may partially explain the increased prevalence of PAD in patients with

diabetes.9

Cigarette smoking has a higher correlation with the development of IC pain than any other risk factor, and the risk increases

dramatically with the number of cigarettes smoked per day and

the duration of smoking history.10 In patients with other cardiovascular risk factors, including hypertension or diabetes, smoking

further increases the rate of claudication development. Smoking

confers a sevenfold increase in risk for PAD compared with not

smoking. In contrast, the risk of coronary artery disease is only

increased twofold in smokers. Thus, the mechanism by which

cigarette smoking causes damage may be different for these two

vascular diseases.11

TABLE 15-1

Annual Incidence of Intermittent Claudication by Age3

Age Group (years) Annual Incidence (%)

40–49 2.0

50–59 4.2

60–69 6.8

70 9.2

TABLE 15-2

Long-Term Incidence of Outcomes in Patients With

Intermittent Claudication12,13

Patient Population

Abrupt Limb

Ischemia (%)

Amputation

(%)

All patients 23 7

Diabetes 31 11

Smokers 35 21

Epidemiologic studies show that IC is nonprogressive in 75%

of patients during a period of 4 to 9 years. The other 25% of

patients with IC have worsening painful ischemic episodes during this period. Although rare, more serious complications can

occur. Ischemic tissue changes, ulceration, and gangrene can

accompany advanced peripheral atherosclerosis. Amputation of

the affected limb may be necessary in up to 5% of patients with

claudication.12 The presence of two independent risk factors,

such as diabetes and cigarette smoking, has an additive effect on

the risk for the development of progressive IC and serious limb

complications (Table 15-2). Finally, disease location in patients

with severe disease may be associated with prognosis, such that

proximal disease is associated with poor outcomes when compared with distal lesions; however, more epidemiological studies

must be conducted to confirm these findings.14

During a relatively short 2-year follow-up of a population with

IC, 3.6% of patients died, whereas 22% experienced a nonfatal cardiovascular event (defined as any cardiac, cerebral, or peripheral

vascular event). Furthermore, 26% experienced a decline in their

walking capability during the same time frame.13,15 Although a

relatively small fraction of patients died during the 2-year observation period, it is paramount to recognize that severe, short-term

morbidity is highly likely in this patient population. IC clearly

reflects generalized atherosclerosis and is associated with considerable morbidity.

Pathophysiology

Intermittent claudication, and its associated pain and impaired

mobility, is the predominant complication of occlusive PAD.

The major cause of occlusive PAD is arteriosclerosis obliterans, defined as the development of atherosclerotic plaques in

the peripheral vasculature. These plaques develop as a result of

endothelial activation associated with conditions such as dyslipidemia, diabetes mellitus, hypertension, and tobacco use. Plaques

result in the proliferation of vascular smooth muscle, with subsequent damage to the vascular structure. The damaged endothelium of the vasculature has impaired vasodilatory capabilities

because secretion of nitric oxide, also known as endotheliumderived relaxing factor, is decreased and secretion of vasoconstrictive substances, such as endothelin, are increased. Both defects

impede blood flow to the extremities. In addition, growth of

atherosclerotic lesions can physically limit blood flow. Exercise may induce IC symptoms in patients who have lesions

with greater than 50% stenosis, whereas patients with lesions

of greater than 80% stenosis can have pain at rest. The lesions

themselves can be unstable and rupture, or adjacent smaller vessels experiencing high hemodynamic pressure caused by nearby

plaques may rupture. Either situation can lead to acute vascular occlusion, analogous to unstable angina or acute myocardial

infarction (MI) in coronary arteries.16

Figure 15-1 illustrates the common sites of atherosclerosis.

Plaques that develop in central vessels (e.g., in the aorta and

iliac artery) are primarily associated with buttock pain and erectile dysfunction. Those confined to the more distal femoral and

333Peripheral Vascular Disorders Chapter 15

Vertebral, basilar,

and middle cerebral

arteries

Thoracic aorta,

femoral and

popliteal

arteries

Internal

carotid

arteries 5

4

Proximal

coronary

arteries

2

Abdominal

aorta and

iliac arteries

1

3

FIGURE 15-1 Sites of severe atherosclerosis in order of frequency.

Adapted with permission from Rubin E, Farber JL. Pathology. 3rd ed.

Philadelphia, PA: Lippincott-Raven; 1999:508.

popliteal arteries characteristically cause thigh and calf pain.

Occlusion of the tibial arteries will produce claudication pain

in the foot. When more than one arterial bed is affected by

severe atherosclerosis, symptoms of IC will be diffuse. Symptoms of IC indicate an inadequate supply of arterial blood to

peripheral muscles. Exercise, including walking, increases the

metabolic demands of the muscles and can lead to claudication pain. Reduced blood supply to the muscles results from

changes in perfusion pressures and vascular tone caused by atherosclerosis.

Atherosclerosis can impair the microcirculation of the peripheral muscles by altering the pressure gradient needed for perfusion of the capillaries. When obstruction develops, perfusion of

tissue distal to the stenotic lesion relies on collateral blood flow.

Collateral circulation consists of new blood vessels that develop

to carry blood around the occluded area.

Erythrocyte deformability is an important factor for in vitro

capillary perfusion.17,18 In areas free of compromised blood flow,

normal red blood cells (RBCs) have the ability to deform when

passing through a small capillary. By aligning themselves in a

planar manner, the RBCs also reduce the viscosity of the blood

suspension, enabling them to pass smoothly through the capillary. In many patients with IC, RBCs have a marked decrease in

this intrinsic ability to deform, which results in increased blood

viscosity. This defect is promoted by chronic tissue ischemia and

hypoxia caused by increased intracapillary leukocyte adherence,

platelet aggregation, and activation of complement and clotting factors.16 The vascular responses to hypoxia are detrimental

because this sequence of events further inhibits blood flow and

oxygen delivery to the tissues (Fig. 15-2).

Clinical Presentation

CASE 15-1

QUESTION 1: J.S. is a 54-year-old, 100-kg man with a history

of type 2 diabetes mellitus, chronic stable angina, dyslipidemia, and tobacco use. His chief complaint today is right

upper thigh pain while walking around the block. The pain

has gradually increased during the past 12 months, but only

recently has become intolerable. The pain is relieved within

minutes after he stops walking. J.S. smokes 1.5 packs of

cigarettes a day.

His most recent laboratory results are significant for the

following results:

Total cholesterol, 290 mg/dL (SI units, 7.49 mmol/L)

Fasting triglycerides, 350 mg/dL (SI units, 3.95 mmol/L)

Low-density lipoproteins (LDL), 188 mg/dL (SI units,

4.86 mmol/L)

High-density lipoproteins (HDL), 32 mg/dL (SI units,

0.83 mmol/L)

Serum creatinine (SCr), 1.0 mg/dL (SI units, 60 mmol/L)

Blood urea nitrogen (BUN), 15 mg/dL (SI units,

0.3 mmol/L)

Hemoglobin (Hgb) A1c, 10.0% (SI units, 0.1)

Fasting glucose, 150 mg/dL (SI units, 8.3 mmol/L)

Blood pressure (BP), 170/95 mm Hg

Heart rate (HR), 89 beats/minute

His posterior tibial artery pulse is not palpable. A

Doppler ultrasound study is performed, and his ankle-tobrachial index is 0.7 (normal, >0.90).

J.S.’s medication list includes isosorbide dinitrate 20 mg

three times daily (TID) (while awake), aspirin 325 mg every

day, and enalapril 10 mg twice daily (BID). His insulin doses

have progressively increased to neutral protamine Hagedorn (NPH) insulin 40 units in the morning and 35 units in

the evening. What risk factors and elements of J.S.’s presentation are consistent with a diagnosis of IC?

J.S.’s medical history illustrates classic risk factors for vascular occlusion and IC, including dyslipidemia (specifically hypertriglyceridemia), diabetes, hypertension, and tobacco use. In

particular, his diabetes is not adequately controlled based on

elevated Hgb A1c and fasting glucose levels, and he is obese. This

constellation of disorders is known as the metabolic syndrome.

These factors, along with smoking, are commonly seen together

and have been linked with insulin resistance or hyperinsulinemia

and accelerated atherosclerosis (Fig. 15-3).19,20 The presence of

angina indicates coronary artery disease, so it is not surprising

that he has peripheral vascular occlusion as well.

The classic pain of IC described by J.S. is associated with exercise of the affected muscle group(s) and subsides with a few

minutes of rest and reperfusion. IC pain also can occur at rest;

however, this type of claudication pain is less common and is

an indication of extensive disease. Other common symptoms of

334 Section 2 Cardiac and Vascular Disorders

RBC

RBC RBC

RBC RBC

Atherosclerotic Plaque Platelet Aggregation

Stasis

Normal Erythrocyte Passing Through Capillary

Inflexible, Rigid Erythrocyte Passing Through Abnormal Capillary

FIGURE 15-2 Erythrocyte inflexibility in

intermittent claudication.

extensive atherosclerosis include cold feet and persistent aching

of the feet during rest or sleep. Restricted blood flow to the

feet along with pooling of blood secondary to inadequate pressure needed to propel blood back up the leg can lead to rubor

(red or purple color of the foot). Other indicators of peripheral

atherosclerosis are the loss of hair from the top of the feet, thickening of the toenails, and absence of sweating of the lower legs

and feet, all caused by poor circulation.16

The results of objective studies performed on J.S. are consistent with IC. Doppler ultrasound of the spine is helpful in

excluding pseudoclaudication caused by spinal stenosis and other

neurogenic or musculoskeletal causes of leg pain. Ultrasound is

also useful to measure BP of the lower extremities. An ankleto-brachial index (ABI) of 0.7 means that the ankle systolic BP

reading is only 70% of the systolic pressure in the brachial artery

supplying blood to the arm. In patients with IC, this is caused

by atherosclerotic obstruction of blood flow in the lower limbs

and subsequent decreased perfusion pressures in the ankle compared with the arm (Table 15-3). The lower the ABI, the more

blood flow to the extremities is compromised and the greater the

severity of symptoms. An ABI less than 0.9 is diagnostic for PAD.

Smoking

Type 2 Diabetes

Hypertension

Central

Obesity

Dyslipidemia

Insulin Resistance

and Hyperinsulinemia

Atherosclerotic

Disease

FIGURE 15-3 The metabolic syndrome in atherosclerosis.

Also, loss of the posterior tibial pulse, as seen in J.S., is common

in those with peripheral vascular occlusion.

For a video that shows an ABI exam, go to

http://thepoint.lww.com/AT10e.

Treatment

THERAPEUTIC OBJECTIVES AND

NONPHARMACOLOGIC INTERVENTIONS

CASE 15-1, QUESTION 2: What is the therapeutic goal in

treating J.S.? What interventions should be initiated to prevent claudication pain and arrest progression of the disease?

The specific treatment goals for J.S. include preventing further claudication pain, lessening the current pain he experiences,

arresting the progression of underlying disease, and decreasing

his risk of cardiovascular events. Achieving these goals will provide J.S. with the best chance of avoiding further mobility impairment, amputation, and cardiovascular events such as stroke or

MI. An important concept that should be stressed when explaining these treatment goals to J.S. is that all his diseases are closely

TABLE 15-3

Severity of Arterial Obstruction as Assessed by

Ankle-to-Brachial Index21

Severity Ankle-to-Brachial Indexa

Normal >0.90

Mild 0.70–0.89

Moderate 0.50–0.69

Severe >0.50

a

Ankle-to-brachial index is the systolic blood pressure in the ankle divided by the

systolic blood pressure in the arm.

335Peripheral Vascular Disorders Chapter 15

TABLE 15-4

Medical Treatment of Peripheral Arterial Disease and

Expected Outcomes8,22

Intervention

Improve Leg

Symptoms?

Prevent Systemic

Complications?

Smoking cessation Yes Yes

Exercise Yes No

Cilostazol Yes No

Statin drugs Yes Yes

Angiotensin-converting

enzyme inhibitors

Yes Yes

Blood pressure control No Yes

Antiplatelet therapya No Yes

a

Aspirin or clopidogrel.

interrelated, and that a beneficial intervention for one disease

is beneficial for all. Interventions that can be initiated include

diet modification; exercise and weight loss; and attainment of

goal blood pressure, lipids, Hgb A1c, and fasting and postprandial blood glucose levels. The American College of Cardiology

and American Heart Association have published guidelines that

thoroughly evaluate the interventions and medications that have

been used to treat IC and PAD.8 Table 15-4 summarizes these recommendations. The two most important things that J.S. can do

for his IC are summed up in five words: “Stop smoking and keep

walking.”23

SMOKING CESSATION

The importance of smoking cessation cannot be overemphasized to patients with IC. It is the most important modifiable factor in preventing the development of rest pain, prolonged limb

ischemia, and the need for amputation, and in achieving an overall reduction in cardiovascular events. Several studies document

improved survival and decreased amputation rates in patients

with IC who stopped smoking compared with patients who

continue to smoke.24,25 Other benefits, such as improved treadmill walking distance, decreased progression to symptoms, and

decreased complications after vascular reconstructive surgery,

have been shown in patients who are able to quit smoking compared with patients who continue to smoke.8,24,26–28 It is also

the intervention that will decrease J.S.’s claudication pain most

rapidly. If J.S. is able to stop smoking, his risk of developing rest

pain or requiring limb amputation will be very low. He also will

decrease his risk of MI and mortality by threefold and fivefold,

respectively. Table 15-5 summarizes the risk of cigarette smoking

and the value of smoking cessation on cardiovascular complications.

TABLE 15-5

Patient Outcomes Based on Smoking Status After

Intermittent Claudication Diagnosis12,24

Patient Population

Outcome

Length of

Follow-up

(years)

Current

Smokers (%)

Past

Smokersa

Rest pain 7 16 0

Myocardial infarction 10 53 11

Amputation 5 11 0

Mortality 10 54 18

a

Quit after intermittent claudication diagnosis.

Many pharmacologic products and strategies are available to

aid patients such as J.S. to stop smoking (see Chapter 88, Tobacco

Use and Dependence). Nicotine itself has harmful effects on the

vasculature via catecholamine release and vasoconstriction, however, and it may play a role in endothelial damage and atherosclerosis progression.29

EXERCISE

An individualized and supervised exercise program has been

endorsed for patients with PAD and will benefit J.S.’s other risk

factors as well.8 The pain associated with IC results in decreased

mobility, and because of deconditioning from lack of exercise,

patients with IC may slowly become dependent on others for

activities of daily living. An exercise program is the most effective

way to both preserve and increase mobility. It is more effective

than the best pharmacologic therapy currently available.30 The

ideal exercise program consists of walking for a minimum of 30 to

45 minutes at least three times a week.8 J.S. should walk as fast and

far as he can until the pain becomes severe; he should then wait

until the pain subsides, and then resume walking.21 At first, J.S.

may experience several painful episodes during each exercise session, but these should gradually decrease as the beneficial effects

of exercise therapy begin to emerge. Studies have documented

that this type of exercise program can more than double the painfree distance a patient with IC is able to walk.31 Additionally, lower

extremity resistance training can provide improved functional

performance measured by the following: quality of life, treadmill walking time, and ability to climb stairs.32 Several surgical

options are available for patients whose lifestyle and functional

status are compromised after failing exercise and pharmacotherapeutic interventions, including surgical bypass of the affected

arteries in addition to angioplasty and stenting.8 An appropriate

exercise program results in superior outcomes compared with

angioplasty and stenting, and equal in terms of walking distance

compared with surgery. Significant complications and mortality

are associated with surgery, however, and when all outcomes

are considered, an exercise program is far more advantageous

than surgery.31 For all patients able to walk, an exercise program

should be supervised and individually designed, and the patient

should understand the importance of exercise to his or her continued mobility.30

Rheologic abnormalities of increased blood viscosity,

impaired RBC filterability, hyperaggregation, and polycythemia

(elevated hematocrit) have been shown to return to normal

in many patients with IC who participate in a regular exercise

program.33 Exercise may offset the need for pharmacologic intervention. The potential mechanisms by which exercise benefits

patients with IC are listed in Table 15-6.

TABLE 15-6

Primary Mechanisms of Symptom Improvement With Exercise

Therapy in Intermittent Claudication30

Decrease of blood viscosity

Metabolic changes in the muscle

Improved muscle metabolism

Improved oxygen extraction

Improved endothelial function and microcirculation

Decreased occurrence of ischemia and inflammation

Atherosclerosis risk factors improved via:

Weight loss

Glycemic control

Blood pressure control

Increased high-density lipoprotein (HDL)

Decreased triglycerides

Decreased thrombotic tendency

336 Section 2 Cardiac and Vascular Disorders

DYSLIPIDEMIA MANAGEMENT

CASE 15-1, QUESTION 3: Is lipid-lowering therapy indicated for J.S.?

Because IC is a consequence of atherosclerosis, arresting the

progression of J.S.’s atherosclerotic disease is important (see

Chapter 13, Dyslipidemias, Atherosclerosis, and Coronary Heart

Disease). The initiation of the nutritional and exercise recommendations outlined in the National Cholesterol Education Program Adult Treatment Panel III and endorsed by the American

Heart Association under therapeutic lifestyle changes,34 as well

as cholesterol-lowering agents, are the cornerstones for attaining this goal. Considerable data suggest that aggressive dietary

and pharmacologic management of dyslipidemia, particularly

lowering low-density lipoprotein cholesterol (LDL-C), leads to

regression of atherosclerotic lesions in the coronary and carotid

vasculature.35–37 In contrast, relatively few prospective data exist

about the effect of successful lipid-lowering therapy on the regression or stabilization of peripheral lesions, or on clinical events in

patients with PAD. A post hoc analysis of a large lipid-lowering

study in subjects with known coronary artery disease treated

with simvastatin, however, demonstrated a significant decrease

in new or worsening IC, suggesting that benefit is seen in the

prevention of clinically symptomatic PAD in high-risk patients.38

The Heart Protection Study randomly assigned patients with

known arterial disease of various types to simvastatin 40 mg

daily or placebo. After 5 years, a 15% decrease was found in

noncardiac revascularizations, including amputations, among

the patients receiving simvastatin.39 Short-term outcomes (e.g.,

6 months to 1 year), such as improved walking distance and

walking time, have also been documented with simvastatin

40 mg/day.40,41

A meta-analysis of 10,049 subjects from several randomized trials using a variety of lipid-lowering therapies in patients

with PAD demonstrated reduced severity of claudication and

decreased disease progression as measured by angiography. A

decrease in mortality did not reach statistical significance.42

Limited data suggest high apolipoprotein [Lp(a)] concentrations may be particularly important in the development of

PAD.43

All patients with evidence of atherosclerotic disease and an

LDL cholesterol greater than 100 mg/dL (SI units, 2.6 mmol/L)

are candidates for a lipid-lowering regimen according to the

National Cholesterol Education Program.34 J.S. has angina and

lower extremity atherosclerosis, both of which indicate a need

for aggressive lipid lowering. His LDL-C is 180 mg/dL, so a

reduction of almost 50% is desired at a minimum. A clinician could argue for a more aggressive LDL goal of less than

70 mg/dL because of the following factors: presence of established cardiovascular disease risk equivalent in the form of PAD,

diabetes, chronic stable angina, cigarette smoking, and metabolic

syndrome.44 Lowering non-HDL cholesterol is the secondary

goals in J.S. and can be reassessed after his LDL goal has been

reached and the effect of therapy on these parameters is measured. In addition to an aggressive dietary management program, a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor agent should be prescribed as initial therapy for

J.S. HMG-CoA reductase inhibitors, exercise, and the American

Heart Association diet will all improve his LDL-C level. They also

have beneficial effects on triglycerides and HDL-C, and the need

for additional therapy can be assessed after the impact of these

measures is determined. There is a paucity of outcome data with

many of the available agents for dyslipidemia; however, after the

effect of a full-dose, high-potency HMG-CoA reductase inhibitor

is realized, addition of omega-3 fatty acid, niacin, or fibric acid

derivative may prove to be beneficial.8,45

MANAGEMENT OF HYPERTENSION

CASE 15-1, QUESTION 4: J.S.’s BP is elevated to

170/95 mm Hg despite enalapril therapy. Because he has

angina, and his HR is 89, a β-adrenergic blocker is considered. Are there alternative antihypertensive therapies that

might be preferable for J.S.?

J.S.’s hypertension has likely contributed to the development

of his atherosclerosis and PAD. Hypertension (see Chapter 14,

Essential Hypertension) has been associated with deficiencies

in the synthesis of vasodilating substances, such as prostacyclin,

bradykinin, and nitric oxide, by the endothelial cells lining the

vasculature. Hypertension also increases concentrations of vasoconstricting substances, such as angiotensin II. An increase in

vascular tone can alter local hemodynamics, especially in the

presence of a stenotic lesion. Although it has not been determined whether normalization of BP has a positive effect on IC,

it is well established that uncontrolled BP, as in J.S., results in

vascular complications such as MI and stroke. In light of J.S.’s

numerous risk factors for these complications, improved management of his hypertension is warranted.

β-Blockers are frequently cited as contraindicated in patients

with IC owing to the potential for unopposed α-adrenergic–

mediated vasoconstriction during peripheral β-blockade. Evidence to document worsening IC by β-blockade is lacking,

however. Overall, controlled studies have been inconclusive,

although a meta-analysis of placebo-controlled trials and studies with control groups concludes that β-blockers do not worsen

claudication.46,47

Angiotensin-converting enzyme (ACE) inhibitors are first-line

agents in patients with PAD.8 Compared with other antihypertensive agents, the data available support their beneficial effects

in this population. Compared with placebo, walking distance is

increased with both perindopril and ramipril in patients with

PAD.48,49 The Heart Outcomes Prevention Evaluation (HOPE)

study of the ACE inhibitor ramipril versus placebo included more

than 4,000 patients with PAD, and this subgroup derived benefit

in terms of decreased mortality, MI, and stroke.50 There is an

overall paucity of data associated with the use of angiotensin

receptor blockers in PAD; however, the ONTARGET trial compared telmisartan, ramipril, and the combination of the two

in patients with vascular disease or high-risk diabetes without

heart failure for a composite end point of cardiovascular death,

MI, stroke, or hospitalization for heart failure. The results indicate equivalency of telmisartan to ramipril for the primary end

point and similar blood pressure reduction; however, the combination group experienced more adverse events without an

increase in benefit. These results allow clinicians more freedom of choice when selecting a first-line agent for the treatment

of PAD.51

Because J.S. has both hypertension and diabetes, his BP goal

is less than 130/80 mm Hg.52 He is already taking an ACE

inhibitor, which is an excellent initial antihypertensive choice

in a patient with diabetes and PAD. The dose of enalapril could

be increased, or a low-dose diuretic, such as hydrochlorothiazide

or chlorthalidone,53,54 could be added; however, given his history of chronic stable angina, the addition of a calcium-channel

blocker or aβ-blocker would benefit him to a greater degree. The

ACCOMPLISH trial compared the combination of benazepril–

amlodipine with benazepril–hydrochlorothiazide, and found a

reduction in cardiovascular events in patients with hypertension

337Peripheral Vascular Disorders Chapter 15

TABLE 15-7