The Epidemiology of Peripheral Artery Disease

Symptoms and measures of peripheral artery disease in epidemiology

Insufficient blood supply to the legs can cause pain and dysfunction. This type of pain is generally known as intermittent claudication (IC), characterized as leg muscle pain occurring when walking and relieved at rest, which is indicative of exercise-induced ischemic pain.

A number of questionnaires have been developed to uniformly identify IC and distinguish it from other causes of leg pain. The first was the Rose questionnaire, also referred to as the World Health Organization questionnaire. However, this questionnaire presents a low sensitivity, ranging from 9% to 68% in different studies. Two other questionnaires attempted to improve the diagnostic performances; The Edinburgh Claudication Questionnaire is a modification of the Rose questionnaire, with 47% to 91% sensitivity and 95% to 99% specificity in different studies. The San Diego Claudication Questionnaire is another modified version of the Rose questionnaire that additionally captures information on the laterality of symptoms ( Table 16.1 ).

Although considered as typical, it should be emphasized that 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. 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 PAD.

Two attempts have been made to qualify different patterns of nontypical pain, both using the San Diego Claudication Questionnaire ( Table 16.2 ). In one report, five categories of symptoms have been proposed: no pain, pain on exertion and rest, noncalf pain, atypical calf pain, and classic claudication (see Table 16.2 ). There is a respectively increasing prevalence of PAD in these five groups. In another study, McDermott et al. proposed a sixth category, splitting the “no pain” group according to whether people walk enough to experience exertional pain (see Table 16.2 ). 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 ankle-brachial index (ABI) values in different categories, but also found several concomitant disorders (i.e., neurological and articular), which can make symptoms of ischemic muscle cramp less typical. More recently, the concept of “masked PAD” has been proposed to cover all situations where patients do not complain of pain despite the presence of PAD: this encompasses patients unable to walk, or other conditions limiting walking distance before the occurrence of ischemia and pain (e.g., general conditions such as heart failure, or local conditions such as joint/muscular diseases), or when pain sensitivity is altered, especially in the elderly and/or conditions responsible for neuropathy (e.g., diabetes). These cases of “masked PAD” should be conceptually distinct from truly asymptomatic PAD, but further studies are necessary to better delineate this subgroup. Masked PAD can explain why a patient can suddenly present with a severe form of PAD without any complaint beforehand.

More severe clinical forms of PAD include leg pain at rest, trophic lesions, or both. In this situation the vitality of the limb is threatened due to severe arterial insufficiency and the risk of limb loss in the absence of medical care is high. Consequently, this clinical pattern has been defined as critical limb ischemia (CLI), grouping typical chronic ischemic rest pain and ischemic skin lesions, either ulcers or gangrene. This situation is more recently defined in the European Society of Cardiology PAD Guidelines as critical limb threatening ischemia (CLTI) because of the high risk of limb loss, not only because of severe ischemia, but also wounds and infection which can be present in the most severe cases.

Incidence and prevalence of peripheral artery disease

The current prevalence of PAD worldwide is estimated at approximately 200 million people. In the United States, pooling and adjusting the data of seven US population studies provided an estimate of approximately 6.8 million people aged ≥ 40 years affected by this condition in the year 2000, corresponding to 5.8% of that population. This estimation includes both people with an abnormal (< 0.90) ABI and those with normal ABI values after lower limb revascularization. A recent meta-analysis also estimated the prevalence of PAD in the United States. In men, this prevalence ranged from 6.5% at age of 60 to 69 to 11.6% in those at age of 70 to 79, and 29.4% in those over the age of 80 years. A similar age-related rise in PAD prevalence was found in women, with a corresponding prevalence rate of 5.3%, 11.5%, and 24.7%, respectively. Given the larger number of women surviving to older age, the burden of PAD (defined as the total number of individuals with prevalent PAD in the population) is significantly greater in women than in men. This is particularly true in low- and middle-income countries.

More recently, several studies shed light on PAD epidemiology in the populations of non-Western countries. In a population cohort of 4055 Chinese men and women aged > 60 years, the prevalence of PAD (ABI < 0.90) was 2.9% and 2.8%, respectively. In one Japanese community study, the prevalence of ABI < 0.90 was very low at 1.4% after the age of 40. In another population-based cohort of 1871 individuals above 65 years of age in two countries in Central Africa, the prevalence was considerably higher, nearing 15%.

Data suggesting that PAD is more common in the black population are compelling in studies from both the United States and Africa. Several large cohort studies have reported that blacks are more likely to have PAD than whites. The prevalence of PAD in the > 40 years old population in 2000 were estimated at 5.5%, 8.8%, 2.8%, 2.6%, and 6.1% in non-Hispanic whites, African-Americans, Hispanics, Asians, and Native-Americans, respectively. The higher prevalence of PAD in African-Americans is consistent in all large American epidemiological studies.

Differences in PAD incidence and prevalence in different ethnic groups could be related to non-genetic factors, for example social and nutritional factors, and these issues are only partially controlled when comparing different ethnic groups in the same country. However, a study performed in a subset of the Multi-Ethnic Study on Atherosclerosis (MESA) population free of PAD and without any of the four traditional risk factors of PAD (smoking, hypertension, diabetes, and dyslipidemia), found that even after adjustments for a full range of anthropometric, biological, and social variables, black subjects had a lower normal ABI, about 0.02 less than non-Hispanic whites. This small difference affects the prevalence of low ABI, overestimating the PAD prevalence by about + 10% in this ethnic group. Nonetheless, even taking this into account, there is still a higher prevalence of PAD in blacks compared to whites. Similar findings have been found in another cohort of siblings of subjects with premature atherosclerosis. Interestingly, hospital-based studies suggest that the anatomic distribution of disease may differ in blacks, with a higher percentage of distal disease in black subjects, even after adjustment for diabetes and other CVD risk factors.

There is also evidence that Asians and Hispanics have a lower prevalence of PAD than whites. A study of Native Americans suggested PAD prevalence comparable to that in non-Hispanic whites. The explanation for these differences among races may in part reflect differences in traditional risk factors and socio-economic status.

Fig. 16.1 shows prevalence estimates of ABI-based PAD in population studies by age in women and men, in high- and low/middle-income countries in 2010. The figure shows a curvilinear relationship of prevalence with age in both genders. In younger populations, PAD is a newer problem for certain geographic regions, notably in the western Pacific and Southeast Asia.

Estimates of PAD incidence are reported somewhat less frequently in the literature, with more data for claudication incidence than for ABI. Fig. 16.2 presents the incidence of IC according to age in available studies. Data from the Framingham study show IC in men rising from < 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. 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, the 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. 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. 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 the oldest age group based on age at baseline exam. 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.

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 Study, the annual incidence of developing PAD based on an 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. The annual incidence in women was higher: 5.9, 9.1, and 22.9 per 1000 for the same age groups. More recently, in a Spanish cohort of 5434 PAD-free subjects aged 35 to 79 years recruited between 2003 and 2006 and followed on average for > 5 years, the cumulative incidence of PAD (based on ABI < 0.90 or clinical events) was estimated at 548 and 234 cases per 100,000 person-years in men and women, respectively.

Data on temporal changes in PAD incidence and prevalence are very scarce. In the Reykjavik study, Ingolfsson and colleagues concluded 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-olds, this rate dropped from 6.0 to 2.0 per 1000 per year. The authors attributed this to decreased smoking and cholesterol levels. In the Framingham study, a decrease of incident IC was reported, from 282 per 100,000 person-years during the 1950 to 1959 period to 225 per 100,000 person-years during the 1990 to 1999 period. More recently, a population-based study in the United Kingdom showed a significant drop in incident cases of symptomatic PAD from 38.6 per 10,000 person-years (men: 51.0; women: 28.7) in 2000 to 17.3 (men: 23.1; women: 12.4) in 2014. Similarly, the prevalence dropped during the same period from 3.4% (men: 4.5%; women: 2.5%) in 2000 to 2.4% (men: 3.1%; women: 1.7%) in 2014.

Sex differences in the incidence and prevalence of PAD are less clear than those of other CVD diseases. Claudication incidence and prevalence have usually been found to be higher in men than women. For example, in the Framingham study, the 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. In the Framingham Offspring Study, 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).

The case for an excess of disease among males is even weaker for PAD diagnosed based on ABI. When using the usual 0.90 ABI threshold to define ABI, the male/female ratio in population studies varies from 0.71 to 1.68. 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. In the CVD Health Study, an 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 adjusting for age and CVD status. In the Atherosclerosis Risk in Communities (ARIC) study, this male/female ratio was similar in whites and blacks, at 0.71. Interestingly, this sex ratio became inverted when using lower ABI thresholds, suggesting more frequent cases of severe PAD among men. However, this also can be explained by potential different normal ABI values in both sexes. It has been suggested that women have multiple risk factors–adjusted lower normal ABI values than men by 0.02. Consequently the same threshold for both sexes would lead to PAD prevalence overestimation in women, which corresponded to a 36% increase in prevalence of PAD in women participating in the MESA study. Also, the gender-ratio varies according to age groups, with an unexpectedly higher female-to-male ratio at younger ages, suggesting that young women may have lower normal values of ABI, leading to an overestimation of PAD rates at younger ages. The female-to-male ratio declines with age ( Fig. 16.3 ) suggesting some false positive PAD diagnoses in women in younger age groups.

Data on the prevalence of CLTI are scarcer. In a 2013 meta-analysis, the prevalence of CLTI from six studies (a total of 82,923) was 0.74% (95% confidence interval [CI], 0.26 to 1.46), with marked heterogeneity among studies (ranging from 0.11% to 1.59%). The contemporary retrospective analysis of the MarketScan database provides the best estimate of CLTI incidence and prevalence in the United States, with a large cohort of approximately 12 million individuals, and well-defined cases by an expert committee. The study reported a prevalence of CLTI estimated at 1.33% among individuals > 40 years of age with an annual incidence of CLTI at 0.35%, which equates to almost 3500 new cases per million individuals per year. All patients with CLTI represented 11.08% (95% CI, 11.03% to 11.13%) of total cases of incident clinical PAD.

Peripheral artery disease risk factors

The epidemiologic assessment of PAD and its associated risk factors is dependent on several methodological issues. First, as aforementioned, 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 an ABI < 0.90 to define this condition. Second, the strongest epidemiological evidence for a causal relationship between disease and putative risk factors comes from studies of incident disease, while the greatest 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, the strength of association between some risk factors and PAD may be underestimated, due to competitive outcomes (e.g., smokers may die because of coronary death prior to the diagnosis of PAD). Fourth, since the risk factors for PAD are themselves interrelated in various ways, adjustments for multiple potential risk factors in a single statistical model are necessary, in order to estimate accurately the independent contribution of any single risk factor. The following discussion of risk factors focuses on the results from five large epidemiologic studies referred to as index studies ( Table 16.3 ). These studies each had over 3000 subjects drawn from the general population, and included both genders. These studies are similar enough in their selection and manner of measuring risk factors, and in their statistical analyses, to allow reasonable comparisons for most of the common risk factors. Table 16.3 also includes 12 other large studies. Although the discussion draws on data from many other studies, data are presented from these five index studies across all the conventional CVD risk factors to provide some consistency and comparability for the reader.

Another important source of information regarding the association between CVD risk factors and PAD comes from the Global Burden of Disease study compiling evidence through epidemiological studies performed until 2010 worldwide ( Fig. 16.4 ).