Epidemiology of Peripheral Artery Disease

Peripheral Artery Disease Compendium
Circulation Research Compendium on Peripheral Artery Disease

Epidemiology of Peripheral Artery Disease
Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease
Lower Extremity Manifestations of Peripheral Artery Disease: The Pathophysiologic and Functional Implications of Leg Ischemia
The Genetic Basis of Peripheral Arterial Disease: Current Knowledge, Challenges and Future Directions
Modulating the Vascular Response to Limb Ischemia: Angiogenic and Cell Therapies
Pharmacological Treatment and Current Management of Peripheral Artery Disease
Endovascular Intervention for Peripheral Artery Disease
Surgical Intervention for Peripheral Arterial Disease
John Cooke, Guest Editor
Epidemiology of Peripheral Artery Disease

Michael H. Criqui, Victor Aboyans
Abstract: New data on the epidemiology of peripheral artery disease (PAD) are available, and they should be
integrated with previous data. We provide an updated, integrated overview of the epidemiology of PAD, a focused
literature review was conducted on the epidemiology of PAD. The PAD results were grouped into symptoms,
diagnosis, prevalence, and incidence both in the United States and globally, risk factors, progression, coprevalence
with other atherosclerotic disease, and association with incident cardiovascular morbidity and mortality. The
most common symptom of PAD is intermittent claudication, but noninvasive measures, such as the ankle-
brachial index, show that asymptomatic PAD is several times more common in the population than intermittent
Downloaded from http://ahajournals.org by on January 9, 2019
claudication. PAD prevalence and incidence are both sharply age-related, rising >10% among patients in their 60s
and 70s. With aging of the global population, it seems likely that PAD will be increasingly common in the future.
Prevalence seems to be higher among men than women for more severe or symptomatic disease. The major risk
factors for PAD are similar to those for coronary and cerebrovascular disease, with some differences in the relative
importance of factors. Smoking is a particularly strong risk factor for PAD, as is diabetes mellitus, and several
newer risk markers have shown independent associations with PAD. PAD is strongly associated with concomitant
coronary and cerebrovascular diseases. After adjustment for known cardiovascular disease risk factors, PAD
is associated with an increased risk of incident coronary and cerebrovascular disease morbidity and mortality.
(Circ Res. 2015;116:1509-1526. DOI: 10.1161/CIRCRESAHA.116.303849.)
Key Words: ankle brachial index ■ intermittent claudication ■ peripheral artery disease ■ prognosis
P eripheral artery disease (PAD) is now the preferred term

for partial or complete obstruction of ≥1 peripheral arter-
ies.1 In this review, PAD refers to atherosclerotic occlusive
has been published from developing and developed countries.2
It is estimated that >200 million people have PAD worldwide,
with a spectrum of symptoms from none to severe.2
disease of the lower extremities. Other terms used for this
condition are peripheral vascular disease, peripheral arterial Symptom Assessment in PAD
occlusive disease, and lower extremity arterial disease. Most It has been long recognized that an insufficient blood supply to
of the existing literature on the epidemiology of PAD comes the legs could cause pain and dysfunction in the same way that
from highly developed countries. Recently, new information coronary artery disease could lead to angina. This type of pain
Original received September 3, 2014; revision received November 10, 2014; accepted November 14, 2015. In February 2015, the average time from
submission to first decision for all original research papers submitted to Circulation Research was 13.9 days.
From the Division of Preventive Medicine, Department of Family and Preventive Medicine, Division of Cardiology, Department of Medicine, University
of California, San Diego, La Jolla, CA (M.H.C.); Department of Cardiology, Dupuytren University Hospital, Limoges, France (V.A.); and INSERM 1094,
Tropical Neuroepidemiology, Limoges School of Medicine, Limoges, France (V.A.).
Correspondence to Michael H. Criqui, MD, MPH, Department of Family and Preventive Medicine, University of California, 9500 Gilman Dr, MC 0607,
La Jolla, CA 92093. E-mail mcriqui@ucsd.edu
© 2015 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.116.303849
1509
1510 Circulation Research April 24, 2015
the patient’s level of activity. In addition, many patients who

Nonstandard Abbreviations and Acronyms
do have ischemic pain have atypical symptoms, including pain
AA African Americans reported as beginning at rest.4,5
ABI ankle-brachial index
ARIC Atherosclerosis Risk in Communities Ankle-Brachial Index
BMI body mass index Because of the limitations of leg pain assessment, more ob-
CHS Cardiovascular Health Study jective measures are important. The measurement of blood
CVD cardiovascular disease pressure at the ankle was proposed as a test for PAD as early
CHD coronary heart disease as 19506 and led to the development of the ankle-brachial in-
CRP C-reactive protein dex (ABI). The ABI is the ratio of the systolic blood pres-
HDL-C high-density lipoprotein cholesterol sure at the ankle to that in the arm. An abnormally low value
HPFS Health Professionals Follow-up Study of ABI is indicative of atherosclerosis in the leg. An ABI of
HR hazard ratio ≤0.90 is commonly used in both clinical practice and epide-
IC intermittent claudication miological research to diagnose PAD, both symptomatic and
MESA Multi-Ethnic Study of Atherosclerosis asymptomatic. IC has been shown to have a low sensitivity
NHW non-Hispanic whites but a high specificity for an abnormal ABI. For example, in
PAD peripheral artery disease the Rotterdam Study, 99.4% of subjects with an ABI of ≥0.9
PAOD peripheral arterial occlusive disease did not have claudication; and among subjects with an ABI
SDPS San Diego Population Study
of <0.9 only 6.3% had claudication.7 In a study of elderly
tHcy total homocysteine
women in the United States, the percentages were 93.3% and
18.3%, respectively.8 Thus, PAD based on the ABI criteria is
much more common than IC in the population. To validate
the ABI, previous studies compared the ABI-based diagnosis
is known as intermittent claudication (IC) and is characterized
with angiography, which was considered the gold standard for
as leg pain associated with walking and relieved by rest. IC determination of atherosclerosis in the legs. Two such studies
is generally indicative of exercise-induced ischemic leg pain, are often cited, in which the sensitivity and specificity of the
primarily in the calf, caused by PAD. Previous studies of PAD ABI were shown to be in the 97% to 100% range.9,10 However,
focused primarily on IC as a marker for PAD. Many patient because angiography presents some risk to patients, it was not
questionnaires have been developed to identify IC and to dis- ethical to perform angiography on patients who were not sus-
tinguish it from other types of leg pain. The first of these was pected to have PAD. Therefore, these studies involved com-
the Rose questionnaire, also referred to as the World Health parisons of patients with angiographically confirmed PAD
Organization questionnaire.3 The San Diego Claudication with young, healthy patients assumed not to have PAD. The
Questionnaire is a modification of the Rose questionnaire sensitivities and specificities calculated are therefore based on
that additionally captures information on the laterality of the ability of the ABI to discriminate between extremes of dis-
symptoms.4 A validated, shortened revision of the San Diego ease and wellness. If measured among patients seen in routine
Claudication Questionnaire is shown in Table 1. Importantly, clinical practice or the population in general, the specificity of
many people with PAD report no symptoms, including some the ABI remains in the 97% range, but the sensitivity is lower,
patients with moderately severe disease. Reporting of leg pain closer to 80%,11 in part due to some patients with PAD with
can be influenced by factors other than PAD severity, such as stiff ankle arteries and false-negative ABIs.12 The ABI has also
Table 1. San Diego Claudication Questionnaire, Brief Version

Circle Answer
1. Do you get pain or discomfort in either Right leg Yes No
leg on walking? Left leg Yes No
(if no, stop)
2. Does this pain ever begin when you are Right leg Yes No
standing still or sitting? Left leg Yes No
3. Does this pain include your calf/calves? Right leg Yes No
Left leg Yes No
4. Do you get it when you walk at an ordinary Right leg Yes No
pace on the level? Left leg Yes No
5. What do you do if you get it when you are Right leg Stop or slow down Continue on
walking? Left leg Stop or slow down Continue on
6. What happens to it if you stand still? Right leg Lessened or relieved Unchanged
Left leg Lessened or relieved Unchanged
Determine pain category separately for each leg as follows: (1) no pain: 1=no; (2) pain at rest: 1=yes and
2=yes; (3) noncalf: 1=yes, 2=no, and 3=no; (4) classic: 1=yes, 2=no, 3=yes, 4=yes, 5=stop or slow down, and
6=lessened or relieved; and (5) atypical calf: 1=yes, 2=no, and 3=yes and not classic.
Criqui and Aboyans Epidemiology of Peripheral Artery Disease 1511
been shown to have high intra- and inter-rater reliability.13 In In line with this, recent data document that in normal subjects,
practice, the ABI is measured using a blood pressure cuff, a the influence of height on the ABI is small.17 On average, ABIs
standard sphygmomanometer, and a Doppler instrument to are slightly lower in women independent of height and slight-
detect pulses. Technical considerations in measuring the ABI ly lower in African Americans (AA).17 This has little clinical
include the choice of ankle pressure for the ABI numera- effect on the diagnosis of PAD at an individual level but may
tor and the choice of arm pressure for the ABI denominator. contribute to an overestimation of PAD prevalence in popula-
Many protocols have been suggested. In an attempt to pro- tion studies. Perhaps, the most significant limitation is arterial
vide the best evidence base for measuring the ABI, an interna- stiffness noted above. Recommendations for PAD assessment
tional working group was assembled. The recommendations when the ABI is >1.40 are given in Table 2.
were published as an American Heart Association Scientific
Statement in 2012.14 Selected key recommendations are sum- Incidence and Prevalence of PAD
marized in Table 2. The recommendations are grouped into 5 The study of PAD epidemiology raises many methodological
categories: (1) measurement of ABI, (2) measurement of sys- issues that should be kept in mind while reviewing the litera-
tolic pressures of the 4 limbs, (3) calculation of ABI, (4) use ture. As discussed earlier, the definition of disease has evolved
and interpretation of the ABI if clinical presentation of PAD, over time, with earlier studies focusing more on IC, as mea-
and (5) interpretation of ABI as a marker of subclinical cardio- sured using Rose and other criteria, and later studies using the
vascular disease (CVD) and risk in asymptomatic individuals. ABI, with a value of ≤0.90, now widely used to define disease.
Within each of these 5 categories, specific issues concerning Uncommon among younger people, the prevalence of PAD
measurement and interpretation of the ABI are addressed. rises sharply with age and affects a substantial proportion of
As a diagnostic test for PAD, the ABI has several limita- the elderly population. Allison et al18 estimated the ethnic-spe-
tions. Occlusive disease distal to the ankle is not detected by cific prevalence in the United States combining data from 7
the ABI; other measures, such as pressure ratios using pres- community-based studies. These studies included representa-
sures measured in the toe, are required for detecting such dis- tion from 5 ethnic groups: non-Hispanic whites (NHW), AA,
tal disease. The ABI is also sensitive to the patient’s height, Hispanics, Asian Americans, and Native Americans. Evidence-
with taller patients having slightly higher ABIs; it is unlikely based adjustments were used for studies that did not consider
that these differences are related to real differences in PAD.15,16 possible subclavian stenosis, previous revascularization for
Table 2. Consensus Recommendations on ABI Measurement

(5) Interpretation of ABI as

(4) Use and Interpretation of a Marker of Subclinical CVD
(2) Measurement of Systolic the ABI if Clinical Presentation and Risk in Asymptomatic
Steps (1) Measurement of ABI Pressures of the 4 Limbs (3) Calculation of ABI of PAD Individuals
1 Doppler Method Sequence of ABI at rest For each leg: divide higher ABI used as a first-line ABI provides incremental
SBP in each arm First arm of the PT or DP pressure noninvasive test for diagnosis information beyond standard
SBP in each ankle First PT artery by higher of the right or of PAD risk scores in predicting future
left arm SBP CVD events
First DP artery
Other PT artery
Other DP artery
Other arm
2 Cuff size If the SBP of first arm is As a diagnostic tool ABI≤0.90 is the threshold ABI≤0.90 or ≥1.40=increased
Width at least greater than SBP of other for patients with PAD for confirming diagnosis of risk of CVD events and mortality
40% of limb arm by at least 10 mm Hg, symptoms, each leg is lower-extremity PAD
circumference repeat BP of first arm and reported separately
disregard first measurement
3 Ankle cuff placement … As a prognostic marker for If ABI>0.90 with clinical ABI between 0.91 and 1.00 is
Just above the CVD, use lower of the left suspicion of PAD=use borderline for CVD risk; further
malleoli and right ABIs (exception: postexercise ABI or other evaluation is appropriate
Straight wrapping noncompressible arteries) noninvasive tests
method
4 Open lesions covered When ABI between Postexercise ankle pressure …
with impermeable 0.80 and 1.00, it is decrease of >30 mm Hg or
dressing reasonable to repeat the postexercise ABI decrease
measurement of >20%=diagnostic criteria
for PAD
5 … … … If ABI>1.40 with clinical …
suspicion of PAD=use toe
brachial index or other
noninvasive tests
ABI indicates ankle-brachial index; BP, blood pressure; CVD, cardiovascular disease; DP, dorsalis pedis; MI, myocardial infarction; and PAD, peripheral artery
disease; PT, posterior tibial; and SBP, systolic blood pressure.
70%
incidence was 1.7 per 1000 at the age of 40 to 54 years; 1.5 per
60% 1000 at the age of 55 to 64; and 17.8 per 1000 at the age of ≥65.
50%
Annual incidence in women was higher: 5.9, 9.1, and 22.9 per
1000, respectively, for the same age groups.25 Sex differences
Prevalence
40%
in the incidence and prevalence of PAD are less clear than those
30% in other CVDs. IC incidence and prevalence have usually been
20%
found to be higher in men than in women. For example, in the
Framingham Study, annual IC incidence for all ages combined
10%
was 7.1 per 1000 in men versus 3.6 per 1000 in women, for a
0% male to female ratio of 1.97.23 In the Framingham Offspring
40 50 60 70 80 90
Age (years) Study, IC prevalence was 1.9% in men versus 0.8% in wom-
NHW AA HS AS AI
en (ratio, 2.38), whereas in the Rotterdam Study, it was 2.2%
Figure 1. Ethnic-specific prevalence of peripheral arterial in men versus 1.2% in women (ratio, 1.83).7,26 However, the
disease in men in the United States.18 AA indicates African Edinburgh Artery Study and the Limburg PAOD Study found
Americans; AI, American Indians; AS, Asian Americans; HS,
Hispanics; and NHW, non-Hispanic whites. much lower male to female ratios of IC prevalence of 1.1 and
1.2, respectively.15,20 The case for an excess of disease among
men is less clear for PAD diagnosed based on ABI. This is true
PAD, or both. The results for men are shown in Figure 1. PAD even in those studies finding a clear male excess with respect
was uncommon before the age of 50 years. Rates rose sharply to IC. For example, in the Framingham Offspring Study, PAD
with age, such that by the age of 80, rates were in the 20% based on ABI was found in 3.9% of men and 3.3% of wom-
range. Strikingly, the rate for AA was about twice that of NHW en, for a ratio of 1.18.26 In the Rotterdam Study, ABI-based
at any given age. Rates for Hispanics, Asian Americans, and PAD was actually lower in men than in women, with preva-
Native Americans were similar for those in NHW. Figure 2 lence of 16.9% and 20.5% for a ratio of 0.82.7 The Limburg
shows the data for women and reveals similar trends, although PAOD Study, which reported a low male to female ratio for IC,
Native Americans have a rate nearly as high as AA. However, reported a similarly low ratio of 1.1 for ABI-based PAD.20 A
the data for Native-American women are limited and come population-based study from Southern Italy found prevalence
from a single study, the Strong Heart Study. Overall, rates were of PAD based on an ABI of <0.90 to be similar in men and
similar for men and women. Worldwide, high-income devel- women, with male to female ratios by the age of 0.89 to 0.99.27
oped countries report similar rates, although somewhat higher In the Cardiovascular Health Study (CHS), an ABI of <0.90
rates have been reported from the Netherlands.7,19,20 Recently, was somewhat more prevalent in men (13.8%) than in women
global estimates of PAD prevalence were published.2 In gen- (11.4%; ratio, 1.21), but the association of disease with sex was
eral, men and women from low-income and middle-income not significant after adjustment for age and CVD status.28 The
countries have modestly lower PAD rates than those in high- greater male excess observed for symptomatic versus ABI-
income countries. diagnosed disease seems to be related to severity of disease. A
Estimates of PAD incidence are reported somewhat less fre- prevalence study in Southern California found that the excess
quently in the literature, with more data based on IC incidence of disease among men increased with the severity of PAD.29 A
than on the ABI. At ≈60 years of age, annual IC incidence report from the Multi-Ethnic Study of Atherosclerosis (MESA)
rates in men have varied from a low value of 0.2% in Iceland21 showed that PAD prevalence (ABI<0.90) was the same in men
to a high value of 1.0% in Israel.22 Data from Framingham and women (3.7%), but borderline values of ABI (0.90–0.99)
Study show IC annual incidence increasing from <0.4 per were much higher in women (10.6% versus 4.3%).30 Other ex-
1000 in men aged 35 to 45 years to 6 per 1000 in men aged planations related to the discrepancies in the sex ratio between
65+ years.23 In women, IC incidence was about half that in IC- and ABI-defined PAD might be related to more frequent
men, although rates in men and women were similar by the
age 65 to 74 years.23 A higher incidence of 1.6% per year was
70%
reported among men and women aged 55 to 74 years in the
Edinburgh Artery Study; however, this study did not apply 60%
strict Rose criteria for probable IC.24 In the Reykjavik Study, 50%
Ingolfsson et al21 used Poisson regression techniques to con-

Prevalence
40%
clude that IC rates among Icelandic men dropped significantly
30%
between 1968 and 1986; among 50-year-old men, their esti-
mate of the rate of IC dropped from 1.7 per 1000 per year in 20%
1970 to 0.6 per 1000 per year in 1984, whereas in men aged 10%
70 years, the rate of IC dropped from 6.0 to 2.0. The authors 0%

attributed this to decreased smoking and cholesterol levels. 40 50 60 70 80 90
Age (years)
There are few studies of PAD incidence based on ABI, given
NHW AA HS AS AI
the time and resources required to periodically retest study
subjects for incident disease. In the Limburg peripheral arterial Figure 2. Ethnic-specific prevalence of peripheral arterial
disease in women in the United States.18 AA indicates African
occlusive disease (PAOD) Study, incidence rates for PAD were Americans; AI, American Indians; AS, Asian Americans; HS,
based on 2 ABI measurements of <0.95. Among men, annual Hispanics; and NHW, non-Hispanic whites.
presentation of some patterns of atypical pain in women,5 as large studies.21,22,25,35–42 Although the discussion draws on data
well as a modestly intrinsic lower ABI in women.17 In general, from many other studies, data are presented from these 5 in-
more severe disease as manifested by lower ABIs or symptom- dex studies across all the conventional CVD risk factors to
atic disease is more common in men. A recent study evaluated provide some consistency and comparability for the reader.
a large representative US sample of ≈12 million insured adults The effect of age and sex on PAD incidence and prevalence is
for PAD and critical limb ischemia incidence and prevalence discussed above.
based on insurance claims.31 From 2003 to 2008, the annual
incidence of PAD was 2.35%, and for critical limb ischemia, it Cigarette Smoking
was 0.35%. The prevalence of PAD was 10.69%, and for criti- Smoking is one of the strongest risk factors for PAD in virtu-
cal limb ischemia, it was 1.33%. ally all studies. Studies vary as to the measurement of smoking,
Global data on trends in PAD prevalence between the years often combining a categorical assessment of smoking status
2000 and 2010 were recently published.2 Over that period, the (current, past, or never) with some measures of current or his-
number of individuals with PAD increased by 28.7% in low- torical volume of smoking, such as pack-years. However, even
income and middle-income countries and by 13.1% in high- with some type of additional adjustment for volume of smok-
income countries. ing, current smoking versus nonsmoking has been shown to
at least double the odds of PAD in most studies, with some
estimates as high as a 4× greater risk among smokers than oth-
PAD Risk Factors ers. Among the index studies, current smoking (versus never
The strongest epidemiological evidence for a causal relation- or former/never) resulted in 1.9 to 3.4× higher odds of PAD in
ship between disease and putative risk factors comes from the 3 studies using such categorization; however, in 2 of these
studies of incident disease. Such studies usually involve the studies, the models also included pack-years of smoking as a
measurement of risk factors at a baseline examination, with significant variable (Table 4). All of the large, population-based
subsequent tracking of incident disease among the subjects. studies that were reviewed found a significant, independent as-
Acute events, such as myocardial infarction and stroke, lend sociation between PAD and smoking. According to recent data
themselves to such study because the date of onset of disease on incident cases of clinical PAD in US male professionals,
is generally documented in the records of healthcare provid- smoking is the most contributive risk factor for occurrence of
ers and recalled by subjects. Conversely, the onset of PAD as PAD, with a population attributable fraction of 44%.42
defined by ABI is often asymptomatic, and in any case, it is Cessation of smoking among patients with IC has been
unlikely to be documented other than through periodic re-ex- shown to improve various functional and physiological
amination of all the subjects, which involves substantial time
measures related to PAD, as well as reducing mortality.43,44

and expense. For that reason, many studies of PAD risk fac- However, because symptomatic patients with PAD have long
tors are based on cross-sectional associations, that is, the asso- been advised to quit smoking, it is possible that observational
ciation between current disease status and current risk factor comparisons of patients who quit smoking with those who do
measurements. Although such studies are potentially informa- not are confounded by other differences in compliance with
tive, the reported associations cannot conclusively prove cau- medical advice between the 2 groups. Randomized trials of
sation because it is not known whether the risk factor preceded this question would raise ethical issues. However, substantial
the disease or vice versa. Caution should, therefore, be exer- bias is unlikely given the large effect size for cigarette smok-
cised in reviewing the results of such cross-sectional studies, ing. In the Health Professionals Follow-up Study (HPFS),
particularly where reverse causation is plausible. For exam- smoking was associated with increased risk of incident clini-
ple, low physical activity might cause IC, but IC might just as cal PAD even after 20 years of smoking cessation, although
plausibly cause low physical activity. It is necessary to adjust this association was substantially diminished beyond 10 years
for multiple potential risk factors in a single statistical model after quitting smoking cigarettes.42
to accurately estimate the unique contribution of any single There are limited data on the association of passive smok-
risk factor because the potential risk factors for PAD are them- ing and PAD. In a Chinese study conducted with women who
selves interrelated in various ways. The estimates presented have never smoked, the hazard ratio (HR) for PAD (either IC
here are based on such multiple adjustments for all traditional or ABI<0.90) after secondhand smoke exposure was signifi-
PAD risk factors, except as noted. Null findings may indicate cant at 1.67, with a significant dose–response relationship,
the lack of a real association but may also be based on insuf- both for the amount and the duration of exposure.45
ficient sample size. Most of the null findings discussed below Similar relationships were reported from 2 studies of never
are based on the failure of the risk factor of interest to remain smokers in Scotland. The first study used reported secondhand
statistically significant in stepwise regression models. The fol- smoke as the exposure variable, whereas the second used sali-
lowing discussion of risk factors focuses on the results from vary cotinine measures.46,47 Smoking seems to have an even
5 large epidemiological studies,26,28,32–34 which are referred more prominent role in PAD than in other atherosclerotic dis-
to as index studies (Table 3). These studies each had >3000 eases. In a comparison of risk factors conducted in the same
subjects drawn from the general population and included both large cohort, Fowkes et al36 found smoking to be associated
men and women. These studies are similar enough in their with a significantly higher relative risk for PAD compared
selection and manner of measuring risk factors, and in their with other CVDs; smoking was the only traditional CVD risk
statistical analyses, to allow reasonable comparisons for most factor for which the odds ratio differed significantly between
of the common risk factors. Table 3 also includes 11 other PAD and other CVDs.
Table 3. Studies of Peripheral Artery Disease in Populations

No. of
Study Name First Author, Year* Subjects Country Population Study Design PAD End point
Index studies
Cardiovascular Health Study Newman, 199328 5084 United States Aged 65+ Cross-sectional ABI<0.9
Framingham Study Murabito, 199732 5209 United States Cross-sectional IC
Rotterdam Study Meijer, 200033 6450 Netherlands Cross-sectional ABI<0.9 (<0.7 also
studied)
Framingham Offspring Study Murabito, 200226 3313 United States Longitudinal ABI<0.9
Multi-ethnic Study of Allison, 200634 6653 United States Cross-sectional ABI<0.9
Atherosclerosis
Other large studies
Quebec Cardiovascular Dagenais,199135 4570 Canada Men only Longitudinal IC
Study
Edinburgh Artery Study Fowkes, 199236 1592 Scotland Cross-sectional ABI and reactive
hyperemia
Israeli Ischemic Heart Bowlin, 199422 10 059 Israel Middle-aged men Longitudinal IC projected
Disease
Reykjavik Study Ingolfsson, 199421 9141 Iceland Men only Longitudinal IC
Honolulu Heart Program Curb, 199637 3450 United States Japanese Cross-sectional and ABI<0.9
American men longitudinal
Limburg PAOD Study Hooi, 200125 2327 Netherlands Longitudinal ABI<0.95
Women’s Health and Aging McDermott, 200038 930 United States Women aged 65+ Longitudinal ABI<0.9
Study
Physicians’ Health Study Ridker, 200139 14 916 United States Male physicians Nested case–control IC or PAD surgery
San Diego Population Study Criqui, 200540 2343 United States Multiethnic Cross-sectional ABI≤0.9, abnormal
waveform, PAD
revascularization
National Health and Nutrition Pande, 201141 7458 United States American men Longitudinal ABI≤0.9
Examination Survey and women aged
40+
Health Professionals Follow- Joosten, 201242 51 529 United States Male health Longitudinal Clinical PAD†
Up Study professionals
ABI indicates ankle-brachial index; IC, intermittent claudication; PAD, peripheral artery disease; and PAOD, peripheral arterial occlusive disease.
*Where multiple articles were published, this refers to the article most frequently referenced herein.
†Includes limb amputation or revascularization, angiography with vascular obstruction ≥50%, ABI≤0.90, or physician-diagnosed PAD.
Diabetes Mellitus mellitus was only of borderline significance, and impaired

Diabetes mellitus is strongly associated with an elevated risk glucose tolerance was not associated with PAD.19 However,
of PAD. Four of the 5 index studies found diabetes mellitus, one study in subjects aged >65 years reported a significant
dichotomized based on different criteria, to be associated with association between the homeostasis model assessment and
PAD after multivariable adjustment, with odds ratios ranging
from 1.89 to 4.05.28,32–34 However, the Framingham Offspring Table 4. Cigarette Smoking and Peripheral Artery Disease
Study found such an association on an age- and sex-adjusted
basis but not in multivariable models.26 Despite its strong as- 95% CI
Odds
sociation with PAD but because of its lower prevalence in Study Variable Ratio Low High
populations when compared with other traditional risk factors, Framingham Study Per current pack/day 1.94 1.69 2.25
the population attributable fraction of type-2 diabetes mellitus Framingham Current smoker 2.00 1.10 3.40
for incident PAD was estimated at 14% in a longitudinal study Offspring Study (vs. former or never)
on US professionals.42 Among other large, population-based Pack-years of smoking 1.03 1.02 1.03
studies, multivariable logistic regression models have often Cardiovascular Current smoker 2.55 1.76 3.68
shown a relationship with diabetes mellitus as a categorical Health Study (vs. former or never)
variable19,22,25,37,40 or various blood sugar measures as linear Pack-years of smoking 1.01 1.01 1.02
variables.48
Rotterdam Study Current smoker (vs. never) 2.69 1.67 4.33
More severe or longstanding diabetes mellitus seems to
Former smoker (vs. never) 1.15 0.75 1.78
be more strongly related to PAD. In the Hoorn Study, it was
shown that known diabetes mellitus was associated with PAD Multi-ethnic Study Current Smoker (vs. never) 3.42 2.48 4.73
of Atherosclerosis
in multivariable analysis, whereas newly diagnosed diabetes
incident PAD.49 Studies conducted in patients with diabetes studies, total cholesterol has usually been found to be associat-
mellitus have shown that duration of diabetes mellitus, level of ed with PAD21,22,36,37 with occasional null findings in multivari-
glycemic control assessed by glycated-hemoglobin, and use able analyses in which other lipid measures are considered.48,60
of insulin are associated with PAD.50–53 According to the HPFS, the population attributable fraction for
Outcomes of PAD in diabetic patients have been shown to PAD related to hypercholesterolemia is at 17%.42
be worse. In one study, diabetic patients with PAD were 5× HDL-C has been shown to be protective against PAD
more likely to have an amputation than other patients with in most studies where it was evaluated, usually in models
PAD; they also had >3× the odds of mortality.54 There is also that also considered total cholesterol. HDL-C was included
some evidence to support a somewhat different anatomic dis- among the potential risk factors in 3 of the 5 index studies
tribution of disease, with more disease in arteries distal to the and the total cholesterol/HDL-C ratio in the fourth, and it was
knee in diabetic versus nondiabetic patients.54,55 Beyond isch- significantly associated with PAD in multivariable analysis
emia, infection has an important role aggravating the risk of in all 4. In 2 studies, both HDL-C and total cholesterol were
amputation in these patients.56,57 significant in multivariable analysis, whereas in 1 study,
HDL-C (but not total cholesterol) was significant. Other
Hypertension and Blood Pressure studies have also shown a protective effect of HDL-C.37,60
The association of hypertension with PAD has been demon- Bowlin et al22 found that non–HDL-C (total cholesterol
strated in most studies in which blood pressure was studied. minus HDL-C) was significantly associated with incident
All 5 of the index studies reported a significant association IC in a large cohort of Israeli men; neither total cholesterol
between hypertension as a categorical variable and PAD. nor HDL-C were significantly associated with disease in
The lowest reported odds ratio was 1.32 as reported in the models that included non–HDL-C. In a comparison of
Rotterdam Study; this is somewhat understated relative to oth- incident cases of IC with healthy controls in the Physician’s
ers, as it was based on a model that included both a categori- Health Follow-up Study (PHFS), Ridker et al39 found that
cal hypertension variable and an adjustment for systolic blood the ratio of total cholesterol/HDL-C was the lipid measure
pressure level, which was also significant.33 Other than this, most strongly associated with disease, with patients in the
odds ratios for hypertension ranged from 1.50 to 2.20. highest quartile having 3.9× the IC risk of patients in the
Most other large, population-based studies have also found lowest quartile; screening for other lipid fractions was judged
a significant, independent association of hypertension or sys- to have little clinical usefulness beyond measurement of this
tolic blood pressures with PAD.25,35,36,40,48 Where both systolic ratio. Previous case–control studies showed a consistent
and diastolic pressures were considered, systolic pressure was relationship between triglycerides and PAD, suggesting
usually found to be associated with PAD, whereas diastolic a uniquely strong relationship with PAD; however, large,
pressure was not significantly associated.28,33,58 Although the population-based cohort studies using multivariable
relative risks associated with hypertension are modest in some modeling later called this into question.36,61 Among the index
studies, its high prevalence, particularly among older patients, studies, only 2 included triglycerides among the potential risk
makes it a significant contributor to the total burden of PAD factors evaluated. In both cases, triglycerides were significant
in the population. For example, in one large study from the in univariate analysis but dropped out of multivariable
Netherlands, the odds ratio for hypertension was 1.32, but its models based on stepwise logistic regression.26,28 Similarly,
attributable fraction (a measure of the proportion of PAD in in the Edinburgh Artery Study cohort and in a large study
the population attributable to hypertension) was 17.0%.33 In of geriatric patients in the United States, triglycerides were
the Framingham Study, 30% of the risk of IC in the popula- not significantly associated with PAD after adjustment for
tion was attributable to blood pressure in excess of 160/100 other lipid measures.36,60 However, other studies have shown
mm Hg.32 An even higher population risk attributable to hyper- triglycerides to be significantly and independently associated
tension, 41%, was recently reported in the HPFS.42 In these 3 with PAD in multivariable analysis.48,51,62 There is also some
latter studies, hypertension was second only to current smok- evidence suggesting that elevated triglycerides may have a
ing as the most contributive risk factor for PAD in population. role in disease progression or more severe PAD.36,58
In summary, although total cholesterol, HDL-C, and tri-
Dyslipidemia glycerides all seem to be associated with PAD on a univari-
In recent studies, the recognition that the total cholesterol to ate basis, in multivariable analysis, triglycerides frequently
high-density lipoprotein cholesterol (HDL-C) ratio is the best drop out as an independent risk factor. It is unclear whether
lipid measure of risk,59 along with the increasing use of medi- total cholesterol is the strongest independent risk factor for
cation, has led to analyses that use both these variables in the PAD; in one comparison of patients with PAD with healthy
same model40 or combine the ratio with medication use in a controls, it was found that mean total cholesterol did not differ
single variable, for example, dyslipidemia.34 Total cholesterol significantly, whereas triglycerides, very low-density lipopro-
has been the most widely studied lipid measure as a potential tein cholesterol, low-density lipoprotein cholesterol, HDL-C,
risk factor for PAD. Total cholesterol was examined as a poten- and the total-cholesterol/HDL-cholesterol ratio all did.63 Total
tial risk factor in 4 of the index studies, and it was significantly cholesterol and HDL-C seem to provide distinct information,
associated with PAD in multivariable analysis in 328,32,33; in the and they lend themselves to summarization in a single ratio.
remaining study, total cholesterol was significant in univari- Irrespective of results from multivariable analysis, simple de-
ate analysis but dropped out of multivariable models in which scriptive statistics and clinical observation both suggest that
other lipid measures were considered.26 Similarly, in other patients with PAD are frequently diabetic or insulin resistant,
with the typical dyslipidemia of insulin resistance (ie, low lead to weight loss, allowing for a spurious inverse correlation
HDL-C and high triglycerides). between obesity and PAD. Ix et al64 evaluated this question in
the CHS of adults aged ≥65 years. In cross-sectional analysis,
Obesity each 5-U increase in BMI was inversely associated with PAD
To date, the preponderance of evidence fails to support a (PR [prevalence ratio], 0.92). However, among people in good
consistent, independent positive association between obe- health who had never smoked, the direction of association
sity and PAD. In one of the few large studies with a positive was opposite (PR=1.20). Similar results were observed be-
finding, Bowlin et al22 estimated an odds ratio of 1.24 (95% tween BMI calculated using weight at the age of 50 years and
confidence interval, 1.05–1.46) for incident claudication re- PAD prevalence (prevalence ratio, 1.30), and between BMI at
lated to a 5.0-kg/m2 difference in body mass index (BMI) in baseline and incident PAD events occurring during follow-up
a study of 10 059 Israeli men. Three of the index studies and (HR, 1.32), among never smokers in good health. Thus, the
many other large, population-based studies have failed to find reported inverse associations between BMI and PAD may be
a significant association between obesity and PAD or claudi- artifactual.
cation after multivariable adjustment.21,25,26,33,34,60 There have As in coronary artery disease epidemiology, there is some
also been many studies, including the other 2 index studies, evidence to suggest that central adiposity may be more closely
in which higher relative weight or BMI was actually shown to related to an increased risk of PAD. Vogt et al8 found that, af-
be protective against PAD. In the Framingham Study, claudi- ter adjustment for BMI, higher waist/hip ratio was associated
cation was significantly inversely related to relative weight in with significantly higher risk of PAD. In a group of patients
men in multivariable analysis and seemed to have a U-shaped with diabetes mellitus, it was shown that waist/hip ratio, but
nonlinear relationship with relative weight in women.23 In an not BMI or body fat percentage, was associated with PAD.51
analysis from the Edinburgh Artery Study, BMI was signifi-
cantly associated with less disease in preliminary multivariable Alcohol Consumption
analysis, although BMI was excluded from the article’s final Evidence for a protective effect of light-to-moderate alcohol
multivariable model because it “suggested a counterintuitive consumption, as seen in coronary heart disease (CHD), is less
effect.”36 The CHS found higher BMI to be significantly pro- consistent for PAD. Two of the 5 index studies considered alco-
tective against PAD after multivariable adjustment in a large hol intake; neither showed alcohol to be significantly associated
sample of Medicare beneficiaries.28 BMI was significantly with PAD in either age- and sex-adjusted or multivariable mod-
protective against PAD (defined based on a combination of els.26,33 However, in a later analysis of data from one of these
ABI, Doppler flow curves, and history of surgery) in the Hoorn studies, a significant protective effect was found in women but
not in men.65 Conversely, a protective effect of alcohol was seen
Study.19 Similarly, the odds of PAD among subjects in the high-

est quintile of BMI compared with the lowest quintile were in men but not in women in the Edinburgh Artery Study, but
found to be significantly reduced in a cross-sectional analysis this association disappeared after adjustment for social class.66
of elderly Japanese American men.37 Subjects with higher BMI In Native Americans, a protective effect of alcohol was seen
were again shown to be at significantly lower risk of PAD in a in multivariable analysis,67 but in elderly Japanese American
study of Taiwanese subjects with diabetes mellitus.52 Finally, men, alcohol intake was found to increase rather than decrease
the multi-ethnic San Diego Population Study (SDPS) reported the risk of incident PAD.37 In a large Chinese population study,
a significant inverse association of BMI and PAD.40 low alcohol intake was associated with decreased prevalence of
Obesity has been implicated in the causes of other risk fac- PAD in men but not in women.68 Data from the PHFS suggest
tors for PAD, such as hypertension, type II diabetes mellitus, that a protective effect related to moderate alcohol consumption
and dyslipidemia. In epidemiology, adjusting for factors that may exist.69 In that study, there was no univariate association
are on the causal pathway between a risk factor and disease is between alcohol and claudication incidence, but adjustment for
known to attenuate the observed strength of that risk factor. cigarette smoking unmasked a significant protective associa-
Therefore, estimates of risks related to obesity in multivari- tion, reflecting the positive correlation of alcohol consumption
able models are estimates of the risk of obesity that artifi- with smoking, a strong risk factor for PAD.
cially ignore most of the mechanisms by which obesity might Race and Ethnicity
reasonably cause PAD. In a few cases, unadjusted models or Data on the association of race with PAD are limited because
models adjusted only for age and sex show a significant as- many of the large studies of PAD have been conducted in NHW
sociation with PAD, although obesity was nonsignificant or groups. Several studies suggest a higher risk of PAD among
protective after multivariable adjustment.26,36,60 However, in blacks. A study conducted in elderly native Africans in 2 cit-
other studies, obesity was found to be either protective or non- ies in Central Africa found high rates of PAD, 15% and 32%.70
significant even in unadjusted models or models adjusted only The CHS, a study of 5084 Medicare beneficiaries in the United
for age and sex.23,28,33,37,48 Thus, the failure to find more cases States, found that nonwhite (mostly black) race was associated
of positive association between PAD and obesity is not simply with an odds ratio of 2.12 for PAD after adjustment for tradition-
an artifact of adjusting for factors on the causal pathway in al risk factors.28 A study of 933 women aged ≥65 years found
multivariable modeling. a higher percentage of black subjects among the PAD (36.3%)
Unaccounted for in the multivariable analyses just cited is versus non-PAD (24.8%) groups.38 In the Atherosclerosis Risk
possible residual confounding by cigarette smoking, which in Communities (ARIC) study, Zheng et al71 found that PAD
is strongly associated with both PAD and lower BMI. In ad- prevalence was higher in AA versus whites in both men (3.3%
dition, chronic illness in older patients, including PAD, may versus 2.3%) and women (4.0% versus 3.3%). The MESA
reported a multivariable odds ratio of 1.67 for blacks versus missed significance after adjustment for other novel risk fac-
NHW.34 The SDPS reported an odds ratio of 2.34 for blacks tors.34 A nested case–control study using the PHFS cohort failed
versus NHW after adjustment for hypertension and diabetes to find any association between quartiles of fasting tHcy and
mellitus,40 and additional analyses also showed no evidence of IC.39 A case–control study of young women in the Netherlands
a greater sensitivity of blacks to traditional CVD risk factors. also failed to find any significant association between fasting
Finally, a synthesis of 3 studies addressing this question report- homocysteine and symptomatic PAD.76 More recently, 2 nested
ed odds ratios of 2.3 to 3.1 for blacks versus NHW adjusted case–control studies within the Nurses Health Study and the
for age and sex; odds ratios of 1.7 to 2.9 after adjustment for HPFS cohorts found homocysteine levels positively associated
traditional risk factors; and odds ratios of 1.5 to 2.0 after further and dietary folate intake inversely associated with risk of PAD
adjustment for novel risk factors, including inflammatory risk in men but not in women.79 Among patients with PAD, disease
factors.72 Thus, this association is in part explained by tradition- progression based on ABI was not significantly different in pa-
al risk factors and in part by novel risk factors, but there is an tients with the highest and lowest 20% of homocysteine levels.80
unexplained residual difference. Interestingly, hospital-based Although it is still possible that homocysteine may be an inde-
studies suggest that the anatomic distribution of disease may pendent risk factor for PAD, it seems that the previous results
differ in blacks, with a higher percentage of distal disease in summarized in the 1995 meta-analysis may have overstated the
black subjects, even after adjustment for diabetes mellitus and importance of homocysteine. Accordingly, a more recent meta-
other cardiovascular risk factors.73 analysis of 14 studies in 2009 showed that homocysteine was
Data on other races and ethnic groups are more limited. A significantly elevated (pooled mean difference, +4.31 μmol/L)
study of Native Americans suggested PAD prevalence com- in patients with PAD compared with controls.81 In the same ar-
parable with that in NHW.67 In a study in Honolulu, Hawaii, ticle, the effect of folate supplementation on PAD was evaluated
Asians were reported to have lower PAD prevalence than com- in 8 clinical trials and showed inconsistent findings.
parable NHW subjects.37 Both the MESA and the SDPS data
suggest somewhat lower rates of PAD in Asians and Hispanics C-Reactive Protein and Fibrinogen
compared with NHW.34,40 In a community-dwelling popula- C-reactive protein (CRP) and fibrinogen are 2 inflammatory
tion aged >40 years living in Japan, a low prevalence of PAD markers that have been shown to be associated with PAD in
(1.4%) has been reported.74 many studies. In an analysis from the PHFS, each was found to
be significantly associated with PAD in multivariable models,
Homocysteine with odds ratios for the upper versus lower population quar-
The association of homocysteine with PAD has been exam- tiles of 2.2 for fibrinogen and 2.8 for CRP.39 However, these
ined in many studies, with conflicting results. A 1995 meta- variables are highly correlated. Of the index studies, CRP was
analysis of early case–control studies conducted in the late studied only in the MESA and it was not significant in multi-
1980s and early 1990s suggested an odds ratio of 6.8 for a variable analysis.34 However, fibrinogen was included in 4 of
5-μmol/L difference in fasting total homocysteine (tHcy).75 the 5 studies and was significantly associated with PAD in mul-
To put this in perspective, the differences between the 25th tivariable analysis in 3 of them.26,33,34 Other studies have also
and 75th percentiles of tHcy among controls in the Physician’s reported significant and independent associations of PAD with
Health Study and a study of women in the Netherlands were CRP76 and fibrinogen.37,80
between 3.5 and 4.0 mmol/L.39,76 The 5-mmol/L difference
noted above is, therefore, not unreasonable as the difference Chronic Kidney Disease
between low and high tHcy levels in the population. In that Several studies have shown an association between chron-
light, an odds ratio of 6.8 might make homocysteine the single ic kidney disease defined according to creatinine levels and
most powerful risk factor for PAD. Interestingly, the odds ra- PAD,82–84 particularly in the case of end-stage renal disease re-
tio for PAD in the meta-analysis was strikingly higher than quiring dialysis.85,86 A recent article evaluated the markers of re-
the odds ratios for coronary artery disease and cerebrovascular nal function in nested case–control studies in men and women.87
disease that were <2 in the same study. β2-Microglobulin and cystatin C were both associated with inci-
However, more recent studies have produced much lower dent PAD in men but not in women. Other studies reported poorer
and frequently nonsignificant estimates of the PAD risk asso- outcomes in patients with PAD in the case of concomitant chron-
ciated with homocysteine. In a large European case–control ic kidney disease, both in terms of limb loss and mortality.88–91
study, Graham et al77 estimated an odds ratio of 1.7 for sub-
jects in the top quintile of tHcy for their control group versus Genetic Factors
all other subjects—a result of only borderline statistical signifi- Genetic factors seem to have a role in PAD, but data are
cance. One population-based study from the Netherlands found limited. Wassel et al92 reported that in the SDPS, family his-
an odds ratio of 1.44 for a 5-μmol/L difference in fasting tHcy, tory of PAD was independently and strongly associated with
based on severe PAD involving surgery or an ABI of <0.5.78 PAD prevalence and severity. This indicates a role for ge-
However, an analysis of a subset of the Rotterdam Study co- netic factors or other shared environmental factors, or both,
hort found no significant relationship between tHcy and PAD, contributing to PAD. Similarly, in the Framingham Study, a
based either on the conventional ABI cut-off of 0.9 or on an family history of IC significantly predicted incident IC.93 In
ABI cut-off of 0.7 for severe disease.33 The MESA reported a study of fraternal and identical twins, Carmelli et al94 esti-
a significant association for homocysteine after multivariable mated that 48% of the variability in ABI could be explained
adjustment for traditional risk factors, but the association just by additive genetic effects. It has also been shown that familial
History of CVD
CRP (per 1 mg/dl)
High HDL-cholesterol
High Cholesterol
Smoking (past)
Figure 3. Odds ratios for peripheral artery disease
Smoking (current) in high-income countries (HIC) and low- to middle-
income countries (LMIC).2 BMI body mass index;
Diabetes
CVD, cardiovascular disease, CRP, C-reactive protein;
Hypertension and HDL, high-density lipoprotein.
BMI (per 1 kg/m2)
Male sex
Age (per 10 yrs)
0.5 1 1.5 2 2.5 3
OR (LMIC) OR (HIC) OR (Global)
hypercholesterolemia, a genetic disorder, is related to a higher shingles, mumps, pneumonia, chronic bronchitis, or peptic
prevalence of PAD.95 ulcer, was independently and significantly related to PAD.76
A meta-analysis of 21 genome-wide association studies in Psychosocial factors were found to be associated with PAD
41 692 people evaluated both categorical PAD (ABI≤0.90) and in one large cohort in Scotland,100 whereas in a large study of
the continuous distribution of ABI as outcomes.96 One genome- Israeli men, anxiety, job-related stress, and manner of cop-
wide significant association on chromosome 9p21, rs10757269, ing with job-related conflicts were all significantly related to
was identified for ABI. Two candidate genes for PAD and 1 incident IC even after adjustment for traditional risk factors.22
single nucleotide polymorphism for coronary artery disease Among patients with PAD, depressive symptoms were found
were associated with ABI, DAB21P (rs13290547), CYBA to be associated with poorer lower extremity functioning.101
(rs3794624), and rs1122608 (LDLR). No significant associa- Other possible risk factors for which some supporting data
tions were found for categorical PAD. Using a categorical PAD exist include antiphospholipid antibodies,102,103 hypothyroid-
definition, including revascularization, Kullo et al97 reported ism,104 sedentary lifestyle,105 and exposure to toxic heavy
that in a genome-wide association studies, the single nucleotide metals.106

polymorphism rs653178 in the ATXN2-SH2B3 locus was sig- A PAD global burden in 2010 project compiled the data
nificantly associated with PAD. However, Wassel et al98 report- on PAD epidemiology and associated risk factors.2 Figure 3
ed from the Candidate-Gene Association Resource consortium presents the meta-analyses of the effect size of 11 risk factors
no strong genetic associations for either categorical PAD or the investigated in at least 3 studies among those summarized in
continuous measure of ABI. The genetic influence on PAD is an Table 3, using multivariate design, as well as the association
active area of investigation. with other CVD. These data suggest that globally cigarette
smoking and diabetes mellitus are the strongest risk factors for
Other Risk Factors PAD and also illustrate the strong overlap of PAD with other
A variety of other potential risk factors for PAD have been CVD (discussed below).
examined. In several studies, various measures of oral health
have been shown to be independently associated with PAD.99 PAD Risk Scores
A study in young women found that self-reported history of PAD risk scoring systems have been proposed, including
various types of infectious diseases, such as chicken pox, a scoring system involving novel biomarkers not routinely
Figure 4. Prevalence and distribution of single-

bed and polyvascular disease in REduction of
Atherothrombosis for Continued Health registry.129
CAD indicates coronary artery disease; CBVD,
cerebrovascular disease; and PAD, peripheral artery
disease.
measured, but none has yet gained acceptance. Of note, the was related to smoking, the total cholesterol to HDL-C ratio,
General Framingham score is used to predict a composite lipoprotein(a), and high-sensitivity CRP, but only diabetes mel-
outcome of CHD, stroke, IC, or congestive heart failure.107 litus was associated with progression in smaller arteries.122
Analyses of prediction of the individual outcome components
showed that an IC specific model and prediction of IC with the Coprevalence of PAD and Other
general score showed high concordance. Atherosclerotic Disease
Given the common risk factors for PAD and other cardiovas-
Progression of PAD cular and cerebrovascular diseases, it is not surprising that
Little is known about the early natural history of PAD, particu- people with PAD are more likely to have these other disorders
larly the progression from asymptomatic to early symptomatic concomitantly and vice versa (Figure 3, global data). Among
disease. The average annual change in ABI has been estimated 5084 Medicare beneficiaries in the CHS, the prevalence of
as −0.01 and −0.02 in various groups.108,109 However, these fig- history of myocardial infarction was 2.5× as high in subjects
ures may be somewhat misleading because an average change with PAD (based on ABI<0.9) versus those without; for angi-
in ABI masks a variety of changes of different directions and na, congestive heart failure, stroke, and transient ischemic at-
magnitudes. tack, the prevalence rates were 1.9, 3.3, 3.1, and 2.3× as high,
A more meaningful approach may be to look at the percent- respectively.28 Conversely, the prevalence of PAD was 2.1× as
age of the population achieving some categorically defined high in patients with a history of myocardial infarction versus
measure of change. The CHS, a population-based study, found those without; the corresponding ratios for angina, conges-
that during 6 years of follow-up, 9.5% of people showed in- tive heart failure, stroke, and transient ischemic attack were
cident PAD, defined as an ABI drop of >0.15 to a level of 1.7, 2.6, 2.4, and 2.1, respectively.28 Other studies have found
≤0.90.110 Nicoloff et al111 found that in 5 years, 37% of pa- similar cross-sectional correlations.71,123,124 One study found
tients experienced a significant (≥0.15) worsening of ABI, correlations between the ABI and coronary artery disease se-
whereas 22% of patients experienced clinical progression of verity estimated by the SYNTAX score.125 Subjects with PAD
PAD based on a change in symptoms or a need for surgical have also been shown to have an elevated prevalence of carot-
intervention. Among 415 English smokers with PAD referred id artery stenosis,126,127 and a similarly modest but significant
for a surgical opinion, about one half experienced a signifi- correlation between the severities of the 2 diseases has been
cant (≥0.14) drop in ABI over the following 48 months.58 In demonstrated.128 The global REduction of Atherothrombosis
a group of German patients with PAD, PAD was reported to for Continued Health registry has highlighted the high preva-
progress in 18.6% of patients during an average follow-up of lence of patients with PAD who also have concomitant coro-
64 months, based on a variety of criteria, including change nary or cerebrovascular disease (Figure 4).129
in ABI.112 Bird et al108 defined a ranked series of 6 categories
of PAD based on ABI and other tests; in a study of patients PAD as a Predictor of Mortality and Morbidity
referred to a vascular laboratory, 30.2% of limbs progressed PAD is prospectively related to morbidity or mortality from
to a more serious category of PAD over an average follow-up other types of atherosclerotic disease, even after adjustment
time of 4.6 years. for known common risk factors. Although PAD seems unlike-
In a study based on angiography, 9.1% of patients were ly to directly cause these other diseases, the presence of PAD
found to have evidence of progression of PAD annually.113 In may serve as a marker for underlying atherosclerotic pro-
a study using development of rest pain or gangrene as the cri- cesses or susceptibilities affecting other vascular beds. These
teria for PAD progression, PAD progressed in 2.5% of patients prospective relationships are clinically important, to the extent
annually.105 One study reported that PAD progressed at a rate that the PAD has prognostic value independent of other known
of ≈3× greater in the first year after diagnosis than in subse- risk factors.
quent years.114 Longer studies of PAD progression tend to be Table 5 provides a summary of studies of the association
conservatively biased because people with faster progression of PAD with various mortality and morbidity outcomes.130–144
are likely to have earlier mortality.115 Table 5 is limited to studies using a noninvasive measure of
Data on risk factors associated with progression of PAD are PAD (usually ABI at various cut points). The clinical use of
relatively sparse. In the CHS, significant independent predictors ABI testing is addressed.14 In addition, included studies re-
of decline were age, cigarette smoking, diabetes mellitus, and quired logistic or proportional hazards regression models,
dyslipidemia.110 One report showed age, diabetes mellitus, clas- with multivariable adjustment for conventional cardiovascular
sic IC, previous intervention, and PAD in the contralateral leg to risk factors. Results are shown with multivariable adjustment
be independently predictive of PAD progression.108 One study and after exclusion of subjects with baseline CVD where such
of English smokers with PAD identified hypertriglyceridemia exclusion was attempted.
as the most important independent risk factor for progression Attempts to elucidate this association epidemiologi-
of PAD and onset of critical ischemia.58 Hemorheologic factors cally began with studies of patients having symptomatic
have been shown to be associated with an increased risk of need PAD in the form of IC. Elevated mortality rates among sub-
for vascular intervention.116 Patients with premature PAD (on- jects with IC were reported in the 1970s and 1980s in the
set of symptoms at or before age 45) seem to have more rapid Framingham cohort, although this excess risk was marked-
progression of disease and generally poorer outcomes.117–121 ly attenuated when subjects with baseline cerebrovascular
One study suggested that PAD progression in large arteries and CHD were excluded.23,145,146 Similarly, a Finnish study
Table 5. PAD and Incident Cardiovascular Morbidity and Mortality

95% CI
Hazard
Study PAD Definition Ratio Low High Model Specifications
Total mortality
Criqui, 1992130 Large-vessel PAD 3.1 1.8 5.3 Adjusted for conventional risk factors; excludes subjects with baseline angina, MI, stroke
(multiple criteria)
Newman, 1993131 ABI<0.9 3.4 1.6 7.1 Adjusted for conventional risk factors; excludes subjects with baseline CVD
Vogt, 1993132 ABI<0.9 3.1 1.5 6.7 Adjusted for conventional risk factors; excludes subjects with baseline CVD
Ogren, 1993133 ABI<0.90 2.3 1.4 3.8 Adjusted for conventional risk factors
Kornitzer, 1995134 ABI<0.9 2.1 0.9 4.8 Adjusted for conventional risk factors other than blood pressure; excludes baseline CHD
Jager, 1999 135
ABI<0.9 1.5 0.8 2.8 Adjusted for conventional risk factors
Hooi, 2002137 ABI<0.7 (vs. >0.95) 2.1 1.6 2.8 Adjusted for conventional risk factors
Murabito, 2003138 ABI<0.9 1.4 0.9 2.1 Adjusted for conventional risk factors
Lee, 2004139 ABI≤0.9 1.1 0.9 1.4 Adjusted for conventional risk factors
Resnick, 2004140 ABI≤0.9 1.7 1.3 2.1 Adjusted for conventional risk factors
Cardiovascular disease mortality
(multiple criteria)
Vogt, 1993132 ABI<0.9 4.5 1.5 6.7 Adjusted for conventional risk factors; excludes subjects with baseline CVD
Jager, 1999135 ABI<0.9 2.4 0.9 6.1 Adjusted for conventional risk factors
Resnick, 2004140 ABI≤0.9 2.5 1.7 3.6 Adjusted for conventional risk factors
Coronary heart disease mortality
(multiple criteria)
Cardiovascular morbidity
Newman, 1993131 ABI<0.9 2.1 1.1 4.1 Adjusted for conventional risk factors
Myocardial infarction
Stroke
All coronary heart disease morbidity and mortality
Ogren, 1993133 ABI≤0.9 2.3 1.2 4.3 Adjusted for conventional risk factors
Abbott, 2000141 ABI<0.8 (vs. >1.0) 2.7 1.6 4.5 Adjusted for conventional risk factors
Criqui, 2010142 ABI<1.0 1.8 1.3 2.7 Adjusted for conventional risk factors; excludes subjects with baseline CVD
ABI>1.4 2.2 1.1 4.2
All stroke morbidity and mortality
Abbott, 2000141 ABI<0.9 2.0 1.1 3.5 Adjusted for conventional risk factors
Tsai, 2001143 ABI<0.9 1.4 0.7 2.6 Adjusted for conventional risk factors
Hollander, 2003 144
ABI<1.01 (vs. >1.17) 1.3 0.9 1.9 Adjusted for conventional risk factors
Murabito, 2003138 ABI<0.9 2.0 1.1 3.7 Adjusted for conventional risk factors
Criqui, 2010142 ABI<1.0 1.6 0.9 3.0 Adjusted for conventional risk factors; excludes subjects with baseline CVD
ABI>1.4 2.7 0.9 7.6
ABI indicates ankle-brachial index; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; MI, myocardial infarction; and PAD, peripheral
artery disease.
failed to find an association between IC and total or CVD and cerebrovascular disease morbidity and mortality, with risk
mortality in men after adjustment for CVD risk factors and ratios of 3.3 for men and 9.0 for women after multivariable
baseline CVD.147 Other studies demonstrated increased adjustment.154 Data from the Edinburgh Artery Study also
mortality risk among claudicants but did not fully adjust showed such an association based on ABI, although after mul-
for the conventional CVD risk factors.35,113,148 However, in tivariable adjustment, the association persisted for nonfatal
a large and methodologically rigorous study, data from the but not fatal stroke.153 However, data from the CHS failed to
18 403 men in the Whitehall cohort were used to show that show a relationship between low ABI and incident stroke.136
after adjusting for CVD risk factors, IC was a significant Another large study, the ARIC Study, showed a significant as-
predictor of CVD mortality, even after excluding subjects sociation between ABI as a continuous variable and ischemic
with baseline disease.149 stroke after multivariable adjustment but failed to show such
The development of the ABI and other noninvasive mea- an association when ABI was categorized based on a cut point
sures of PAD permitted further investigation of the associa- of 0.80.143 The MESA reported associations with incident
tion of PAD and CVD. In 1985, it was first demonstrated that stroke for both low ABI (HR, 1.56) and high ABI (HR, 2.69),
a combination of noninvasive measures, including ABI, was but both were of borderline significance because of modest
prospectively related to all-cause mortality, even after adjust- numbers.142 Sutton-Tyrrell et al155 also reported elevated stroke
ment for CVD risk factors and exclusion of subjects with risk in people with both low and high ABIs.
baseline CVD.150 Relative risks in this study were in the range A meta-analysis of 16 population-based cohort studies
of 4 to 5; a later reanalysis of the same cohort with additional evaluated the association of ABI with subsequent coronary
mortality follow-up demonstrated elevated relative risks for events, CVD mortality, and total mortality.156 An ABI of
CVD and CHD in particular, with no significant increase in ≤0.90 was associated with approximately twice the 10-year
noncardiovascular death.130 event rates in each of these 3 categories. In addition, these
In the 1990s, many other prospective studies confirmed that results held across the full range of Framingham Risk Score
ABI was related to CVD, based on either mortality or com- categories. The ABI was also evaluated as a continuous vari-
bined mortality and morbidity. This was found to be true in able. As shown in Figure 5, there was a graded association of
a variety of populations: vascular laboratory patients,115,151,152 increasing risk with decreasing ABIs <1.00, with an HR of 4
elderly patients with hypertension,131 elderly women,132 an for ABIs of ≤0.60. Risk was essentially flat for ABIs in the
employment-based cohort from Belgium,134 the Edinburgh normal range, 1.00 to 1.40.
Artery Study cohort,153 and the CHS cohort.136 Most of these Population studies suggest that a high ABI, >1.40, is also
studies controlled for various known CVD risk factors and associated with elevated risk of CVD. In the meta-analysis
the presence of CVD at baseline. The relative risks reported of 16 population studies, ABIs of >1.40 were associated
ranged from ≈2 to 5. Many of these studies also found PAD with a modest but significant increase in total mortality,
to be significantly associated with incident CHD in particular, with an HR of ≈1.3.156 Such high ABIs are caused by stiff,
although the CHS failed to find such associations for either often calcified ankle arteries, which may mask underlying
total myocardial infarction or angina.136 PAD.12 Recently, the MESA reported that both low (<1.00)
The data on the association of PAD with cerebrovascular and high (>1.40) ABIs were associated with an increased
disease are less conclusive. A 1991 study showed a strong risk of incident CVD events, even after adjustment for tradi-
association between multiple noninvasive measures of PAD tional and novel risk factors.142 Also, this was the first report
Figure 5. Hazard ratios for total mortality in men and women by ankle-brachial index (ABI) at baseline for all studies combined in
the ABI collaboration.155
to show that the ABI predicted events independent of other Disclosures

measures of extant atherosclerosis; specifically, coronary Dr Aboyans declares modest conflict of interest with the fosllowing
artery calcium, carotid intimal-medial thickness, and major companies: AstraZeneca, Bayer Healthcare, Bohrinhger Ingelheim,
ECG abnormalities. Evidence is contradictory as to whether Pfizer, and Sanofi. Dr Criqui reports no conflicts.
the increased risk with a high ABI is restricted to people
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Epidemiology of Peripheral Artery Disease

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Peripheral Artery Disease Compendium

Circulation Research Compendium on Peripheral Artery Disease

Epidemiology of Peripheral Artery Disease

P eripheral artery disease (PAD) is now the preferred term

the patient’s level of activity. In addition, many patients who

Table 1. San Diego Claudication Questionnaire, Brief Version

Table 2. Consensus Recommendations on ABI Measurement

(5) Interpretation of ABI as

Ingolfsson et al21 used Poisson regression techniques to con-

70 years, the rate of IC dropped from 6.0 to 2.0. The authors 0%

measures related to PAD, as well as reducing mortality.43,44

Table 3. Studies of Peripheral Artery Disease in Populations

Diabetes Mellitus mellitus was only of borderline significance, and impaired

Study.19 Similarly, the odds of PAD among subjects in the high-

CRP (per 1 mg/dl)

Age (per 10 yrs)

0.5 1 1.5 2 2.5 3

OR (LMIC) OR (HIC) OR (Global)

that in a genome-wide association studies, the single nucleotide metals.106

Figure 4. Prevalence and distribution of single-

Table 5. PAD and Incident Cardiovascular Morbidity and Mortality

to show that the ABI predicted events independent of other Disclosures

terial disease affecting the lower extremities. Br J Surg. 1969;56:676–679.

population. Circulation. 1985;71:510–515. Med. 2012;17:85–93. doi: 10.1177/1358863X11436195.

doi: 10.1016/j.ejvs.2012.05.019. 677. doi: 10.1111/j.1365-2796.2007.01863.x.

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