Version May 2024
INTRODUCTION — Atherosclerosis is a systemic disease of the large and medium-sized arteries causing luminal narrowing (focal or diffuse) due to the accumulation of lipid and fibrous material between the intimal and medial layers of the vessel. Atherosclerosis of the arteries of the lower extremities is defined as peripheral artery disease (PAD). An ankle-brachial index (ABI) ≤0.9 is sensitive and specific for arterial stenosis/occlusion [1].
Although other disease processes can lead to narrowing of the limb arteries (eg, inflammation, thrombosis) and symptoms of arterial insufficiency, atherosclerosis is by far the most prevalent etiology. The lower extremity vessels are affected more commonly than the upper extremity vessels.
Ischemic symptoms result when there is an imbalance between the supply and demand for blood flow. The clinical manifestations of PAD depend upon the location and severity of arterial stenosis or occlusion, and range from mild extremity pain with activity (ie, claudication) to limb-threatening ischemia. For patients found to have asymptomatic PAD, the risk of adverse limb events is less compared with symptomatic patients; however, the risk of adverse cardiovascular events remains elevated. However, for those patients with PAD who continue to smoke or have diabetes or renal insufficiency, the clinical manifestations can progress rapidly and unpredictably.
The epidemiology, risk factors, and natural history of peripheral artery disease are reviewed here. The clinical manifestations and management of peripheral artery disease are discussed elsewhere. (See "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Management of claudication due to peripheral artery disease".)
An overview of upper extremity atherosclerotic disease is provided separately. (See "Upper extremity atherosclerotic disease".)
EPIDEMIOLOGY AND RISK FACTORS — The worldwide prevalence of lower extremity peripheral artery disease (PAD) is between 3 and 12 percent. In 2010, 202 million people around the world were living with PAD [2]. In Europe and North America, an estimated 27 million individuals are affected with approximately 413,000 inpatient admissions annually attributed to PAD [3]. The majority of individuals with PAD (70 percent) live in low/middle income regions of the world, including 55 million individuals in southeast Asia and 46 million in the Western Pacific Region [2]. The number of individuals with PAD increased by 29 percent in low/middle income regions and 13 percent in high income regions from 2000 to 2010 compared with the preceding decade [2].
In a report from the National Health and Nutrition Examination Survey (NHANES) from the United States, in which PAD was defined as an ankle-brachial index ABI <0.9 in either leg, the prevalence of PAD among adults aged 40 years and over in the US was 4.3 percent, corresponding to approximately 5 million individuals [4]. PAD is more prevalent in older individuals, in those with certain ethnicities, families with atherosclerosis, and in those with risk factors for cardiovascular disease. In the NHANES study, more than 95 percent of those with PAD had one or more cardiovascular disease risk factors.
Risk factors that favor the development of PAD are similar to those that promote the development of coronary heart disease (CHD) [4-7]. However, the Scottish Heart Health Extended Cohort identified some risk factor differences [8]. Among over 15,000 males and females aged 30 to 75 years who were free of PAD or CHD and followed for 15 to 25 years, 19.7 percent developed CHD and 3.2 percent developed PAD. PAD and CHD shared seven of the nine of the ASSIGN risk score variables, including age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure, and four biomarkers (N-terminal pro b-type natriuretic peptide [NT-pro-BNP], cotinine, high-sensitivity C-reactive protein, and cystatin-C). For PAD, markers associated with inflammation and tobacco smoking predominated, while total cholesterol and body mass were less important. The highest ranked adjusted hazard ratios in PAD were age, high-sensitivity C-reactive protein, systolic blood pressure, expired carbon monoxide, cotinine, socioeconomic status, and lipoprotein(a). Diabetes mellitus was also an important risk factor but not the most common cause of PAD. These identified differences in risk factors for PAD versus CHD may indicate subtle differences in pathophysiology.
The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD have identified the risk groups that are associated with an increased prevalence of PAD and earlier onset of symptomatic PAD [9-11]. Patients in these groups should be evaluated for PAD. These include:
●Age ≥70 years
●Age 50 to 69 years with a history of smoking or diabetes
●Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis
●Known atherosclerosis at other sites (eg, coronary, carotid, renal artery disease)
Several large studies have evaluated the incidence and prevalence of these factors, alone or together, in patients with PAD.
●The Health Professionals Follow-up Study tracked 44,985 males in the United States without a history of cardiovascular disease at baseline for a median follow-up of 24.2 years (1986 to 2011) [12]. There were 537 cases of incident PAD (defined as limb amputation or revascularization, angiogram reporting vascular obstruction ≥50 percent, ABI <0.9, or physician-diagnosed PAD). Each risk factor (smoking, hypertension, hypercholesterolemia, type 2 diabetes) was significantly and independently associated with a higher risk of PAD after adjustment for the other three risk factors, and confounders. Males without any of the four risk factors had a lower risk of PAD compared with all other males in the cohort (hazard ratio [HR] 0.23, 95% CI 0.14-0.36). The age-adjusted incidence rates (cases per 100,000 person-years) were 9 for no risk factors, 23 for one risk factor, 47 for two risk factors, 92 for three risk factors, and 186 for four risk factors. The population-attributable risk for PAD associated with these four risk factors was 75 percent.
●Similarly, a study evaluating data from the United States National Health and Nutrition Examination Survey (NHANES) determined the cumulative effects of known risk factors for peripheral artery disease [13]. Risk factors for PAD used in the model included age, sex, race/ethnicity, hypertension, diabetes, chronic kidney disease, and smoking. The likelihood of PAD increased with each additional risk factor present. With one risk factor present relative to no risk factors, the risk for PAD was not significant (odds ratio [OR] 1.5, 95% CI 0.9-2.6). For two risk factors, the risk for PAD was nearly quadrupled (OR 3.7, 95% CI 2.3-6.1), and for three risk factors the risk was increased 10-fold (OR 10.2, 95% CI 6.4-16.3). Smoking was the single factor associated with the highest risk for PAD. Non-Hispanic Black Americans and females, who had the highest prevalence rates, were particularly sensitive to this cumulative effect.
●In the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program study that included 6979 subjects, the prevalence of PAD in individuals at high risk for PAD (50 to 69 years of age and diabetes mellitus or >10 pack-year history of smoking, or >70 years of age) was 29 percent [5]. Of these, 13 percent had PAD only, and 16 percent had evidence of PAD and coronary artery disease (CAD).
Age — The prevalence of PAD increases progressively with age, beginning after age 40 [4,14-19]. As a result, PAD is a growing clinical problem in the United States and other developed countries due to an aging population. (See "Overview of established risk factors for cardiovascular disease", section on 'Age and sex'.)
Individuals over 70 are at a significantly increased risk for PAD due to age alone [20], while risk for those who are younger is due to other factors, most commonly cigarette smoking [21]. However, only half of aged adults with PAD are symptomatic from lower extremity PAD, often because of other comorbidities that limit mobility, such as arthritis, cardiac disease, and pulmonary disease [22].
The relationship between PAD prevalence and age was illustrated in the NHANES study [4,21]. The prevalence of PAD was:
●0.9 percent between the ages of 40 and 49
●2.5 percent between the ages of 50 and 59
●4.7 percent between the ages of 60 and 69
●14.5 percent age 70 and older
●23.2 percent for those over 80
Traditional risk factors for ABI may be absent in patients older than 80 years, particularly those with infrapopliteal disease [23].
Sex — Sex-related differences in the risk for cardiovascular disease have been described. (See "Overview of established risk factors for cardiovascular disease", section on 'Age and sex'.)
PAD is cited historically as more prevalent in males overall compared with females. However, the population-based prevalence of PAD in females has not been fully evaluated. In population studies, the prevalence of PAD in females is at least as high as that of males across all age groups but increases to a greater extent in females after age 70 compared with males of the same age [24-28].
An epidemiologic model based upon a systematic review of the prevalence of PAD around the world was used to compare predicted PAD prevalence in three high-income and five low-/middle-income World Health Organization (WHO) regions [2].
●Sex-specific prevalence increased with age (eg, for males, 5.4 percent, 45 to 49 years; 18.8 percent, 86 to 89 years).
●Prevalence in males was lower in low-/middle-income regions compared with high-income regions (eg, 2.9 versus 5.4 percent for males 45 to 49 years; 14.9 versus 18.8 percent for males 85 to 89 years).
●Prevalence was higher in females, especially at younger ages in low-/middle-income regions (6.31 versus 5.3 percent for females 45 to 49 years; 15.2 versus 18.4 percent for females 85 to 89 years).
In a review of 133,750 females and 71,996 males who underwent voluntary screening for PAD (ie, Lifeline), females were significantly more likely to have ABI ≤0.9 (4.1 versus 2.6 percent) [29]. In a large review, incident cardiovascular disease varied by type of presentation (eg, myocardial infarction, transient ischemic attack, PAD, abdominal aortic aneurysm), age, and sex [30]. The risk difference between men and females for an initial presentation of peripheral artery disease was most pronounced for males aged 50 to 59, with a twofold increase compared with females.
In a population study of individuals 60 to 90 years of age in Sweden, females had a higher prevalence of PAD compared with males, when ABI only was used to diagnose PAD (asymptomatic: 12.6 versus 9.4 percent). In this study, the prevalence of severe limb ischemia was higher in females compared with males (1.5 versus 0.8 percent) [31]. Similar results were found in a retrospective review of 231 consecutive patients diagnosed with PAD following referral to a vascular laboratory [26]. The prevalence of severe limb ischemia was 13.2 percent in females and 4.3 percent in males. The difference was likely related to the significantly higher incidence of hypercholesterolemia (88.2 versus 73 percent), metabolic syndrome (78 versus 43 percent), and diabetes (67.6 versus 42.9 percent) found in the female patients.
Whether there is any effect of hormone replacement therapy in postmenopausal females on the development of PAD is largely unknown. One study of 847,982 postmenopausal females found that in spite of an increased prevalence of several atherosclerotic risk factors among females who used hormone replacement therapy, they were significantly less likely to have PAD (3.3 versus 4.1 percent) [32]. The benefits and risks of hormone replacement therapy are discussed in detail elsewhere. (See "Menopausal hormone therapy: Benefits and risks".)
Ethnicity — Ethnicity-related differences in prevalence rates of PAD and for risk factors known to be associated with PAD have been identified. The prevalence of PAD is higher in African Americans than non-Hispanic White Americans [4,33-35]. The difference does not appear to be completely explained by differences in the prevalence of risk factors for atherosclerosis [36]. African and Hispanic Americans have higher rates of diabetes and hypertension, whereas White Americans are more likely to have hypercholesterolemia [27].
The NHANES study found an increased prevalence of PAD for African Americans (males and females), and also Hispanic-American females compared with non-Hispanic White Americans (19.2 and 19.3 percent, respectively, versus 15.6 percent) [4].
Similarly, in the San Diego Population Study, a survey of 2343 randomly selected participants, African Americans had a significantly higher prevalence of PAD (7.8 versus 4.9 percent) compared with non-Hispanic White Americans [34]. In this study, PAD was defined as an ABI ≤0.9, an abnormal Doppler waveform, or prior revascularization for PAD. Although African Americans had significantly higher rates of diabetes, hypertension, and greater body mass index, the increased risk for PAD was maintained after adjustment for these and other variables. Hispanic and Asian Americans had somewhat lower rates of PAD than non-Hispanic White Americans, but the difference was not significant. In a multiethnic Asian (Chinese, Malays, and Indians) population study from Singapore, PAD was present in 4.3 percent of the population, and a high ABI >1.4 was rare [37]. A systematic review identified 14 studies comparing prevalence between South Asian and White European individuals and found a significantly lower risk of PAD in those from South Asian with coronary artery disease (OR 0.47, 95% CI 0.39-0.56) and diabetes (OR 0.44, 95% CI 0.30-0.63) [38].
Socioeconomic status — A study using the Global Burden of Disease database found that the global age-standardized mortality rate (ASMR) from PAD remained higher in higher sociodemographic index (SDI) areas, while the rate of death in lower SDI regions increased. The ASMR was higher in males but decreased with age [39].
A second study involving data from the Chronic Renal Insufficiency Cohort Study (CRIC) reported that, after adjusting for cardiovascular risk factors, all lower levels of annual household income were associated with increased incidence of PAD relative to a baseline annual income of >$100,000 [40]. Hazard ratios were 1.7 for those under $25,000 annual income and 1.6 for those below $100,000. Education was not associated with PAD.
Family history and genetic factors — Patients with a family history of cardiovascular disease appear to be at increased risk, although the relative contributions of genetics and environmental factors are not fully elucidated but continue to be an active area of investigation. (See "Overview of established risk factors for cardiovascular disease", section on 'Family history' and "Overview of possible risk factors for cardiovascular disease", section on 'Genetic markers'.)
The risk of PAD is increased in families identified with early-onset atherosclerosis, but no single genetic marker has been identified for PAD in this population [41]. Patients with early-onset atherosclerosis are a separate subgroup distinct from patients with familial hypercholesterolemia, which is discussed elsewhere [42,43]. (See 'Early-onset atherosclerosis' below.)
Atherosclerotic disease likely results from numerous genes interacting with each other and the environment [44]. Studies that have investigated heritable factors in the development of PAD include family and twin studies, ABI variance analysis, and gene studies [41-43,45-51].
Several studies have found that 20 to 50 percent of the variance in ABI can be explained by genetic factors [45-47]. However, in spite of finding such correlations, investigators of the National Heart, Lung, and Blood Institute Twin study found no significant difference in the prevalence of PAD for identical (monozygotic) compared with fraternal (dizygotic) twins (33 versus 31 percent) [45]. In contrast, a study using data from the Swedish Twin Registry and the national patient discharge registry found that traditional cardiovascular risk factors were significantly more prevalent in twins with PAD compared with those without PAD [48]. Concordances and correlations were higher in monozygotic compared with dizygotic twins, suggesting genetic influences in PAD. The risk of PAD for persons whose twin had PAD was significantly increased compared with persons whose twin did not have PAD (OR 17.7, 95% CI 11.7-26.6 for monozygotic twins; OR 5.7, 95% CI 4.1-7.9 for dizygotic twins). Genetic effects accounted for 58 percent of the phenotypic variance among the twins, and nonshared environmental effects accounted for approximately 42 percent.
A case control study that compared 2296 patients with PAD with 4390 controls found that a family history of PAD was present significantly more often in patients with PAD than in controls even after adjusting for conventional risk factors (OR 1.97, 95% CI 1.60-2.42) [52]. The association was stronger in younger subjects (age <68 years), and a greater number of affected relatives with PAD was also more strongly associated with PAD.
A meta-analysis of possible genetic susceptibility to PAD found no strong supportive evidence for most genetic polymorphisms but did identify three genes that may be important variants (IL6-174 G/C, ICAM1 1462 A/G, and CHRNA3 831C/T) [49]. In one genotyping study, a discovery meta-analysis found a strong association between rs10757269 on chromosome 9 near CDKN2B and ABI [53]. The Million Veteran Program identified similarities and differences among various vascular beds [54]. This genome-wide association study involving over 30,000 individuals identified 19 PAD loci, 11 of which were associated with disease of the coronary, cerebral, and peripheral vascular beds. However, variants in the RP11-359M6.3, HLA-B, CHRNA3, and F5 loci appeared to be specific for PAD and were related to hemostatic mechanisms, potentially highlighting a pathogenic role for thrombosis (figure 1).
The chromosome 9p21 (Chr9p21) locus, identified in 2007, was first associated with coronary artery disease and myocardial infarction, but it may have a more general role in vascular pathology [55]. Additional associations have been demonstrated for carotid artery plaque and plaque progression, peripheral artery disease, and aneurysmal disease. (See "Epidemiology, risk factors, pathogenesis, and natural history of abdominal aortic aneurysm".)
Smoking — Cigarette smoking correlates significantly with cardiovascular disease. The mechanism by which cigarette smoke promotes the development and progression of atherosclerosis is not clearly understood, but its effects include endothelial damage, arterial smooth muscle proliferation, thrombophilia, inflammation, increased sympathetic tone, and other metabolic abnormalities [56-60]. In the NHANES study, the risk for PAD was increased in active cigarette smokers, but no association was found for other forms of tobacco exposure [21]. On average, a diagnosis of PAD is made approximately a decade sooner in cigarette smokers than in nonsmokers [61].
A systematic review that included 55 original studies performed in North America, South America, Europe, Australia, and Africa assessed the magnitude of increased risk of PAD in current smokers relative to never smokers (OR 2.71, 95% CI 2.28-3.21), and ex-smokers relative to never smokers (OR 1.67, 95% CI 1.43-1.81) [62]. Most studies (47/55) used ABI to define PAD; the remainder used symptoms of claudication. The Erfurt Male Cohort (ERFORT) Study, which followed 1160 males aged 40 to 59 years every five years, also associated smoking with an increased risk of incident intermittent claudication (hazard ratio [HR] 2.20, 95% CI 1.24-3.92) [63]. In another study, ongoing cigarette smoking was associated with the largest decline in ABI compared with other risk factors [64].
Smoking appears to be a more powerful risk factor for PAD than for CAD [62,65,66]. In the Edinburgh Artery Study, the adjusted relative risk for PAD in heavy smokers compared with nonsmokers was 2.72 (95% CI 1.13-6.53), but lower for CHD at 1.61 (95% CI 0.91-2.85) [65,66]. A separate meta-analysis evaluating the risk of CHD in smokers identified a relative risk of 1.72 for males and 1.92 in females [67].
A significant relationship between cigarette dose and risk for PAD has been reported [5,7,68]. In the PARTNERS program study discussed above, patients aged 50 to 69 years of age with a history of cigarette smoking more than 10 pack-years or a history of diabetes had an incidence of PAD similar to those ≥70 years of age [5]. The Framingham Heart Study found that the risk for developing claudication was directly related to the number of cigarettes smoked, with a 1.4-fold risk increase for every 10 cigarettes smoked per day [7]. In another study, the hazard ratio for PAD was 2.52 (95% CI 1.49-4.25) for 10 pack-years, 6.75 (95% CI 4.33-10.52) for 10 to 29 pack-years, and 11.09 (95% CI 6.94-17.72) for ≥30 pack-years [68]. A greater number of pack-years of smoking is also associated with increasing disease severity, negative effects on the patency of vascular reconstruction, and an increased risk of amputation and cardiovascular mortality following revascularization [61]. Passive exposure to smoke appears to increase vascular endothelial inflammation and may increase the risk for atherosclerotic plaque development in children and adults [69]. (See "Secondhand smoke exposure: Effects in adults", section on 'Cardiovascular disease and stroke' and "Secondhand smoke exposure: Effects in children", section on 'Atherogenesis'.)
Smoking cessation decreases morbidity related to PAD; however, risk of progression of PAD is significantly greater in former smokers compared with never smokers [68,70,71]. The Edinburgh Arterial Study found a decreased risk of claudication for patients who stopped smoking compared with those who continued to smoke [72]. Smoking cessation is also associated with a decreased risk of graft failure following lower extremity bypass surgery [73]. These effects are limited if the patient reduces cigarette consumption rather than eliminating smoking altogether [74]. Because the effect of smoking cessation on quality of life and survival is not immediately evident, patients require a high level of support to initiate and maintain smoking cessation [75,76]. (See "Overview of smoking cessation management in adults".)
Hypertension — Hypertension is strongly associated with the development of atherosclerosis in males and females. (See "Overview of established risk factors for cardiovascular disease", section on 'Hypertension'.)
In the United States, the prevalence of hypertension in adults is approximately 30 percent [77]. However, among those with an abnormal ABI, the prevalence of hypertension in the Rotterdam Study was 60 percent [78]. The risk of developing symptoms of PAD, such as intermittent claudication, in those with hypertension was twice that of those without hypertension in the Framingham study [7,79]. The NHANES study found that hypertensive patients also have an even higher prevalence of asymptomatic PAD [4] and, further, that patients with PAD were less likely to have antihypertensive treatment compared with those who have other forms of cardiovascular disease [80]. The association between hypertension and PAD among patients older than 60 years of age was particularly strong in those with untreated and poorly controlled hypertension [14].
In a cohort of over 1.25 million patients aged 30 years or older without baseline cardiovascular disease, including 20 percent with baseline treated hypertension, the associations of several cardiovascular diseases, including PAD with systolic hypertension, diastolic hypertension, or both, were studied [81]. PAD had the strongest association of all cardiovascular diseases with pulse pressure (HR 1.23, 95% CI 1.20-1.27]). In another large database review that included over 4.2 million individuals, a 20 mmHg higher than usual systolic blood pressure was associated with a 63 percent higher risk of peripheral artery disease (OR 1.62, 95% CI 1.59-1.66) [82].
Hypertension together with smoking is a major factor for progression of PAD in patients with diabetes mellitus, but there is no evidence that adequate control of hypertension impacts disease progression [83]. (See 'Natural history and progression of PAD' below.)
Diabetes — Diabetes is a coronary artery disease risk equivalent. Patients with diabetes have more advanced arterial disease at initial diagnosis and poorer outcomes than nondiabetic patients [84,85]. (See "Overview of established risk factors for cardiovascular disease", section on 'Diabetes mellitus'.)
The NHANES study found an increased risk for PAD in patients with diabetes (OR 2.71, 95% CI 1.03-7.12), a level of risk exceeded only by smokers (OR 4.46, 95% CI 2.25-8.84) [4]. A prospective cohort study with more than 20 years follow-up found an increased risk of death (HR 2.9, 95% CI 1.3-4.0) for patients with diabetes and PAD, compared with those without diabetes [86]. (See "Overview of peripheral artery disease in patients with diabetes mellitus".)
Poor glycemic control also incrementally increases the risk of atherosclerosis. A systematic review identified 13 studies evaluating hyperglycemia and cardiovascular risk, and found a 26 percent increase in risk for every 1 percent increase in HbA1c [87].
Diabetes also increased the risk for developing symptomatic PAD (OR 2.6) in the Framingham Heart Study, which followed subjects for 38 years [7]. The effect of diabetes on graft patency has varied between studies, with the majority finding no difference in patency rates [88,89]. However, retrospective reviews have reported increased mortality and amputation in patients with diabetes [90-93]. In one study, the perioperative (30-day) mortality rate for patients with diabetes following aortic or lower extremity revascularization was 9.6 percent compared with 2.2 percent for those without diabetes [91]. Although the risk of amputation in patients with diabetes is related to the severity of PAD, infection and neuropathy are also contributing factors. In a review of the Veterans Aging Cohort Study, microvascular disease (presence of neuropathy or retinopathy from microvascular disease) significantly increased the risk for amputation (relative risk [RR] 3.7, 95% CI 3.0-4.6) [93]. PAD alone conferred a 13.9-fold increased risk of amputation, and a combination of PAD and microvascular disease was associated with a 22.7-fold increase. Not all patients with microvascular disease had diabetes, but there was a strong association between the two. Furthermore, those with microvascular disease had a twofold increased risk of major adverse cardiovascular events; the combination of PAD and microvascular disease conferred a 3.9-fold risk increase. Microvascular disease was also associated with more distal amputations.
While alcohol use has typically been associated with a protective effect, one review found that heavy alcohol use in patients with type II diabetes was associated with an increased risk for lower extremity PAD (OR 6.25, 95% CI 1.78-22.65) [94]. The increased risk remained after adjusting for all other factors, including smoking, body mass index, and sex. A dose-response relationship was also found between prolonged alcohol consumption and PAD.
Chronic kidney disease — Many guidelines do not specifically identify chronic kidney disease (CKD) as a risk factor for PAD. However, an association between PAD and CKD is being recognized and reported with increasing frequency. While an increased risk has generally been recognized for patients with severely reduced renal function, a growing number of studies have suggested an increased risk for even mild to moderately reduced renal function [95-97]. CKD is considered a coronary heart disease risk equivalent. (See "Chronic kidney disease and coronary heart disease" and "Overview of established risk factors for cardiovascular disease".)
Metabolic syndrome — Metabolic syndrome (a constellation of obesity, hypercholesterolemia, hypertension, and insulin resistance) is associated with increased risk for cardiovascular disease. (See "Overview of established risk factors for cardiovascular disease", section on 'Metabolic syndrome'.)
The following studies illustrate the relationship between metabolic syndrome and PAD:
●In a cross-sectional study, 60 percent of patients with PAD also had metabolic syndrome, but the metabolic syndrome score did not significantly correlate with the extent of disease [98].
●In the Second Manifestations of Arterial Disease (SMART) study, patients with PAD and metabolic syndrome had a higher incidence of vascular events (vascular death, stroke, myocardial infarction) compared with patients with PAD and no metabolic syndrome (15 versus 8 percent) [99].
●A prospective cohort study that followed 27,111 females without baseline cardiovascular disease over an average of 13.3 years found that females with metabolic syndrome had a 62 percent increased risk for future symptomatic PAD compared with those without metabolic syndrome [100].
Hyperlipidemia — Patients with certain lipid and lipoprotein abnormalities [eg, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a)] have an increased risk for cardiovascular disease, and adverse long-term cardiovascular outcomes. (See "Overview of established risk factors for cardiovascular disease", section on 'Lipids and lipoproteins' and "Lipoprotein(a)".)
Patients with PAD are more likely to have increased levels of triglycerides and/or cholesterol, lipoprotein (a), apolipoprotein B, and very low density lipoprotein, compared with patients without PAD [101-103]. Conversely, the levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I and A-II levels, the "protective" lipoproteins, are lower in these patients [104].
Lipoprotein (a) is a significant independent risk factor for PAD. Lipoprotein (a) is genetically determined and controlled by a single gene locus. In the Québec Cardiovascular Study, the risk of intermittent claudication was doubled in males with higher concentrations of plasma lipoprotein (a) [105-107]. Patients with premature PAD have lipoprotein (a) levels that are fourfold higher than controls [108]. Lipoprotein (a) levels vary between ethnic populations, with otherwise healthy African Americans having levels that are almost twice those of White Americans [109].
In the Framingham study, a fasting cholesterol level >7 mmol/L (270 mg/dL) was associated with a doubling of the incidence of intermittent claudication relative to a lower fasting cholesterol level; for each 40 mg/dL increase in total serum cholesterol, the odds of developing symptomatic PAD increased by 1.2 [7]. In the Physicians Health Study, the ratio of total to HDL cholesterol was the best independent predictor of occurrence of PAD [110]. Another study reported a correlation between triglyceride glucose (TyG) index and chronic limb-threatening ischemia (CLTI) [111]. A TyG index of 9.13 was 70.8 percent sensitive and 65.2 percent specific in identifying the risk for CLTI (OR 5.8).
Treatment of hyperlipidemia may decrease the risk of progression of PAD and the incidence of intermittent claudication. In the Heart Protection Study, the cholesterol lowering agent simvastatin decreased overall mortality by 12 percent, and vascular mortality by 17 percent [112].
Heavy metal exposure — Excess exposure to heavy metals (arsenic, lead, cadmium, mercury) is associated with incident cardiovascular disease and increased cardiovascular mortality [113-116]. The risk for PAD specifically has been studied for arsenic, cadmium, and lead [117-120]. There are no data as to whether treatment of any of these heavy metal exposures alters PAD risks.
In a review using data from the NHANES, after adjusting for known risk factors, comparing the highest with lowest quartiles, the risk for PAD trended higher for cadmium (OR 2.82, 95% CI 1.36-5.85) and for lead (OR 2.88, 95% CI 0.87-9.47) [118].
In later prospective cohort studies in a Native-American population, increased exposure to arsenic or cadmium was independently associated with incident PAD [120,121]. In one of these studies, arsenic methylation increased the risk for noncompressible vessels (ABI >1.4; HR 2.04, 95% CI 1.02-3.41); however, there was no association for ABI <0.9 [121]. Urine cadmium was also significantly associated with PAD (ABI <0.9) after adjusting for cardiovascular risk factors including smoking status (HR 1.96, 1.32 to 2.81 for the highest versus lowest tertile) [120].
In a separate systematic review, high arsenic exposure was associated with PAD (pooled RR 2.17, 95% CI 1.47-3.20) and also with coronary heart disease (pooled RR 1.89, 95% CI 1.33-2.69) [122]. High arsenic levels may also increase homocysteine levels. (See 'Homocysteine' below.)
Homocysteine — Homocysteine was one of the earliest biomarkers to be studied in association with the development of atherosclerosis [123]. Elevated homocysteine is associated with earlier-onset atherosclerosis and is present in up to 40 percent of patients with PAD [124]. Homocysteine is thought to promote smooth muscle proliferation, increase arterial wall inflammation, and increase levels of plasminogen activator inhibitor. Homocysteine also interferes with nitric oxide released by endothelial cells. Excess homocysteine leads to vessel thickening, luminal stenosis, and thrombus formation.
Although a more rapid progression of PAD in patients with increased homocysteine has been described in some studies [41,125], this finding is not uniform [35]. However, no study has shown that homocysteine-lowering therapy reduces PAD progression or improves outcomes [126].
Other biomarkers — Other biomarkers are increasingly being studied as a means to identify those at higher risk for development of atherosclerosis. Based on the Scottish Heart Health Extended Cohort study, N-terminal pro b-type natriuretic peptide [NT-pro-BNP], cotinine, high-sensitivity C-reactive protein, and cystatin-C are risk factors for PAD [8]. Biomarker risk factors for PAD were not entirely consistent with those for CHD. For PAD, high-sensitivity C-reactive protein, indicative of inflammatory state, and expired carbon monoxide and cotinine, associated with tobacco abuse, as well as lipoprotein (a), were associated with higher rates of PAD development. (See "Overview of possible risk factors for cardiovascular disease", section on 'Vitamins, antioxidants and homocysteine'.)
Another study reported 11 other biomarkers as significantly elevated in patients with PAD [127]. Biomarkers included the secretoglobin family 3A member 2, osteoprotegerin, urokinase-type plasminogen activator surface receptor, serum macrophage chemokine ligand 16, matrix metalloproteinase 9, p-selectin, growth differentiation factor 15, elafin, cystatin-B, trefoil factor 3, and fatty acid-binding protein 4.
Tissue plasminogen activator activity appears to be associated with asymptomatic lower extremity arterial disease. In a study of subjects previously unknown to have PAD, tissue plasminogen activator activity at baseline and at the 10-year follow-up significantly predicted the presence of sign(s) of PAD (OR 1.78, 95% CI 1.02-3.10) [128]. Age, hypertension, and HbA1c were also independent risk factors in this study for development of PAD at 10 years.
HIV infection — The mechanisms by which human immunodeficiency virus (HIV) might increase atherogenesis are unclear but may be related to endothelial dysfunction, platelet activation, and increased inflammation.
Among over 90,000 participants in the Veterans Aging Cohort Study, the rate of incident PAD events per 1000 person-years was significantly higher among HIV-positive compared with HIV-negative veterans (11.9 versus 9.9 percent). The risk was highest among those with time-updated HIV viral load >500 copies/mL and CD4 cell counts <200 cells/mm3 [129]. It is important to note that incident PAD events were defined based upon the reported diagnosis codes, rather than based upon ankle-brachial indices. Also, since this study was almost exclusively males, it is not possible to determine whether HIV in females confers the same risk.
In a review of patients with an established diagnosis of PAD who have undergone a lower extremity procedure, symptomatic patients with HIV were more likely to present with CLTI compared with those who are asymptomatic (66.2 versus 43.6 percent) [130]. Both asymptomatic and symptomatic patients were also at greater risk for minor and major amputation compared with uninfected controls (minor: 7.5 and 6.7 versus 2.6 percent, respectively; major: 12.9 and 27.4 versus 7.0 percent, respectively).
ANATOMIC PATTERNS OF DISEASE — Atherosclerotic disease tends to be well localized within a particular vascular segment (eg, aortoiliac, femoropopliteal, infrapopliteal), usually occurring in the proximal or mid portions of the arterial bed. Less commonly, however, the disease can occur more distally. Among the various vascular beds, atherosclerotic disease appears to follow patterns, which may also have a bearing on the natural history and progression of disease.
Asymptomatic — Subclinical atherosclerosis is prevalent in asymptomatic middle-aged individuals. The Progression of Early Subclinical Atherosclerosis (PESA) study evaluated the presence, distribution, and extent of subclinical atherosclerosis in 4184 asymptomatic participants aged 40 to 54 years using carotid, abdominal, and iliofemoral artery ultrasound and noncontrast coronary artery computed tomography (CT) [131]. Subclinical atherosclerosis was present in 63 percent of participants (71 percent of males, 48 percent of females). Nearly one-half of the participants were classified as having intermediate or generalized disease. Plaques were most common in the iliofemoral arteries (44 percent), followed by the carotid arteries (31 percent) and aorta (25 percent), whereas coronary artery calcification was present in 18 percent. Most participants with a high Framingham Heart Study (FHS) risk had subclinical disease, but extensive atherosclerosis was also seen in low-risk individuals. A second study that also used arterial ultrasound and noncontrast coronary CT identified atherosclerotic plaques in 72 percent of middle-aged males, which were most common in femoral arteries (54 percent), coronary arteries (38 percent), and carotid arteries (34 percent) [132].
In a study of whole body magnetic resonance (MR) angiography with contrast among 1531 asymptomatic participants (577 males, median age of cohort 53.5 years) at low-to-intermediate risk for cardiovascular disease, 747 (50 percent) demonstrated disease in one or more vessels [133]. The coronary arteries were not assessed. Vascular stenoses were distributed throughout the body with no localized distribution, with approximately 3.5 percent of the arteries in the neck (eg, carotids and vertebrals), torso (eg, abdominal aorta, iliac), and extremities (eg, femoral, popliteal) demonstrating stenoses of >50 percent. While imaging is typically not necessary or indicated clinically to assess asymptomatic patients, this study does demonstrate prevalence of disease in a low-to-intermediate risk group.
Symptomatic — In addition to the vascular bed that is producing symptoms, patients with symptomatic disease are at risk for developing additional lesions in the same or other vascular beds, which underscores the need for ongoing, longitudinal follow-up. (See "Overview of lower extremity peripheral artery disease", section on 'Surveillance following revascularization'.)
A review of 13,827 patients admitted at a single institution over a 40-year period (1948 to 1983) identified five major patterns of symptomatic atherosclerotic disease [134,135]:
●Type I: The coronary arterial bed (32 percent, mean age 55, 84 percent male)
●Type II: The major branches of the aortic arch (eg, carotid, subclavian) (17 percent, mean age 62, 65 percent male)
●Type III: The visceral arterial branches of the abdominal aorta (3 percent, mean age 49.4, 60 percent male)
●Type IV: The abdominal aorta and lower extremity arteries (42 percent, mean age 59, 80 percent male)
●Type V: A combination of two or more of these categories occurring simultaneously (6 percent, mean age 61, 73 percent male)
Important findings of this classic study included:
●Disease of the aorta and lower extremity arteries was the most prevalent, followed by coronary heart disease. By contrast, visceral vessel disease and combined patterns were the least prevalent.
●The onset of symptomatic disease varied with the arterial bed affected. Patients with coronary heart disease and visceral artery disease presented at a younger age compared with those in the other categories.
●Rates of disease progression varied with arterial bed. More rapid progression of disease occurred most frequently in those with aortic arch branch disease and visceral artery disease. The individual's sex did not influence the rate of progression; however, the risk for recurrence or progression of disease in the same category and in a new category was significantly greater in younger patients. In most other studies evaluating the natural progression of disease of the aorta and lower extremities, symptoms tend to remain stable [136]. Patients who continue to smoke cigarettes and those with diabetes mellitus are generally at the highest risk for progression of disease. (See 'Natural history and progression of PAD' below.)
●Disease of the abdominal aorta and lower extremity arteries had the highest incidence of developing disease in a new category, whereas those with coronary heart disease had the lowest incidence. The association between coronary heart disease and extracranial atherosclerotic carotid disease is well known. In one retrospective review, the severity of carotid artery stenosis significantly correlated with the extent of coronary heart disease [137]. Atherosclerotic disease of the renal artery branches is relatively common in patients with aortic disease, estimated at 22 to 59 percent of patients [138-140].
●Patients initially diagnosed with aortic arch branch disease had a greater tendency to develop disease of the abdominal aorta and lower extremity arteries, and vice versa. In other series, among patients with disease of the aorta and lower extremity arteries, a hemodynamically significant carotid lesion is present in 12 to 25 percent of patients [141-143]. The Atherosclerosis Risk in Communities (ARIC) study [144], and the Edinburgh Artery Study [145] documented an increased risk of stroke in these patients.
In the lower extremity, patterns of atherosclerotic disease have also been described [146,147]. Femoropopliteal disease is the most common anatomic location, occurring in approximately 50 percent in retrospective reviews [148-150]. However, among those with earlier-onset disease, the aortoiliac segment appears to be more commonly affected. However, atherosclerotic lower extremity arterial disease is a multisegmental disease in approximately two-thirds of symptomatic patients [149,151]. Patients with aortoiliac disease are likely to have disease involving the femoral and tibial vessels as well. Among patients with diabetes, more distal disease affecting the tibial vessels predominates [146].
NATURAL HISTORY AND PROGRESSION OF PAD — The clinical manifestations of PAD depend upon the location and severity of arterial stenosis or occlusion and range from mild extremity pain with activity (eg, claudication) to limb-threatening ischemia. While the risk of adverse limb events is less for asymptomatic individuals compared with symptomatic patients, clinical manifestations can develop or progress rapidly and unpredictably in those with PAD who continue to smoke, or those with concomitant diabetes or renal insufficiency.
The factors that predict progression of PAD were evaluated in a longitudinal study involving 403 patients using a standard questionnaire, clinical examination, ankle-to-brachial index (ABI), and the toe-brachial index (TBI) over a mean follow-up of 4.6 years [64]. The following findings were noted:
●Among patients with follow-up ABI decrements exceeding 0.3 (the study author's definition of progression), significant risk factors after adjustment included current cigarette smoking (hazard ratio [HR] 3.2, 95% CI 1.51-6.8), ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol (per unit) (HR 1.35, 95% CI 1.05-1.73), elevated high-sensitivity C-reactive protein (per 1 mg/L) (HR 1.37, 95% CI 0.99-1.90), and elevated lipoprotein (a) (per 1 mg/dL) (HR 1.37, 95% CI 1.03-1.82).
●Diabetes, hypertension, triglycerides, homocysteine, and body mass index (BMI) were not significant for large vessel disease progression as measured by changes in ABI. However, among patients with a significant decrement in TBI (decrement exceeding 0.27), diabetes was the only significant predictor of progression.
Similar findings were noted in the National Health and Nutrition Examination Survey (NHANES) [4] and Multi-Ethnic Study of Atherosclerosis (MESA) studies discussed above [35]. In the NHANES study, the risk of PAD was significantly increased in current smokers and patients with diabetes, hypertension, and hyperlipidemia. Other significant risk factors for PAD were being a Black person and decreased renal function. Each of these factors were also independently predictive of PAD progression, and many had synergistic effects. (See 'Epidemiology and risk factors' above.)
In a systematic review of observational studies, increasing age, male sex, smoking, and concurrent cardiovascular disease were all predictors of disease progression [152]. During follow-up (ranging from 1 to 13 years), approximately 7 percent of asymptomatic PAD patients progressed to claudication, and 21 percent of claudication patients were diagnosed as having chronic limb-threatening ischemia, with 4 to 27 percent undergoing amputations. However, with respect to sex, a population cohort study did not identify any significant differences in the composite risk of major adverse cardiovascular events for females with PAD compared with males, although males may be at increased risk for adverse limb events compared with females [153].
Asymptomatic PAD — Most patients with PAD are unaware of their disease. Fewer than 50 percent of PAD patients and approximately 30 percent of their physicians are aware that PAD is present [154].
PAD is a strong predictor of adverse cardiovascular outcomes [155]. The annual cardiovascular event rate is 5 to 7 percent for patients with PAD [3]. In the AGATHA study, patients with PAD in one vascular bed had a 35 percent chance of having disease in at least one other peripheral territory, and 50 percent had cerebrovascular or coronary heart disease [156]. There was a 2 to 3 percent nonfatal myocardial infarction rate, and a twofold to threefold increase in the occurrence of angina compared with age-matched controls. Asymptomatic PAD is also a risk factor for increased mortality [72,155,157], and mortality associated with asymptomatic and symptomatic PAD may not differ [155]. Even mild asymptomatic PAD increases the risk of cardiovascular death [72]. For each decrement of 0.1 in ABI, mortality increases approximately 13 percent [158]. The increased risk is due to cardiovascular causes but also includes nonvascular etiologies, most of which are neoplasms related to smoking. Clearly, identifying patients with asymptomatic PAD is important to institute risk factor modification to reduce adverse cardiovascular outcomes. Screening asymptomatic patients for PAD is discussed elsewhere. (See "Screening for lower extremity peripheral artery disease".)
The risk of progression from asymptomatic PAD to ischemic limb symptoms that require intervention is generally low but may be underestimated. PAD progression as measured by changes in ABI is similar for asymptomatic and symptomatic patients. The decline in ABI closely relates to the baseline value of ABI at the time of initial diagnosis; a more rapid decline is seen in patients with lower initial ABI values [157]. One study of 117 patients found a 30 percent progressive decline in ABI [86]. Another study that focused on functional capacity found a greater decrease over time for those with abnormal ABI, despite a lack of symptoms, compared with those with normal ABI over a two-year time period [22]. In a systematic review, the cumulative incidence over five years for progression from asymptomatic PAD patients to intermittent claudication was 7 percent [152].
In the Framingham Heart Study, 381 males and females were followed for 38 years [7]. The risk of developing intermittent claudication in asymptomatic patients was increased in patients with elevated serum cholesterol (odds ratio increase of 1.2 for each 40 mg/dL [1 mmol/L] elevation), cigarette smoking (odds ratio increase 1.4 for each 10 cigarettes smoked per day), moderate hypertension (odds ratio increase 1.5 for mild and 2.2 for moderate hypertension), and diabetes mellitus (odds ratio 2.6) [7]. In patients with diabetes, 28 percent of patients had progression of disease, regardless of symptoms [86]. Other studies have also demonstrated a decline in ABI over time that is not necessarily associated with the development of symptoms. On the other hand, the Edinburgh Artery study found no change in ABI over five years in asymptomatic patients [72].
Intermittent claudication — The most common symptom among patients with PAD is intermittent claudication, which is a reproducible muscular pain with ambulation that is relieved with rest. Intermittent claudication is discussed in more detail elsewhere. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)
The natural history of intermittent claudication is characterized by slow symptom progression. Chronic limb-threatening ischemia (CLTI; ie, rest pain, tissue loss) seldom occurs; however, revascularization (endovascular, surgical bypass) in patients with claudication can increase the progression to CLTI. In a long-term study of 1244 patients with intermittent claudication, predictors of progression to CLTI included diabetes, a lower initial ABI, and greater number of pack-years of smoking [159]. Based upon several population studies, the estimated risk of major amputation in patients with intermittent claudication is approximately 7 percent over a five-year period and 12 percent over a 10-year period [160].
Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) on PAD estimated the following rates of limb and cardiovascular outcomes at five years in patients with intermittent claudication [9-11]:
●Stable claudication in 70 to 80 percent
●Worsening claudication in 10 to 20 percent
●Chronic limb-threatening ischemia in 1 to 2 percent
●Nonfatal myocardial infarction or stroke in 20 percent
●Death in 15 to 30 percent (75 percent due to cardiovascular causes)
Intermittent claudication as a manifestation of PAD is a strong marker for generalized atherosclerosis and other cardiovascular and cerebrovascular morbidity and mortality [161-163]. In older studies, the 5- and 10-year mortality rates among patients with intermittent claudication were 30 to 42, and 50 to 65 percent, respectively [164,165]. In a later study that compared all-cause and cardiovascular mortality in patients with and without PAD, all-cause and cardiovascular mortality at five years for patients with PAD was 19 and 7.3 percent in asymptomatic patients, and 24 and 7.7 percent in symptomatic patients, a difference that was not significant between these groups, but was significantly greater compared with patients without PAD for whom all-cause and cardiovascular mortality was 9.5 and 2.4 percent, respectively [155].
The degree of impairment in symptomatic patients may also predict mortality. In a study that identified 1048 males and females with and without PAD, lower baseline walking impairment questionnaire (WIQ) stair-climbing scores were associated with a higher risk of all-cause and cardiovascular mortality compared with the higher WIQ stair-climbing scores (hazard ratio 1.7, 95% CI 1.08-2.66 and 3.11, 95% CI, 1.3-7.5, respectively) [166]. However, lower WIQ speed or distance scores did not increase risk for all-cause or cardiovascular mortality among the PAD participants.
The importance of PAD as a marker for coexistent coronary artery disease cannot be overstated. The association between cardiovascular disease and symptomatic PAD has been noted in many studies. Patients with intermittent claudication also have a relative increase in the incidence of tumor and tumor-associated death, probably due to a high prevalence of smoking [167].
In addition to high morbidity and mortality, patients with intermittent claudication have a poor quality of life and high rates of depression [168,169]. The adverse impact of intermittent claudication on the patient's physical and emotional well-being appears to be directly related to walking ability [170].
Chronic limb-threatening ischemia — Chronic limb-threatening ischemia (CLTI, formerly termed critical limb ischemia) is a clinical syndrome defined by the presence of PAD in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration [171]. CLTI is manifested in 1 to 2 percent of patients with symptomatic PAD. The clinical manifestations of CLTI are discussed in detail elsewhere. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Symptoms'.)
The natural history of untreated CLTI is difficult to elucidate since patients undergo medical management to prolong survival, and in the era of endovascular therapies, many will undergo some form of intervention attempting limb salvage. In a systematic review, the five-year cumulative incidence of patients with claudication that deteriorated or progressed to CLTI was 21 percent [152].
Risk factors that increase the risk for CLTI include diabetes (fourfold risk), smoking (threefold risk), and hypercholesterolemia (twofold risk) [64,159].
Patients with CLTI are at immediate risk for limb loss. Amputation rates remain high at 25 percent, and long-term survival is poor. Nearly 25 percent of patients presenting with CLTI will suffer a cardiovascular death within one year of their initial diagnosis [5,172]. In one review, only 50 percent of patients presenting with CLTI were alive with both limbs intact at the end of one year [5]. In studies of patients with nonreconstructible disease, 40 percent of patients with CLTI underwent amputation within six months, and 20 percent died within the same time period [3].
Limb salvage and long-term survival are significantly worse in patients with diabetes and those who continue to smoke [173].
Progression of disease in selected populations — Patients with early-onset atherosclerosis, diabetes, or end-stage kidney disease have a higher risk for progression of PAD and worse prognosis.
Early-onset atherosclerosis — Early-onset or premature atherosclerosis is defined as PAD presenting prior to 50 years of age. Patients with early-onset atherosclerosis are more frequently male, are active smokers, have diabetes, and more often present with CLTI [174-177]. A defect in coagulation or fibrinolysis is identified in up to 75 percent of patients with early-onset atherosclerosis [178-180]. In one study, 30 percent had hypercoagulable states, and 47 percent had platelet aggregation defects [178].
Outcomes are poor in this group of PAD patients.
●One review identified an 8 percent risk of transient ischemic attack, 9 percent risk of stroke, and 60 percent risk of coronary artery disease [41]. Surgery was undertaken for CLTI in 62 percent of patients, and 38 percent demonstrated further progression of disease following revascularization.
●Late amputation rates were significantly higher in a study of patients with early-onset atherosclerosis compared with an older cohort of control patients (17 percent versus 3.9 percent) [177]. Nearly half of the early-onset atherosclerosis patients underwent contralateral amputation within two years.
●Mortality rates for younger patients with PAD are higher than for older patients, but the difference has not been found to be significant [177,181]. However, compared with age-matched controls, patients with early-onset atherosclerosis demonstrate significantly higher mortality (26 versus 1.7 percent) [177]. In another review, 32 percent of younger patients undergoing major amputation died within one year of surgery; 20 percent died within five years [181].
Diabetes — Diabetes is associated with a higher prevalence of PAD, and increased risk for adverse outcomes [182]. In the Prevention Of Progression Of Arterial Disease and Diabetes (POPADAD) trial, 16 percent of 1276 asymptomatic patients with diabetes and PAD progressed to intermittent claudication, 3 percent to CLTI, and 1.6 percent to a major amputation at six years [183]. Medical therapies (aspirin or antioxidants) had no influence on these numbers. (See "Overview of peripheral artery disease in patients with diabetes mellitus".)
Chronic kidney disease — Peripheral artery disease is common among patients with end-stage kidney disease and is associated with a poor prognosis. Even mild-to-moderate chronic kidney disease increases the risk of incident PAD, with a strong association between albuminuria and amputation. Moreover, patients with end-stage kidney disease are at increased risk for vascular calcification, which independently increases the risk of cardiovascular morbidity and mortality. PAD in this population is discussed elsewhere.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Peripheral artery disease and claudication (The Basics)")
●Beyond the Basics topics (see "Patient education: Peripheral artery disease and claudication (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The prevalence of peripheral artery disease (PAD) increases progressively with age, beginning after 40 years of age. As a result, PAD is growing as a clinical problem due to the aging population in the United States and other developed countries. As such, a standard review during the examination of older patients should always include questions related to a history of walking impairment, extremity pain with ambulation, and the presence of nonhealing wounds. (See 'Introduction' above.)
●Risk factors for peripheral artery disease are similar to those that promote the development of coronary atherosclerosis (ie, smoking, hypertension, hyperlipidemia, diabetes, and metabolic syndrome). Other factors include age, sex, ethnicity, family history and genetic influences, and possibly homocysteinemia. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD identified the following groups at risk for lower extremity PAD. Patients in these groups should be evaluated for PAD. (See 'Epidemiology and risk factors' above.)
•Age ≥70 years
•Age 50 to 69 years with a history of smoking or diabetes
•Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis
•Known atherosclerosis at other sites (eg, coronary, carotid, renal artery disease)
●The prevalence of PAD increases progressively with age, beginning after 40 years of age. Individuals over 70 are at a significantly increased risk for PAD due to age alone, while the risk for younger individuals is due to other factors, most commonly cigarette smoking. Early-onset atherosclerosis, or premature atherosclerosis, is defined as PAD presenting prior to 50 years of age. Patients with early-onset atherosclerosis more often present with CLTI and have poor overall outcomes. (See 'Age' above and 'Early-onset atherosclerosis' above.)
●Sex- and ethnicity-related differences in prevalence of PAD have been documented. PAD is cited historically as more prevalent in males overall compared with females. However, the population-based prevalence of PAD in females has not been fully evaluated. The prevalence of PAD in females is at least as high as that of males across all age groups but increases to a greater extent in females after age 70 compared with males of the same age, with African Americans having a higher prevalence of PAD compared with non-Hispanic White Americans, and Hispanic and Asian Americans having a somewhat lower rate of PAD than non-Hispanic White Americans. (See 'Sex' above and 'Ethnicity' above.)
●For patients found to have asymptomatic PAD, the risk of adverse limb events is less compared with symptomatic patients; however, the risk of adverse cardiovascular events remains elevated. Among those with intermittent claudication, 70 to 80 percent have stable claudication, 10 to 20 percent develop worsened claudication, and only approximately 1 to 2 percent progress to CLTI. Revascularization in patients with claudication is associated with an increased risk for progression to CLTI. The prognosis for limb loss or survival is significantly worse in those with early-onset atherosclerosis, patients with diabetes or end-stage kidney disease, and for those who continue to smoke. (See 'Natural history and progression of PAD' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.
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