Asymptomatic peripheral artery disease

INTRODUCTION — Peripheral artery disease (PAD) comes to clinical attention due to reduced blood flow that most commonly affects the lower extremities causing a spectrum of signs and symptoms ranging from discomfort, cramping or pain with ambulation (ie, intermittent claudication), to ischemic rest pain and difficulties with wound healing. However, many individuals who have PAD report few or no classical symptoms, potentially due to functional limitations or adaptation, due to neuropathy, or they may have atypical symptoms that are not recognized as being due to PAD. There is increasing interest in this "asymptomatic" or "subclinical" population, who are typically identified based on an abnormal ankle-brachial index.

The prevalence, risk factors, disease progression, and management of individuals with asymptomatic PAD are reviewed. The clinical features and management of symptomatic PAD are discussed separately. (See "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Management of claudication due to peripheral artery disease" and "Management of chronic limb-threatening ischemia".)

DEFINITION — Asymptomatic PAD is the presence of typical atherosclerotic lesions in the peripheral vasculature that has not been recognized by classical symptomology or functional deficits attributable to those lesions [1-5]. Given the lack of clear-cut symptoms, the diagnosis of asymptomatic PAD is now primarily made based on the presence of appropriate risk factors and an ankle-brachial index (ABI) ≤0.9 obtained for screening or to investigate reduced distal pulses on physical examination. The presence of atherosclerotic lesions seen in imaging studies may also identify the condition. The increasing presence of diabetes and noncompressible vessels further complicates the use of ABI as a diagnostic test for this condition. (See 'Clinical presentations' below.)

●Guidelines suggest not obtaining ABI for people with low or no risk for cardiovascular disease [5-7]. (See "Screening for lower extremity peripheral artery disease".)

●For those at moderate-to-high risk for cardiovascular disease, guidelines from the American College of Cardiology and American Heart Association suggest performing ABI to identify PAD. Patients at risk include adults:

•≥65 years of age

•≥50 years of age with other atherosclerotic risk factors or a family history of PAD

•<50 years of age with diabetes and at least one other atherosclerotic risk factor

●For patients with evidence of atherosclerotic disease in other vascular beds (eg, cerebrovascular, mesenteric), ABI to detect lower extremity PAD should be considered.

●Other patient groups in whom ABI may be useful include patients with diabetes, chronic renal disease, radiation exposure, posttransplant, and human immunodeficiency virus [8,9].

PREVALENCE AND RISK

Prevalence — Estimates of the prevalence of PAD (as defined by ankle-brachial index (ABI) ≤0.9) vary widely [1,10,11]. Some, but not all studies also include ABI >1.4. The clinical subset of asymptomatic PAD represents the largest proportion of patients with PAD [1,12]. For every patient with typical intermittent claudication, there are two to five cases of asymptomatic PAD [13]. A systematic review of screening for PAD in asymptomatic patients reported an overall yield of 17 percent (range 1 to 42 percent) [14].

In the Aragon Workers' Health Study (AWHS), which used arterial ultrasound and noncontrast coronary computed tomography (CT), atherosclerotic plaques were seen in 72 percent of the cohort (men 40 to 59 years) [15]. Among nearly 7000 primary care patients 70 years or older or 50 to 69 years with risk factors for atherosclerosis (history of cigarette use or diabetes), PAD was identified in 29 percent; over half of cases were newly diagnosed using the ABI [2]. In the Progression of Early Subclinical Atherosclerosis (PESA) study, subclinical atherosclerosis (defined as the presence of atherosclerotic plaque on imaging) was present in 63 percent of participants (71 percent of males, 48 percent of females); common femoral artery plaque was most common (44 percent) [16]. Most participants with a high Framingham Heart Study (FHS) risk had subclinical disease, but extensive atherosclerosis was also seen in low-risk individuals. In a systematic review, the yield for PAD screening in low-risk populations was 1 to 4 percent [14]. In a study sample of 1017 adults aged 60 to 69 years (average age 66 years) that excluded individuals with major chronic disease but did include smokers and patients with diabetes, the prevalence of PAD was 2 percent, but the prevalence was 6.6 percent in current smokers [17].

The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program evaluated ABI in 6417 patients 70 years of age or older, or 50 through 69 years of age and a history of cigarette smoking or diabetes [2]. An ABI ≤0.9 identified PAD in 1865 patients (16 percent previously unknown diagnosis). The mean ABI was 0.78 and was similar for those who were newly diagnosed and those who had a prior diagnosis.

Risk factors — Patients who develop PAD have well-defined risk factors. The most important risk factors associated with atherosclerosis, in general, include: (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease", section on 'Epidemiology and risk factors'.)

●Increasing age

●Cigarette smoking

●Hypertension

●Diabetes mellitus

●Chronic kidney disease

●Dyslipidemia

The American Heart Association/American College of Cardiology guideline for PAD provided the following age-related associations [18]:

●Age 65 or older

●Age 50 to 64 with risk factors for atherosclerosis (as listed above)

●Age <50 with diabetes mellitus and one additional risk factor for atherosclerosis (as listed above)

After adjusting for conventional risk factors, low ABI is an independent predictor of cardiovascular risk and may improve traditional methods of cardiovascular risk assessment [4,14,19-33]. In a meta-analysis that included 12 cohort studies with over 57,000 participants, the pooled risk for cardiovascular disease was significantly increased for low versus normal ABI (morbidity: risk ratio [RR] 2.03, 95% CI 1.72-2.41; mortality: RR 2.29, 95% CI 1.98-2.64) [29]. (See 'Risk for cardiovascular events' below.)

Beyond simply using the ABI value, evidence also suggests that functional assessment of walking fitness can help identify those at higher cardiovascular disease risk [34,35]. In one study, poor walking fitness was as strong an independent cardiovascular disease risk factor as smoking and diabetes [35]. Whether walking fitness in part helps identify those with functionally important occult PAD remains unclear.

Risk estimation of cardiovascular disease risk can also use multivariable prediction tools (eg, Framingham general risk score (calculator 1 and calculator 2), QRISK). The updated QRISK3 score is a prediction algorithm for cardiovascular disease that uses traditional risk factors (age, systolic blood pressure, smoking status and ratio of total serum cholesterol to high-density lipoprotein cholesterol) together with body mass index, ethnicity, measures of deprivation, family history, chronic kidney disease, rheumatoid arthritis, atrial fibrillation, diabetes mellitus, and antihypertensive treatment [36]. The assessment of cardiovascular risk and risk calculators are reviewed separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

Markers for cardiovascular disease risk include C-reactive protein, apoprotein B, low-density lipoprotein subparticles, homocysteine, and coronary artery calcification [37,38]. Whether walking fitness in part helps identify those with functionally important occult PAD remains unclear. (See "Overview of established risk factors for cardiovascular disease", section on 'Inflammation' and "C-reactive protein in cardiovascular disease".)

Risk for cardiovascular events — Data support the link between asymptomatic PAD and increased risk for myocardial infarction, stroke, and overall mortality [24,39,40]. The increased risk for death is due to cardiovascular causes but also includes nonvascular etiologies, most of which are neoplasms related to smoking.

●Cardiovascular death – There may be no difference in mortality for those with asymptomatic compared with symptomatic PAD [22]. Even mildly asymptomatic PAD increases the risk of cardiovascular death [4,24,28,41,42]. A prospective cohort study included 6880 representative unselected patients ≥65 years of age with monitored follow-up over five years [22]. According to physician diagnosis, 5392 patients had no PAD, 836 had asymptomatic PAD (ABI <0.9), and 593 had symptomatic PAD. The risk of death was similar for patients with symptomatic compared with asymptomatic patients with PAD but was significantly higher compared with those without PAD. The event risk was higher for symptomatic compared with asymptomatic patients for the composite of all-cause death or severe vascular event (myocardial infarction, coronary revascularization, stroke, carotid revascularization, or lower-extremity peripheral vascular events; hazard ratio [HR] 1.48, 95% CI 1.21 to 1.80), but not for any revascularization, cardiovascular events alone, or cerebrovascular events alone.

●Abdominal aortic aneurysm – The presence of PAD, even asymptomatic PAD, increased the risk for abdominal aortic aneurysm (AAA) in a prospective study. In the Atherosclerosis Risk in Communities Study (ARIC) study, among 14,148 participants, 530 (3.7 percent) developed incident AAA over a median follow-up of 22.5 years [43]. The risk of incident AAA was increased for symptomatic PAD (HR 4.91, 95% CI 2.88-8.37), and asymptomatic PAD with ABI≤0.9 (HR 2.33, 1.55-3.51), compared with the reference ABI >1.1 to 1.2. Crude 15-year cumulative incidence of AAA in these three groups were 12.3, 3.9, and 1.5 percent, respectively. The associations remained significant after accounting for other potential confounders.

DISEASE PATTERNS AND ASSOCIATED VASCULAR BEDS — Atherosclerosis is systemic disease and as such patients with PAD commonly have atherosclerotic disease in other vascular beds (eg, coronary, carotid, renal, mesenteric). Individuals identified with atherosclerotic disease in any vascular bed have an increased risk for future cardiovascular morbidity and mortality. (See 'Risk for cardiovascular events' above.)

Atherosclerotic disease affects multiple vascular beds (eg, cardiac, cerebrovascular, peripheral, visceral) but tends to be well localized within a particular vascular bed. As with the lower extremity, atherosclerotic disease appears to follow patterns, which may also have a bearing on the natural history and progression of disease and associated end-organ dysfunction. While imaging is not typically necessary or indicated clinically to assess asymptomatic patients (see 'Further evaluation' below), the following studies demonstrate the general pattern of atherosclerotic disease in low-to-intermediate risk groups.

●In the PESA study, the presence, distribution, and extent of atherosclerotic lesions was evaluated in 4184 asymptomatic participants aged 40 to 54 years using carotid, abdominal, and iliofemoral artery ultrasound and noncontrast coronary artery CT [16]. Plaques were found in 63 percent of those studied and were most common in the iliofemoral arteries (44 percent), followed by the carotid arteries (31 percent), aorta (25 percent), and coronary arteries (18 percent). Nearly one-half of the participants were classified as having intermediate or generalized disease.

●In the AWHS study, atherosclerotic plaques were most common in femoral arteries (54 percent), coronary arteries (38 percent), and carotid arteries (34 percent) [15]. 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 artery disease [44].

●In a study of whole body magnetic resonance angiography with contrast among 1531 asymptomatic participants (577 men, 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 [45]. The coronary arteries were not assessed. Vascular stenoses were distributed throughout the body, 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.

●In an autopsy study of 121 patients who had no clinical symptoms of PAD prior to their death, advanced plaques (American Heart Association ≥4) were present in 72 percent of common iliac arteries, and were associated with generalized atherosclerosis and cardiovascular disease events [46].

In a classic review, the natural history of 13,827 patients admitted to a single institution over a 40-year period (1948 to 1983) was reviewed and five major patterns of atherosclerotic disease were identified and classified [47,48]:

●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)

Disease of the aorta and lower extremity arteries were the most prevalent, followed by coronary arteries. By contrast, visceral vessel disease and combined patterns were the least prevalent. 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 later series, among patients with disease of the aorta and lower extremity arteries, a hemodynamically significant carotid lesion was present in 12 to 25 percent of patients [49-51]. The Atherosclerosis Risk in Communities (ARIC) study [52], and the Edinburgh Artery Study [20], documented an increased risk of stroke in these patients. A separate study of patients with stroke documented an 18.8 percent prevalence of PAD; 60 percent had no lower extremity PAD symptoms [53]. The onset of symptomatic disease and rate of disease progression varied with arterial bed [47,48]. Patients with coronary artery disease and visceral artery disease presented symptomatically at a younger age compared with those in the other categories. More rapid progression of disease was most frequent for aortic arch branch disease and visceral artery disease. 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 later studies evaluating the natural progression of disease of the aorta and lower extremities after symptomatic presentation, patients tended to remain stable [54]. Patients who continued to smoke cigarettes and those with diabetes mellitus generally had the highest risk for disease progression.

PAD can affect any segment (eg, aortoiliac, femoropopliteal, infrapopliteal) [55,56]. Femoropopliteal disease is the most common anatomic location, occurring in approximately 50 percent in retrospective reviews [57-59]. Patients with aortoiliac disease are likely to have disease involving the femoral and tibial vessels as well. PAD usually occurs in the proximal or mid portions of the arterial segment, but disease can occur more distally. In patients with diabetes, occlusive disease is often localized to the more distal segments of the arterial bed [55,60].

CLINICAL PRESENTATIONS — PAD not associated with reported symptoms is most often diagnosed because of the finding of an abnormal ankle-brachial index (ABI), or less often, reduced distal pulses on physical examination. Atherosclerosis or arterial calcification might also be detected as an incidental finding on imaging such as plain radiography, duplex ultrasound, or CT [61-63]. It is important to interpret the ABI in the context of the patient's risk factors for atherosclerosis and clinical condition to avoid overlooking symptomatic disease or other conditions. (See 'Evaluate asymptomatic category' below.)

Abnormal ABI — The report of an abnormal ABI may be the result of screening (eg, self-directed test) evaluation of a patient with known atherosclerosis in another vascular bed, or testing to evaluate an unrelated condition (eg, extremity trauma evaluation). (See "Screening for lower extremity peripheral artery disease".)

The ABI is a simple and accurate test for PAD that can be performed in the clinic or at the bedside [6,64-66]. The higher resting systolic blood pressure at the ankle is compared with the higher systolic brachial pressure, and the ratio of the two pressures defines the ABI. An ABI ≤0.9 identifies significant arterial obstruction. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index'.)

Some authors have suggested using the lowest ankle pressure for calculating the ABI[17]. For ABI obtained in a clinic setting or at the bedside, multiple measurements may be more useful compared with a single ABI determination [67]. If the examiner is not confident with their measurements or the measurements are inconsistent, the patient can be sent to the vascular laboratory for formal ABI testing.

Interpretation — While the ABI remains an accurate and validated test for arterial obstruction, it is not specific for atherosclerosis as the cause of obstruction. ABI results also need to be interpreted in the light of the patient's functional level. However, atherosclerotic disease is by far the most common cause of arterial obstruction, particularly for lower extremity arterial disease in the context of risk factors for atherosclerosis. (See 'Clinical evaluation' below.)

●False positive: obstruction not due to atherosclerosis – Patients with arterial obstruction that is not due to atherosclerotic disease can exhibit a reduced ABI. Some of these conditions occur in younger patients (eg, popliteal entrapment syndrome), which may help to distinguish them from those with PAD. Many of these individuals are asymptomatic. Additional vascular imaging may be warranted for patients with abnormal ABI and other clinical features that suggest nonatherosclerotic vascular disease. (See "Overview of peripheral vascular problems in athletes" and "Nonatheromatous popliteal artery diseases causing claudication or limb-threatening ischemia".)

However, other conditions (eg, thrombosed aneurysm, arterial embolism) occur with similar risk factors as PAD. These conditions more often present suddenly with symptoms (eg, acute limb ischemia) or incidentally on imaging studies. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Differential diagnosis of PAD'.)

●False negative: normal or increased ABI is due to mural calcification – Patients with PAD can have an ABI>0.9 [68]. This is more likely to occur with noncompressible arteries, which can lead to a falsely elevated ABI. In these cases, arterial waveforms should be obtained and reviewed to determine if there is PAD present with falsely elevated pressures at rest. A high ABI >1.4 in the context of symptomatic disease is a common finding in patients with diabetes. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'High ABI' and "Evaluation of the diabetic foot", section on 'Comprehensive foot examination'.)

Incidental imaging finding — With the increasing use of cross-sectional imaging, identification or arterial calcification and atherosclerotic plaque is now more prevalent. This often leads to consultations to a vascular specialist to determine the clinical significance and the need for risk factor modulation.

CLINICAL EVALUATION — When a patient presents with a diagnosis of "asymptomatic PAD," it is important to verify the presumed diagnosis by obtaining or verifying the ankle-brachial index (ABI), evaluating the presence of atypical symptoms that would reclassify the patient as having "symptomatic" PAD, and also evaluating the patient's medical history for conditions that reduce their activity level such that symptoms are not likely to be provoked.

Evaluate asymptomatic category — The following categories have been used to describe the types of individuals who may be described as having "asymptomatic" PAD:

Atherosclerotic lesion with no flow reduction — Asymptomatic individuals may have atherosclerotic disease that has not progressed to the extent that blood flow is reduced, and the tissues of the lower extremity remain well perfused at rest and during activity. These patients are truly "asymptomatic" with subclinical atherosclerosis.

Activity level not sufficient to provoke symptoms — Asymptomatic individuals with PAD may have disease that reduces blood flow, and the level of blood flow is sufficient at rest; however, these patients may be more sedentary and the level of their daily activity is insufficient to provoke symptoms [40]. There are many reasons why an individual may be less active including mobility problems (eg, joint disease), systemic illness (eg, cardiomyopathy), neuropathy, and balance issues, among others.

Asymptomatic patients who are less physically active are be more likely to develop leg symptoms with provocation [69]. In one study, patients with asymptomatic PAD who did not walk more than six blocks per week were regarded as having "asymptomatic/inactive" PAD, and those who walked more than six blocks per week were classified as having "asymptomatic/active" PAD. Significantly more participants in the asymptomatic/inactive group developed leg pain during a 6-minute walk test compared with those in the asymptomatic/active group (89 versus 33 percent) [70].

Whether clinical manifestations will develop in the future in those with asymptomatic PAD depends upon the location and severity of stenotic lesions, the development of collateral vessels, and changes in the individual's activity level relative to the level of flow reduction. "Inactive" PAD may reflect less cardiovascular reserve that portends a worse overall prognosis compared with individuals with PAD who display symptoms [40].

Misinterpreted symptoms — An individual with PAD may, in fact, be symptomatic. PAD is frequently unrecognized by clinicians and can be overlooked even when the patient has symptoms or symptoms are attributed to another cause [2,3,70,71]. In the lower extremity, one report noted that a classic description of claudication symptoms (ie, exertional extremity pain) was reported in only 32 percent of patients; 48 percent had atypical symptoms [70]. In the PAD Awareness, Risk, and Treatment study, among symptomatic patients, classic claudication was present in <15 percent [2]. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Atypical extremity pain'.)

Evaluate risk for progression — The risk of progression from asymptomatic lower extremity PAD to ischemic limb symptoms that requires vascular intervention is generally low, but may be underestimated [54]. In a systematic review of observational studies, the cumulative incidence over five years for progression from asymptomatic PAD to intermittent claudication was 7 percent [72]. Increasing age, male sex, smoking, and concurrent cardiovascular disease were all predictors of progression. 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 [73].

PAD progression as measured by changes in ABI is similar for asymptomatic and symptomatic patients, and while the risk of adverse limb events is less for individuals who are asymptomatic, clinical manifestations can develop or progress rapidly and unpredictably in those with PAD who continue to smoke or those with concomitant diabetes or chronic kidney disease. Progression to chronic limb-threatening ischemia (CLTI) occurs in 1 in 10 patients with established PAD, but is more likely in patients with diabetes [74,75].

The decline in ABI closely relates to the baseline value of ABI at the time of initial diagnosis; a more rapid decline in symptomatic patients is seen in patients with lower initial ABI values [23]. One study of 117 patients reported a 30 percent progressive decline in ABI [76]. Other studies have 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 [4]. Another study that focused on functional capacity reported 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 [77].

In the Framingham Heart Study, 381 males and females were followed for 38 years [78]. The risk of developing claudication in asymptomatic patients was increased in patients with elevated serum cholesterol (odds ratio [OR] increase of 1.2 for each 40 mg/dL [1 mmol/L] elevation), cigarette smoking (OR increase 1.4 for each 10 cigarettes smoked per day), moderate hypertension (OR increase 1.5 for mild and 2.2 for moderate hypertension), and diabetes mellitus (OR 2.6) [78]. In patients with diabetes, 28 percent of patients had progression of disease, regardless of symptoms [76].

The factors that predicted progression of PAD were evaluated in a longitudinal study of 403 patients using a standard questionnaire, clinical examination, ABI, and the toe-brachial index (TBI) over a mean follow-up of 4.6 years [79]. 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).

●Hypertension, triglycerides, homocysteine, and body mass index were not significant for large vessel disease progression as measured by changes in ABI.

●Diabetes was not cited as a significant factor for large vessel disease progression; however, due to mural calcification leading to varying degrees of noncompressibility, ABI is less accurate in this population. Diabetes was the only significant predictor of progression among patients with a significant decrement in TBI (decrement exceeding 0.27).

Similar findings were noted in the National Health and Nutrition Examination Survey (NHANES) [71] and Multi-Ethnic Study of Atherosclerosis (MESA) studies [80]. 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 decreased renal function and being from a Black population. Each of these factors were also independently predictive of PAD progression, and many had synergistic effects.

High-risk for progression — Patients with early-onset atherosclerosis, diabetes, or end-stage kidney disease have a higher risk for progression of PAD and a worse prognosis.

Early-onset atherosclerosis — Early-onset or premature atherosclerosis is defined as atherosclerotic associated pathology diagnosed before the age of 50 to 55 years [81]. Patients with early-onset atherosclerosis are more frequently male and are active smokers. Those with PAD more often develop CLTI [82-86]. A defect in coagulation or fibrinolysis is identified in up to 75 percent of patients with early-onset atherosclerosis [87-89]. In one study, 30 percent had hypercoagulable states, and 47 percent had platelet aggregation defects [87].

Outcomes are poor in this group of patients.

●One review identified an 8 percent risk of transient ischemic attack, 9 percent risk of stroke, and 60 percent risk of coronary heart disease [90]. Surgery was needed 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) [86].

●Mortality for these younger patients is increased [86,91]. Compared with age-matched controls, patients with early-onset atherosclerosis demonstrate significantly higher mortality (26 versus 1.7 percent) over five years [86]. In one review, 32 percent of younger patients undergoing major amputation died within one year of surgery; 20 percent died within five years [91].

Diabetes — Diabetes is associated with a higher prevalence of PAD and increased risk for adverse outcomes [92]. In the Prevention Of Progression Of Arterial Disease and Diabetes (POPADAD) trial, 16 percent of 1276 asymptomatic patients with diabetes and PAD (defined as ABI ≤0.99) progressed to intermittent claudication, 3 percent to CLTI, and 1.6 percent to a major amputation at six years [93]. Medical therapies (aspirin or antioxidants) had no influence on these numbers. As noted above, in patients with diabetes and PAD, disease is often localized to the more distal portions of the arterial bed [60]. (See "Overview of peripheral artery disease in patients with diabetes mellitus".)

Chronic kidney disease — PAD is common among patients with chronic kidney disease (CKD) and is associated with a poor prognosis. Diabetes superimposed on CKD compounds CKD-related PAD. Even mild-to-moderate CKD 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.

Further evaluation — Asymptomatic PAD does not require further imaging, and no current guidelines recommend any follow-up. An abnormal ABI is sufficiently accurate for identifying arterial obstruction, such that verifying a diagnosis of PAD in an at-risk asymptomatic patient is generally not necessary.

When asymptomatic PAD is diagnosed based on imaging studies, we suggest obtaining an ABI.

For patients with identified risk factors and an abnormal ABI, ongoing monitoring of ABI can be incorporated into risk factor modulation and monitoring of medical therapy. It is important to note that some asymptomatic PAD patients, particularly those with diabetes, can develop limb-threatening ischemia without an antecedent history of PAD symptoms. (See 'High-risk for progression' above.)

As discussed above, while the prevalence of atherosclerosis in other vascular beds (eg, coronary, carotid, renal) is higher in patients with asymptomatic PAD compared with those without PAD, there is no evidence to suggest that vascular imaging for atherosclerosis in other arterial beds in the absence of some other clinical suspicion improves clinical outcomes.

However, if risk factors are lacking and the clinical features suggest an alternative diagnosis for vascular obstruction, appropriate diagnostic studies should be pursued.

MANAGEMENT — For patients with asymptomatic PAD, the question arises on whether to institute risk reduction strategies with an aim toward preventing progression and complications, preserving functional status, or reducing the risk for future adverse cardiovascular events [5].

Our approach – As discussed above, patients with asymptomatic PAD often have known cardiovascular disease affecting other vascular beds and most others have cardiovascular risk factors that would already qualify them for risk reduction strategies. (See 'Evaluate asymptomatic category' above.)

For other individuals with asymptomatic PAD, treatment is individualized accounting for overall cardiovascular risk and weighing the potential risk reduction with potential complications. Our approach to management is as follows:

●For all patients identified with PAD, including those who have been termed as having asymptomatic PAD, we suggest lifestyle modification and identification and modulation of CV risk factors.

●For patients with asymptomatic PAD at risk for progression, we suggest the same medical therapies as with symptomatic disease including antiplatelet and statin therapy. This includes patients with diabetes, hypertension, hypercholesterolemia, chronic kidney disease, those who continue smoking and those with early onset atherosclerosis. (See 'Evaluate risk for progression' above.)

Lifestyle modification — Lifestyle modification includes smoking cessation, exercise, and dietary modification for weight control, as needed. Smoking cessation is recommended for anyone. (See "Overview of smoking cessation management in adults" and "Benefits and consequences of smoking cessation".)

Exercise programs can reduce functional impairment for those with asymptomatic PAD. Among 417 individuals with PAD, the annual decline in six-minute walking performance was smaller in a subset of asymptomatic patients who walked for exercise three or more times per week compared with asymptomatic participants who walked fewer than three times per week [94]. In a trial, 882 males with early PAD detected by screening were randomly assigned to "usual care," or a "stop smoking and keep walking" program [95]. At 12 months, more participants in the intervention group improved their maximum walking distance (23 versus 15 percent) and reported walking more than three times per week for recreation (34 versus 25 percent). (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

Healthy diet and weight control is reviewed separately. (See "Healthy diet in adults" and "Obesity in adults: Overview of management".)

Potential medical therapies — Guidelines conflict regarding management of individual identified with asymptomatic PAD [96]. The results of studies specifically looking at outcomes of patients with asymptomatic PAD are reviewed below. Several clinical trials and observational studies of patients with established atherosclerosis, including PAD have shown that medical treatments (eg, vorapaxar, low dose rivaroxaban, aspirin, statins, evolocumab) reduce adverse limb events. Medical therapies for secondary prevention of cardiovascular disease and outcomes of therapies in patients with symptomatic PAD are reviewed elsewhere. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of lower extremity peripheral artery disease", section on 'Management'.)

Aspirin — It may be reasonable to treat patients identified with asymptomatic PAD given the systemic nature of atherosclerotic disease and beneficial outcomes in patients with symptomatic PAD [97-99]. The American Heart Association/American College of Cardiology PAD guideline recommends antiplatelet therapy as reasonable if the ankle-brachial index (ABI) is ≤0.9 [18] The European Society of Cardiology guideline recommends against routine antiplatelet therapy in asymptomatic patients [100]. The Society for Vascular Surgery guideline provides no specific recommendation [5]. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

In trials of patients with asymptomatic PAD, aspirin compared with placebo did not significantly reduce the incidence of cardiovascular events [93,101,102]. The alternative thresholds used to define PAD in these trials have raised concerns. As such, these neither support nor rule out the efficacy of aspirin in patients with asymptomatic PAD.

●A trial in 3350 asymptomatic screened individuals aged 50 to 75 years with an ABI <0.95 (lowest ABI pressure) reported no difference in rates of coronary events, stroke, or revascularization for those randomly assigned to receive aspirin 100 mg daily or placebo over a mean of 8.2 years [101]. Aspirin was associated with a nonsignificant increased risk of major hemorrhage (hazard ratio 1.71, 95% CI 0.99-2.97).

●In the Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial, 1300 patients with diabetes and asymptomatic PAD (defined as ABI ≤0.99) were randomly assigned to aspirin or placebo [93]. The composite endpoint (death from coronary heart disease or stroke, nonfatal myocardial infarction or stroke or major amputation for chronic limb-threatening ischemia) was similar between the groups.

Statin therapy — Like aspirin, statin therapy can be considered in individuals with asymptomatic PAD with risk factors for progression based on the benefits seen in patients with symptomatic PAD, in whom various studies have demonstrated improvements in total and pain-free walking distance [103-105], limb outcomes [106-108], and reduced cardiovascular morbidity and mortality [104,106,107]. Guidelines from the ACCF/American Heart Association PAD and European Society of Cardiology recommend statin therapy [18,100], while the Society for Vascular Surgery provides no specific recommendation [5]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

The effectiveness of lipid-lowering in patients with asymptomatic PAD has not been addressed in randomized trials [109]. In a retrospective cohort study, patients with an ABI ≤0.95 and individuals without clinically recognized cardiovascular disease were matched 1:1 by inclusion date and propensity score for statin treatment [110]. The matched-pair cohort included 5,480 patients. At a median follow-up of 3.6 years, the incidence of major adverse cardiovascular events was lower for new statin users compared with nonstatin users (19.7 versus 24.7 events per 1,000 person-years, respectively). Total mortality was also lower (24.8 versus 30.3 per 1,000 person-years, respectively).

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 5^th to 6^th 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 10^th to 12^th 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

●Asymptomatic PAD – Asymptomatic peripheral artery disease (PAD) is defined as the presence of typical atherosclerotic lesions in the peripheral vasculature that has not been recognized by classical symptomology or functional deficits attributable to those lesions. A diagnosis of asymptomatic PAD is primarily made based on the presence of appropriate risk factors and an ankle-brachial index (ABI) ≤0.9 obtained for screening or because of reduced distal pulses on physical examination, but the presence of atherosclerotic lesions seen in imaging studies may also identify the condition. The implications of functional measurement irrespective of the value of an ABI have been raised as a measure of asymptomatic PAD. (See 'Definition' above.)

●Prevalence and risk for PAD – The clinical subset of asymptomatic PAD represents the largest proportion of patients with PAD, with approximately three individuals with asymptomatic PAD for every one individual with symptomatic PAD. Individuals with asymptomatic PAD have an increased risk for future cardiovascular morbidity and mortality. (See 'Prevalence and risk' above.)

Risk factors for PAD include the following risk factors for atherosclerosis (see 'Risk factors' above):

•Increasing age

•Cigarette smoking

•Diabetes

•Chronic kidney disease

•Other cardiovascular risk factors such as hypertension, dyslipidemia, and cardiovascular risk equivalents (eg, aneurysmal disease)

•Known atherosclerotic disease in the coronary, carotid, renal, visceral, or upper extremity arteries

•Age 65 or older

•Age 50 to 64 with risk factors for atherosclerosis

•Age <50 with diabetes mellitus and one additional risk factor for atherosclerosis

●Clinical evaluation – For patients who are diagnosed with asymptomatic PAD based on an abnormal ABI, it is important to interpret the ABI in the context of the patient's risk factors for atherosclerosis and clinical condition to avoid overlooking symptomatic disease or other conditions. Asymptomatic PAD can be categorized as follows (see 'Clinical evaluation' above):

•No flow reduction – These individuals have atherosclerotic disease, but flow is not reduced. The tissues remain well perfused at rest and during activity. These patients are truly "asymptomatic" with subclinical atherosclerosis.

•Flow reduction but low activity level – These individuals have atherosclerotic disease that reduces blood flow, and the tissues of the lower extremity remain well perfused at rest, but the patient has a reduced level of the activity and is unlikely to complain of classical symptoms.

•Flow reduction and atypical and/or misinterpreted symptoms – An individual diagnosed with asymptomatic PAD may, in fact, be symptomatic. Symptoms consistent with PAD can frequently be overlooked or might be attributed to another cause. In the lower extremity, the classic description of claudication symptoms is present in only about one-third of patients.

●Disease patterns and progression – The risk of progression from asymptomatic lower extremity PAD to ischemic limb symptoms that requires vascular intervention is generally low. PAD progression as measured by changes in ABI is similar for asymptomatic and symptomatic patients. The risk of adverse limb events is less for individuals who are asymptomatic, but clinical manifestations can develop or progress rapidly and unpredictably. Risk factors for progression include age, male sex, continued smoking, diabetes, chronic renal disease, and atherosclerotic disease in other vascular beds. (See 'Disease patterns and associated vascular beds' above.)

●Management – Patients with asymptomatic PAD often have known cardiovascular disease affecting other vascular beds and most have cardiovascular risk factors that indicate the need for risk reduction strategies. For other individuals with asymptomatic PAD, treatment is individualized accounting for overall cardiovascular risk and weighing the potential benefits of risk reduction with potential complications. Treatment aims to prevent PAD progression and complications, preserve functional status, and reduce the risk for future adverse cardiovascular events. Our approach to management is as follows (see 'Management' above):

•Lifestyle modification is recommended for all patients with atherosclerosis and includes smoking cessation, exercise, and dietary modification for weight control, as needed. (See 'Lifestyle modification' above.)

•Patients with asymptomatic PAD at risk for progression are appropriate for all interventions recommended for patients with established cardiovascular disease including aspirin and statin therapy. This includes patients with diabetes, hypertension, hypercholesterolemia, chronic kidney disease, early onset atherosclerosis, and those who continue to smoke. (See 'Evaluate risk for progression' above and 'Potential medical therapies' above.)