Screening for lower extremity peripheral artery disease

INTRODUCTION — Peripheral artery disease (PAD) of the lower extremities is a common cause of impaired ambulation and is a leading cause of lower extremity wounds and amputations. It is also associated with atherosclerosis elsewhere in the body. Thus, individuals with PAD are at significantly increased risk of cardiovascular and cerebrovascular events and mortality.

There is substantial evidence that the majority of cases of PAD go undetected in routine clinical practice [1,2]. As a result, there is considerable interest in detection of PAD through routine screening [3-6]. However, a systematic review of guidelines for peripheral artery disease screening found divergent recommendations among the eight screening guidelines identified from major organizations [7]. In the absence of a randomized trial evaluating outcomes of screening in asymptomatic individuals, critical questions regarding the objectives of screening, appropriateness of screening, and optimal approach to screening need to be addressed.

This topic will review the rationale and recommendations for screening for PAD with a focus on the use of the ankle-brachial index (ABI) as a screening test. Clinical features of lower extremity PAD and noninvasive diagnostic tests for PAD are discussed separately. (See "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Noninvasive diagnosis of upper and lower extremity arterial disease".)

PREVALENCE OF PAD — Approximately 20 percent of adults older than 55 years have peripheral artery disease (PAD) [8], although estimates of the prevalence of PAD vary widely. Worldwide, the estimated prevalence in high-income countries ranged from 5.3 percent (for individuals 45 to 49 years of age) to 18.5 percent (for individuals 85 to 89 years old) in data collected from 2000 to 2010 [9]. A large study in the United States that was conducted in 1999 to 2004 estimated that about 7.1 million community-dwelling Americans were diagnosed with PAD [10]. Globally, it is estimated that over 200 million people have PAD [9,11]. The incidence of PAD reportedly increased significantly over the preceding decade (by 28.7 percent in low- and middle-income countries, and by 13 percent in high-income countries).

It is well documented that undiagnosed PAD is common. In a study of almost 7000 primary care patients ages 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 [1]. Over half of these cases were new diagnoses found by ankle-brachial index (ABI) screening during the study; the remainder of the patients with PAD had prior documentation of the diagnosis. The prevalence of asymptomatic PAD in generally healthy populations, compared with clinic populations, is significantly lower. 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 by ABI screening (ABI <0.90) was 2 percent, but the prevalence was 6.6 percent in current smokers [12]. PAD was not significantly more common in subjects with diabetes.

Risk factors for PAD — In addition to age, major risk factors for PAD are similar to those for other cardiovascular diseases (CVD): smoking, hyperlipidemia, hypertension, diabetes mellitus, and the diagnosis of atherosclerosis in other sites [1,2,13,14]. Smoking is a particularly strong risk factor for PAD and is two to three times more strongly associated with PAD than with coronary heart disease (CHD) [15].

Guidelines from the Trans-Atlantic Inter-Society Consensus (TASC), a consortium of professional organizations, define increased risk for PAD as the presence of one of the following [3]:

●Age <50 years with diabetes and one additional risk factor (smoking, dyslipidemia, hypertension, or homocysteinemia)

●Age 50 to 69 years with history of smoking or diabetes

●Age ≥70 years

●Abnormal lower extremity pulses

●Leg symptoms with exertion or ischemic rest pain

●Known coronary, carotid, or renal atherosclerosis

In a 2011 update of their 2005 guideline, the American College of Cardiology/American Heart Association (ACC/AHA, in collaboration with other participants of the TASC consortium) recategorized risk as age ≥65 years [16].

DIAGNOSING PAD — Peripheral artery disease (PAD) is frequently unrecognized by clinicians and can be overlooked even when the patient has symptoms [1,2,13]. Primary care clinicians are often unaware that patients have PAD, even when the patient is aware of his or her diagnosis [1].

Classic claudication symptoms are found in only a minority of patients with PAD [17]. Classic intermittent claudication is defined as exertional calf pain that causes a person to stop walking and resolves within 10 minutes of rest. In a report of 460 consecutive PAD patients, only 32 percent had classic intermittent claudication [17]. Twenty percent had no exertional leg pain and almost half (48 percent) had atypical symptoms, such as rest and exertional leg pain, leg pain other than in the calf, pain that did not cause the patient to stop walking, or pain that lasted more than 10 minutes after cessation of exercise. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

Asymptomatic patients with PAD may simply be more sedentary than those with intermittent claudication symptoms. Support for this hypothesis was provided by a study of patients with PAD in which those who never experienced symptoms had poorer functional performance and poorer quality of life than patients with PAD and exertional leg pain [18].

Ankle-brachial index — Findings from clinical examination (eg, skin temperature, peripheral pulses, or bruits) have poor sensitivity in the detection of PAD in asymptomatic patients [19]. The ankle-brachial index (ABI) is a simple, accurate, and relatively inexpensive test that assesses the ratio of systolic pressures in the lower versus upper extremities using Doppler ultrasound [20]. Techniques for performing this assessment are discussed separately. (See "Noninvasive diagnosis of upper and lower extremity arterial disease".)

ABI predicts angiography results more accurately than is possible using history and physical examination alone [3]. In patients undergoing diagnostic testing, ABI has excellent overall accuracy compared with angiography (area under the receiver operating characteristic [ROC] curve = 0.95) in detecting significant PAD (stenoses ≥50 percent) [21]. For patients in whom there is clinical suspicion of PAD, an ABI cutoff of <0.9 has been reported to have a sensitivity ranging from 79 to 95 percent, with specificity consistently >95 percent [3]. Little information is available on the sensitivity and specificity of ABI when used in asymptomatic patients without other known vascular disease (ie, a screening population). A modified approach to calculating ABI (using the lowest ankle pressure for each leg divided by the highest brachial pressure) has been demonstrated to have a higher positive test rate in a screening population [12], but this approach requires validation and a more complete assessment of its impact on specificity and sensitivity.

The ABI is considered sufficiently accurate so that verifying the diagnosis using arterial angiography is generally not recommended. Lower extremity angiography is appropriately reserved for those with advanced disease in whom surgical intervention is being considered [3].

RATIONALE FOR SCREENING — The rationale for screening to detect patients with asymptomatic peripheral artery disease (PAD) is based upon two possible objectives [3]:

●To identify early PAD and intervene to prevent progression and complications directly related to PAD.

●To identify patients at high risk for coronary heart disease (CHD) or other cardiovascular disease (CVD) to aggressively treat risk factors and prevent events related to CVD.

To achieve the first objective, the risk of progression from asymptomatic PAD to critical leg ischemia would need to be high enough to warrant intervention in individuals identified by screening, the interventions would need to be safe and have proven efficacy for the prevention of PAD progression, and the interventions would need to be those that would not otherwise be implemented in the absence of screening.

Similarly, to achieve the second objective, the risk of CHD or stroke in patients who otherwise had not been identified as high-risk would need to be significant, the interventions would need to be proven safe and effective for prevention of CHD or other CVD events in patients identified with asymptomatic PAD, and the interventions would need to be those otherwise not indicated if screening for PAD were not performed [3,4].

PAD as a risk factor for other cardiovascular disease — Recommendations to use ankle-brachial index (ABI) testing for screening selected populations are mainly based upon identifying patients at high risk for CVD, with the expectation that this would lead to more aggressive risk factor modification than would occur in the absence of screening. PAD screening is one of a host of proposed tests for identification of high CVD-risk patients, including estimation of CVD risk using multivariable prediction tools, such as the Framingham CVD risk score. Other studies include C-reactive protein, apoprotein B, low-density lipoprotein (LDL) subparticles, homocysteine, and computed tomography (CT) cardiac screening. The marginal utility that these tests add to widely used risk scores is unclear. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "C-reactive protein in cardiovascular disease" and "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

It is well established that PAD is a risk factor for other CVD and that the risk is greater with more advanced PAD [22-28].

●A large international registry of patients found that 5.4 percent of patients with established PAD had a major cardiovascular event (cardiovascular death, myocardial infarction, or stroke) at one year, and 21 percent experienced these endpoints or hospitalization for an atherosclerotic event [25]. These rates were comparable to event rates for patients with coronary artery or cerebrovascular disease.

●Eleven-year follow-up in the Cardiovascular Health Study found, after controlling for other risk factors, an almost twofold increased risk for mortality in participants with ABI 0.71 to 0.8 (hazard ratio [HR] 1.80) and 0.81 to 0.9 (HR 1.73) compared with those with ABI 1.1 to 1.2 [26].

●In a meta-analysis of nine studies evaluating ABI and subsequent cardiovascular outcomes for patients with ABI 0.8 to 0.9 compared with those with normal ABI, likelihood ratios for CHD, stroke, and cardiovascular death were 2.5, 2.5, and 5.6, respectively [24]. More than half of the patients with low ABI were asymptomatic and identified through screening.

Half of those with PAD have known CVD [29] and the majority of the rest have other major risk factors for PAD that would qualify them for aggressive risk factor modification [1,2,13]. However, ABI remains an independent predictor of cardiovascular risk after adjusting for conventional risk factors and has some incremental value in assessing risk [30-33]. A meta-analysis of sixteen cohort studies comparing cardiovascular risk predicted by the Framingham risk score compared with risk predicted by the ABI found that inclusion of the ABI in the cardiovascular risk stratification would lead to reclassification of risk and change in treatment recommendations, such as lipid-lowering therapy as recommended by the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines, for about one-fifth of men and one-third of women [34]. A review that included this meta-analysis and several smaller subsequent trials concluded that overall the magnitude of risk reclassification is likely to be clinically unimportant [35].

INTERVENTIONS FOR ASYMPTOMATIC PAD — While risk factor modification is essential for all patients with peripheral artery disease (PAD) to reduce their risk of cardiovascular disease (CVD; control of tobacco use, hyperlipidemia, hypertension, hyperglycemia, and increasing exercise), the effect of such interventions on progression of PAD per se is uncertain.

Intervening for PAD outcomes — About 5 to 10 percent of individuals with asymptomatic PAD develop symptoms of PAD over five years [36]. Critical leg ischemia occurs infrequently (1 to 2 percent of patients with PAD) but is more likely to affect patients with concomitant diabetes [8].

Evidence suggests that smoking cessation and gradually progressive walking programs can slow disease progression and improve PAD symptoms and functional impairment for patients with symptomatic PAD [8,37]. Supervised exercise was more effective than stent revascularization for improving treadmill walking performance in a randomized trial of individuals with symptomatic PAD [38]. A clinical trial of 882 men with PAD detected by screening with a claudication questionnaire and ankle-brachial index (ABI) found that, compared with "usual care," a "stop smoking and keep walking" program resulted in about a 50 percent increase in the number of men who improved their maximum walking performance at 12-month follow-up [39]. Whether exercise can prevent progression of PAD in truly asymptomatic patients is not clear from these data. (See "Management of claudication due to peripheral artery disease".)

There is scant evidence whether treatment for other risk factors, such as elevated lipids and blood pressure, affects PAD onset and progression. Benefit of different lipid-lowering agents on total walking distance and pain-free walking distance was demonstrated in a meta-analysis of several small trials [40]. One cross-sectional study found that statin therapy was associated with better ambulatory function in patients with known PAD, independent of cholesterol levels [41].

However, interventions directed at preventing PAD progression are either universally recommended (increased physical activity and smoking cessation) or are more important for CVD morbidity and mortality reduction (treatment for elevated blood pressure and dyslipidemia). There is no evidence to suggest that early revascularization in selected patients with asymptomatic PAD prevents progression to symptomatic disease [5,6].

Intervening for CVD outcomes — Serious cardiovascular complications are more common than serious complications of PAD; therefore, aspirin therapy, blood pressure control, and statin therapy should be primarily based upon cardiovascular risk assessment. Some observational studies, with adjustment for known cardiovascular risks, suggest that use of statins, aspirin, and antihypertensive agents in patients with established PAD are independently associated with reduced long-term mortality [42]. However, since these treatments are generally recommended for all patients with an elevated CVD risk, the benefits of PAD screening in patients with known increased risk for CVD is unclear.

Assessment for PAD has intuitive appeal for helping to guide treatment decisions for patients at intermediate risk of CVD after conventional risk factor appraisal. However, it is not known whether patients identified at increased risk because of low ABI would receive greater benefit from treatment, or that awareness of increased risk would make patients more likely to comply with recommended interventions. Furthermore, it is unclear whether a normal ABI should make clinicians and patients less likely to treat.

Aspirin — Data supporting aspirin for primary prevention of CVD (coronary heart disease [CHD] and stroke) are less conclusive than for secondary prevention. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Use of antiplatelet drugs for patients with symptomatic PAD is recommended by multiple guidelines and supported by results of a meta-analysis of 12 randomized in patients with intermittent claudication that found that use of antiplatelet agents (including aspirin or thienopyridine), compared with placebo, reduced all-cause mortality and cardiovascular mortality [43]. Patients with asymptomatic PAD, however, were excluded from this analysis.

Although measuring ABI could identify a population at increased risk for CVD compared with the general population, the effectiveness of primary prevention has not been proven in this higher-risk group. A trial in 3350 asymptomatic screened individuals aged 50 to 75 years with an ABI <0.95 found no difference in rates of coronary events, stroke, or revascularization for those randomly assigned to receive aspirin 100 mg daily or placebo [44]. Aspirin was associated with a statistically nonsignificant increased risk of major hemorrhage (hazard ratio [HR] 1.71; 95% CI 0.99-2.97).

Walking — Substantial evidence suggests that functional assessment of walking fitness can help identify those at higher CVD risk [45,46]. In one study, poor walking fitness was as strong an independent CVD risk factor as smoking and diabetes [46]. Whether walking fitness in part helps identify those with functionally important occult PAD is unclear.

Statins — A meta-analysis of randomized trials found that lipid-lowering therapy, primarily statins, reduced cardiovascular mortality and morbidity in people with diagnosed PAD [40]. Eighteen trials (10,049 participants) with varying inclusion criteria were included in the meta-analysis; although pooled results from all trials did not find a statistically significant effect on mortality or cardiovascular events, a subgroup analysis that excluded one trial in which treatment (probucol) had a detrimental effect on lipid levels did identify significantly improved cardiovascular and mortality outcomes. The effectiveness of lipid-lowering in patients with asymptomatic PAD was not addressed.

Intervening for overall mortality reduction — In the Viborg Vascular (VIVA) trial, a randomized controlled study of one-time screening for three diseases (PAD, abdominal aortic aneurysm [AAA], and hypertension) in men aged 65 to 74 years, a reduction was seen in overall mortality (HR 0.93, 95% CI 0.88-0.98) at 4.4 years compared with the non-screened group. For those who screened positive, pharmacotherapies and AAA repair, if appropriate, were offered. The screened group had higher rates of initiation of statins, higher rates of antiplatelet and blood pressure therapies, and higher AAA repair surgery rates than the control group [47]. However, because the VIVA participants appeared to have poor adherence to standard CVD prevention guidelines (eg, using statins and antiplatelet therapies and controlling blood pressure in patients with CVD risk scores >7.5 percent) prior to study enrollment, it is unclear if ABI testing contributed to decreased overall mortality separate from any effect it may have had on increasing use of preventive therapies.

RECOMMENDATIONS AND GUIDELINES — We suggest not screening for peripheral artery disease (PAD) with ankle brachial index (ABI) pending results of future studies that may show a specific benefit.

Guideline recommendations for screening with ABI vary. The US Preventive Services Task Force (USPSTF) concluded again in 2018, as it had in 2013, that evidence is insufficient to assess the balance of benefits and harms of screening for PAD and cardiovascular disease (CVD) risk with the ABI in asymptomatic adults [48]. A systematic review found screening for PAD with an ABI had low sensitivity (right leg, 20 percent [95% CI 10-34%] left leg, 15 percent [95% CI 7-27%]). Moreover, treatment (with aspirin or exercise) for screen-detected PAD lacked beneficial effect in most studies. However, the included studies had important limitations and there were no trials of the effects of ABI screening alone on morbidity or mortality among asymptomatic adults [49].

Data lend support to low ABI being an independent risk factor for myocardial infarction, stroke, and overall mortality, and ABI adds incremental value to stratification of CVD risk beyond the factors used to calculate the Framingham risk score. Nonetheless, it remains to be determined whether screening asymptomatic individuals with ABI has benefits beyond conventional screening for elevated CVD risk factors used to determine if statin, antiplatelet, and blood pressure treatments are warranted [50].

Recommendations for screening for 10-year CVD risk and for statins and blood pressure therapies for those with elevated CVD risk are described in detail separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Overview of primary prevention of cardiovascular disease" and "Overview of established risk factors for cardiovascular disease".)

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: Screening for peripheral artery disease".)

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SUMMARY AND RECOMMENDATIONS

●Lower extremity peripheral artery disease (PAD) is caused by occlusion of vessels beyond the bifurcation of the aorta and is due to atherosclerosis in the vast majority of cases. (See 'Introduction' above.)

●Risk factors for PAD are (see 'Risk factors for PAD' above):

•Age <50 years with diabetes and one additional risk factor (smoking, dyslipidemia, hypertension, or homocysteinemia)

•Age 50 to 69 years with history of smoking or diabetes

•Age ≥70 years

•Known coronary, carotid, or renal atherosclerosis

PAD is also suggested by the presence of abnormal lower extremity pulses, or by symptoms of claudication or ischemic rest pain.

●A low ankle-brachial index (ABI; <0.9) has 90 percent sensitivity and 95 specificity for PAD. Claudication is uncommon in patients with PAD. In the absence of screening, PAD is not diagnosed in more than one-half of patients who meet ABI criteria for PAD. (See 'Diagnosing PAD' above.)

●The rationale for screening for PAD involves both the potential to intervene to prevent progression of PAD and to decrease risk for other cardiovascular disease (CVD). The association between low ABI and risk for major cardiovascular events is well established and a low ABI is an independent risk factor. (See 'Rationale for screening' above.)

●Progression from asymptomatic PAD to limb-threatening disease is uncommon and interventions directed at preventing PAD progression are universally recommended (increased physical activity and smoking cessation). (See 'Intervening for PAD outcomes' above.)

●Interventions for patients with low ABI to decrease the risk of other CVD include aspirin, lipid-lowering therapy, and walking. A randomized trial of aspirin in patients with asymptomatic PAD did not reduce rates of coronary events, stroke, or revascularization. It is not known if statin therapy will benefit individuals who have a positive ABI screening but whose CVD risk is low by conventional risk factors (such as Framingham CVD Risk Score). It is uncertain if ABI adds to conventional CVD risk assessment methods and how ABI compares with other interventions to supplement conventional CVD risk assessment, such as measuring the coronary calcium score. (See 'Intervening for CVD outcomes' above and "Coronary artery calcium scoring (CAC): Overview and clinical utilization" and "Screening for coronary heart disease".)

●Guidelines from several organizations suggest ABI screening for higher-risk individuals. The US Preventive Services Task Force (USPSTF) concluded that evidence was insufficient to make a recommendation regarding ABI screening. (See 'Recommendations and guidelines' above and 'Society guideline links' above.)

●We suggest not screening asymptomatic individuals to detect PAD or CVD risk using ABI measurements (Grade 2C). (See 'Recommendations and guidelines' above.)