Peripheral Arterial Disease

Ioanna Tzoulaki, Imperial College London, London, UK

F Gerry R Fowkes, University of Edinburgh, Edinburgh, UK
Ó 2017 Elsevier Inc. All rights reserved.

Definition of Peripheral Arterial Disease (PAD)
Peripheral arterial disease (PAD) is defined ranging from the
broad to the specific. For many, PAD defines a wide variety
of disorders that obstruct the blood supply to the arteries of
the noncoronary circulation. However, PAD is also used solely
to describe obstructive disease in the arteries to the legs. Here,
we define PAD by the latter definition. Other terms have been
used to describe this disorder including peripheral vascular
disease, peripheral arterial occlusive disease, arteriosclerosis
obliterans, and lower extremity arterial disease.
Clinical Presentation and Natural History
of the Disease
Peripheral arterial disease remains asymptomatic for long
periods of time and only presents clinically when it is relatively
advanced. The cardinal symptom of PAD is intermittent claudi-
cation (IC), a cramping leg pain, which is brought on by ambu-
lation/exercise and relieved by rest. Some patients develop
‘atypical’ leg pain, which presents with lower extremity discom-
fort on exertion but does not consistently resolve with rest.
More severe forms of the disease include critical limb ischemia
(CLI), characterized by persistent rest pain becoming worse
when the legs are elevated, for example, in bed at night. In
more severe cases, patients develop gangrene and ulceration
and may undergo leg amputation or other surgical intervention.
Acute limb ischemia denotes a sudden decrease or worsening of
limb perfusion causing a potential threat to limb viability.
The prognosis of patients with PAD is characterized by an
increased risk of cardiovascular disease affecting other arterial
beds such as coronary heart disease and stroke. Progression
of local disease in the legs is less common (Figure 1). In fact,
patients with IC in most cases either improve or stabilize.
Less frequently, worsening of claudication may require surgical
intervention and finally amputation. For example, after 5 years’
follow-up of the Edinburgh Artery Study, out of 116 identified
claudicants at baseline, only 29% still had symptoms of claudi-
cation, 8% had surgical revascularization or amputation, and
1% had developed leg ulcers (Leng et al., 1996). In contrast,
amputation rates are much higher (10–40%) once symptoms
of CLI (rest pain, tissue loss) commence. Asymptomatic disease
has also been shown to progress slowly over time with approx-
imately 11% of asymptomatic individuals showing significant
progression of disease over 5 years (Aboyans et al., 2006).

PAD population (50 years and older)

Initial clinical presentation

Asymptomatic PAD Atypical leg pain Claudication Critical limb ischemia

20– 50% 40– 50% 10– 35% 1– 2%

1-year outcomes

Alive with 2 limbs Amputation CV mortality

50% 25% 25%
5-year outcomes

Limb morbidity CV morbidity and mortality

Stable Worsening Critical limb ischemia Nonfatal CV event Mortality

claudication claudication 1– 2% (MI or stroke) 20% 15– 30%
70– 80% 10– 20%
Amputation CV causes Non-CV causes
75% 25%

Figure 1 Natural history of peripheral arterial disease (PAD). Reprinted with permission from Norgren, L., Hiatt, W.R., Dormandy, J.A., Nehler,
M.R., Harris, K.A., Fowkes, F.G., On Behalf of the TASC II Working Group, 2007. Inter-society consensus for the management of peripheral arterial
disease (TASC II). J. Vasc. Surg. 45, S5–S67.

International Encyclopedia of Public Health, 2nd edition, Volume 5 http://dx.doi.org/10.1016/B978-0-12-803678-5.00328-3 449

450 Peripheral Arterial Disease
Prevalence and Incidence of PAD
PAD is a relatively common disease that affects many adults
worldwide. For example, approximately 8 million out of 300
million people suffer from PAD in the United States (Hirsch
et al., 2001). Overall, the estimated prevalence of the disease
is highly dependent on the age of the population and the
criteria used to define the disease. For example, it was estimated
that 12–20% of Americans age 65 and older have PAD yet only
about 25% of PAD patients undergo treatment (Becker et al.,
2002).
Intermittent Claudication
Most epidemiological studies use IC as a symptomatic marker
of PAD, which is usually assessed via the World Health Organi-
zation (WHO) IC questionnaire. The estimated prevalence is
small in men and women under 55 years but increases rapidly
in those aged 55 and above. Overall the prevalence of claudica-
tion ranges between 0.4% and 14.4% (Dormandy and Ruther-
ford, 2000). Figure 2 shows a calculated mean prevalence by
age weighted by study sample size as reported by the
Trans-Atlantic Inter-Society Consensus (TASC) Working Group
on the management of peripheral arterial disease. The inci-
dence of PAD follows a similar trend. In the Framingham Heart
Study, the age-specific annual incidence of intermittent claudi-
cation for ages 30–44 years was 6 per 10 000 men and 3 per
10 000 women; this incidence increased to 61 per 10 000
men and 54 per 10 000 women ages 65–74 years (Kannel
et al., 1970). Sex differences are most apparent in
middle-aged populations with men showing a higher preva-
lence or incidence of disease whereas in older populations
sex differences are minimal in keeping with an equilibration
in the frequency of cardiovascular disease between men and
women at older ages. Ethnic differences in the prevalence of
PAD also exist, with a higher prevalence/incidence in the
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
30–34 35–39 40–44 45–49
Age-group
Figure 2 Mean prevalence of intermittent claudication in large population studies. Reprinted with permission from Norgren, L., Hiatt, W.R.,
Dormandy, J.A., Nehler, M.R., Harris, K.A., Fowkes, F.G., On Behalf of the TASC II Working Group, 2007. Inter-society consensus for the manage-
ment of peripheral arterial disease (TASC II). J. Vasc. Surg. 45, S5–S67.
United States of PAD in subjects with black ethnicity. Some
studies suggest that the prevalence of PAD in persons of
Hispanic origin is similar to or slightly higher than that in
whites (Criqui et al., 2005).
Asymptomatic Disease
For every individual with IC there are another 3 with asymp-
tomatic disease causing a 50% or greater stenosis of the arteries
supplying the legs (Hiatt et al., 1995). Therefore, the prevalence
of asymptomatic disease is higher than that estimated on the
basis of IC symptoms alone and ranges between 3% and
10%, increasing to 15–20% in populations older than 70 years
of age. Asymptomatic disease may be assessed by noninvasive
modalities. The most commonly used test is the ankle brachial
index (ABI), which is the ratio of the ankle to the brachial
systolic blood pressure (Figure 3). An ABI less than unity (or
less than 0.9 in practice) at rest is highly suggestive of signifi-
cant arterial obstruction in the legs. Other noninvasive tests
include pulse palpation, flow velocity determination, and
duplex ultrasound. In the San Diego Study, Criqui et al.
(1985) used a battery of three different diagnostic tests (ABI,
pulse wave analysis, and pulse examination) along with the
WHO questionnaire in 613 men and women. The estimated
prevalence of PAD was 12%, which was considerably greater
than that estimated by the claudication questionnaire
alone (2.2%). In a high-risk population (aged >70 years or
50–69 years with a cardiovascular risk factor) the prevalence
of asymptomatic disease was found to be 29% (Hirch et al.,
2001).
Critical Limb Ischemia
CLI is rare, affecting between 0.05% and 0.24% of the
general population (Dormandy and Rutherford, 2000). In
1995 there were approximately 20 000 people with CLI in
50–54 55–59 60–64 65–69 70–74
 Peripheral Arterial Disease 451

Higher right-ankle pressure Interpretation of ABI

Right ABI >1.30 Non-compressible
Higher arm pressure
0.91–1.30 Normal
0.41–0.90 Mild-to-moderate peripheral
Higher left-ankle pressure arterial disease
Left ABI 0.00–0.40 Severe peripheral arterial
Higher arm pressure
disease

Right-arm Left-arm
systolic pressure systolic pressure

Right-ankle DP DP Left-ankle
systolic pressure systolic pressure
PT PT

Figure 3 Measurement of the ankle brachial index (ABI). Reprinted with permission from Hiatt, W.R., 2001. Medical treatment of peripheral arterial
disease and claudication. N. Engl. J. Med. 344, 1608–1621.

the UK, thus an annual incidence of approximately 400
per million per year (Vascular Surgical Society of Great
Britain and Ireland, 1995). In other Western countries, the
incidence of CLI has been estimated to be between 500
and 1000 per million per year. These estimates have
been based on the number of amputations performed and
the assumption that 25% of people with CLI require
amputation.
been shown to be approximately double that for coronary
heart disease. Smoking has also been associated with
progression of PAD. Patients with IC who continued to
smoke have been shown to more often develop CLI and to
have higher amputation rates than those patients with IC
who quit smoking.

Smoking
Risk Factors for PAD Diabetes

The underlying cause of PAD is, in the vast majority of cases, Hypertension
atherosclerotic disease. Thus, risk factors for PAD are those
Hypercholesterolemia
associated with atherosclerotic disease and are similar to those
of coronary heart disease and stroke. Figure 4 shows the range C-reactive protein
of relative risks for PAD as estimated by epidemiological
studies for some important factors including cigarette smoking, 0.5 1 2 3 4 5
diabetes, dyslipidemia, and hypertension. Relative risk

Smoking
Most risk factors for PAD are almost identical to those asso-
ciated with coronary heart disease. However, some, such as
smoking, would appear to be particularly important in the
development of peripheral atherosclerosis. Overall, the prev-
alence of symptomatic PAD is increased 2.6-fold in current
smokers (Willigendael et al., 2005). In addition, the risk
ratio in smokers compared to nonsmokers for PAD has
Figure 4 Risk of developing lower extremity PAD. The range for each
risk factor is estimated from epidemiological studies. The relative risks
are estimated for current versus ex-smokers and nonsmokers, presence
versus absence of diabetes and hypertension, and top versus bottom
quartile of C-reactive protein. The estimate for hypercholesterolemia is
based on a 10% risk for each 10 mg per dl rise in total cholesterol.
Reprinted with permission from Norgren, L., Hiatt, W.R., Dormandy,
J.A., Nehler, M.R., Harris, K.A., Fowkes, F.G., On Behalf of the TASC II
Working Group, 2007. Inter-society consensus for the management of
peripheral arterial disease (TASC II). J. Vasc. Surg. 45, S5–S67.
452 Peripheral Arterial Disease
Diabetes
People with diabetes have an approximately two-to fourfold
increase in prevalence of PAD compared to nondiabetics
(Luscher et al., 2003). The duration and severity of diabetes
would appear to correlate with the incidence and extent of
PAD. Increased rates of absent pedal pulses, femoral bruits,
and decreased ABI in people with diabetes have also been
shown. Moreover, patients with diabetes are more likely to
develop severe symptomatic forms of the disease, such as rest
pain or ulceration as well as IC, and have more aggressive
progression of PAD. Patients with IC and diabetes have been
shown to have a 35% risk of sudden ischemia and a 21% risk
of major amputation compared to claudicants without diabetes
who had 19% risk of sudden ischemia and 3% risk of major
amputation. In addition, amputation or gangrene was 10 times
more frequent in PAD subjects with diabetes than in those
without diabetes (Dormandy and Rutherford, 2000).
Hypercholesterolemia
The effect of blood lipids on PAD is less well established. In
fact, elevated cholesterol levels seem to be associated some-
what less with PAD than with coronary heart disease. A
protective effect of increased high-density lipoprotein (HDL)
cholesterol has been observed in several studies. An association
between increased triglycerides and PAD has been reported by
many but the strength of this association is reduced by multi-
variate analysis and the effect of triglycerides on PAD remains
unclear. In the Physicians Health Study, low-density lipopro-
tein (LDL) cholesterol, HDL cholesterol, triglycerides, and ratio
of total HDL cholesterol were compared as predictors of PAD;
the ratio of total HDL cholesterol was found to have the great-
est independent effect (Ridker et al., 2001).
Hypertension
High blood pressure is likely to be a risk factor for PAD but may
not be as strong as others such as smoking. Approximately
50–92% of claudicants have hypertension and subjects with
elevated blood pressure have a 2.5- to 4-fold increased risk of
developing IC prospectively (Makin et al., 2001). However,
the relation between high blood pressure and PAD is not
consistent between studies.
Other Risk Factors
Other major cardiovascular risk factors such as obesity and
physical inactivity are less well established in peripheral athero-
sclerosis. Few studies have examined the relationship between
obesity, mainly measured by the body mass index (BMI); inci-
dent PAD and the overall evidence for an association was weak.
The role of physical activity as an etiological factor is particu-
larly difficult to evaluate in PAD because symptomatic disease
often results in reduced physical activity. A relatively weak asso-
ciation between a physically active lifestyle and a reduced risk
of developing PAD has been observed.
A series of novel risk factors have been proposed over the
past few years as potential risk factors for cardiovascular
disease. Although most studies have focused on coronary heart
disease some evidence exists for PAD. Among these newly
proposed markers of atherosclerosis, C-reactive protein
(CRP), a marker of activated inflammation, has received
considerable attention. However, the clinical utility of CRP
for cardiovascular disease prediction is currently open to
question. For example, the Edinburgh Artery Study reported
a 40% increased risk of PAD for people with CRP levels in
the top third of the distribution but a small added value of
CRP over and above that of traditional cardiovascular risk
factors (Tzoulaki et al., 2007). Other factors such as
fibrinogen and D-dimer have been associated with the
presence and development of the disease but again the
evidence to date would suggest that measuring these plasma
markers in patients in primary care is not justified.
PAD and Presence of Other Cardiovascular Diseases
Patients suffering from PAD face an increased risk of other
cardiovascular events, which is equal to or greater than that
of patients with clinical coronary arterial disease. This may be
at least partly due to concomitant coronary and cerebrovascular
disease in these patients. Among patients with IC, 40–60%
have coexisting coronary disease and 26–50% have coexisting
cerebrovascular disease. The reported coprevalence is highly
dependent on the sensitivity of the diagnostic tools used to
define atherosclerotic disease, whether PAD, coronary heart
disease, or stroke. More sensitive diagnostic techniques corre-
late with higher coprevalence of diseases. Also, among subjects
with asymptomatic PAD (ABI 0.9), the percentage of coexisting
cardiovascular disease is higher than those without PAD and
ranges between 56% and 71%. Finally, ABI has been shown
to correlate well with measures of arterial disease in other
vascular beds such as carotid intima media thickness and coro-
nary artery calcium levels.
PAD and Prediction of Cardiovascular Morbidity and Mortality
Patients with PAD have been shown to have an increased risk
of angina, heart failure, fatal and nonfatal myocardial infarc-
tion (MI), fatal and nonfatal stroke, and cardiovascular
disease; all cause mortality as reported by large-scale epidemi-
ological studies (Figure 1). Patients with IC have an
approximately threefold increase in cardiovascular mortality
risk (Leng et al., 1996). Also, claudicants have 2.5 times
higher all-cause mortality rates than nonclaudicants. Asymp-
tomatic PAD defined by an ABI 0.9 is associated with future
MI and stroke with risk ratios ranging between 1.1–2.7 and
1.1–2.0, respectively. Also a twofold risk for cardiovascular
mortality has been observed in those with ABI 0.9 (Heald
et al., 2006). Lower cut-off points for the ABI (ABI 0.8) have
been associated with greater cardiovascular risks. PAD is
also a powerful predictor of all-cause mortality: subjects
with asymptomatic PAD have a 1.6 relative risk of death
compared to healthy individuals. Mortality and morbidity
risks are incrementally higher in patients with asymptomatic,
symptomatic, and severe PAD. Patients with CLI have
a 20% mortality rate within 1 year (Figure 1). The 30-day
mortality of those experiencing acute limb ischemia is approx-
imately 15%.

Conclusions
PAD is a common problem in the community causing
considerable morbidity and is an indication of an increased
risk of major cardiovascular events and mortality. The
increased aging of the population and improved survival
of atherosclerotic patients following myocardial infarction
and stroke would suggest that the burden of PAD will
persist for the foreseeable future and will be a major consid-
eration for the public health challenge of reducing cardio-
vascular disease.
See also: Cardiovascular Disease Prevention; Coronary Heart
Disease; Exercise Therapy for Heart Failure Patients in Canada;
Global Trends in Cardiovascular Disease; Heart Failure.
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disease in the United States: results from the National Health and Nutrition
Examination Survey, 1999–2000. Circulation 110, 738–743.