Peripheral arterial disease (PAD) is one of the several terms referring to a partial or complete obstruction of one or more arteries below the aortic bifurcation. Although the term PAD is sometimes inclusive of all peripheral arteries and/or any etiology, in this chapter PAD refers to atherosclerotic occlusive disease of lower extremity arteries. Other terms used for this affliction in the literature are peripheral vascular disease (PVD), peripheral arterial occlusive disease (PAOD), and lower extremity arterial disease (LEAD).

The epidemiologic data regarding this condition have evolved dramatically over the past three decades. Initially, only symptomatic PAD was studied. However, with the development of investigative methods applicable in epidemiology, several studies have suggested that during the natural course of this disease, symptomatic PAD is preceded by a long period of asymptomatic disease. These studies showed that asymptomatic PAD is not innocuous, since patients at this initial stage of the disease are already at a higher risk of cardiovascular events. Consequently, the more recent studies have used objective investigation methods and typically include both symptomatic and asymptomatic forms of the disease. This has led to better estimates of PAD prevalence and incidence. PAD that exhibits typical symptomatology, usually in the form of leg pain brought about by walking, has been conservatively estimated to reduce the quality of life in at least 2 million Americans and in some cases leads to revascularization or amputation.¹ Recent estimates place the total number of persons with PAD in the United States at more than 8 million.²

It was recognized as long ago as the 18th century that an insufficient blood supply to the legs could cause pain and dysfunction. This type of pain is known as intermittent claudication (IC) and is characterized as leg muscle pain occurring when walking and relieved at rest. IC is generally indicative of exercise-induced ischemic pain.

Early studies focused primarily on claudication as the chief symptomatic manifestation of PAD. A number of patient questionnaires have been developed to uniformly identify claudication and to distinguish it from other types of leg pain. The first of these was the Rose questionnaire, also referred to as the World Health Organization questionnaire.³ However, despite initial good results of the questionnaire to accurately detect PAD, this questionnaire is known as to present a low sensitivity, from 68% down to 9% in different studies.⁴ Two attempts have been made to improve the diagnostic performances. The Edinburgh Claudication Questionnaire⁵ is a modification of the Rose questionnaire, presenting 47% to 91% sensitivity and 95% to 99% specificity in different studies.^5,6,7 The San Diego Claudication Questionnaire is another modified version of the Rose questionnaire and additionally captures information on the laterality of symptoms.⁸ The interviewer administered form of the San Diego Claudication Questionnaire is presented in Table 1-1.

Although considered as typical, it should be emphasized that the classical IC is not the sole clinical pattern related to PAD. Besides rest pain, occurring at a more evolved stage of the disease, several patterns of atypical pain can be related to PAD. For example, in the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, more than half of the PAD patients reported symptoms, but few reported classic Rose claudication.⁹ In another similar study in a large Dutch population, the typical “Rose” claudication was reported only in 1.6%, whereas overall 6.6% had different patterns of vascular claudication, including other localization than calves.¹⁰ The definitional distinctions used to separate IC from other types of leg pain make the former more specific to arterial disease, but less sensitive to other types of pain that may in some cases be related to arterial disease. Spinal stenosis can cause leg pain during exercise that is similar to arterial IC. Neurogenic IC accounts for almost 5% to 10% of patients with claudication referred to vascular clinics,¹¹ but this ratio is unknown in general population.

Two attempts, both using the San Diego Claudication Questionnaire (Table 1-2), have been made to qualify different patterns of nontypical pain. In one report, five categories of symptoms have been proposed⁸: no pain, pain on exertion and rest, noncalf pain, atypical calf pain, and eventually classic claudication (Table 1-2). A respectively increasing prevalence of PAD was found in these five groups. In another study, McDermott et al.¹² proposed a sixth category by splitting the “no pain” group according to whether people walk enough to experience exertional pain (Table 1-2). They also divided atypical leg pain according to whether the subject stops or carries on with this pain. The authors not only found different mean ABI values in different categories, but also found several concomitant disorders (i.e., neurological and articular), which can make symptoms ischemic muscle cramp less typical.¹²

Patients with PAD may present more severe clinical forms of PAD, with pain in the legs at rest, trophic lesions, or both. In this situation the vitality of the limb is threatened because of severe arterial insufficiency and the risk of limb loss in the absence of medical care is high. Consequently, this clinical pattern is defined as critical limb ischemia (CLI), grouping typical chronic ischemic rest pain and ischemic skin lesions, either ulcers or gangrene.¹³

In addition to difficulties to define PAD according to different symptoms categories, it is now well established that atherosclerosis may have been developing for many years before claudication begins, and the extent to which it occurs is influenced by factors other than disease per se, such as the patient’s level of activity.¹⁴ For all these reasons, another method of diagnosing PAD was needed.

Low blood pressure at the ankle was proposed as a test for PAD as early as 1950¹⁵ and led to the development of a simple measure called the ankle–brachial index (ABI). Also sometimes called the ankle–brachial pressure index (ABPI)¹⁶ or the ankle–arm index (AAI),¹⁷ the ABI is the ratio of the systolic blood pressure at the ankle to that in the arm. An abnormally low value of ABI is indicative of atherosclerosis of the lower extremities. The ABI has been shown to have good receiver operating curve characteristics as a test for PAD. Although there is no clear-cut threshold to confirm or exclude the presence of PAD, an ABI less than or equal to 0.90 is commonly used in both clinical practice and epidemiologic research to define PAD. More recently, it has been suggested that an ABI between 0.90 and 1.00 is correlated to atherosclerotic disease in other vascular territories,¹⁸ and is associated with higher rates of IC¹⁹ and CV events than in subjects with ABI >1.00.^20,21,22 In a large German primary care cohort, compared to the reference group with an ABI ≥1.1, mortality rates were increased for ABI values within the 0.9 to 1.1 interval.²³ At least for the 0.9 to 1.0 ABI interval, it is suggested to consider this situation as “borderline PAD.” It is estimated that one out of four subjects with an ABI in the interval 0.90 to 1.00 actually have PAD.²

The major interest of ABI-defined PAD is in that it covers both symptomatic and asymptomatic PAD. In the Rotterdam study, 99.4% of subjects with ABI ≥0.9 did not have claudication, but only 6.3% of subjects with ABI <0.9 had claudication.²⁴ In a study of elderly women in the United States, these percentages were found to be 93.3% and 18.3%, respectively.²⁵ In the Wang et al. study, even in limbs with ABI ≤0.50, considered as severe PAD, 17% of limbs did not present any exertional pain.¹⁹ In the general population, it is estimated that for every prevalent case of typical IC, two to five^10,14,26 other asymptomatic cases are generally found with the use of ABI. On this basis it maybe said that PAD defined by ABI is much more common than claudication in the general population, and large numbers of patients without IC can be shown to have a low (<0.90) ABI.

To validate the ABI, early studies compared the ABI result to angiography, considered as the “gold standard” for the visualization of atherosclerosis in the legs. Two such studies are often cited, in which the sensitivity and specificity of the ABI were shown to be in the 97% to 100% range.^27,28 However, because angiography is an invasive investigative method with a potential risk of complication, it was not ethical to perform it on subjects who were not suspected to have PAD. Therefore, these studies involved comparisons of patients with angiographically confirmed PAD with young, healthy individuals assumed not to have PAD. The sensitivities and specificities calculated are therefore based on the ability of the ABI to discriminate between extremes of disease and health. Using also angiography as the gold standard, Lijmer et al. studied the verification bias, related to the fact that only highly suspect cases are deferred to angiography.²⁹ Even after correcting the diagnostic performance results by the estimation of this selection bias, they found an area under the ROC curve at 0.95 when using ABI to detect >50% stenosis at angiography.²⁹ In that study, the corrected sensitivity and specificity of an ABI <0.91 was estimated respectively at 79% and 96%. This lower sensitivity can be explained in part by some PAD patients with stiff peripheral arteries and false negative ABIs.^30,31,32 Another explanation can be different normal values in both sexes and different ethnic groups (see below).³³

The ABI has been demonstrated to have a strong association with cardiovascular (CVD) risk factors and disease outcomes. In the Cardiovascular Health Study cohort, a dose–response relationship was demonstrated between ABI and cardiovascular disease risk factors, as well as a both clinical and subclinical cardiovascular disease.²⁶ In the Edinburgh Artery Study, asymptomatic patients with an ABI <0.9 were shown to have a higher risk of developing claudication and higher mortality.³⁴ In one clinical study, patients with ABI <0.9 and who did not have exertional leg pain were shown to have poorer lower extremity functioning, even after adjustment for traditional risk factors and comorbidities.³⁵ The ABI correlates with the ability to exercise as measured on an accelerometer,³⁶ and an ABI <0.6 is related to the development of walking impairment.³⁷ Thus, even aside from its association with claudication, the ABI is considered as a powerful marker for functional outcomes, risk factors, and associated diseases that one would expect of a measure of PAD. The ABI has also been shown to have high intra- and interrater reliability.³⁸

In practice, the ABI is measured using a blood pressure cuff with a standard sphygmomanometer and a Doppler instrument to detect pulses. The pressure measurements are made after a rest in a supine position for 5 minutes. It is recommended to measure ankle pressure in both legs at the dorsalis pedis and posterior tibial arteries. The higher pressure measurement in each ankle has traditionally been used as the numerator of the ABI for that ankle. Using the lower or average pressure can substantially change estimates of PAD prevalence; one study reported 47% prevalence based on the higher pressure versus 59% based on the lower.³⁶ Results of two recent studies support the use of the average of dorsalis pedis and posterior tibial pressures as the ankle pressure for each leg, based on superior reproducibility in repeated tests and closer statistical association with leg function.^36,39 Recently, comparing to color Duplex used as the reference, Schröder et al. reported an improved diagnostic performance when the lower pressure was used to determine the ankle’s pressure instead of the higher pressure, with sensitivities at 89% versus 68% and specificities at 93% versus 99%, respectively.⁴⁰ Similar findings are reported by Niazi et al.,⁴¹ who reviewed ABI results of 208 limbs versus digital substraction angiography and found that compared to the use of the higher pressure, the mode using the lower pressure as the ABI numerator was more sensitive (84% vs. 69%), although less specific (64% vs. 83%), but with a higher overall diagnostic accuracy (80% vs. 72%). However, the relative predictive value of the higher versus the average or the lower of the two ankle pressures for CVD risk factors or clinical events has not yet been evaluated in general population. Practice also differs as to the brachial pressure used as the denominator of the ABI; the same brachial pressure is usually used for both the left and right ABIs in the same patient, but that pressure maybe the right arm, the average of both arms, or the highest of both arms. A recent study supports the use of the average of the left and right arms, based on superior reproducibility,³⁹ but another study shows a strong correlation between PAD and subclavian stenosis, suggesting the highest arm pressure should be used in the ABI calculation.⁴² A useful compromise is to average the brachial pressures if the absolute difference is <10 mm Hg.^35,36,37 Based on the numerators and denominators described, separate ABIs are calculated for the left and right legs of each subject. In epidemiologic analyses, the unit of analysis is either the leg, with appropriate statistical adjustments for intraindividual correlation, or the subject, with disease status classified based on the “worst” limb, that is, the limb with the lowest ABI.

The ABI has several limitations as a measure of PAD. Occlusive disease located in arteries distal to the site of pressure measurement is not detected by the ABI. Other measures, such as pressure ratios using pressures measured in the toe, are required for detecting such distal disease. It is suggested that ABI would also be sensitive to the subject’s height, with taller patients having slight higher ABIs; but this is not constant in all studies.^43,44,45 Similarly, it has been noted in several studies that the ABI in the left foot are slightly lower on average than the ABI in the right foot.^43,44 It is unlikely these differences are related to real differences in PAD.

Arterial calcification (medial calcinosis) can make the arteries of the ankle incompressible and lead to artificially high values of the ABI. This is particularly common in patients with diabetes.^46,47 Values of the ABI above 1.5 are often excluded in epidemiologic analyses, and should be viewed with suspicion clinically.^{25,26,48,49,50} In two large population-based studies in the United States, the proportion of patients with such elevated values was around one half of 1%.^26,50 Some investigators use the more conservative cutpoint of 1.3. New evidence suggests 1.4 maybe a good compromise.^18,19 A recent report suggests that in more than 80% of cases with an ABI >1.40, concomitant occlusive disease can be identified when using other diagnostic methods.³² This can explain the similar rates of IC and association with subclinical disease in other vascular beds found in this ABI range, compared to an ABI <0.90.^18,19

Currently, the prevalence of PAD in North America and Europe is estimated at approximately 27 million people, with a majority of these subjects being unaware of their condition.⁵¹ Recently, after pooling and adjusting the data of seven U.S. population studies, Allison et al. estimated that 6.8 million people aged ≥40 years in the year 2000 had PAD in this country, corresponding to 5.8% of this population.² This estimation includes both people with an abnormal (<0.90) ABI and those with normal ABI values after lower limb revascularization.

This prevalence is very low among younger people, but increases sharply after the age of 55 to 60 years. For example in the San Diego Population Study, the risk of PAD doubled for each decade, independent from other risk factors.³¹ Almost 20% of individuals over the age of 70 years have this disease. Table 1-3 presents the prevalence of PAD in epidemiological studies using an ABI <0.90 for PAD definition. Figures 1-1 and 1-2 show prevalence estimates of ABI-based PAD in population studies by age in women and men. Although the estimates vary somewhat, prevalence appears to be well under 5% before age 50, around 10% by age 65, and in excess of 25% in patients 80 years of age or older. All studies show this curvilinear relationship of prevalence to age in both genders, although there is some variability in the age at which prevalence begins to increase most dramatically.

Estimates of PAD incidence are reported somewhat less frequently in the literature, with more data for claudication incidence than for ABI. Figure 1-3 presents the incidence of IC according to age in available studies. Data from the Framingham Study show IC in men rising from less than 0.4 per 1000 per year in men aged 35 to 45 years to over 6 per 1000 per year in men aged 65 years and older.⁷² Incidence among women ranged from 40% to 60% lower by age, although estimates in men and women were similar by age 65 to 74. In a group of Israeli men, incidence of claudication ranged from 6.3 per 1000 per year at ages 40 to 49 to 10.5 per 1000 at age 60 and greater.¹ In a study of 4570 men from Quebec, claudication incidence rose from 0.7 per 1000 per year at ages 35 to 44, to 3 per 1000 per year at ages 45 to 54, 7 per 1000 per year at ages 55 to 63, and 9 per 1000 at age 65 and greater.⁷³ In the Speedwell study, which followed English men aged 45 to 63 years for 10 years, claudication incidence per 1000 per year ranged from 3.1 in the youngest to 4.9 in oldest age group based on age at baseline exam.⁷⁴ A higher incidence of 15.5 per 1000 per year was reported among men and women aged 55 to 74 in the Edinburgh Artery Study; however, this study did not apply strict Rose criteria for probable claudication.²⁰ Figure 1-3 shows incidence rates by age for various studies identifying PAD based on IC.^{1,73,74,75,76} Of note, the greater variability for IC incidence compared to data obtained by ABI might reflect a less standardized assessment of the former.

There are very few ABI-based studies of PAD incidence, given the time and resources required to periodically retest study subjects for incident disease. In male participants of the Limburg PAOD Study, annual incidence of ABI <0.95 was 1.7 per 1000 at ages 40 to 54; 1.5 per 1000 at ages 55 to 64; and 17.8 per 1000 at ages >65 and greater.⁷⁷ Annual incidence in women was higher: 5.9, 9.1, and 22.9 per 1000 for the same age groups.⁷⁷

Data on temporal changes in PAD incidence and prevalence are very scarce. In the Reykjavik Study, Ingolfsson and colleagues⁷⁵ used Poisson regression techniques to conclude that IC rates among Icelandic men dropped significantly between 1968 and 1986. Among 50-year-old men, the estimate of claudication rates dropped from 1.7 per 1000 per year in 1970 to 0.6 per 1000 per year in 1984, while in 70-year-old men it dropped from 6.0 to 2.0 per 1000 per year.⁷⁵ The authors attributed this to decreased smoking and cholesterol levels. In the Framingham Study, Murabito and colleagues presented a decrease of incident IC, from 282 per 100 000 person-years during the 1950–59 period to 225 per 100 000 person-years during the 1990–1999 period.⁷⁸

Sex differences in the incidence and prevalence of PAD are less clear than those in other cardiovascular disease. Claudication incidence and prevalence have usually been found to be higher in men than in women. For example, in the Framingham Study, annual claudication incidence for all ages combined was 7.1 per 1000 in men versus 3.6 per 1000 in women, for a male/female ratio of 1.97.⁷² In the Framingham Offspring Study,⁵⁰ claudication prevalence was 1.9% in men versus 0.8% in women (ratio = 2.38), while in the Rotterdam study it was 2.2% in men versus 1.2% in women (ratio = 1.83).²⁴

The case for an excess of disease among male is even weaker for PAD diagnosed based on ABI. When using the usual 0.90 ABI threshold to define ABI (Table 1-3), the male/female ratio in population studies varies from 1.68 in the Hoorn and San Diego Population Studies^31,58 to 0.71 in the ARIC study.^60,71 This is true even in those studies finding clear male excess with respect to claudication. For example, in the Framingham Offspring Study, the male/female PAD prevalence ratio based on ABI <0.90 was of 1.18.²⁴ In the Cardiovascular Health Study, ABI <0.9 was somewhat more prevalent in men than women (13.8% vs. 11.4%, ratio = 1.21), but the association of disease with sex was not significant after adjustment for age and CVD status.²⁶ In the Atherosclerosis Risk in Communities (ARIC) study, this male/female ratio was similar in whites and blacks, at 0.71.⁷¹ Interestingly, this sex ratio became inverted when using lower ABI thresholds,⁷¹ suggesting more frequent cases of severe PAD among men. However, this can also be explained by potential different normal ABI values in both sexes. Recently, it has been suggested that women have a multiple risk factors adjusted 0.02 lower normal ABI values than men.³³ Consequently, the same threshold for both sexes would lead to PAD prevalence overestimation in women, which was estimated at +36% in the Multi-Ethnic Study on Atherosclerosis (MESA).³³

The prevalence of chronic CLI ranges from 0.05% to 0.1% of the general population.^13,79

Prior to the literature review, it should be kept in mind that PAD epidemiology encounters several methodological issues. First, as mentioned above, the definition of disease has evolved over time, with earlier studies focusing more on claudication, defined by Rose and other criteria, and later studies using the ABI, with a value less than or equal to 0.90 now widely used to define disease. Second, while the strongest epidemiological evidence for a causal relationship between disease and putative risk factors comes from studies of incident disease, the great majority of the available epidemiological studies on PAD are cross-sectional. While such studies are informative, the reported associations are more subject to bias than prospective studies. Caution should therefore be exercised in reviewing the results of such cross-sectional studies, particularly where reverse causation is plausible. For example, low physical activity might cause claudication, but claudication might just as plausibly cause low physical activity. Third, since the potential risk factors for PAD are themselves interrelated in various ways, adjustments for multiple potential risk factors in a single statistical model is mandated, in order to estimate accurately the independent contribution of any single risk factor. The estimates presented below (Table 1-4) are based on such multiple adjustments for all traditional PAD risk factors, except as noted. Null findings may indicate the lack of a real association, but may also be based on insufficient sample size. Most of the null findings discussed below are based on failure of the risk factor of interest to remain statistically significant in stepwise regression models, which vary as to their algorithms for variable selection.

Smoking

Smoking is the single most important risk factor for PAD in virtually all studies. The relation was first identified by Erb in 1911, reporting a threefold risk excess of IC in smokers.⁸⁰ The population attributable risk for smoking and IC calculated in cross-sectional studies ranges from 14% to 53%.⁸¹ For current smoking, this attributable risk was estimated at 18% to 26% when PAD was defined by the ABI.^14,17 Studies vary as to their measurement of smoking, often combining a categorical assessment of smoking status (current, past, or never) with some measure of current or historical volume of smoking; these multiple approaches to measurement make comparisons difficult (Table 1-4). However, even with some type of additional adjustment for volume of smoking, current smoking has been shown to at least double the odds of PAD versus nonsmoking, with some estimates as high as a six times greater risk than among nonsmokers. All large, population-based studies that were reviewed have found a significant, independent association between PAD and smoking (Table 1-4).

In several studies, an increasing risk of IC and PAD was found with the growing amount of cigarettes smoked, but smoking cessation was systematically followed by a consistent decrease of PAD occurrence or progression. Smoking cessation was followed by a rapid decline in the incidence of IC,⁷⁵ and the IC risk for ex-smokers 1 year after quitting approximates that for nonsmokers.^73,75 Cessation of smoking among patients with claudication has been shown to improve various functional and physiologic measures related to PAD as well as reduce mortality.^82,83,84 However, because symptomatic PAD patients have long been advised to quit smoking, it is possible that observational comparisons of patients who quit smoking with those who do not are confounded by other differences in compliance with other medical advice between the two groups. Randomized trials of this question would raise ethical issues. However, substantial bias is unlikely given the large effect size for cigarette smoking.

Because of the substantial decline of smoking in general population following smoking ban legislation in several western countries, the relative influence of smoking on incident PAD is changing. In a 50-year trend of IC in the Framingham Study, the proportion of smokers in incident cases dropped from 42% in the 1950s to 16% during the 1990s.⁷⁸

Diabetes

Diabetes is strongly associated with elevated risk of PAD, although the evidence for an independent role in multivariable analysis is not entirely consistent (Table 1-4). IC was more frequently observed in case of diabetes in the Framingham,⁸⁵ Quebec,⁷³ Speedwell,⁷⁴ and Israeli civil servants¹ studies, whereas this association was not found in the Reykjavik Study.⁷⁵ In the Edinburgh Study, the association between diabetes and IC was nonsignificant, whereas a significant inverse relationship was found with the ABI.⁵⁶ In Table 1-4, only 2 out of 11 population studies including the ABI measurement in the disease definition did not find a significant association between diabetes and PAD in multivariate models.^24,63 In positive studies, according to different models used, the adjusted-risk excess for PAD in patients with diabetes ranged from⁵⁹ +53% to almost³¹ +700% (Table 1-4).

More severe and/or longstanding diabetes appears to be more strongly related to PAD. In the Hoorn Study, it was shown that known diabetes was associated with PAD in multivariable analysis, while newly diagnosed diabetes was only of borderline significance and impaired glucose tolerance was not associated with PAD.⁵⁸ In that study, after excluding known diabetics, none of the common glycemic indices that were tested was significantly associated with PAD based on ABI, although significant associations were observed when the PAD criteria were broadened to include patients with additional criteria. Studies conducted in patients with diabetes have shown that duration of diabetes and use of insulin are associated with PAD.^86,87,88

Outcomes of PAD in patients with diabetes have been shown to be worse. In one study, diabetic patients with PAD were five times more likely to have an amputation than other patients with PAD, and also had over three times the odds of mortality.⁸⁹ There is also some evidence to support a somewhat different anatomic distribution of disease, with greater involvement of the profunda femoris and crural arteries in patients with diabetes.^89,90,91,92

Because of the dramatic epidemic of diabetes in western countries, the proportion of diabetes-related PAD may increase dramatically. In the Framingham Study, the proportion of incident cases with diabetes increased from 5% in the 1950s to 11% in the 1990s.⁷⁸

Hypertension and Blood Pressure

The association of hypertension with PAD has been demonstrated in most studies in which blood pressure was studied. All major epidemiological studies reported a significant association between hypertension as a categorical variable and PAD (Table 1-4). The lowest reported odds ratio was 1.32 as reported in the Rotterdam Study; this is somewhat understated relative to the others, as it was based on a model that included both a categorical hypertension variable and an adjustment for systolic blood pressure level that was also significant.¹⁷ Each time both systolic and diastolic pressure were considered, systolic pressure was usually found to be associated with PAD, while diastolic pressure was not significantly associated^17,26,93 or had a nonlinear relationship with PAD.⁵⁹