Lower Extremity Arterial Disease: General Considerations

CHAPTER 108
Lower Extremity
Arterial Disease:
General Considerations
HASAN H. DOSLUOGLU
Based on a chapter in the seventh edition by John V. White
Chronic lower extremity ischemia due to peripheral arterial
disease (PAD) is the most common cause of walking disability

seen by vascular specialists. The manifestations of chronic
lower extremity ischemia often include pain (Table 108-1)
produced by varying degrees of ischemia, ranging from no or
atypical leg symptoms to typical exertional muscular pain
(intermittent claudication, IC) to ischemic rest pain. Patients
may have more than one cause for their extremity pain,
making diagnosis and management more difficult (see Chapter
14). The challenge for the vascular specialist is to recognize
the presence of lower extremity ischemia, quantify the extent
of local and systemic disease, determine the degree of functional impairment related to PAD, identify and control modifiable risk factors, and establish a comprehensive treatment
program.
CLASSIFICATION
Claudication
The typical patient with IC experiences calf symptoms
ranging from fatigue to aching while walking. Pain or discomfort may also occur in the thigh or buttock. The pain sensation results from ischemic neuropathy involving small
unmyelinated A delta and C sensory fibers and a local intramuscular acidosis from anaerobic metabolism enhanced by
the release of substance P.1 The symptoms of intermittent
claudication are alleviated by a brief period of rest, after
which the patient can resume walking. Initially, the symptoms do not occur with regularity; they occur intermittently
when walking, and the distance walked before symptoms are
noticed is generally similar on different outings. As the
process progresses, symptoms occur more frequently and after
shorter distances.
Asymptomatic patients with a reduced ankle-brachial
index (ABI) but no symptoms may have significant impairment of leg function when tested objectively. Among 460
patients with PAD, 91 had no symptoms; of these, 28 were
less active and appeared to control their symptoms through
a reduction in walking speed and distance, whereas 63
remained active, walking more than 6 blocks a week.2 When
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subjected to a 6-minute walking test, however, the 63 active

patients performed in a manner similar to claudicants, walking
slightly farther but with a slower maximal velocity. Thus
some patients may be asymptomatic because of their poor
medical condition and functional capacity. McDermott etal3
compared 72 asymptomatic patients with PAD to those with
claudication (n = 215) and 292 with no PAD. They found
that asymptomatic subjects with PAD had worse functional
performance, worse quality of life, and more adverse calf
muscle characteristics compared with persons with IC, as well
as with the sedentary, asymptomatic, age-matched group of
non-PAD persons. This underscores the impact of PAD even
in asymptomatic patients who limit their activity to control
symptoms or because of other medical illness.
Disease Location
Claudication often results from a single level of arterial
disease, such as the iliac artery or the superficial femoral
artery, but can result from multilevel disease. Collateral
vessels can reconstitute the artery distal to a single site of
stenosis or occlusion and provide distal flow. Symptoms of
claudication associated with PAD usually manifest in the
muscle groups below the hemodynamically significant lesion.
Three major patterns of arterial obstruction are possible:
inflow disease, outflow disease, and a combination of the two.
Inflow disease refers to lesions in the suprainguinal vessels,
most commonly the infrarenal aorta and iliac arteries. Occlusive lesions of the infrarenal aorta or iliac arteries commonly
lead to buttock and thigh claudication. In men, if the stenoses or occlusions are bilateral and are proximal to the origins
of the internal iliac arteries, vasculogenic erectile dysfunction
may be present as well (see Chapter 82).
Although buttock and thigh claudication may be the first
symptoms, with continued ambulation, these patients may
exhibit classic symptoms of intermittent calf claudication
resulting from inadequate perfusion of the entire leg while
walking. Outflow disease consists of occlusive lesions in the
lower extremity arterial tree below the inguinal ligament, from
the common femoral artery to the pedal vessels. Superficial
femoral artery stenosis or occlusion is the most common lesion
associated with intermittent claudication, which leads to calf
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CHAPTER 108 Lower Extremity Arterial Disease: General Considerations
Table 108-1
Vascular Pain Syndromes

Etiology
Character of Pain
Location/Presentation
Intermittent claudication
Arterial perfusion inadequate to

meet demands of working
skeletal muscle metabolism
Lumbosacral neurospinal nerve
root compression
Burning, cramping, aching
Venous claudication
Proximal venous occlusion
Bursting
Compartment syndromes
Arterial insufficiency resulting

from venous congestion and
compartment tissue
hypertension
Dissection or hematoma resulting
from direct trauma, shear, or
stretch
Aortic rupture
Vasculitic inflammation
Localized
Buttocks, hips, thighs, calves

Occurs with walking, exercise;
relieved by rest
Extends from buttocks to feet
Occurs with walking; relieved by
sitting or bending over while
walking
Engorgement of exercising
extremity
Anterolateral aspect of leg (calf)
Nondiabetic rest pain
Chronic ischemic neuropathy

Positional malperfusion of
sensory nerves
Diffuse, poorly localized, aching,

burning
Nondiabetic ulcer
Ischemic necrosis of sensory

nerves
Tissue destruction
Unremitting, severe, aching,

burning
Paradoxical decrease in pain,
insensate, anesthetic
Chronic pain in lower extremity
and foot
Widespread loss of sensation in
distal leg and foot
Aching, burning
Neurogenic claudication
Aorta and large-artery pain
Gangrene
Diabetic foot
Nonischemic diabetic neuropathy

Structural changes of foot
Atheroembolization (blue
toe syndrome)
Distal embolization from

proximal source
Pain after stroke
Ischemia secondary to
hemorrhage or tumor
Vasoconstriction/ vasodilatation
Abnormal arterial reactivity
Small-artery erythromelalgia
(Raynauds syndrome,
vasospastic form)
Small-artery Raynauds
phenomenon (vasoocclusive form)
Small-vessel Buergers
disease (thromboangiitis
obliterans)
VENOUS DISORDERS
Post-thrombotic syndrome
Varicosities
Superficial phlebitis
Lymphatic disease
Diffuse, deep aching or burning

May be associated with distal
paresthesias or numbness
Tearing, ripping, boring along line

of dissection, with possible
distal ischemia
Sudden, burning, penetrating
Diffuse, aching, poorly localized
Intracranial
Substernal, interscapular (aorta)

initially; then also from ischemic
organs (bowel, kidneys, legs)
Peritoneal, retroperitoneal, pleural
Midback (aorta), tenderness over
affected artery
Distal foot
Initially presenting in recumbent
position, dissipating in
dependent position
Shallow, nonhealing pallid erosion
of skin of distal foot
Initially toes or heel
Nonhealing ulceration and toe
gangrene
Soft tissue bacterial infection
Cyanosis, ischemic changes in toes
or distal foot secondary to digital
or branch artery occlusion
Ipsilateral to neurologic deficit
Dull, aching digital pain with

vasoconstriction
Reperfusion or vasodilatation
produces fiery burning pain
Severe, unremitting distal digital
pain; may be refractory
Coolness, pallor, numbness,

cyanosis, hyperemia
Severe, unremitting, aching,

burning, agonizing
Upper and lower extremities
Prior lower extremity deep

venous thrombosis
Mild itching, burning; localized

ulcer pain
Incompetent valvular system

Chemical irritation of peripheral
vein or infection
Idiopathic, iatrogenic, or resulting
from infection
Pain develops secondary to
cellulitis or lymphangitis
Diffuse aching or burning

Well-localized tenderness along
vein
Localized
Lower extremity edema, secondary

varicosities, hyperpigmentation,
stasis ulcer formation
Lower extremities
Inflammation, palpable cord along
course of vein
Site of inflammation
Vasoconstriction/vasodilatation
Digital and palmar artery
occlusion resulting from
autoimmune conditions
Nonatherosclerotic necrotizing
process involving arteries,
veins, and nerves
Excellent arterial inflow with poor
collateralization
Fingertip ulceration or necrosis
Continued
SECTION 18 LOWER EXTREMITY ARTERIAL DISEASE
Condition
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SECTION 18 Lower Extremity Arterial Disease
Table 108-1
Vascular Pain Syndromecontd
Condition
POSTAMPUTATION PAIN
Acute
Late
Etiology
Character of Pain
Location/Presentation
Wound-related and secondary to

obligatory section of major
nerves
Neuropathic phenomena
Ill-fitting prosthesis, progressive
stump ischemia, deep venous
thrombosis, neuroma
Incisional
Ranging from mild itching
sensation to severe,
incapacitating pain
Localized
Amputation site/stump
Phantom limb
discomfort with ambulation and relief with rest. No specific

thigh or foot symptoms are associated with superficial femoral
artery occlusion. Because the deep femoral artery provides
collateral circulation to and reconstitution of the popliteal
artery, isolated superficial femoral artery occlusion without
distal disease is rarely the cause of more advanced forms of
ischemia. Popliteal and tibial artery occlusions are more commonly associated with limb-threatening ischemia, owing to
the paucity of collateral vascular pathways beyond these
lesions. As isolated lesions, they are usually not the cause of
IC and become clinically significant in patients with tissue
loss. They are typically seen in older adults and in patients
with diabetes and end-stage renal disease. Long-term corticosteroid therapy has also been reported to be associated with a
distally accentuated, calcifying peripheral atherosclerosis,
inducing arterial incompressibility comparable to patients
with renal failure or diabetes.4 Patients with a combination of
inflow and outflow disease may have widespread symptoms of
IC affecting the buttock, hip, thigh, and calf. These symptoms
frequently begin in the buttock and thigh and then involve
the calf muscles with continued ambulation; however, they
may appear in reverse order if the distal disease is more severe
than the inflow disease. Severe combined inflow-outflow
disease may result in limb-threatening ischemia.
In a review of 400 patients with PAD who underwent a
first digital subtraction arteriogram of the lower limbs,
Aboyans etal5 found that proximal PAD was associated with
greater prevalence of male sex and smoking, whereas more
distal PAD was associated with older-age, diabetes, hypertension, and renal failure (P <.05). They found that proximal
PAD was associated with a worse prognosis, after adjustments
for age, sex, cardiovascular disease, critical leg ischemia, and
treatments, but these results need to be confirmed in a more
general population of patients with PAD.
Nonatherosclerotic Causes of Claudication

Intermittent claudication in younger individuals may be
caused by popliteal artery entrapment syndrome or adventitial cystic disease of the popliteal artery (see Chapter 115),
chronic compartment syndrome (see Chapter 163), or
kinking or endofibrosis of the iliac arteries. The pain of
popliteal entrapment, produced by extrinsic compression of
the popliteal artery by the gastrocnemius muscle during leg
movement, is similar to that of IC and has the same
Amputation stump
pathophysiologic mechanism as that associated with PAD.6

Popliteal adventitial cystic disease produces similar symptoms. Chronic compartment syndrome causes exercise-related
discomfort only in the anterolateral aspect of the calf. The
cellular basis for the anterior compartment muscular pain
associated with chronic compartment syndrome is ischemia
resulting from diminution of the muscular arteriovenous pressure differential owing to venous congestion and compartment tissue hypertension.7 Iliac artery endofibrosis with
kinking is characterized by thickening of vessel intima due to
subendothelial accumulation of loose connective tissue containing variable amounts of collagen, elastin, and smooth
muscle cells, resulting in progressive stenosis and impaired
flow, and has been most commonly described in competitive
cyclists. It causes mostly unilateral pain, cramping, or numbness, which may become apparent only at maximal exercise.8
Nonatherosclerotic causes of IC are listed in Box 108-1.
Critical Limb Ischemia

Critical limb ischemia (CLI) is the most severe form of PAD
and represents approximately 1% of the total number of
BOX 108-1
NONATHEROSCLEROTIC CAUSES OF
INTERMITTENT CLAUDICATION
Thromboangiitis obliterans
Popliteal aneurysm
Aortic coarctation
Fibromuscular dysplasia
Takayasus disease
Pseudoxanthoma elasticum
Remote trauma or radiation injury
Thrombosis of persistent sciatic artery
Peripheral emboli
Arteritis
Popliteal entrapment
Primary vascular tumor
Adventitial cyst of popliteal artery
Endofibrosis of external iliac artery (iliac artery syndrome in cyclists)
Modified from Norgren L, etal: TASC II Working Group, Inter-Society
Consensus for the Management of Peripheral Arterial Disease (TASC II).
J Vasc Surg 45(Suppl S):22, 2007.
arterial perfusion may only be decreased to a specific region

of the foot (angiosome, see Chapter 116), which may require
increasing the flow to that specific angiosome to expedite
ulcer healing.16
Ischemic gangrene occurs when resting limb blood flow is
insufficient to maintain cellular viability. Tissue death inexorably extends to the junction of threshold blood flow for
tissue viability. Initially, the pain may be severe, resulting
from not only ischemic neuropathy but also ischemic injury
of the skin and subcutaneous sensory nerves, osteomyelitis,
and ascending infection. As the course of ischemic necrosis
progresses, pain may actually decrease as a result of complete
ischemic death of the nerves and other pain-producing
tissues. Progression to gangrene occurs in 40% of patients
with DM, compared with only 9% in nondiabetic patients
with CLI.17
Limb-threatening ischemia usually requires the presence
of severe PAD at two or more levels, the additive effects of
which severely limit flow through collateral beds and result
in profound distal ischemia. The pattern of arterial obstruction often affects sequential vascular beds, such as femoropopliteal and infrapopliteal arteries, but it may affect parallel
beds, such as superficial femoral and deep femoral vessels.
Both patterns prevent collateralization and reconstitution
of the more distal arterial tree. In patients with diabetes,
arterial occlusive disease primarily affects the crural and pedal
arteries.18
EPIDEMIOLOGY
The prevalence of PAD has been the subject of numerous
investigations over the past several decades19-22 The best
method of assessing the prevalence of chronic lower extremity arterial occlusive disease is to record the ABI and correlate
it with risk factors.
Prognostic Value of Ankle Brachial Index

ABI results are recommended to be reported with noncompressible values defined as greater than 1.40, normal values
1.00 to 1.40, borderline 0.90 to 0.99, and abnormal 0.90 or
less.23 The ABI correlates well with the mortality risk associated with PAD, regardless of whether leg symptoms are
present. Feringa etal performed a longitudinal study of 3209
subjects followed for 8 years after recording baseline resting
and postexercise ABIs. In this study, lower resting ABI values,
lower postexercise ABI values, and a greater drop in resting
ABI were associated with a higher incidence of death.24 In a
cohort of 6880 unselected subjects 65 years old who were
monitored for over 5 years in the German Epidemiological
Trial on Ankle Brachial Index Study Group,25 836 had
asymptomatic PAD (ABI <0.9) and 593 had symptomatic
PAD. The composite endpoint of all cause death, myocardial
infarction or stroke was similar in symptomatic and asymptomatic patients with PAD, both of which carried significantly higher risk than subjects without PAD. Because 21%
of subjects had symptomatic or asymptomatic PAD, the
patients with PAD.9 The natural history of CLI differs significantly from that of claudication. CLI is associated with a
higher risk of limb loss in the absence of revascularization,
whereas claudication rarely progresses to the point of requiring amputation. In patients with CLI, the arterioles become
maximally vasodilatated and insensitive to vasodilatory
stimuli as a result of the chronic exposure to vasorelaxing
factors. These dilatated peripheral arterioles have decreased
wall thickness and cross-sectional area, leading to edema,
which is aggravated by keeping the limb dependent. Chronic
ischemia also results in changes in structure and function of
endothelial cells, and coupled with platelet activation, leukocyte adhesion result in microthrombi formation in the
capillaries. All these changes result in impaired tissue oxygen
exchange at the capillary level.10,11
The common major manifestations of CLI are rest pain
and ischemic ulceration or gangrene of the forefoot or toes,
representing a reduction in distal tissue perfusion below
resting metabolic requirements. Rest pain is usually described
as a burning sensation or as an uncomfortable coldness or
paresthesia of sufficient intensity to interfere with sleep. The
ischemic neuropathy in CLI may also cause numbness, and
since many patients also have diabetes, it may be difficult to
determine how much of the neuropathic changes are caused
by ischemia alone.12 The discomfort is worsened by leg elevation, because of the loss of the gravitational pull of blood to
the foot; it is relieved by placing the limb in a dependent
position, such as dangling it off the side of the bed. In patients
with typical ischemic rest pain localized to the forefoot,
occurring with elevation and relieved by dependency, the
clinical diagnosis is objectively confirmed by hemodynamic
measurements such as systolic ankle pressure less than
50mmHg, toe pressure less than 30mmHg, or ABI less
than 0.40. It is important to note that patients with diabetic
foot ulcers may have inadequate blood flow for healing even
with perfusion levels that exceed these criteria for CLI. In
fact, the term CLI was never intended to be applied to
patients with diabetes and foot wounds.13
Ischemic ulcers usually represent the effect of repetitive
soft tissue trauma, often very mild in degree, with erosion of
the overlying skin. Skin repair is hampered by inadequate
tissue perfusion, oxygenation, and cellular replication. Arterial ulceration in a nondiabetic patient is characterized by a
shallow, nonhealing, pallid erosion of the skin in the distal
footin a distribution similar to that of rest pain. The pain
of such ulcerations, described as aching or burning, is often
unremitting and severe and is occasionally refractory to even
high-dose oral narcotic analgesics. It is the result of not only
chronic, severe ischemic neuropathy but also actual exposure
of the sensory nerves in the skin at the site of the ulcer.
Diabetic foot ulcerations are broadly divided into ischemic,
neuroischemic, and neuropathic ulcers. In recent studies,
more than 50% of diabetic foot ulcers are of ischemic or
neuroischemic origin.14,15 Therefore ischemia needs to be
excluded in all ulcers using objective assessment, since PAD
is the most important limiting factor for healing of ischemic
or neuroischemic diabetic foot ulcers. In some patients,
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1664
ACCF/AHA 2011 writing group recommended ABI diagnostic screening for patients 65 years or for patients 50 with
a history of smoking or diabetes.23
Prevalence of PAD
Prevalence Based on ABI
In the United States, a comprehensive effort to establish the
prevalence of PAD using ABI was undertaken in the National
Health and Nutrition Examination Survey (NHANES) from
1999 to 2000,26 involving 9000 individuals 40 years of age or
older. ABIs and a complete data set were available for analysis
in 2174 participants. The overall prevalence of PAD (defined
as an ABI <0.90) was 4.3% (95% confidence interval [CI],
3.1% to 5.5%). Although prevalence was slightly higher in
men than in women, the prevalence dramatically increased
with age, rising from 0.9% in those younger than 50 years to
14.5% in those 70 years or older (Fig. 108-1). Statistically
significant associations between PAD and the common risk
factors of hypertension, diabetes, hypercholesterolemia, and
smoking were also noted.
Prevalence Based on Demographics

The relationships of PAD to age, gender, race, and ethnicity
have been confirmed by several studies. In the AHA writing
groups meta-analysis,27 the prevalence of PAD was noted to
increase with age for both men and women. Using the U.S.
census data from 2010, they found that the number of females
with PAD was higher among U.S. adults 40 years of age.
Data adapted from the ABI Collaboration Study, including
480,325 person-years of follow-up of 24,955 men and 23,339
women from the general population who had ABIs measured
at baseline and during follow-up, showed that although the
ABI correlated with total and cardiovascular mortality rates,
which were similar in women compared with men, the risks
of morbidity and mortality were increased in women with
ABI values either <0.90 or 1.40.28
In a primary care setting, 403 patients stratified by race
and gender were evaluated with ABIs to determine the prevalence of PAD.29 Study subjects included white, black, and
Prevalence (%)
25
20
15.0%
Male
Female
13.7%
15
6.7%
10
5
0.6% 1.1%*
1.9%*
3.1%*
2.8%
0
4049
5059
6069
70 and older
Age group (yr)
Figure 108-1 Prevalence of peripheral arterial disease by age and

gender in adults 40 years and older, United States, 1999-2000 (n =
2174). (Redrawn from Selvin E, et al: Prevalence of and risk factors for
peripheral arterial disease in the United States: results from the National
Health and Nutrition Examination Survey, 1999-2000. Circulation 110:738743, 2004.)
Hispanic women and men. No gender differences were noted,

but as with the NHANES data, black women had a significantly greater prevalence of PAD than did white or Hispanic
women. A follow-up study using NHANES data from 1999
to 2004 reevaluated the prevalence of PAD in the general
population and in ethnic subpopulations.30 Overall, nonHispanic black men and women (19.2% prevalence) and
Mexican American women (19.3% prevalence) had a higher
prevalence of PAD than did non-Hispanic white men and
women (15.6% prevalence). These studies clearly demonstrate that there is a high prevalence of lower extremity PAD
in the United States, affecting an estimated 8 to 12 million
people. Further, PAD is now reported to be associated with
equal morbidity and mortality and comparable, or possibly
higher, cost compared with coronary heart disease and
stroke.27,31 The prevalence is higher in some ethnic subpopulations and in those with uncontrolled risk factors, including
hypertension, smoking, hypercholesterolemia, diabetes, and
renal failure, although in the German Epidemiological Trial,25
48% of patients with asymptomatic PAD were reported to
have never smoked, 66% did not have diabetes, and 15% to
16% did not have hypertension or hyperlipidemia. Because
of PADs high prevalence and substantial mortality risk,
even in the absence of symptoms, it is essential to identify
and treat patients with PAD. Adding reduced ABI to traditional risk factors increases the sensitivity of the identification of patients with moderate to high risk of cardiovascular
mortality.
Prevalence Based on Risk Factors

Hypertension increases the risk of developing symptoms of
IC 2.5-fold in men and 3.9-fold in women,32,33 and is present
in 55% of patients with PAD.34 The relationship between
diabetes and IC has also been well documented.32,33,35 PAD
prevalence is 20% to 30% higher in diabetics than in the
general population,36 and the risk of developing PAD correlates with the severity and duration of diabetes.37 Patients
with diabetes are more likely to have symptomatic PAD, with
a 3.5-fold increased risk in men and an 8.6-fold increased risk
in women.38 Metabolic syndrome is estimated to be present
in at least 25% of the population.39 This syndrome is defined
as having three or more of the following: blood pressure
elevation (130mmHg/85mmHg), triglyceride count
150mg/dL, high-density lipoprotein count 50mg/dL for
women or 40mg/dL for men, fasting blood glucose 110mg/
dL, and abdominal obesity (BMI 30kg/m2 or waist circumference 102cm in men, 88cm in women). An analysis of
data from three National Health and Nutrition Examination
Surveys (NHANES, 1999-2004) involving 5376 asymptomatic participants 40 years and older showed that 38% of the
population with PAD also had metabolic syndrome, and the
prevalence of PAD (ABI <0.9) was 7.7% and 3.3%, respectively in those with and without metabolic syndrome.40
Cigarette smoking is a long-established stimulus for
atherosclerosis and increases the risk that PAD will develop
in men and women.32,35 A lifetime smoking history

Odds ratio
1
Male gender (cf female)

Age (per 10 years)
Smoking
Hypertension
Dyslipidemia
Hyperhomocysteinemia
Race (Asian/Hispanic/
black vs. white)
C-reactive protein
Renal insufficiency
Figure 108-2 Approximate odds ratios for risk factors for symptomatic peripheral arterial disease. (Redrawn from Norgren L, etal: TASC II
Working Group, Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 45:S9A, 2007.)
exceeding 25 pack years has been reported to be associated

with increased risk of PAD (HR 2.72) compared with those
who never smoked41; the risk is higher in women than in
men, and smoking cessation is associated with substantial
risk reduction for development of PAD.42 The severity of
arterial occlusive disease is proportional to the number of
cigarettes smoked,43 and each additional risk factor independently increases the risk of developing symptomatic PAD
(Fig. 108-2).
NATURAL HISTORY
Asymptomatic Disease
Patients with asymptomatic PAD may eventually develop
symptoms of claudication or may demonstrate little progression of their disease. The Edinburgh Artery Study found that
patients with asymptomatic PAD had no statistically significant drop in ABI over the 5 years of observation.44 Regardless
of whether symptoms are present, individuals with PAD,
identified by an ABI less than 0.90, have higher morbidity
and mortality than age-matched controls with normal ABIs.
The risks are inversely related to the amount of physical
activity the patient undertakes each day. Evaluating the
natural history of 460 patients with ABI-proven PAD, investigators noted that reduced physical activity correlated with
increased mortality and cardiovascular events.45 Therefore
patients who attempt to control or eliminate their lower
extremity PAD symptoms by reducing their walking actually

worsen their risk of myocardial infarction (MI), stroke, and
death. This asymptomatic group of patients with PAD should
be managed medically in the same way as those with symptoms of IC.
Impact of Female Gender

Women with PAD were reported to experience faster functional decline than men with PAD. McDermott etal46
assessed 380 men and women with PAD using a 6-minute
walk test and assessment of mobility disability at baseline and
yearly for up to 4 years, and used CT to assess calf muscle
characteristics biannually. They found that at 47 months of
follow-up, women with PAD were more likely to become
unable to walk for 6 minutes continuously, had a higher
incidence of mobility loss, and had faster declines in walking
capacity compared with men. The more rapid deterioration
in women with PAD was attributed to the poorer functional
performance and smaller baseline calf muscle mass, resulting
in women being closer at baseline to the thresholds for
immobility.
Impact on Future Health

The presence of PAD in asymptomatic patients was also
found to be a significant risk factor for future disability. In the
Cardiovascular Health Study of 4705 participants 65 years of
age and older who had ABI measured between 1992 and
1993, lower baseline ABI values were found to be associated
with increased risk of late-incident mobility disability and
activities of daily living disability during a 6-year follow-up.47
Most recently, Leeper etal assessed 725 PAD patients using
a customized symptom-limited ramp treadmill protocol
between 1997 and 2011 and found that exercise capacity was
the strongest independent predictor of death, with each additional MET achieved being associated with age-adjusted 18%
and 20% reductions in all-cause and cardiovascular mortality,
respectively (P <.001 for both), surpassing all classical risk
factors and all measured exercise tests.48
Intermittent Claudication
Impact on Extremity
The natural history of IC is marked by slow progression to
shorter walking distances, but it rarely reaches the level of
CLI. Only about one fourth of patients with IC ever deteriorate significantly, and deterioration is most frequent during
the first year after diagnosis (6% to 9%) compared with 2%
to 3% per annum thereafter.49 This is especially true if risk
factors are controlled. Of 224 nondiabetic patients with IC
followed for 6 years, only 8% of those who stopped smoking
progressed to rest pain, whereas 79% of those who continued
to smoke developed signs of CLI.50 Similarly, in a long-term
study of 1244 claudicants, only insulin-requiring diabetes,
low initial ABI, and high pack-years of smoking predicted
progression to ischemic rest pain and ischemic ulceration.51
The risk of major amputation is less than 5% over a 5-year
period.44
Diabetes
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1666
Quality of Life
Reduced independent mobility and the discomfort imposed
by IC profoundly impact a patients quality of life. The Short
Form (36) Health Survey (SF-36), a generic quality-of-life
instrument that includes eight domains to assess physical and
emotional function, has been used extensively to document
the effect of claudication on quality of life.52 In a study of 68
claudicants, scores in all eight domains were reduced compared with nonclaudicants, especially physical function and
role limitations due to emotional impact.53 These findings
were extended in a community-based study of 53 patients
with documented IC and 327 controls without claudication.54
Using the Rose Intermittent Claudication Questionnaire and
the SF-36, the investigators noted reductions in physical
function, role limitations due to physical dysfunction, role
limitations due to emotional dysfunction, and changes in
bodily pain, energy, and general health perception in patients
with IC. Only social function and mental health appeared to
be unaffected. The adverse impact of IC appears to be directly
related to walking ability. Limitations on ambulation give rise
to broad physical and emotional effects, as documented in a
study of 80 claudicants evaluated with the Walking Impairment Questionnaire, SF-36, ABI, and 6-minute walking
test.55 The results of the 6-minute walking test correlated well
with quality-of-life scores. Patients with shorter walking distances during the walking test had worse scores in the physical function and role limitations due to physical dysfunction.
Association with Systemic Atherosclerosis

The presence of PAD as documented by an ABI less than
0.90 is also a strong marker for the presence of coronary artery
disease (CAD) and cerebrovascular disease (CVD). In the
PAD Awareness, Risk, and Treatment: New Resources for
Survival (PARTNERS) study, which assessed 6979 patients
aged 70 years or older or aged 50 to 69 years with diabetes or
a history of smoking, symptomatic CAD or CVD was identified in 16% of study subjects with an ABI less than 0.90.56 In
the Reduction of Atherothrombosis for Continued Health
(REACH) Registry,57 which included an international, prospective cohort of 68,236 patients with either established
atherosclerotic arterial disease (CAD, PAD, CVD; n =
55,814) or at least three risk factors for atherothrombosis (n
= 12,422), the overall cardiovascular death, MI, or stroke
rates in 1 year were 4.5% for patients with CAD, 6.5% for
patients with CVD, and 5.4% for patients with PAD. The
3-year MI/stroke/vascular death rates in the 32,247 patients
in this registry were significantly higher for patients with
symptomatic disease when compared with those with risk
factors only (12% vs. 6%, P <0.001).58 In another study, the
fate of 2777 male claudicants was documented over a 15-year
period, and mortality rates of 42% and 65% at 5 and 10 years,
respectively, were noted.59 MI accounted for 66% of the
deaths among the 1363 claudicants who died during the study
period. The risk of cardiac or cerebrovascular disease increases
with lower ABI values, as confirmed by the Atherosclerotic
Risk in Communities Study.60
Thus the natural histories of asymptomatic PAD and IC

are similar and marked by a significantly elevated risk of fatal
cardiac and cerebrovascular events, despite the rather small
risk of progression to CLI.

Impact on Extremity
The natural history of CLI is grim; approximately 40% of
affected individuals lose their legs and 20% die within 6
months of onset. However, an increasing number of patients
with CLI receive some form of active treatment, with over
half receiving revascularization, and the amputation rate may
be decreasing. An estimation of the primary treatment of CLI
patients and their status a year later is shown in Fig. 108-3.
Meta-analyses of patients who had popliteal-distal bypass or
infrapopliteal angioplasty showed similar limb salvage rates
of about 87% at 12 months and 82% at 3 years.61,62 A steady
but slow decrease in amputation rates in the last decade has
been reported, based on various U.S. national and state
databases.63-65 Patients with CLI appear to have a more
aggressive form of PAD, with involvement of several segments of the lower extremity arterial tree, especially infrapopliteal vessels. Not all patients with CLI progress through
stages of worsening claudication before advancing to the
severely ischemic level. In a prospective study on stump
healing in 713 below-knee amputations, more than half the
patients were noted to have no symptoms 6 months before
presenting with CLI that required amputation.66 Because of
this unpredictability of development of CLI, interruption of
the disease process before the development of CLI is not
always possible.
In several studies of patients with CLI due to unreconstructable arterial occlusive disease, the reported natural
history is widely variable, with major amputation rates
ranging from 14.3% to 46.4%.67-70 These variable outcomes
likely reflect inconsistencies in the definition and application of the term CLI in the initial patient cohorts. The risk
of major amputation appears to be inversely proportional to
Primary treatment
A year later
Medical
treatment only
25%
CLI
resolved
25%
Primary
amputation
25%
Revascularization
50%
Continuing
CLI
20%
Dead
25%
Alive
amputated
30%
Figure 108-3 The estimate of the initial treatment and status a year
later of patients presenting with chronic critical limb ischemia.
(Redrawn from Norgren L, etal: TASC II Working Group, Inter-Society
J Vasc Surg 45:S11, 2007.)
Quality of Life
The traditional methods of assessing outcomes and quality of
care in patients with CLI such as survival and limb salvage
is increasingly noted to be inadequate, and functional outcomes, such as maintenance of ambulatory status and independent living status, achievement of healed wound status,
avoidance of repeat hospitalizations, and interventions, are
proposed as more meaningful parameters in these patients. A
disease-specific questionnaire for CLI has not been developed; however, the Vascular Quality of Life (VascuQol)
Questionnaire, which was designed as a disease-specific tool
for patients with PAD, is accepted to be applicable to patients
with CLI.72 Using such questionnaires will enable a more
comprehensive assessment and patient-oriented approach to
patients presenting with CLI, rather than focusing only on
amputation-free survival.
Association with Systemic Atherosclerosis

As would be expected given the systemic nature of atherosclerosis, severe PAD is often associated with advanced coronary artery and cerebrovascular disease. CAD has been
estimated to be present in approximately half of patients with
CLI.73,74 This strong association results in an exceedingly high
mortality from MI and stroke among patients presenting with
CLI, significantly higher than those with PAD alone. A
review of major series reporting the fate of patients with CLI
noted that 26% died within 1 year of diagnosis75 and had 5and 10-year mortality of 50% and 70%, respectively.74,76,77 In
patients with diabetes who are known to have a twofold
increased cardiovascular mortality compared with nondiabetics, the development of diabetic foot ulcers is associated with
even more significant increase in all-cause and cardiovascular
mortality.78 In a meta-analysis of eight studies including
17,830 patients with 81,116 person-years of follow-up, diabetic foot ulcer was found to be associated with an increased
risk of all-cause mortality, fatal myocardial infarction, and
fatal stroke.79
Impact of Medical Treatment

Aggressive risk modification has not been adequately studied
in patients with CLI. In the multicenter, randomized trial of
edifoligide for the prevention of vein graft failure in lower
extremity bypass surgery (PREVENT III) in 1404 patients
with CLI, only statin use was found to be associated with
improved survival 1 year after revascularization, whereas beta
blockers and antiplatelet medication use had no effect on
survival.80 In a study of patients with diabetic foot ulcers,
aggressive cardiovascular risk management resulted in a

decrease of mortality from 48% to 27% following induction
of a protocol involving risk factor screening, antiplatelet
agent, a statin, an ACE inhibitor, and selective use of beta
blockers.81 Given the preponderance of evidence showing
benefit of medial management of atherosclerosis, it is logical
to extend such treatment to patients with CLI.
DIAGNOSIS
History and Physical Examination
Conducting a complete history and physical examination of
patients with PAD is important, and focus on the legs, as well
as systemic risk factors (see Chapter 14), is essential. Vasculogenic and neurogenic claudication must be differentiated,
as must different causes for leg ulcers, and other nonvascular
etiologies for leg symptoms). Many patients with PAD have
been increasingly recognized as having either atypical leg
symptoms (such as leg muscle symptoms that are present at
rest and with exercise) or are insufficiently active to produce
typical symptoms. A latent phase that is difficult to detect as
part of a routine clinical history also seems to occur during
the systemic atherosclerotic process. Women may be more
likely than men to present with atypical leg symptoms, and
they may be more likely to be assessed as asymptomatic. In
the Walking and Leg Circulation Study (WALCS) cohort of
460 participants, atypical exertional leg symptoms were twice
more likely to be reported by the 187 women as compared
with the men.82
Risk Factor Assessment

Atherosclerosis is a pathologic process related to human
aging. A stepwise increase in the incidence of IC occurs with
each passing decade of age (Fig. 108-4). Many other risk
factors seem to accelerate the development and growth of
atherosclerotic lesions (Box 108-2). The classic risk factors,
including hypertension, diabetes mellitus, hyperlipidemia,
chronic renal insufficiency, and cigarette smoking, as well as
other less frequently recognized factors, must be identified
and defined. It is essential to control modifiable risk factors
to slow the progression of atherosclerosis and enhance the
benefits of any eventual vascular intervention.
Suspicion of unrecognized and uncontrolled risk factors
for accelerated atherosclerosis, such as hyperhomocysteinemia or hypercoagulability, should be raised in cases characterize by the absence of commonly recognized risk factors, a
sudden symptom onset (especially in younger individuals),
or a more rapidly progressive form of PAD. McCully examined the autopsy results of 194 consecutive patients and correlated the extent of atherosclerosis with serum cholesterol
and other risk factors.83 The mean serum cholesterol of
patients who died of complications from arterial occlusive
disease was not extremely high (187mg/dL [4.84mmol/L]);
65% had a total serum cholesterol level less than 200mg/dL
(5.18mmol/L), and 92% had a total serum cholesterol level
the ABI. In a prospective study of 142 patients harboring

169 severely ischemic limbs with ulceration who could
not undergo revascularization, only 15% of patients with
an ABI greater than 0.50 required major amputation,
whereas 34% of those with an ABI less than 0.50 sustained
major limb loss at the end of 1 year.71 This abysmal natural
history of CLI propels most vascular specialists to attempt
to recommend revascularization to reduce the risk of
limb loss.
1667
1668
8
7
Prevalence (%)
6
5
4
3
2
1
0
3034 3539 4044 4549 5054 5559 6064 6569 7074
Age group (yr)
less than 250mg/dL (6.48mmol/L). In 66% of patients with

severe systemic atherosclerosis, elevated serum cholesterol,
hypertension, and diabetes were absent. This study strongly
supports the effort to actively search for other, less common
risk factors.
An elevated homocysteine level, which is often not measured during routine health assessments, may increase the
patients likelihood of developing PAD nearly sevenfold.84
A meta-analysis of more than 3000 patients in 14 crosssectional and prospective studies showed that patients with
PAD had homocysteine levels that were 4.31 mmol/L
(ranging from 0.70 to 10.46) higher than those of controls
without PAD.85 Unfortunately, folate supplementation has
not been found to benefit patients with elevated homocysteine levels in any randomized study, and it was found
to be detrimental in subgroups with higher (>12 mmol/L)
levels.86
Hypercoagulable States
Hypercoagulable states are more common in patients who
require vascular reconstruction for the treatment of lower
BOX 108-2
RISK FACTORS FOR ATHEROSCLEROSIS

Advanced age
Race (non-Hispanic blacks)
Male gender
Hyperfibrinogenemia
Diabetes mellitus
Smoking
Hypercoagulability
Hypertension
Elevated C-reactive protein
Dyslipidemia
Chronic renal insufficiency
Modified from Norgren L, etal: TASC II Working Group, Inter-Society
J Vasc Surg 45(Suppl S):S7-S9, 2007.
Figure 108-4 Weighted mean prevalence of intermittent

claudication (symptomatic peripheral arterial disease) in
large population-based studies. (Redrawn from Norgren L,
etal: TASC II Working Group, Inter-Society Consensus for the
Management of Peripheral Arterial Disease (TASC II). J Vasc Surg
45:S7A, 2007.)
extremity arterial occlusive disease.87 In a cross-sectional

study of 181 claudicants, 110 CLI patients and 210 controls,
Sartori etal88 found that fibrinogen was higher in patients
with CLI compared with those with claudication and controls; homocysteine and FVIII were higher in patients with
PAD than in controls, but were similar in patients with CLI
and claudication; the prevalence of lupus anticoagulant
increased in patients with CLI compared with those with
claudication and controls; and the prevalence of FII 20210A
allele was higher in patients with CLI compared with those
with claudication and controls. These data suggest that the
presence of two or more thrombophilic risk factors raise the
likelihood of PAD being more severe, justifying the need for
larger longitudinal studies. Although our understanding of
these additional risk factors has increased in the last decade,
the question as to whether controlling these factors will ultimately improve outcomes is still unresolved.
DIAGNOSTIC STUDIES
Hematologic Studies
At initial presentation, a patient with manifestations of
PAD should undergo a battery of basic hematologic studies
to characterize risk factors and identify end-organ involvement (Box 108-3). The hemoglobin and hematocrit levels
yield potential information about blood hemorheology and
other forms of distal perfusion inhibitors, such as secondary
polycythemia from cardiopulmonary disease. Elevated platelet counts may suggest the risk of thrombotic occlusions.
BOX 108-3
INITIAL HEMATOLOGIC EVALUATION OF CLAUDICANTS

Complete blood count, including white blood cells and platelets
Fasting blood glucose
Serum creatinine
Fasting lipid profile
Urinalysis
Modified from Dormandy JA, et al: Management of peripheral arterial
disease (PAD). TASC Working Group, TransAtlantic Inter-Society Consensus
(TASC). J Vasc Surg 31(1 Pt 2):S1-S296, 2000.
Lipid Profile
A fasting lipid profile, consisting of total cholesterol, highdensity lipoprotein, low-density lipoprotein, and triglyceride
concentration, is an important part of patient screening
and risk stratification (see Chapter 29). Lipid abnormalities
may underlie the progression of atherosclerosis. Although
the impact of elevated cholesterol or low-density lipoproteins
on the course of atherosclerosis has thus far been more
clearly defined in patients with coronary artery disease than
in those with PAD, it is likely that lipids accelerate PAD
as well.89 The impact of diabetes on the progression of
atherosclerosis may be worsened in the setting of lipid
abnormalities.90 Careful lipid control may reduce the risk
of coronary, cerebral, and peripheral artery morbidity and
mortality.91
C-Reactive Protein
An increasing body of evidence suggests that atherosclerosis
is an inflammatory process with an elevation in inflammatory
markers (see Chapter 26). Of the many markers, highsensitivity C-reactive protein (CRP) is the leading biomarker
for clinical application because of its relatively long half-life
and stability, and it should be obtained to evaluate the
patients inflammatory status. CRP has a strong correlation
with a reduced ABI. CRP levels were evaluated in 370
patients with an ABI less than 0.90 and compared with levels
in 231 patients with an ABI greater than 0.90.92 Levels of
this inflammatory marker were associated with ABI in
patients with cardiac and cerebrovascular disease. CRP was
not associated with ABI in patients without arterial occlusive
disease in these vascular beds (P = .026). In a prospective
cohort of PAD patients undergoing lower extremity vein
bypass surgery, the mean CRP was 12mg/L, which was an
independent predictor of 5-year all-cause mortality, even
after controlling for lipid levels and other risk factors.93 CRP
was shown to have a significantly inverse correlation over
time and predicted progression of PAD over 12 years in the
Edinburgh Artery Study.94 Thus this easily measured inflammatory marker serves as an indicator not only of worsening
lower extremity arterial occlusive disease but also of increased
risk of cardiac and cerebrovascular disease.
Hypercoagulable States
An evaluation for hypercoagulable states should be undertaken when such a condition is suspected clinically on the
basis of prior thrombotic events or a familial history (see
Chapter 38). Despite the plethora of tests available for the
BOX 108-4
SECONDARY HEMATOLOGIC EVALUATION BASED ON

CLINICAL SUSPICION
Thrombin, prothrombin times
Activated partial thromboplastin time
Protein S, protein C assays
Factor V Leiden assay
Lupus anticoagulant assay
Heparin-induced platelet antibodies
Platelet adhesiveness, aggregability
Fibrinogen, plasminogen levels
Antithrombin III activity
Anticardiolipin antibody assay
Modified from Dormandy JA, et al: Management of peripheral arterial
disease (PAD). TASC Working Group, TransAtlantic Inter-Society Consensus
(TASC). J Vasc Surg 31(1 Pt 2):S1-S296, 2000.
specific diagnosis of hypercoagulable states, the best screening

test is a carefully performed patient history. Random thrombotic events without a specific cause should raise the suspicion of a clotting disorder. Hypercoagulable states can be
identified in a significant proportion of patients with arterial
occlusive disease.87 When such a condition is suspected, a
broad range of testing may be required (Box 108-4).
Homocysteine
Patients who develop manifestations of PAD at an early age,
without other identifiable risk factors, should have a plasma
homocysteine level documented (see Chapter 26). High
levels of homocysteine indicate hyperhomocysteinemia,
which may accelerate atherosclerosis through a variety of
mechanisms.95,96 High levels of this amino acid may be toxic
to endothelial cells and reduce their ability to generate and
release nitric oxide. Excessive concentrations of homocysteine also may promote medial smooth muscle cell proliferation
and arterial wall inflammation and increased levels of
plasminogen activator inhibitor. As a result, arterial wall
atherosclerotic plaque formation may be increased and
thromboresistance decreased. Patients with hyperhomocysteinemia may develop clinically apparent vascular disease and
coronary artery occlusive disease at a young age in the absence
of other risk factors.97
The relationship between increased levels of homocysteine and vascular disease in older patients is not as well
defined. Taylor etal evaluated homocysteine levels in 214
patients with symptomatic arterial occlusive disease and
tracked ABIs over time.98 They found a more rapid pro
gression of occlusive disease in patients with elevated
homocysteine levels, after correction for other variables.
Although other authors failed to identify a similar
impact,100 because treatment of hyperhomocysteinemia with
the oral administration of folate and other vitamins and
nutrients is relatively simple, many vascular specialists believe
that evaluation for this potential cause of accelerated atherogenesis should be undertaken.101
A fasting blood glucose or hemoglobin A1c level is an

important test for all patients who initially present with
PAD because diabetes is such a significant risk factor for
claudication and more advanced forms of ischemia. Increased
serum creatinine levels may indicate the presence of intrinsic
renal disease, especially in the presence of diabetes. Nutritional assessment by measuring serum albumin and prealbumin levels should be considered especially in patients
with CLI.
1669
1670
BOX 108-5
Cardiac and Cerebrovascular Evaluation

The systemic nature of atherosclerosis has a significant impact
on all vascular beds to a greater or lesser extent. The presence
of coronary artery and cerebrovascular disease must be
assessed in all patients with a new onset of manifestations of
PAD who have not undergone such studies.
Cardiac Disease
Patients undergoing peripheral vascular surgery are at high
risk (>5% likelihood) of having a perioperative MI, and they
frequently manifest more than one of the clinical predictors
of MI, heart failure, or death (Box 108-5). The evaluation
of patients for cardiac disease should be directed toward
identifying the presence of disease and determining its severity (See Chapter 39). This evaluation can be done most
effectively in a stepwise manner. The guidelines for patient
assessment developed by the American Heart Association
and the American College of Cardiology provide a framework
for this aspect of patient care.102 Algorithms for the peri
operative management of cardiovascular disease are based
on clinical markers, functional capacity, and surgery-specific
risk (Fig. 108-5). Resting left ventricular function alone is
not a specific indicator of perioperative MI.103
Cerebrovascular Disease
Patients with lower extremity ischemia also have an
increased incidence of carotid artery stenosis. Araki etal104
conducted a cross-sectional study in 543 patients with PAD
and 314 control subjects using CT scans and carotid duplex
exams. The authors found the prevalences of carotid artery
stenosis of 70% and 50% to be higher in patients with
PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%,
respectively, P <0.01); they also found the incidence of cerebral infarcts and lacunar infarcts to be higher in patients
with PAD than in controls (15.0% vs. 9.8%, 41.0% vs.
13.4%, respectively, P <0.05). Thus we recommend that presenting patients or patients with progressive PAD should
undergo carotid artery duplex imaging, and conversely,
patients with cerebrovascular disease should be screened for
the presence of PAD.
Step 1
Need for
emergency
noncardiac
surgery?
CLINICAL PREDICTORS OF INCREASED PERIOPERATIVE

CARDIOVASCULAR RISK
Unstable coronary syndromes
Unstable or severe angina (CCS class III or IV)*
Recent MI
Decompensated HF (NYHA functional class IV; worsening or
new-onset HF)
Significant arrhythmias
High-grade atrioventricular block
Mobitz II atrioventricular block
Third-degree atrioventricular block
Symptomatic ventricular arrhythmias
Supraventricular arrhythmias (including atrial fibrillation) with
uncontrolled ventricular rate (HR >100 beats/minute at rest)
Symptomatic bradycardia
Newly recognized ventricular tachycardia
Severe valvular disease
Severe aortic stenosis (mean pressure gradient > 40mmHg, aortic
valve area < 1.0cm2, or symptomatic)
Symptomatic mitral stenosis (progressive dyspnea on exertion,
exertional presyncope, or HF)
Adapted from Fleisher LA, etal: Executive summary. A report of the
American College of Cardiology/American Heart Association Task Force on
Practice Guidelines [Writing Committee to revise the 2002 Guidelines on
Perioperative Cardiovascular Evaluation for Noncardiac Surgery]. J Am Coll
Cardiol 50:1707-1732, 2007.
CCS, Canadian Cardiovascular Society; HF, heart failure; HR, heart rate;
MI, myocardial infarction; NYHA, New York Heart Association.
*May include stable angina in patients who are unusually sedentary.
The American College of Cardiology National Database Library defines a

recent MI as one occurring more than 7 days ago but less than or equal to
1 month ago (within 30 days).
Risk Stratification for Patients with

Considering the high risk of early and late cardiovascular
complications following revascularizations (especially open
procedures), patients with CLI present a particularly challenging group to treat. In the multicenter randomized Bypass
versus Angioplasty in Severe Ischemia of the Leg (BASIL)
Trial, the patients who had bypass initially and were alive
Yes
Operating
room
Perioperative surveillance
and postoperative risk
stratification and risk
factor management
Yes
Evaluate and treat

per ACC/AHA
guidelines
Consider
operating room
Yes
Proceed with
planned surgery
No
Step 2
Active cardiac
conditions
No
Step 3
Low risk
surgery
Figure 108-5 Cardiac evaluation for noncardiac surgery based on active clinical conditions,
known cardiovascular disease, or cardiac risk
factors in patients aged 50 years or older. For
clinical risk factors, see Box 108-2. For active
clinical conditions, see Box 108-5. ACC/AHA,
American College of Cardiology/American Heart
Association. (Redrawn from Fleisher LA, etal: Executive summary. A report of the American College
of Cardiology/American Heart Association Task
Force on Practice Guidelines [Writing Committee
to revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery].
J Am Coll Cardiol 50:1707-1732, 2007.)
Table 108-2
1671
The Variables, Output Methods, and Early and Late Outcomes for Low-, Medium-, and High-Risk Groups in
Finland Vascular (FINNVASC); Prevention of Infrainguinal Vein Graft Failure (PREVENT) III (Modified); and
Bypass Versus Angioplasty in Severe Ischemia of the Leg (BASIL) Scoring Systems
PREVENT III
BASIL
Variables
1 point each for:

Diabetes mellitus
Foot gangrene
CAD
Urgent operation
Dialysis = 4 points
Tissue loss = 3 points
Age >75 years = 2 points
CAD = 1 point
Output methods
1-4 on sum points
Outcomes*
30-day mortality or amputation

0 points: 7.7% (4.8%)
1 point: 6.4% (7.5%)
2 points: 11.1% (10.1%)
3 points: 20.4% (15.9%)
4 points 27.3% (22.2%)
3 points = low risk

4-7 points = medium risk
8 points = high risk
1-year AFS
3 points 86% (88%)
4-7 points 73% (64%)
8 points 45% (45%)
Tissue loss
Body mass index
Creatinine
CAD
Bollinger Score
Ankle pressure
Smoking status
6-, 12-, and 24-month mortality
calculated by model A-E
Survival 6, 12, 24 months
A: 71%, 57%, 40%
B: 84%, 75%, 63%
C: 90%, 84%, 76%
D: 97%, 96%, 93%
E: 97%, 95%, 92%
*Percentages in parentheses show validation data set.

AFS, Amputation-free survival; CAD, coronary artery disease.
with an intact limb for more than 2 years lived longer than
those who initially had angioplasty.105 In an effort to stratify
these patients for risk of early and late mortality and amputation, as well as to identify those who are unlikely to survive
to benefit from aggressive revascularization, a variety of
scoring systems were developed and validated, including the
following: Finland National Vascular (FINNVASC),106 Prevention of Infrainguinal Vein Graft Failure (PREVENT)
III,107 and Bypass versus Angioplasty in Severe Ischemia of
the Leg (BASIL) scoring systems.108 Patients were classified
based on risk factors identified on multivariate analysis (Table
108-2). All three of these scoring systems were independently
validated and can be used to predict amputation-free survival
and to help in the decision making for planning treatment
modality for patients with CLI.107,109,110
Exclusion of Associated Aneurysms

A significant body of information supports screening patients
with PAD for the presence of infrarenal abdominal aortic
aneurysms. Barba etal111 performed abdominal ultrasound
in 1166 consecutive patients with chronic limb ischemia
and found abdominal aortic aneurysms (>3.0cm) in 13%,
which was more prevalent in men (13.6%) than in women
(4.1, P = 0.02), and only 1.5% had abdominal aortic aneurysms
>5cm. The prevalence increased with age, being 5.4% in
younger (<55) men, 14.8% in men between 65 and 74 years
of age, and 17.1% in men and 10.3% in women over age 75.
In a Swedish study of 5924 patients undergoing duplex imaging
for the evaluation of stenoses and aortic aneurysms,112 the
prevalence of aneurysms was 7.3% in men older than 60 years
with occlusive disease of a major artery (carotid, renal, or lower
extremity), compared with 4.0% in the absence of such stenoses. Although the aneurysms detected in each of these studies
were generally below the threshold for intervention, the low

risk of screening patients with clinically significant PAD seems
to justify doing so, especially in men older than 60.
Vascular Laboratory and Imaging Studies

The decision to recommend surgical or percutaneous intervention for a patient with lower extremity arterial occlusive
disease is based on many factors, including symptoms, degree
of functional impairment, comorbid conditions, and location
and severity of occlusive lesions. In addition, the anatomic
pattern of the disease may have a significant impact on the
type of procedure that can be used to improve distal perfusion. A clear understanding of the extent of PAD is required
before a therapeutic plan can be established.
Vascular Laboratory
Disease Severity. In most patients with lower extremity ischemia, the initial vascular laboratory measurement of segmental arterial pressure and the calculation of ABI are sufficient
to identify the presence of arterial occlusive disease and localize the segment involved. Pressures and pressure gradients are
not sufficient indicators of patency and occlusion because of
the variable presence of calcium within the arterial walls of
patients with PAD. A high or even supranormal ABI can be
recorded in patients with severe calcific arterial occlusive
disease, commonly seen in diabetics and dialysis-dependent
patients. Pressures and indices must be correlated with pulse
volume recording and Doppler waveform analysis. Toe pressures, transcutaneous oxygen pressure (tcPO2), and various
skin perfusion pressure techniques have been proposed
to assess global and regional foot perfusion to detect and
quantify the presence and hemodynamic impact of arterial
occlusive disease.113
FINNVASC
1672
Table 108-3
Fontaine Grade
Stages of Chronic Limb Ischemia

Rutherford
Category
Clinical Description
Objective Criteria
Normal treadmill or reactive hyperemia test
Completes treadmill exercise*; AP after exercise >50mmHg but at least 20mmHg
lower than resting value
Between categories 1 and 3
Cannot complete standard treadmill exercise*; AP after exercise <50mmHg
I
IIa
0
1
Asymptomatic
Mild claudication
IIb
2
3
Moderate claudication
Severe claudication
III
Ischemic rest pain
Resting AP <30-50mmHg; ankle or metatarsal PVR flat or barely pulsatile;

TP <30mmHg
IV
Minor tissue loss
Major tissue loss,
Resting AP <50-70mmHg; ankle or metatarsal PVR flat or barely pulsatile;

TP <40mmHg in nondiabetics, <50mmHg in diabetics; tcPO2 <30mmHg
Same as Rutherford 5 (Fontaine IV)
From Rutherford RB, etal: Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 26(3):517-538, 1997; and Norgren L,
etal: TASC II Working Group, Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 45:S34, 2007.
AP, Ankle pressure; PVR, pulse volume recording; tcPO2, transcutaneous oxygen; TP, toe pressure.
*Five minutes at 2 miles per hour on a 12% incline.
Grades II and III correspond to critical limb ischemia.
Nonhealing ulcer or focal gangrene with diffuse pedal ischemia.
Extending above transmetatarsal level, or foot no longer salvageable.
For patients with palpable pulses but disproportionately

disabling symptoms or those capable of undergoing an exercise therapy program, exercise testing in the vascular laboratory can be helpful.114 Commonly, after the recording of ankle
pressures at rest, a patient walks at 3.5km/hr on a treadmill
at a 12% incline until the onset of claudication-like symptoms. At that time, ankle pressures are measured again. A
more than 20% decrease in ankle pressures for more than 3
minutes after the cessation of exercise indicates vascular claudication.115 No decrease or a small decrease in pressure after
exercise suggests a nonvascular cause of symptoms, even in
the presence of decreased peripheral pulses. Other regimens
measure the distance walked per unit time or maximal
walking distance. Although each of these methods has proponents, perhaps the most important factor is the use of a
consistent methodology to follow patients. The combination
of ankle pressure and exercise response can also be used to
classify the patients degree of ischemia (Table 108-3).
Disease Location. Identifying the anatomic locations of
hemodynamically significant lesions is crucial in planning
intervention in either the claudicant or, especially, the
patient with CLI. Currently, color-guided duplex imaging,
gadolinium-enhanced magnetic resonance imaging, computed tomographic angiography, and intra-arterial subtraction angiography) are the most frequently used imaging
modalities for the delineation of arterial anatomy. These
modalities are discussed in detail in their respective chapters
(see Chapters 16, 19, 22, and 23).
Imaging Modality Selection

Patients with borderline renal function, especially those with
diabetes, present a special challenge to the vascular specialist.
Because of the risks of renal failure associated with iodinated
contrast agents116 and nephrogenic systemic fibrosis induced
by gadolinium,117 the decision to proceed to advanced imaging
of lower extremity inflow and outflow vessels for the planning

of intervention can be problematic. Selective catheterization
and angiogram using diluted contrast at the popliteal artery
or even infrapopliteal arteries allow excellent imaging even
of the pedal arteries using minimal iodinated contrast
volumes. Improvements in image processing have also
renewed the interest in carbon dioxide angiography, which
has no adverse effect on renal function, although it may be
difficult to clear in patients with severe chronic obstructive
pulmonary disease.118 However, small supplemental doses of
iodinated contrast averaging between 10 and 40mL may be
needed to better define the arterial anatomy in certain
situations.119
The optimal choice of arterial imaging studies depends
on the type of anticipated intervention. Visser etal performed a Markov analysis to determine the best testing
strategies for the evaluation of claudicants.120 Using test
sensitivity, incidence and type of complications associated
with the test, implications of a missed lesion, and the cost
of overtreatment based on test results, the authors evaluated
the cost-effectiveness of duplex imaging, MRA, and digital
subtraction conventional angiography. They found that if
treatment considerations were limited to angioplasty in
patients suspected of having suitable lesions, MRA was more
cost-effective than conventional angiography. Likewise,
digital subtraction angiography proved superior to duplex
ultrasound and MRA if surgery was anticipated. Although
the difference in overall cost of these diagnostic modalities
was small (<$1800 lifetime costs), the results of the study
indicate that the pretreatment evaluation of claudicants is
generally simple, and the need for multiple imaging studies
is uncommon.
A comprehensive systematic review comparing duplex
ultrasound, MRA, and computed tomography for the diagnosis of lower extremity ischemia concluded that contrastenhanced MRA has better overall accuracy than the other
TREATMENT
The decision of when and how to treat IC or CLI can be
difficult (see Chapter 109). Nonetheless, in view of the high
risk associated with systemic atherosclerosis, all patients
should attempt to control cardiovascular risk factors and
implement risk-reduction strategies to decrease the risk of MI
and stroke. However, based on a recent analysis of data from
the National Health and Nutrition Examination Survey
(NHANES) between 1999 to 2004, statin use was reported
only in 30%, angiotensin-converting enzyme inhibitor/
angiotensin receptor blocker use in 25%, and aspirin use in
only 36% of patients aged 40 with PAD, corresponding to
5.0 million adults with PAD not taking statins, 5.4 million
not taking ACEI/ARB, and 4.5 million not taking aspirin.
The use of multiple preventive therapies was associated with
65% lower all-cause mortality in patients with PAD without
known cardiovascular disease.122
Antiplatelet Therapy
The mainstay of cardiovascular risk reduction is antiplatelet
therapy (see Chapter 35). Numerous studies have demonstrated that aspirin in doses ranging from 75 to 325mg/day
significantly lowers the risk of MI and stroke in patients with
symptomatic PAD123,124; however, the benefit of aspirin in
asymptomatic PAD patients is less clear.125-127 Clopidogrel is
a suitable alternative to aspirin for risk reduction in patients
with symptomatic PAD. In very-high-risk patients who are
not considered at increased risk of bleeding, a combination
of aspirin and clopidogrel may be beneficial.23 A statistically
significant benefit, documented by a reduction in MI, stroke,
or death, was noted in patients with symptomatic lower
extremity ischemia treated with aspirin and clopidogrel compared with those who received aspirin and placebo.128
interventions, and amputation rates in both men and women

(see Chapter 27).129-131
Treatment of Hyperlipidemia
The treatment of hyperlipidemia with a statin to achieve
a low-density lipoprotein level less than 100mg/dL (2.59
mmol/L) is recommended for all patients with PAD (<70mg/
dL in those who are at very high risk of ischemic events) to
reduce the risk of MI. This recent recommendation from the
Adult Treatment Panel III of the National Cholesterol Education Program is based on the fact that patients with lower
extremity ischemia are at high or very high risk of cardiac
events (see Chapter 29).132
Treatment of Hypertension
Control of hypertension to achieve a systolic blood pressure
less than 140mmHg and a diastolic pressure less than
90mmHg (less than 130/80mmHg in those with diabetes
or renal insufficiency) should be implemented (see Chapter
30). TASC II guidelines consider ACEI and thiazide diuretics
first-line therapy for patients with PAD to reduce the risk of
cardiovascular events.74 -Adrenergic blockers are also an
excellent class of drugs for this purpose, especially in those
with concomitant coronary artery disease due to their cardioprotective effects. Although there has been theoretical
concern that a reduction in systolic pressure might worsen
symptoms of lower extremity ischemia, this does not appear
to occur. A meta-analysis of six major studies addressing this
issue concluded that beta blockade does not reduce walking
distance or worsen the pain of IC133
Treatment of Diabetes and Other Risk Factors

Careful management of diabetes is also essential to reduce the
likelihood of adverse cardiovascular events and the progression of PAD (see Chapter 28). Other risk factors, such as
dietary indiscretion and inactivity, should be identified and
addressed. Each patient with chronic lower extremity ischemia must have a comprehensive treatment plan for the
control of risk factors as soon as the diagnosis of PAD is
established. Once this is done, the patient will be better
prepared for any subsequent intervention that might be
required for limb salvage and improvement in walking ability
and quality of life.
SELECTED KEY REFERENCES

Smoking Cessation
Smoking cessation is also critical for reducing atherosclerotic
risk and is central to the medical management of patients
with PAD. Smoking is associated with progression of
atherosclerosis, an increased incidence of death due to
coronary artery disease, and accelerated graft failure after
lower extremity revascularization.129,130 Smoking cessation
reduces death from coronary heart disease, lower extremity
Diehm C, Allenberg JR, Pittrow D, Mahn M, Tepohl G, Haberl RL, Darius

H, Burghaus I, Trampisch HJ; German Epidemiological Trial on Ankle
Brachial Index Study Group: Mortality and vascular morbidity in older
adults with asymptomatic versus symptomatic peripheral artery disease.
Circulation 120:20532061, 2009.
This is another excellent longitudinal study on a large group of patients showing
that the all-cause death, all cause death/myocardial infarction/stroke, or cardiovascular events alone were similar between symptomatic and asymptomatic patients
with PAD. As a result, the recommendation for diagnostic testing for ABI was
decreased to age 65 in the 2011 ACCF/AHA focused update of the guideline for
imaging modalities when evaluating the entire arterial

segment from abdominal aorta to foot.121 As noted by Visser
etal, this systematic review also confirmed that when a single
arterial segment of the leg above or below the knee is to be
evaluated, two-dimensional time-of-flight MRI is the most
cost-effective study.
Although the vascular specialist has the ability to visualize
specific portions of the arterial tree with increasing detail and
ease, diagnostic tests beyond the standard vascular laboratory
assessment should be reserved for patients in whom a percutaneous or open intervention is planned.
1673
1674
the management of patients with peripheral artery disease (updating the 2005
guideline).
Dormandy JA, Rutherford RB: Management of peripheral arterial disease
(PAD). TASC Working Group. Trans-Atlantic Inter-Society Consensus.
J Vasc Surg 31:S1S296, 2000.
Excellent compendium of information and references regarding PAD. Divided
into sections on epidemiology, IC, acute limb ischemia, and critical limb ischemia,
this document is unique in its analysis of the literature, reviewing all major references prior to 1999. It identifies areas of diagnosis and treatment for which there
is adequate information and provides clear recommendations.
Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann
KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb
JFACC/AHA: 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of
the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Writing Committee to Revise the 2002
Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac
Surgery) Developed in Collaboration With the American Society of
Echocardiography, American Society of Nuclear Cardiology, Heart
Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for
Cardiovascular Angiography and Interventions, Society for Vascular
Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol
50:17071732, 2007.
These recent guidelines provide excellent recommendations and algorithms for
the assessment and treatment of cardiac disease in patients who require intervention
for vascular disease.
Garg P, Tian L, Criqui MH, Ferrucci L, Guralnik JM, Tan J, McDermott
MM: Physical activity during daily life and mortality in patients with
peripheral arterial disease. Circulation 114:242248, 2006.
This longitudinal epidemiologic study followed 460 patients for more than 4 years
to confirm the relationship between higher activity levels and longer life span,
underscoring the need to design treatment strategies for PAD patients that permit
an increased level of activity.
Hirsch AT, Allison MA, Gomes AS, Corriere Ma, Duval S, Ershow AG,
Hiatt WR, Karas RH, Lovell MB, McDermott MM, Mendes DM,
Nussmeier NA, Treat-Jacobson D; American Heart Association Council
on Peripheral Vascular Disease; Council on Cardiovascular Nursing;
Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology;
Council on Epidemiology and Prevention: A call to action: women and
peripheral artery disease: a scientific statement from the American Heart
Association. Circulation 125:14491472, 2012.
This scientific statement from the AHA reviews prevalence, the natural history,
presentation modes, access to cardiovascular health care, diagnostic methods,
revascularization and outcomes in women and how they differ from men, and
present evidence base of low PAD awareness and knowledge.
Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL,
Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D,
Stanley JC, Taylor LM, Jr, White CJ, White J, White RA, Antman EM,
Smith SC, Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ,
Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B:
American Association for Vascular Surgery; Society for Vascular Surgery;
Society for Cardiovascular Angiography and Interventions; Society for

Vascular Medicine and Biology; Society of Interventional Radiology;
ACC/AHA Task Force on Practice Guidelines Writing Committee to
Develop Guidelines for the Management of Patients With Peripheral
Arterial Disease; American Association of Cardiovascular and Pulmonary
Rehabilitation; National Heart, Lung, and Blood Institute; Society
for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular
Disease Foundation. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity,
renal, mesenteric, and abdominal aortic): a collaborative report from
the American Association for Vascular Surgery/Society for Vascular
Surgery, Society for Cardiovascular Angiography and Interventions,
Society for Vascular Medicine and Biology, Society of Interventional
Radiology, and the ACC/AHA Task Force on Practice Guidelines
(Writing Committee to Develop Guidelines for the Management of
Patients With Peripheral Arterial Disease): endorsed by the American
Association of Cardiovascular and Pulmonary Rehabilitation; National
Heart, Lung, and Blood Institute; Society for Vascular Nursing; Trans
Atlantic Inter-Society Consensus; and Vascular Disease Foundation.
Circulation 113:e463e654, 2006.
These guidelines represent an extension of the original Trans-Atlantic InterSociety Consensus document. A broader approach is taken, with significant
emphasis on atherosclerosis involving the carotid, coronary, and peripheral arteries.
This document provides evidence-based recommendations for the diagnosis and
treatment of PAD, as well as its associated disorders.
Hooi JD, Stoffers HE, Kester AD, Rinkens PE, Kaiser V, van Ree JW,
Snotterus JA: Risk factors and cardiovascular diseases associated with
asymptomatic peripheral arterial disease. The Limburgh PAOD study.
Scand J Prom Health Care 16:177182, 1998.
This longitudinal study established that asymptomatic patients with a reduced
ABI have an incidence of cardiovascular disease comparable to those with a reduced
ABI and IC. This and other similar reports confirmed that the presence of PAD,
whether symptomatic or not, is an indicator of systemic atherosclerosis.
Leeper NJ, Myers J, Zhou M, Nead KT, Syed A, Kojima Y, Caceres RD,
Cooke JP: Exercise capacity is the strongest predictor of mortality in
patients with peripheral arterial disease. J Vasc Surg 57:728733, 2013.
This study assessed 725 PAD patients referred for exercise testing who were
followed for a mean of over 11 years. The baseline exercise capacity was found to
be significantly higher in survivors than in those who died, and each additional
MET achieved was found to be associated with age-adjusted 18% and 20% reductions in all-cause and cardiovascular mortality, respectively.
Weatherley BD, Nelson JJ, Heiss G, Chambless LE, Sharrett AR, Nieto FJ,
Folsom AR, Rosamond WD: The association of the ankle-brachial index
with incident coronary heart disease: the Atherosclerotic Risk in Communities (ARIC) study, 1987-2001. BMC Cardiovasc Disord 7:3, 2007.
This excellent longitudinal epidemiologic study confirmed the strong relationship
between ABI and risk of an adverse cardiovascular event. This and similar studies
reinforced the need to comprehensively treat all patients with evidence of PAD,
regardless of whether the disease is symptomatic.
The reference list can be found on the companion Expert Consult website
at www.expertconsult.com.
CHAPTER 108 Lower Extremity Arterial Disease: General Considerations 1674.e1
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Lower Extremity Arterial Disease: General Considerations

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CHAPTER 108

Based on a chapter in the seventh edition by John V. White

Chronic lower extremity ischemia due to peripheral arterial

disease (PAD) is the most common cause of walking disability

subjected to a 6-minute walking test, however, the 63 active

CHAPTER 108 Lower Extremity Arterial Disease: General Considerations

Vascular Pain Syndromes

Arterial perfusion inadequate to

Burning, cramping, aching

Proximal venous occlusion

Arterial insufficiency resulting

Buttocks, hips, thighs, calves

Nondiabetic rest pain

Chronic ischemic neuropathy

Diffuse, poorly localized, aching,

Ischemic necrosis of sensory

Unremitting, severe, aching,

Aorta and large-artery pain

Nonischemic diabetic neuropathy

Distal embolization from

Pain after stroke

Diffuse, deep aching or burning

Tearing, ripping, boring along line

Substernal, interscapular (aorta)

Dull, aching digital pain with

Coolness, pallor, numbness,

Severe, unremitting, aching,

Upper and lower extremities

Prior lower extremity deep

Mild itching, burning; localized

Incompetent valvular system

Diffuse aching or burning

Lower extremity edema, secondary

Fingertip ulceration or necrosis

SECTION 18 LOWER EXTREMITY ARTERIAL DISEASE

SECTION 18 Lower Extremity Arterial Disease

Vascular Pain Syndromecontd

Wound-related and secondary to

discomfort with ambulation and relief with rest. No specific

Nonatherosclerotic Causes of Claudication

pathophysiologic mechanism as that associated with PAD.6

Critical Limb Ischemia

CHAPTER 108 Lower Extremity Arterial Disease: General Considerations

arterial perfusion may only be decreased to a specific region

Prognostic Value of Ankle Brachial Index

SECTION 18 LOWER EXTREMITY ARTERIAL DISEASE

SECTION 18 Lower Extremity Arterial Disease

Prevalence Based on Demographics

Age group (yr)

Figure 108-1 Prevalence of peripheral arterial disease by age and

Hispanic women and men. No gender differences were noted,

Prevalence Based on Risk Factors

CHAPTER 108 Lower Extremity Arterial Disease: General Considerations

Male gender (cf female)

exceeding 25 pack years has been reported to be associated

extremity PAD symptoms by reducing their walking actually

Impact of Female Gender

Impact on Future Health

SECTION 18 LOWER EXTREMITY ARTERIAL DISEASE

SECTION 18 Lower Extremity Arterial Disease

Association with Systemic Atherosclerosis

Thus the natural histories of asymptomatic PAD and IC

Critical Limb Ischemia

CHAPTER 108 Lower Extremity Arterial Disease: General Considerations