Peripheral Artery Disease: New Concepts, Treatments and Disparities

Abstract

Peripheral artery disease (PAD) is a prevalent and underdiagnosed atherosclerotic condition affecting over 10 million adults in the United States. PAD is a marker of systemic vascular disease and a strong predictor of myocardial infarction, stroke, and mortality. Despite its clinical importance, PAD remains underrecognized due to variable presentation, limitations in screening, and disparities in diagnosis and treatment. This review examines contemporary PAD epidemiology, diagnostic strategies—including the ankle-brachial index—and evidence-based management approaches, from supervised exercise to surgical revascularization. It also highlights the evolving debate on PAD screening guidelines and presents emerging evidence favoring targeted screening in high-risk populations. Importantly, the review explores structural inequities, racial and ethnic disparities, and geographic variation in PAD-related outcomes, particularly amputation. These disparities persist even after adjustment for comorbidities and socioeconomic factors. Addressing PAD effectively requires comprehensive strategies that include early diagnosis, equitable access to care, and policy initiatives.

Introduction

Lower extremity peripheral artery disease (PAD) is an atherosclerotic, obstructive disease process that affects the arteries from the aorto-iliac segment to the pedal arteries. It is a common form of cardiovascular disease that is estimated to affect 10–12 million individuals in the United States who are >40 years old, and as many as 236 million people worldwide. (1) The actual prevalence of PAD is unknown, as awareness of PAD is limited among both patients and health care professionals,(2; 3) and screening guidelines are often conflicting. (4) (5) (6) This lack of awareness and disease recognition is particularly concerning, as not only is PAD a major cause of disability, it is a marker for concurrent cardiovascular disease and a strong predictor of future myocardial infarction (MI) and stroke. (7) In this manuscript, we will review PAD epidemiology and risk factors, disparities related to PAD, clinical guidelines for assessment and diagnosis, and treatment options.

PAD Epidemiology and Risk factors

PAD is the third leading cause of atherosclerotic morbidity, following coronary artery disease (CAD) and stroke, and has a growing global impact. Between 2000–2010, the number of people living with PAD increased by 13.1% in high-income countries and 28.7% in low and middle-income countries. (8) Advanced age, diabetes mellitus (DM), smoking, chronic kidney disease (CKD), hypertension (HTN) and hyperlipidemia are the major risk factors for PAD. Of these risk factors, DM and smoking have a particularly strong association with the development of PAD.

PAD and DM

Once considered a purely ischemic process, the influence of DM on the prevalence of PAD has substantially changed the risk profile of disease. Patients with DM have an estimated 2–4 x increased risk of developing PAD during their lifetimes and risk increases with worsening glycemic index control. (9) With each 1% increase in HbA1C from baseline, there is an associated 14.2% increased relative risk of major adverse cardiovascular events (MACE) (10) and a 21–28% increased risk of PAD. (11) Up to 34% of patients with DM will develop a foot ulcer over their lifetimes – 50% of which will become infected and require hospitalization, or an emergency room visit. (12; 13) Although many DM foot ulcers are neuropathic in origin, the prevalence of PAD in patients with a DM-related foot ulcer is 50%, and patients with both DM and PAD have a 4 x higher risk of amputation than the national average.(14)

PAD and smoking

Smoking is a major modifiable risk factor of PAD and is associated with a three-to-four-fold increase in the risk of developing PAD. (15) Unfortunately, registry data indicates that 22% of patients with symptomatic PAD continue to use tobacco. (16) Cigarette smoking induces endothelial dysfunction, oxidative stress, and production of inflammatory and proatherogenic cytokines, causing a prothrombotic state with platelet aggregation and vasoconstriction. (15) A dose-response relationship between smoking and the incidence of PAD has been demonstrated and it has a significantly closer association than the relationship between smoking and CAD or stroke; even more disconcerting is that the elevated risk of PAD for smokers persists even after 30 years of smoking cessation (although it is still reduced compared to that of an active smoker). (17)

PAD risk based on sex, race and ethnicity

Contrary to traditional belief, PAD does not affect men more than women. (18) Rather, men are more likely to present with “classic” PAD symptoms while women are more likely to have atypical or asymptomatic disease.(19) Recent population-based studies estimate that the prevalence of PAD in women may even be slightly higher than men. (20) Overall, women are less likely to be prescribed optimal medical therapy for PAD, more likely to present with more severe disease, and less likely to have interventions for PAD than men. (21; 22)

There are also significant race and ethnicity related risk factors for PAD that persist despite controlling for confounding variables. In a 2007 study evaluating data from 7 community-based studies in the United States, Black men were found to have the highest prevalence of PAD compared to other racial and ethnic groups, as were Black women.(23) A more recent study estimated lifetime risk of developing PAD to be 30% for Black men and 27% for Black women compared to 22% for Hispanic/Latino men and women and 19% for White men and women. In addition, this study found that despite adjusting for conventional risk factors, Black race independently increased the odds for developing PAD (aOR 1.65; 95% CI 1.48–1.84). (24)

PAD related health disparities

Significant variation in PAD-related amputation risk has been documented across socioeconomic, racial, ethnic, and geographic lines.(25),(26),(27),(28; 29) ((30) (31) While elevated prevalence of diabetes, cardiovascular disease, and tobacco use contributes to this risk, communities facing economic hardship and chronic external stressors experience disproportionately higher amputation rates. (32) Suggesting that health inequities and issues related to the social drivers of health may be at the root of these disparities.

A substantial body of literature details racial and ethnic disparities in PAD-related amputations. (25; 33–45) Although these disparities are often attributed to confounding factors like socioeconomic status and comorbidities, multiple studies have demonstrated that Black and Latino/Hispanic patients face higher risks of major amputation (above the ankle) than White patients, even after adjusting for disease severity, access to care, and other risk factors(25; 31; 33; 36; 39–41; 44) Similar findings have been reported in Native American/American Indian populations. (46; 47) Geographic disparities also persist. Rural communities show consistently higher PAD-related amputation rates compared to urban areas, with rurality itself identified as a risk factor.(13; 29; 30; 48) Intersectionality further compounds these inequities.(49; 50) Examples include findings that rural Black patients have a higher risk for amputation than their urban Black counterparts, (51) and higher-than-expected amputation rates for diabetic foot ulcers, beyond what would be anticipated if rural and racial risk factors were simply additive.(52)

Of particular concern, race and ethnicity independently predict primary amputation (i.e.: amputation without attempt at revascularization). (33; 36; 38; 39; 41; 44; 51; 53) This suggests the presence of additional, unmeasured contributors, including structural inequities,(54; 55) implicit bias, (56) (57) and potentially biologic differences. (55; 58) Though researchers caution against interpreting race as a biological variable.(59; 60)

PAD Screening

The role of screening for peripheral artery disease (PAD) in asymptomatic individuals has been debated for decades. Since 1996, the U.S. Preventive Services Task Force (USPSTF) has advised against routine screening, citing insufficient evidence to assess benefits and harms, an opinion reaffirmed in 2005, 2013, and 2018 recommendations.(4) In contrast, beginning as early as 2011 and formally by 2015, every major medical and surgical society involved in PAD management has recommended screening high-risk asymptomatic individuals. (61) (5) These include patients aged ≥65, individuals >50 with atherosclerosis risk factors, and patients <50 with diabetes and at least one other risk factor.

The ankle-brachial index (ABI), a non-invasive and inexpensive test, is the standard tool for PAD screening. Opponents argue that abnormal ABI results may prompt unnecessary advanced imaging, such as Computed Tomography Angiography (CTA), Magnetic Resonance Angiography (MRA), or invasive catheter-based angiography and overtreatment. A 2023 New York Times article, “They Lost Their Legs, Doctors and Health Care Giants Profited,” underscored the potential for harm when abnormal findings in asymptomatic individuals are exploited by aggressive practitioners. (62) The USPSTF has also raised concerns about risks associated with initiating antiplatelet therapy or statins based solely on a PAD diagnosis.

Professional societies, including the American College of Cardiology, American Heart Association, Society for Vascular Surgery, and Society for Interventional Radiology strongly support targeted screening to reduce cardiovascular events and limb-related complications. In a 2018 joint response to the USPSTF, these groups highlighted four key concerns: 1) the USPSTF assessed screening in the general population rather than high-risk groups; 2) several important studies, including a Danish trial showing reduced mortality with screening, were excluded from consideration; (6) 3) references opposing antiplatelet/statin use were of limited relevance; and 4) the recommendation may worsen disparities, particularly among non-White patients, who are more likely to present with atypical or asymptomatic PAD and are at greater risk for amputation. (63)

To address these gaps and improve access, several societies have supported the Amputation Reduction and Compassion (ARC) Act, most recently reintroduced on January 9, 2025. The bill proposes Medicare and Medicaid coverage of PAD screening for high-risk individuals without cost-sharing and includes provisions for education, alternative payment models, and quality measures aimed at reducing PAD-related amputations. (64)

PAD Clinical Presentation and Natural History

The majority of patients with peripheral artery disease (PAD) are either asymptomatic (20–50%) or present with atypical symptoms (40–50%), while only 10–30% experience classic claudication, defined as exertional leg pain relieved within 10 minutes of rest. Just 1.3% initially present with limb-threatening ischemia (Fig. 1). (7) Notably, many “asymptomatic” patients demonstrate functional impairment, having unconsciously modified their activity to avoid leg pain. (65) Studies indicate these individuals may be as limited as those with claudication, with many developing symptoms during objective walking tests. (65) (66) Furthermore, asymptomatic PAD patients face a significantly increased 5-year risk of cardiovascular morbidity and mortality compared to those without PAD. (67)

Figure 1:

Clinical Presentation and 5-Year outcomes of People with Symptomatic PAD

CLTI – chronic limb threatening ischemia, ALI – acute limb ischemia, MI – myocardial infarction

Patients with “atypical” leg symptoms may report pain at rest, discomfort that does not impede walking, or pain that inconsistently resolves with rest. (68) These presentations often overlap with other conditions such as neuropathy, arthritis, or spinal stenosis, complicating diagnosis. As a result, patients may consult multiple specialists without receiving appropriate management for PAD, thus missing critical cardiovascular risk reduction strategies. Accordingly, patients with exertional leg symptoms and risk factors for atherosclerosis should be evaluated for PAD.

Among symptomatic PAD patients, the 5-year cardiovascular event or mortality risk may reach 20%.(5) However, from a limb-related perspective, most patients will have stable or progressively worsening claudication, with only 5–10% progressing to limb-threatening ischemia (Fig. 1). Limb-threatening ischemia includes chronic limb-threatening ischemia (CLTI) and acute limb ischemia (ALI). CLTI—defined by ischemic rest pain, nonhealing wounds, or gangrene lasting over two weeks—is the predominant form encountered in vascular surgery and accounts for most PAD-related amputations. (69) ALI, by contrast, is a sudden reduction in limb perfusion that can result from embolism (e.g., atrial fibrillation, aneurysm) or in-situ thrombosis of a native vessel or prior revascularization. In ALI, depending on the level of pre-existing ischemia, limb viability can be compromised within six hours, requiring prompt revascularization.

PAD Diagnosis

History and Physical Exam

The presenting signs of PAD can be highly variable, and assessment begins with identifying patients at risk. This includes any patient ≥ 65, any patient > 50 with risk factors for atherosclerosis, and patients < 50 with DM and one atherosclerotic risk factor. Any patient with known atherosclerotic disease in another vascular bed should also be considered at increased risk. These patients require a comprehensive medical history to assess exertional leg symptoms, lower extremity rest pain, lower extremity wounds and other ischemic skin changes. Location, frequency, exacerbating factors and alleviating factors are all important for assessing leg pain as well. On physical exam, careful assessment for abnormal pulses should be performed, including the femoral, popliteal, dorsalis pedis and posterior tibial arteries, taking care not to mistake the provider’s own pulse for that of the patient. Additional physical exam findings include wounds, asymmetric hair growth, muscle atrophy and dependent rubor (rubor that pales upon leg elevation).

In addition to a careful and thorough history, it’s important to be aware of non-PAD etiologies of leg pain that may mimic PAD. These include musculoskeletal abnormalities, spinal disease and neuropathy. Tables 1 and 2 provide a thorough review of the history and physical exam findings pertinent to PAD as well as the differential diagnoses. (1)

Table 1:

History and Exam Findings with PAD

History

Physical Exam

Claudication Aching, cramping, muscle fatigue or discomfort causing a limp Occurs in the muscle group(s) distal to the arterial occlusion (includes erectile dysfunction in aortoiliac occlusion) Exacerbating factors: longer than typical distance, rushed pace/exercise, uphill or uneven terrain Alleviating factors: resolves within 10 minutes of no activity Rule out: joint pain, leg weakness without walking pain, pain that improves with movement, pain that does not resolve within minutes Ischemic rest pain Rule out: isolated neuropathy without cardiovascular risk factors Nonhealing wound Rule out: venous leg ulcer (medial malleolus)

Sparse hair growth Dystrophic nails Dry or shiny skin Dependent rubor (and pallor with elevation) Weak pulse palpation (femoral, popliteal, dorsalis pedis, posterior tibial arteries) Gangrene Pedal ulcer or wound, especially if non- or slow-healing Anterior tibial wound, especially if non- or slow-healing

Table 2:

Differential Diagnoses for Non-Arterial Leg Pain

Condition	Location	Characteristic
Hip arthritis	Lateral hip, groin	Aching, not quickly relieved
Foot/ankle arthritis	Ankle, foot, arch	Aching, not quickly relieved
Nerve root compression	Radiates down leg	Sharp pain, improved by change in position and standing
Spinal stenosis (eg, degenerative disc disease)	Bilateral buttocks, posterior legs	Relief by lumbar spine flexion, worse with standing
Popliteal (Baker’s) cyst	Behind knee, upper calf	Calf tenderness, not intermittent
Venous claudication	Entire leg	Tight, bursting pain with walking, relieved with leg elevation
Chronic compartment syndrome	Anterior or posterior calf muscles	Tight, bursting pain in highly developed muscles/athletes

Imaging

Diagnostic modalities for PAD range from non-invasive studies, like the ankle-brachial index (ABI) and arterial duplex, to more invasive, including CTA, MRA and angiography. It is important for the primary care practitioner to understand the role of each modality in the diagnosis and treatment of PAD, as well as the potential pitfalls.

Ankle-Brachial Index

The ABI is a simple, non-invasive test that compares the blood pressure of the brachial artery to the pedal arteries. Blood pressure is checked using a cuff in each arm, and then in each leg. The ABI is the ratio of the higher systolic pressure in the ipsilateral dorsalis pedis and posterior tibial arteries, divided by the higher of the left and right brachial artery systolic pressures. (70) In symptomatic patients resting ABI has a sensitivity of 69% and a specificity of 83–99%.(71) The normal range for ABI is 0.9–1.2 and anything less than 0.9 is considered a positive study. In patients with symptoms consistent with claudication, but normal, or borderline ABIs, an exercise ABI can be performed. In this study, the patient ideally walks on a treadmill at an incline for 5 minutes or until they develop pain and the ABI is measured immediately afterwards (and at several time points until the numbers normalize). A positive test is defined by a decrease in ankle pressure of ≥20mmHg, ≥20% decrease from baseline, decrease of ABI of ≥0.2, or failure of ABI to return to baseline within 3 minutes. This test should not be performed if someone has abnormal ABIs at baseline. Some limitations to this test are reproducibility, as many vascular labs do not have access to treadmills, and patient limitations, as many high-risk patients are limited by other cardiovascular, pulmonary and musculoskeletal issues.

Toe-Brachial Index

A major issue with ABI is that its sensitivity drops dramatically in patients with DM and CKD due to the medial calcinosis that affects their vessels (therefore making them difficult to compress and artificially elevating the readings). The digital arteries are less impacted by this process and therefore toe pressures, or toe brachial indices (TBI) can be used as an alternative study in patients with DM and CKD. Of note however, this can still be inaccurate, and the addition of doppler waveforms can help to enhance sensitivity in this patient population. (71)

Due to the increased interest in screening patients for PAD, a number of companies have arisen that offer ABI and TBI testing units that are not dependent on a vascular technologist and are more automated. These products represent a promising technology for individuals in low-resourced environments, who may not have easy access to a vascular lab. A review of these products is outside the scope of this review; however, these systems have varying degrees of accuracy and should be held against the known sensitivity and specificity of ABI.

CTA and MRA

Although valuable studies, these are not appropriate for confirmation of ABI findings or for making a diagnosis in PAD. The risks of the studies do not outweigh the benefits and should be reserved for use by specialists who may require them for surgical planning.

Catheter Angiography

Catheter angiography is a fluoroscopic technique utilized to visualize the arterial anatomy using intra-arterial injection of contrast dye and x-rays. Angiography is an invasive procedure that carries risk of complications and is not indicated as a screening tool. There is no role for an angiogram in an asymptomatic patient to confirm a PAD diagnosis, and primary care practitioners should be wary of specialists who do disproportionately large numbers of “diagnostic” angiograms.

PAD Treatment

Non-Invasive Treatment

The non-surgical management of PAD is critically important. Aggressive treatment of atherosclerosis prevents progressively worsening disease in the limb and also reduces the risk of MACE. In patients who do eventually require revascularization, patients who are already medically optimized have better surgical outcomes. (72) (73) (74)

Exercise

Supervised exercise therapy is the most effective non-interventional approach to reducing the symptoms of intermittent claudication. Regular walking increases calf blood flow, improves endothelial function, improves metabolic function, decreases inflammation and improves pain-free walking distances.(75) A Cochrane review of 32 RCTs concluded that exercise programs improved pain-free and maximum walking distances compared to usual care. (76) A meta-analysis of 25 RCTs focused on supervised treadmill exercise compared to no exercise improved walking distance by 180 meters. (77) As of 2017, the Centers for Medicare and Medicaid Services provides insurance coverage of up to 36 sessions of supervised treadmill exercise over a 12-week period for patients diagnosed with claudication, but unfortunately, demand is greater than the available services. Further studies evaluating the effectiveness of structured, non-supervised exercise programs, mobile applications, and distance coaching are underway, and funding mechanisms to improve access and availability of supervised exercise therapy are needed.

Anti-thrombotic therapy

In 2022, the USPSTF recommended against the use of daily aspirin for primary prevention of MACE in the general adult population. (78) Patients with PAD, even asymptomatic PAD, have a higher cardiac risk profile than the general adult population and expert consensus among vascular specialists is that patients with PAD and no contraindication should be prescribed an anti-thrombotic medication. The most commonly used drug is aspirin, but P2Y12 receptor antagonists and low-dose direct oral anticoagulants are also used in patients with more complex disease and/or after revascularization. Although it should not be considered appropriate as a single agent anti-platelet medication, cilostazol, a phosphodiesterase IIIa inhibitor, inhibits platelet aggregation, acts as a vasodilator, and improves pain-free walking distance when combined with an exercise program.

A summary of clinical trials regarding selection of anti-thrombotic medications are available in Supplemental Table 1.

Lipid-lowering therapy

High-dose statins reduce mortality, MACE, major adverse limb events and improve symptomatic outcomes in patients with PAD.(79) A low-density lipoprotein (LDL) goal of <70mg/dL is recommended in all patients with PAD, but even if that goal is achieved with other drugs, high-dose statins like atorvastatin 40–80mg or rosuvastatin 40mg are recommended due to their pleomorphic effects. Namely, in translational studies statins have been shown to improve endothelial function, inhibit smooth muscle proliferation, and stabilize plaque. (80) In various clinical studies, starting high intensity statins at the time of PAD diagnosis improved limb loss and mortality rates. (81) (82)

Operative Treatment

While all patients with PAD should be on optimal medical therapy and can benefit from supervised exercise therapy, revascularization is often needed to preserve a functional limb. For patients with intermittent claudication, the decision to pursue revascularization can be difficult depending on a patient’s severity of limb-based symptoms, comorbidity profile, anatomic distribution of arterial occlusive disease, and the expected durability of the revascularization performed. Opinions across different surgical and interventional specialists vary widely regarding the threshold for intervention in patients with claudication, as well as what constitutes an appropriate intervention. For the sake of transparency, both authors of this paper are vascular surgeons and abide by the Society for Vascular Surgery’s appropriate use criteria for intermittent claudication, this document provides a myriad of clinical scenarios to assist in decision making. (83)

For patients with CLTI, the goal of revascularization is to restore blood flow to the extremity to reduce pain, heal wounds, and/or prevent major limb amputation. The SVS Wound, Ischemia, Foot Infection (WIfI) staging system estimates the risk of limb amputation and the likelihood that revascularization will be of benefit. (84) The 2019 Global Vascular Guidelines on the Management of CLTI describes many of the challenges in treating these patients, notes the weakness of many of the clinical recommendations, and reinforces the need for more prospective data to make strong, evidence-based plans that include a combination of medical and surgical therapies. (69)

Due to the high degree of heterogeneity in clinical presentations, limb-based symptoms, patterns of occlusive disease, treatment durability, and life expectancy there is significant debate around preferred revascularization strategies. Historically, long segment arterial occlusions were treated with open surgical bypass, but the evolution of endovascular devices has allowed increasingly complex and long lesions to be treated percutaneously. In CLTI caused by infrainguinal occlusive disease, there are three randomized controlled trials comparing open to endovascular treatment:

• Bypass versus angioplasty in severe ischaemia of the leg (BASIL-1), 2005. Amputation free survival was similar at six months, but for the 70% who survived for 2 years, amputation free survival was better in the open surgical bypass group. (85)

• Bypass versus Angioplasty for Severe Ischaemia of the Leg with infra-popliteal disease (BASIL-2), 2023: The risk of limb amputation and death was higher in the open bypass group compared to the endovascular group (1·35 [95% CI 1·02–1·80]; p=0·037), but outcomes were largely driven by fewer deaths in the best endovascular treatment group. (86)

• Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia (BEST-CLI), 2022: Major adverse limb event-free survival was significantly better in patients who had bypass surgery using a single segment great saphenous vein compared to best endovascular therapy (0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). (87)

Open Surgical Techniques

The general principle for surgical revascularization is either to remove or to bypass the diseased arterial segment. Focal lesions in superficial locations such as the common femoral artery are often treated with thromboendarterectomy, wherein the artery is opened, the plaque removed, and the artery closed with a patch angioplasty to avoid re-stenosis. The most common complication, occurring in 7–16% of groin incisions, is surgical site infection. (88) (89)

For longer and/or deeper occlusive disease that is prohibitive of endarterectomy, a bypass can be performed. This requires adequate arterial inflow and outflow vessels, and consideration of the conduit material and position. Autologous vein is the most durable conduit, (90) (91) but must be at least 3mm in diameter to be used. If no suitable vein is available, there are a variety of prosthetic conduits available for revascularization, but long-term patency suffers. Complications after infrainguinal bypass surgery include surgical site infection and graft occlusion.

Endovascular Techniques

The general principles of endovascular intervention center on choice of arterial access point and associated sheaths, catheters, and wires to reach and ultimately cross the lesion to be treated. Once the occlusion is crossed, the goal is to restore patency and re-perfuse the distal tissue. Balloon angioplasty (including drug coated balloons) with or without a stent is the mainstay of endovascular therapy. There are multiple treatment adjuncts like atherectomy or intravascular lithotripsy that may remove or reshape bulky atherosclerotic plaques to improve the luminal gain achieved by balloon angioplasty. Due to the rapid pace of innovation and lack of comparative effectiveness trials,(92) there are no clear guidelines on best endovascular therapy. Endovascular revascularization is less likely to be a durable treatment in smaller more distal lesions, longer lesions, total occlusions, multi-focal and multi-level disease, poor distal run-off, and recurrent stenoses. (93) (94)

The most common complication of endovascular therapy is related to the access site, and include hematoma (3–4%), bleeding, pseudoaneurysm (1%), or access artery occlusion. (95) There is also the potential for distal embolization of plaque and loss of future bypass target vessels when endovascular therapy is used, and this should be considered when treating. Regardless of therapy type selected (open or endo), re-occlusion and disease progression is a common issue and surveillance with ultrasound and life-long follow-up with re-intervention is necessary to maintain long-term patency.

Conclusions

PAD remains a major public health concern with significant implications for cardiovascular morbidity, limb loss, and health equity. Despite advances in diagnosis and treatment, under recognition and disparities in care persist, particularly among racially and socioeconomically marginalized populations. Improving outcomes requires early identification of at-risk patients, appropriate use of non-invasive diagnostics, and timely initiation of guideline-directed therapies. Equally critical is addressing structural barriers to care and expanding access to screening and treatment through policy initiatives. A multifaceted approach is essential to reduce preventable amputations and close the persistent gaps in PAD-related health outcomes.