Research priorities for peripheral artery disease: A statement from the Society for Vascular Medicine

Abstract

Lower-extremity peripheral artery disease (PAD) affects approximately 236 million people worldwide and at least eight million people in the United States (US). Despite availability of new therapies that prevent major adverse cardiovascular events (MACE), these and major adverse limb events (MALE) remain common and occur more frequently in people with PAD, either with or without coronary artery disease (CAD), compared to people with CAD who do not have PAD. The most effective therapies to prevent cardiovascular events are not identical in people with PAD and those with CAD. Walking impairment and the risk of lower-extremity amputation are significantly greater in people with PAD compared to those without PAD. This report from the Society for Vascular Medicine (SVM) proposes and summarizes high-priority topics for scientific investigation in PAD, with the goal of improving health outcomes in people with PAD. To develop this report, a multidisciplinary team of scientists and clinicians reviewed literature, proposed high-priority topics for scientific investigation, and voted to rank the highest priority topics for scientific investigation. Priorities for clinical scientific investigation include: determine the current prevalence of PAD in the US by age, sex, race, and ethnicity; improve methods to diagnose PAD; develop new medical therapies to eliminate walking impairment; and improve implementation of established therapies to reduce rates of MACE and MALE in people with PAD. Priorities in basic science and translational science investigation include: developing animal models that closely resemble the vascular, skeletal muscle, and platelet pathology in patients with PAD and defining the genetic and epigenetic contributors to PAD and PAD-associated outcomes. Successful investigation of these research priorities will require more well-trained investigators focused on scientific investigation of PAD, greater and more efficient enrollment of diverse patients with PAD in randomized clinical trials, and increased research funding dedicated to PAD.

Keywords

peripheral artery disease (PAD)intermittent claudication cardiovascular disaese mobility scientific priorities clinical research clinical trial translational research basic science research

Introduction

Lower-extremity peripheral artery disease (PAD), defined as stenotic or occlusive disease of the aorta and lower-extremity arteries, is a common manifestation of atherosclerotic cardiovascular disease (CVD). Based on late 20th century data, approximately eight million people in the United States (US) were estimated to have PAD.¹ Because of the growing prevalence of diabetes and population aging, it is likely that the number of people living with PAD in the US is now higher. In 2015, approximately 236 million individuals worldwide were estimated to have PAD.² Established risk factors for PAD include older age, tobacco use, diabetes, hypertension, dyslipidemia, and family history.³ Chronic kidney disease (CKD), elevated lipoprotein(a), chronic inflammation, and environmental toxins are also associated with the presence of PAD.³ In the US, compared to White individuals, Black individuals are at higher risk for PAD and for PAD-related complications such as amputation.⁴

People with PAD have a higher risk for major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular-related death, compared to people with coronary artery disease (CAD) or stroke who do not have PAD.^5,6 People with PAD are also at higher risk of major adverse limb events (MALE), defined as severe lower-extremity ischemia requiring revascularization or amputation.^6,7 Compared to people without PAD, people with PAD have walking-related leg discomfort, greater difficulty walking distances, reduced quality of life, and reduced ability to fully participate in vocational and recreational activities.⁷ Despite these adverse consequences, PAD remains underdiagnosed and often unrecognized by clinicians and patients.^8,9

Guidelines for many medical therapies for PAD are extrapolated from studies of patients with CAD or stroke.^7,10 Despite the high prevalence of CAD and cerebrovascular disease in people with PAD, optimal treatments to prevent MACE in patients with PAD are not identical to those for patients with CAD or stroke.^7,10 Few large clinical trials to prevent MACE or MALE have been conducted in populations comprised entirely of PAD participants. Furthermore, guideline-recommended medical therapies are underused in this patient population.⁹ Despite advances in endovascular technologies, revascularization approaches, and identification of highly effective exercise programs, little progress has been made to eliminate the walking difficulty and functional limitations associated with PAD. Only one drug, cilostazol, is US Food and Drug Administration (FDA) approved and recommended by clinical practice guidelines for the treatment of leg symptoms during walking in patients with PAD. Although cilostazol has been demonstrated to improve walking performance in multiple randomized clinical trials of PAD participants, its benefits are modest, and it is often discontinued due to adverse effects.^7,10 Supervised walking exercise therapy (SET) and structured community-based walking exercise significantly improve walking impairment in people with PAD.^7,10 Although a National Coverage Determination by the Centers for Medicare & Medicaid Services has improved availability of SET in some regions of the US, SET is underprescribed and participation rates and adherence to SET are poor.^7,11 Biologic pathways by which cilostazol and walking exercise improve walking performance in PAD are unknown.

This document from the Society for Vascular Medicine (SVM) proposes research priorities for scientific investigation of PAD in the domains of basic science, translational science, epidemiology, clinical science, and implementation. For each domain, potential challenges to scientific investigation are summarized. The document is intended for funding agencies, industry, academic institutions, medical societies, scientists, and other interested entities. The document aims to stimulate scientific investigation of PAD with the primary goal of improving health, mobility, and other outcomes for people with PAD.

Methods

A multidisciplinary group of experts and scientists focused on PAD was convened by the SVM Research, Quality, and Publications (RQP) Committee. Members were selected with the goal of engaging diverse experts in epidemiology, basic science, translational science, clinical science, implementation science, and health equity related to PAD. A literature search was performed in February 2023, and updated in October 2024, to identify articles relevant to priorities for the scientific investigation of PAD. Subject headings and keywords used for the search included pathophysiology, translational research, treatment, implementation science, diagnosis, management, biomarkers, and artificial intelligence. Additional references were identified by searching reference lists and from author feedback. Working groups were formed based on scientific disciplines. Each group developed a list of research priorities within their assigned domain. Co-authors of this document voted independently on the entire combined list to identify the highest priorities for scientific investigation of PAD research across all domains (Table 1).

Table 1.

Ranked scientific priorities for peripheral artery disease (PAD).

Rank	Research domain	Research objective
1.	Epidemiology	Determine the current prevalence of PAD in the United States by age group, sex, race, and ethnicity
2.	Clinical research	Develop novel diagnostic methods with high sensitivity and specificity for PAD
3.	Clinical research	Establish whether a PAD screening program can improve outcomes
4.	Clinical research	Develop and test therapies to prevent MACE and MALE in dedicated trials of people with PAD
5.	Clinical research	Identify novel and effective medications to improve walking performance in PAD
6.	Basic research	Improve animal models so that they more accurately represent PAD pathophysiology in humans, including comorbidities and exposure to risk factors such as cigarette smoking
7.	Basic research	Identify new genetic and epigenetic factors associated with PAD
8.	Basic research	Establish the role of arterial calcification and thrombosis in the pathophysiology of PAD
9.	Translational research	Delineate biologic pathways associated with improved walking performance in PAD
10.	Translational research	Define the characteristics and significance of microvascular disease in PAD
11.	Translational research	Improve understanding of factors that determine perfusion limitations in PAD
12.	Clinical research	Identify optimal devices and techniques for lower-extremity revascularization among women and men, respectively
13.	Clinical research	Identify optimal metrics for measuring outcomes in response to exercise, medications, and revascularization interventions for improving mobility in PAD
14.	Translational research	Characterize skeletal muscle abnormalities in PAD and define their significance
15.	Clinical research	Develop and validate risk stratification metrics
16.	Clinical research	In randomized clinical trials and longitudinal studies, systematically collect and characterize MALE outcomes
17.	Basic research	Develop novel therapies to mitigate chronic lower-extremity atherothrombosis
18.	Epidemiology	Characterize racial, ethnic, sex, and socioeconomic disparities in PAD
19.	Basic research	Define new biologic pathways that stimulate therapeutic angiogenesis
20.	Clinical research	Develop and validate new surrogate outcomes for PAD
21.	Clinical research	Develop novel therapies to reduce kidney disease in PAD
22.	Clinical research	Identify optimal methods of exercise therapies for PAD
23.	Translational research	Identify novel risk factors for PAD
24.	Translational research	Characterize the effects of lower-extremity ischemia on peripheral nerve function and describe clinical significance
25.	Epidemiology	Define environmental toxins and novel risk factors for PAD

Research topics are ranked in order of priority based on author voting.

MACE, major adverse cardiovascular events; MALE, major adverse limb effects.

Results

For each discipline of scientific investigation, the following paragraphs present an overview of the current state of scientific investigation, potential challenges to scientific investigation of PAD, and a summary of research priorities.

Basic science

The pathogenesis of atherosclerosis differs in some respects between the lower-extremity, coronary, and cerebrovascular arteries, in part because of differences in artery size and arterial flow rates. Biologic processes associated with both CAD and PAD include dyslipidemia, insulin resistance, inflammation, calcification, endothelial dysfunction, and thrombosis. However, the strength of association can differ between these distinct arterial beds.³ For example, thrombosis and certain lipoproteins, such as lipoprotein(a), appear more strongly associated with PAD pathogenesis than with CAD pathogenesis.¹² Understanding the biologic processes responsible for PAD may lead to more effective interventions to prevent or treat PAD. It is possible that the most effective interventions to prevent or treat CAD may have less potent effects in people with PAD.

Preclinical models that improve understanding of the development of lower-extremity atherosclerosis, collateral vessel formation, angiogenesis, microvascular function, thrombosis, and skeletal muscle health and mitochondrial energetics are likely to inform the development of new PAD treatments.¹³ For example, preclinical models have shown that vascular endothelial growth factor (VEGF)_165b, an antiangiogenic VEGF-A isoform, blocked VEGFR1 to inhibit ischemia-induced angiogenesis.^14,15 Inhibiting VEGF_165b activated VEGFR1-STAT3 and stimulated angiogenesis in animal models of PAD, independently of nitric oxide availability.¹⁵ Preclinical models have also shown that chronic ischemia impairs normal lower-extremity skeletal muscle structure and physiology, including mitochondrial function and skeletal muscle fiber structure.¹⁶ In addition, people with PAD have fatty infiltration of calf muscle and reduced calf muscle area; more severe lower-extremity ischemia is associated with greater fatty infiltration and smaller calf muscle area, independently of physical activity.¹⁷ Future studies using preclinical models for PAD should evaluate the biologic pathways and consequences associated with these skeletal muscle pathophysiologic changes and identify treatments to resolve them.

Challenges for basic science research on PAD

Cell culture and in vivo models can inform the discovery of the pathophysiology responsible for PAD, such as contributions of endothelial dysfunction and platelet reactivity to the development of lower-extremity atherosclerosis and limb response to ischemia. Although delineating these processes separately may be helpful, these processes do not occur in isolation in humans. Difficulty replicating the complexity of multiple coexistent comorbid conditions in humans with preclinical models may explain why so few novel diagnostic methods and therapeutic interventions have been successfully translated from basic science observations to clinical care of patients with PAD.

Typical in vitro models evaluate angiogenesis by measuring the tube-like vessel formation of endothelial cells cultured on Matrigel substrate in a variety of conditions including response to potential therapeutic agents. These models provide information about endothelial cell actions after gene knockdown or in response to hypoxia but typically do not allow evaluation of how these processes interact with other components of the vessel wall, such as vascular smooth muscle cells, circulating immune cells, or platelets. Although co-culture and bioengineered organoid models (stem cell-derived 3D culture systems) are under development for PAD treatment, including models that incorporate endothelial cells and smooth muscle cells from humans with PAD using induced pluripotent stem cell (iPSC) technology, these processes likely oversimplify the complex biology of PAD, which also often includes ongoing exposures to the adverse effects of cigarette smoking, hyperglycemia, insulin resistance, and other damaging processes.

Murine models of PAD that are based on ligation or excision of the femoral artery, followed by evaluation of limb perfusion during recovery with laser Doppler and comparison to the nonischemic limb, can provide information about how arterial flow is restored after an acute ischemic insult.¹⁸ However, this model is typically implemented in mice without atherosclerosis and without the vascular and myopathic changes or comorbidities that occur in humans with chronic PAD.

Priorities for basic science investigation of PAD

First, investigation should delineate the pathophysiology underlying the development and progression of lower-extremity atherosclerosis, including genetic and epigenetic factors (Table 2). Second, interventions and biologic pathways that successfully ameliorate chronic lower-extremity atherothrombosis in animals should be identified and characterized. Third, animal models that better represent chronic PAD in the setting of common comorbidities, such as end-stage kidney disease, diabetes, vascular calcification, and smoking, are needed. Fourth, basic science studies should characterize the quality of capillary growth in animal models of PAD.

Table 2.

Basic science priorities for peripheral artery disease (PAD).

Category	What is known	What is unclear	Examples of proposed science
1. Discover approaches to ameliorate chronic atherothrombosis in the lower extremity	• Biology of atherosclerosis in the lower extremities differs from atherosclerosis in the coronary arteries. • Available animal models of hindlimb ischemia largely reflect response to acute ischemia. • Specific risk factors including CKD, smoking, and diabetes mellitus are associated with significantly more adverse outcomes.	• How well do animal models reflect chronic PAD? • How can specific risk factors for PAD be optimally represented in animal models?	• Develop new preclinical models that better represent chronic lower-extremity atherothrombosis in humans. • Develop animal models for CKD and PAD. • Develop biomarkers in animal models that predict treatment response and might be applied in human studies.
2. Develop models that represent the interactions of the multiple tissues involved in PAD pathogenesis (blood vessels, skeletal muscle, platelets)	• Chronic ischemia-reperfusion injury alters muscle energetics. • Thrombosis is a major contributor to the pathophysiology of PAD and is common after revascularization.	• How do blood vessels interact with skeletal muscle tissue? • How is skeletal muscle best targeted as a therapeutic approach? • What is the optimal strategy for representing PAD-related atherothrombosis in vitro?	• Develop organoids to model cell type interactions in blood vessels. • Co-culture models with blood vessels and skeletal muscle to evaluate effects of ischemic insults. • Conduct large dataset sequencing and omics studies to identify skeletal muscle targets for therapies. • Delineate how ischemia affects mitochondrial activity in the context of PAD.
3. Delineate biological mechanisms that link genetic and epigenetic changes to the pathophysiology of PAD	• Multiple genetic markers are associated with PAD in humans. • Epigenetic alterations reflect cumulative effects of risk factors in PAD.	• How do genetic markers stimulate biologic processes to cause PAD?	• Establish large biobanks including genetic, epigenetic, transcriptomic, and proteomic information linked to clinical outcomes in well-characterized cohorts of people with PAD. • Develop cell-based studies to investigate the significance of genetic changes identified in human ‘omics’ studies. • Identify drugs to target specific pathways that cause PAD from omics studies.
4. Study specific disease processes in the limb, including arterial calcification, stent/graft thrombosis, restenosis in stent/graft	• Diabetes and older age are associated with lower-extremity arterial calcification. • Thrombosis and restenosis are biologically distinct from atherogenesis. • Thrombosis appears to be a prominent component of PAD but is less prominent in coronary artery disease.	• What are the optimal approaches to measure and treat in vivo calcification? • How can new stents/grafts be altered to reduce thrombosis and restenosis?	• Develop animal models that accurately represent arterial thrombosis, mitochondrial dysfunction, synthetic bypass conduits, and restenosis in people with PAD. • Develop preclinical models that distinguish aortoiliac, tibial, and microvascular forms of PAD.
5. Characterize therapeutic angiogenesis	• Patients with PAD often have chronic thrombosis of lower-extremity arteries that reduces lower-extremity perfusion.	• What is the quality and abundance of capillaries in people with PAD compared to those without? • What factors stimulate angiogenesis in PAD? • What is the role of VEGF_165b in stimulating angiogenesis?	• Characterize the quality of capillary growth in animal models of PAD. • Characterize the role of VEGF_165b in compensatory angiogenesis in animal models of PAD.

CKD, chronic kidney disease; VEGF, vascular endothelial growth factor.

Translational science

Translational science applies discoveries from basic science to diagnosis and treatment of humans. In translational science, proteomics, genomics, or transcriptomics can identify targets for interventions to prevent PAD or improve diagnosis or treatment of PAD. Inherited polymorphisms that disrupt normal smooth muscle cell physiology, facilitate thrombosis, and increase cigarette smoking behavior have been associated with the development and progression of PAD.¹⁹ For example, a translational science study found that the gene variant F5 p.R506Q was more specific for the presence of PAD compared with other atherosclerotic diseases and was associated with increased thrombosis.¹⁹ This work identified Factor Xa inhibition as a potential therapeutic strategy to prevent progression of PAD.¹⁹ Similarly, discovery of a gene variant responsible for gain of function of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the abundance of receptors that remove low-density lipoprotein (LDL) cholesterol from blood, led to the development of PCSK9 inhibitors, which subsequently reduced cardiovascular lower-extremity adverse events in people with PAD.²⁰ The discovery of protease-activated receptors (PARs) as stimulators of thrombosis associated with adverse limb outcomes facilitated the discovery of vorapaxar and rivaroxaban to prevent MALE.^19,21
–23 A report that thrombus often exists in distal arteries of legs with severe ischemia, even without atherosclerotic plaque, supported testing the efficacy of antithrombotic drugs in patients with PAD to prevent PAD progression.²⁴ Separately, in a murine model of chronic limb-threatening ischemia (CLTI), the effect of ischemia on platelet activation was partially inhibited in platelet-specific, extracellular-regulated protein kinase 5 (ERK5) knockout mice.²⁵

Challenges for translational science in PAD

Potential challenges to translational science in PAD include difficulty assembling highly effective multidisciplinary teams of basic and clinical scientists for collaboration, the need for more investigators trained in translational science, the absence of an optimal animal model for studying PAD, and the need for more and larger biobanks from well-characterized, well-defined, and representative cohorts of people with PAD that include blood and other tissue samples, including from diverse racial and ethnic groups.

Priorities for translational science in PAD

First, biologic pathways that improve walking performance in response to exercise interventions should be delineated (Tables 1 and 3). Delineating these biologic pathways can identify therapeutic targets for improving walking performance in PAD. Second, the characteristics and significance of microvascular disease in people with PAD should be defined. The microvasculature is defined as very small arterioles and capillaries, less than 0.30 mm in size. Third, biologic pathways that increase lower-extremity perfusion should be defined, including biologic pathways that improve capillary quality and density. Fourth, skeletal muscle abnormalities caused by lower-extremity ischemia should be fully defined, including abnormalities in mitochondrial structure, mitochondrial activity, myofiber health, denervation of lower-extremity skeletal muscle, and peripheral neuropathy. Fifth, biobanks of blood, tissue, and imaging from diverse PAD populations, including from different racial and ethnic groups, are needed.

Table 3.

Translational science priorities for peripheral artery disease (PAD).

Category	What is known	What is unclear	Examples of proposed science
1. Cardiovascular disease risk factors	• Diabetes and smoking are more closely linked to the development of PAD than CAD. • Former cigarette smokers remain at lifelong increased risk of PAD, but this phenomenon is not observed in CAD. • Patients with PAD and CKD have a high prevalence of medial arterial calcinosis in the lower extremities. • Severe PAD is more common in people who have both CKD and diabetes compared to people without CKD and diabetes.	• What are the biologic pathways responsible for different strengths of association of risk factors for PAD and CAD? • Why does only a subset of all people with CAD or cerebrovascular disease develop PAD? • Why is diabetes more strongly associated with infrapopliteal disease, and why are people without PAD more likely to have proximal atherosclerosis? • What is the role of thrombosis in the development and progression of PAD? • How do artery size, compliance, and flow affect the development of PAD? • What biologic factors are responsible for medial arterial calcinosis in patients with PAD and CKD? • Do CKD and PAD develop simultaneously, or does one commonly precede the other?	• Proteomic, genomic, and transcriptomic scientific discoveries could delineate biologic pathways of these differences.
2. Biology of lower-extremity perfusion in PAD	• Perfusion is reduced by atherosclerotic blockages of arteries in PAD.	• To what extent are capillaries damaged in PAD? • Do capillaries increase to compensate for reduced perfusion in PAD? • What is the quality of capillary function in PAD? • What is the role of VEGF_165b in perfusion?	• Human lower extremity skeletal muscle biopsies from humans could help delineate differences in capillaries between people with and without PAD.
3. Pathophysiologic changes in lower-extremity skeletal muscle in PAD	• People with PAD have structural damage to mitochondria compared to those without PAD. • Mitochondrial activity is significantly impaired in people who have the most severe forms of PAD, such as CLTI. • People with PAD have aberrant patterns of mitochondria in skeletal muscle, including sections devoid of mitochondria.	• Are skeletal muscle changes due to ischemic damage or compensatory changes in PAD? • What is the specific etiology of mitochondrial dysfunction in PAD? • What are the abnormalities in nonmitochondrial aspects of lower-extremity skeletal muscle, such as capillaries, satellite cells, myoglobin, and fibrosis? • Can restoring perfusion improve skeletal muscle health?	• Human lower-extremity muscle biopsies should be performed before and after lower-extremity revascularization. • Mitochondrial respirometry should be measured before and after exercise interventions. • Proteomics, genomics, and transcriptomics of muscle should be performed before and after revascularization.
4. Microvascular disease in PAD	• Microvascular disease is more common in people with PAD compared to those without. • Microvascular disease is associated with increased cardiovascular event rates.	• What is the underlying pathology of microvascular disease in PAD? • Is there an association of walking performance with the number and quality of capillaries in lower-extremity muscle of people with PAD?	• Human lower-extremity muscle biopsies should be obtained in patients with all stages of PAD to fully characterize capillary health compared to patients without PAD.
5. Biologic pathways by which walking exercise improves walking ability in PAD	• Home-based walking exercise that induces lower-extremity ischemia, improves walking performance in PAD. • Home-based walking exercise that does not induce ischemia does not improve performance.	• What is the role of exercise in stimulating capillary growth? • How does exercise-induced hypoxia and oxidative stress affect lower-extremity skeletal muscle and perfusion? • What are the effects of exercise on endothelial nitric oxide synthase activity in PAD?	• Human leg muscle biopsies should be performed before and after exercise interventions in PAD. • Effects of exercise on oxidative stress, eNOS activity, and inflammation should be delineated.
6. Peripheral nerve function in PAD	• Patients with severe PAD have reduced peroneal nerve function. • Preliminary evidence of muscle biopsies suggests the presence of muscle denervation in patients with PAD. • Peroneal nerve damage is associated with walking impairment in PAD.	• What are the effects of lower-extremity ischemia on motor neuron function and denervation? • What are the biologic pathways by which lower-extremity nerve dysfunction affects walking and performance in PAD?	• Human leg muscle biopsies should be performed before and after lower-extremity revascularization to identify the specific effects of lower-extremity ischemia on peripheral and motor nerve function. • Human leg muscle biopsies should be performed before and after exercise interventions in PAD.

CAD, coronary artery disease; CKD, chronic kidney disease; CLTI, chronic limb-threatening ischemia; eNOS, endothelial nitric oxide; VEGF, vascular endothelial growth factor.

Epidemiology

Several aspects of risk factors for PAD remain unclear. First, cigarette smoking and diabetes are stronger risk factors for PAD than for CAD or stroke.³ A cohort of people aged 45–64 years from the Atherosclerosis Risk in the Community (ARIC) study demonstrated that 20 years after smoking cessation, the risk of coronary heart disease returned to that of someone who never smoked cigarettes, but the risk of developing PAD remained elevated for up to 30 years after smoking cessation.²⁶ Second, traditional atherosclerotic risk factors, such as diabetes, smoking, use of smokeless tobacco, and genetic risk do not entirely explain the development of PAD. Higher levels of apolipoprotein B, lipoprotein(a), small low-density lipoprotein particles, and triglyceride-rich lipoproteins have been associated with a higher incidence of PAD, independently of traditional atherosclerotic disease risk factors.^26
–30 Third, inflammation and thrombosis appear to be involved in the pathophysiology of PAD, but less is known about biologic processes that promote inflammation and thrombosis in the development of PAD.

Race, ethnicity, geography, and socioeconomic status and PAD

In epidemiologic studies in the US, PAD disproportionately affects Black people, those with low socioeconomic status, and women of Native American descent.^3,4 Although fewer data are available for people who are Hispanic, amputation rates are higher in Hispanic compared to White people with PAD.⁴ These associations are not explained by the higher prevalence of atherosclerotic disease risk factors in these individuals.^3,4 In the US, amputation rates from PAD are higher in Black compared to White people and are also more common in people living in Southern regions of the US compared to those living in other geographic areas of the US.⁴ Etiologies of these disparities are not fully characterized. Furthermore, among participants in the Veterans Affairs Birth Cohort Study who received care in the Veterans Health Administration, there were no race-based differences in PAD incidence at a median follow up of 3.9 years.³¹

Environmental factors and PAD

Environmental exposure to lead, cadmium, and air pollution have been associated with increased prevalence of PAD, but these associations are poorly defined.^3,32
–35 Xylitol sweetener was associated with enhanced platelet reactivity in vitro, and data from the UK biobank suggested that artificial sweetener was significantly associated with increased rates of cardiovascular events, including PAD.^36,37 Preliminary evidence identified micro-plastics or nano-plastics as potential risk factors for cardiovascular disease.³⁸ The effects of climate change that increase exposure to air pollution or wildfire smoke and reduce one’s ability to engage in healthy behaviors, such as walking exercise or access to a healthy diet, could potentially increase risk for PAD and contribute to adverse health outcomes in people with PAD.

Chronic kidney disease (CKD) and PAD

Approximately 12–38% of people with CKD also have PAD, and PAD is more common in people with CKD compared to those without CKD.^39,40 Severe PAD is more common in people with both CKD and diabetes compared to people without these conditions. Pathophysiologic processes associated with co-existent CKD and PAD are unclear, including whether CKD and PAD develop simultaneously or whether one commonly precedes the other.

Challenges to epidemiologic study of PAD

Valid epidemiologic study of PAD requires assembling large cohorts of people, thoroughly characterizing them and their environment, and following them longitudinally. This requires substantial infrastructure and resources. Including meaningfully large proportions of underrepresented minorities, such as Native American populations, in epidemiologic studies can be difficult. Causal inferences can also be challenging, particularly for characteristics such as reduced physical activity and PAD, because reduced physical activity may be a cause but is also a consequence of PAD.

Priorities for epidemiologic research of PAD

First, an accurate current estimate of the number of people living with PAD in the US and the prevalence of PAD by age in the US is needed (Table 4). Second, the current prevalence of PAD among diverse racial and ethnic groups in the US should be determined. Third, biologic pathways associated with the common co-existence of PAD and CKD should be defined, including whether these conditions develop simultaneously or whether one typically precedes the other. Fourth, associations of race and ethnicity with clinically important outcomes such as MACE, MALE, and severity of walking impairment should be defined. Fifth, associations of environmental toxins, such as micro-plastics, macro-plastics, and exposure to air pollution, with PAD-related outcomes should be defined. Sixth, the effects of climate change, such as extreme heat, on PAD-related outcomes should be established.

Table 4.

Epidemiologic investigation priorities for peripheral artery disease (PAD).

Category	What is known	What is unclear	Examples of proposed science
1. Risk factors associated with PAD	• Traditional atherosclerotic disease risk factors such as smoking and diabetes are associated with greater risk of PAD than CAD. • People who quit smoking remain at lifelong increased risk of PAD. • Higher levels of relatively novel lipid markers are independently associated with higher rates of PAD.	• What novel biomarkers might better identify someone at high risk of PAD compared to traditional risk markers? • Why does smoking cessation not eliminate increased lifetime risk of PAD? • Does elevated lipoprotein(a) contribute directly to the development and progression of PAD?	• Collect data on novel risk factors, including genetic and environmental risk factors, in the development and progression of PAD. • Identified novel risk factors should be investigated as targets for novel therapies in PAD.
2. Racial, ethnic, and geographic disparities	• Black people with PAD have a higher prevalence, poorer functional performance, and more adverse limb outcomes than White people with PAD. • People in the Southeast US have higher amputation rates than other parts of the country.	• What is the prevalence of PAD in patients of Hispanic ethnicity and other races, including Asian and Native American races? • What are PAD outcomes in less-studied populations, e.g., Hispanic, Native American, or Asian people? • Do factors like reduced access to care or social determinants of health contribute to geographic disparities?	• Population-based studies focused on PAD should include large proportions of participants from underrepresented racial and ethnic minority groups. • Registry data, or data from large datasets (e.g., Medicare beneficiaries), should identify social determinants of health associated with adverse PAD outcomes to identify opportunities to improve care.
3. Environmental toxins and risk factors	• Exposure to lead, cadmium, and air pollution may be associated with increased risk of PAD. • Micro- and nano-plastics were identified in histology samples from carotid artery atheroma. • Artificial sweeteners have been associated with incident MACE and increased risk of incident PAD.	• How do environmental toxins and exposures affect PAD outcomes? • How might climate change affect toxin exposure and PAD outcomes? • What other toxins contribute to the development and progression of PAD? • How are micro- and nano-plastics associated with outcomes in PAD? • How are artificial sweeteners associated with adverse outcomes in PAD?	• Epidemiologic studies should collect data on a variety of environmental toxins (e.g., ultra-processed foods, food additives) that may increase risk for PAD and increase adverse outcomes in patients with established PAD. • The effects of the consequences of climate change on the development and progress of PAD should be studied. • Associations of micro- and nano-plastics and artificial sweeteners on the development and progression of PAD should be studied.
4. Diagnostic testing and screening for PAD	• PAD is underdiagnosed. • The ABI is an inexpensive, noninvasive, and simple tool for identification of PAD. • Patients with calcified lower-extremity arteries associated with CKD, diabetes mellitus, and older age often have inaccurate ABI results.	• Can blood omics or combinations of blood testing or other biologic markers be identified that have greater sensitivity than ABI for PAD detection? • What methods have the highest sensitivity for diagnosing PAD in patients with lower-extremity artery calcification? • Does ABI screening or system-wide diagnostic testing for PAD improve outcomes? • Are there inexpensive strategies that are more sensitive than ABI to detect PAD?	• Population studies should define disparities in PAD that exist by race, ethnicity, socioeconomic status, and other specific communities. • Outcomes associated with ABI testing and screening should be defined in large populations. • Alternative diagnostic strategies should be developed that have greater sensitivity for PAD than the ABI, particularly in patients with peripheral artery calcification.

ABI, ankle–brachial index; CAD, coronary artery disease; CKD, chronic kidney disease; MACE, major adverse cardiovascular events; PAD, peripheral artery disease; US, United States.

Clinical science

Walking impairment in PAD

A typical early manifestation of PAD is walking impairment, which may be insidious and associated with leg discomfort, weakness, or other leg symptoms during walking.^7,41,42 Even people with PAD who report no leg pain with walking have significantly greater difficulty walking longer distances than people without PAD, and other people with PAD limit walking activity to avoid ischemic leg symptoms.^42
–44 Consequently, many people with PAD report stabilization or improved leg symptoms over time, even as their walking endurance and mobility progressively worsens.⁴⁴

Cilostazol is the only medication currently recommended by US clinical practice guidelines to improve walking performance in PAD.¹⁰ Cilostazol has modest effects on walking performance and is associated with adverse effects, such as headache and palpitations, that frequently result in cessation of the drug.^7,10 No new medical treatments for walking impairment in PAD have been approved by the FDA since 1999. A barrier to identifying new therapies for walking impairment in PAD is the limited understanding of how ischemia-related pathophysiologic changes in lower-extremity skeletal muscle, capillaries, and peripheral nerves contribute to walking impairment in PAD.

Lower-extremity revascularization for PAD

In the US, more than 300,000 lower-extremity surgical or endovascular revascularization procedures are performed annually for Medicare beneficiaries who have PAD without limb-threatening ischemia, and rates of these procedures are increasing.^44
–46 Lower-extremity revascularization significantly improves walking impairment in people with PAD and has benefits that are similar in magnitude to supervised walking exercise for PAD.⁴⁷ However, restenosis after revascularization is relatively common.^44
–47 Restenosis is associated with adverse outcomes, including repeat revascularization.⁴⁵ The most ideal combinations of medications, exercise, and other adjunctive treatments before and after lower-extremity revascularization to maximize walking ability and minimize morbidity in patients with PAD remain unclear.

Exercise treatment for PAD

Supervised walking exercise on a treadmill and structured community-based walking exercise are first-line therapies for PAD-related walking impairment.¹⁰ Structured community-based exercise is defined by walking exercise in or around the home, with monitoring and guidance by a health professional. Some structured community-based exercise interventions have been highly effective, but others have been ineffective compared to a nonexercise control group.⁷ Although SET is consistently comprised of walking exercise on a treadmill three times weekly in the presence of a coach, the frequency, type, and amount of exercise in structured community-based exercise interventions have varied. For structured community-based walking exercise, exercise that induced ischemic leg symptoms was shown to be necessary for efficacy.⁴⁸ Other characteristics necessary for highly potent community-based exercise interventions remain unclear, including the nature and frequency of coach interactions or methods to help patients with PAD adhere to walking exercise that induces ischemic leg symptoms.⁴⁹ Exercise interventions that do not include walking, such as arm ergometry and leg ergometry, have significantly improved walking performance in people with PAD, but their benefit and specific role compared to walking exercise remain unclear.^49,50 Importantly, for many people with PAD, exercise interventions significantly improve walking performance but do not eliminate ischemic leg symptoms.

Major adverse cardiovascular events (MACE)

Many treatments for secondary prevention of MACE in people with PAD, such as LDL-lowering therapies, antiplatelet drugs, glucagon-like peptide-1 receptor agonists, and other drugs are derived from subgroups of PAD populations from larger clinical trials of patients at high risk for cardiovascular events.^51
–54 However, people with PAD have significantly higher rates of MACE than those with CAD or stroke who do not have PAD.³ PAD represents a distinct CVD for which the efficacy and safety of therapies should not necessarily be extrapolated from larger trials comprised predominantly of patients with CAD. For example, the EUCLID trial showed that more intensive P2Y₁₂ inhibition with ticagrelor was not more effective than clopidogrel for preventing MACE in PAD, even though ticagrelor was superior to clopidogrel in clinical trials of patients with acute coronary syndrome.^55,56

Major adverse limb events (MALE)

A major source of morbidity for patients with PAD are MALE. However, MALE are often not systematically collected in large randomized clinical trials of patients with CVD, representing a missed opportunity to identify effective and safe therapies for preventing MALE. Among the subset of 3787 patients with symptomatic PAD in the TRA2°P-TIMI 50 trial, 150 acute limb ischemic events occurred in 108 participants at the 3-year follow up (i.e., 2.8% of participants at the 3-year follow up). Of these, 56% were due to surgical graft thromboses and 27% consisted of in situ thromboses in native vessels.⁵⁷ The VOYAGER PAD trial examined the effects of low-dose rivaroxaban in addition to low-dose aspirin on a 5-point composite outcome of irreversible harm events that included MACE and MALE and resulted in FDA approval of rivaroxaban for preventing MALE.⁵⁸ The absence of routine collection of MALE in large, randomized trials can have adverse consequences. When the CANVAS trial reported an increased risk of lower-extremity amputation with sodium-glucose cotransporter 2 (SGLT2) inhibitors, insufficient data were collected to better understand this potential risk, which was subsequently determined to be a spurious finding, but may have temporarily prevented some patients with PAD from receiving an SGLT2 inhibitor to prevent cardiovascular events.⁵⁹

Chronic limb-threatening ischemia (CLTI)

CLTI represents an advanced form of severe PAD, associated with ischemic rest pain, ischemic foot ulcers, or gangrene. People with CLTI have significantly higher rates of mortality and amputation and have poorer quality of life compared to people without CLTI.⁶⁰ The prognosis for patients with CLTI is poor, often because other severe comorbidities, such as CKD and cancer, are common in CLTI.⁶⁰ Several staging systems can assess risk and guide treatment for people with CLTI, but these staging systems, such as the Global Anatomic Staging System (GLASS) and the Wound, Ischemia, foot Infection (WIfI) classification, have not been validated in large cohorts.⁶⁰ Few large, high-quality, clinical trials to improve outcomes in patients with CLTI have been completed.^61,62 Deep venous arterialization is a relatively new minimally invasive transcatheter procedure in which an artery of the leg is connected to a deep vein of the foot, with the goal of improving blood flow in patients with CLTI who are not candidates for amputation.⁶³

Screening for PAD with the ankle–brachial index (ABI)

A study of 350 US primary care practices in 2000 reported that among 1865 patients aged 70 years and older or aged 50–69 years with a history of diabetes or smoking who were found to have an ABI < 0.90, approximately 45% were not aware of their PAD diagnosis.⁶⁴ To improve rates of PAD diagnosis, the American Heart Association suggests that screening people at increased risk for PAD with the ABI is reasonable (Class: 2a, Level of Evidence: B-R).¹⁰ In contrast, the most recent United States Preventive Services Task Force (USPSTF) report indicated that there was insufficient evidence to screen for PAD with the ABI.⁶⁵

Challenges to clinical research investigation of PAD

First, recruiting PAD participants for randomized clinical trials of diagnostic or therapeutic interventions is difficult, in part because mobility impairment, older age, and comorbid diseases can make study participation difficult for people with PAD. Future investigation could focus on efficient completion of randomized clinical trials that effectively identify new therapies while minimizing participant burden. Second, the insidious nature and underdiagnosis of PAD can make identifying people with PAD for clinical trials more difficult. Third, insufficient numbers of investigators with experience and expertise in the scientific investigation of PAD, including conduct of high-quality clinical trials, is a barrier to the discovery and evaluation of new therapies for PAD. Fourth, though optimal therapies to prevent MACE and MALE in PAD can differ from those with CAD or stroke, identifying optimal therapies for individuals with PAD can require enrollment of thousands of participants followed longitudinally for multiple years. This is costly and challenging. Fifth, because of their poor prognosis and high rates of severe comorbid disease, patients with CLTI are rarely included in randomized clinical trials of medical therapies for cardiovascular disease. Notably, the Best Endovascular vs Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial demonstrated that randomized clinical trials of patients with CLTI can be successfully completed and informative.⁶¹

Priorities for clinical scientific investigation of PAD

First, clinical trials should identify treatments to reduce MACE and MALE in people with PAD (Table 5). These treatments should be tested in trials comprised entirely of people with PAD. Second, future large-scale clinical trials, including in populations of people with CAD and stroke, should collect MALE outcome data. Third, clinical trials are needed to identify highly effective medications that improve walking performance in PAD. Because PAD is characterized by both impaired lower-extremity perfusion and lower-extremity skeletal muscle abnormalities, consideration should be given to studies of therapies that improve lower-extremity perfusion and skeletal muscle health and function. Fourth, the etiology of restenosis after lower-extremity revascularization should be identified, and interventions to prevent restenosis should be studied. Fifth, innovative engineering methods should be used to develop revascularization devices associated with improved long-term patency for patients with PAD, including those patients who are not candidates for lower-extremity revascularization with existing devices because of the distribution of their lower-extremity atherosclerosis. Sixth, adjunctive medical treatments to improve limb outcomes after revascularization should be identified. Seventh, clinical investigation should identify which patients will benefit from revascularization and at what point in their disease course they will most benefit. Eighth, uniform definitions of lower-extremity outcomes for clinical trials should be established to facilitate comparisons across studies. Ninth, future studies should identify treatments to prevent limb loss, death, and other adverse outcomes in people with CLTI. These should include larger and more definitive clinical trials of deep venous arterialization for CLTI.

Table 5.

Clinical science priorities for peripheral artery disease (PAD).

Category	What is known	What is unclear	Examples of proposed science
1. Lower-extremity revascularization for PAD	• The durability of endovascular and bypass procedures in lower-extremity arteries is greater in larger, more proximal, lower-extremity arteries. • Lower-extremity revascularization improves walking performance related to PAD. • Supervised exercise therapy and revascularization together improve walking performance better than either therapy alone.	• What are the optimal stents, devices, and vessel preparation for lower-extremity revascularization based on characteristics like disease location and vessel calcification? • Can adjunctive medications, supplements, or home-based exercise improve walking performance when combined with lower-extremity revascularization compared to revascularization alone?	• Determine optimal timing for revascularization in patients with impaired walking performance related to PAD. • Determine the optimal antithrombotic strategy after lower-extremity revascularization. • Determine whether other adjunctive medications or home-based exercise can improve walking performance or vessel patency after intervention. • Identify effective lower-extremity revascularization techniques that are durable in all lower-extremity vessels. • Assess whether optimal endovascular or bypass therapies differ between men and women.
2. Medications and other medical treatments for improving walking performance in PAD	• Cilostazol is the only medication recommended to improve walking performance but has modest benefits for improving walking ability in PAD and has frequent adverse effects. • Gene therapies and stem cell therapies have not demonstrated consistent efficacy for improving walking performance in PAD.	• What are the biologic processes that result in walking impairment related to PAD, and what medications can target these processes safely?	• Randomized clinical trials of highly promising, accessible, and safe therapies to improve walking performance in PAD are needed. • Randomized clinical trials are needed to assess whether combinations of therapies are better than individual treatments for improving walking performance in PAD. • Delineate biologic pathways through which effective therapies may be acting (e.g., flow-mediated dilation, lower-extremity perfusion, skeletal muscle mass, or mitochondrial activity).
3. Exercise therapy for PAD	• Supervised treadmill exercise improves treadmill walking performance in PAD. • Home-based exercise can improve walking ability in PAD, but variability exists in the magnitude of efficacy.	• What is the most optimal, effective, and accessible structured community-based walking exercise intervention for PAD? • What accounts for the observed variability in response to exercise?	• Clinical trials should directly compare the durability of supervised and home-based walking exercise for both objective and subjective outcomes in PAD. • Characteristics of people who are more responsive to exercise treatments should be identified. • Clinical trials should determine whether certain medications in combination with exercise can improve walking performance more than exercise alone.
4. Therapies to prevent MACE and MALE in people with PAD	• People with PAD have higher rates of MACE and MALE than people with CAD. • Some therapies (such as antiplatelet therapies) vary in effectiveness between people with PAD and those with CAD. • Lower-extremity obstruction in PAD contains more thrombosis than CAD.	• What is the optimal combination of therapies to prevent MACE and MALE in people with PAD?	• Enroll dedicated populations of people with PAD in research to test treatments that prevent MACE and MALE. • Define why certain preventive therapies are more effective in people with PAD than in those with CAD and vice versa.
5. Validated risk stratification tools	• An increasing number of novel therapies are available to reduce MACE and/or MALE in patients with PAD. • There is heterogeneity among patients with PAD regarding the adverse effects and benefits of therapies.	• What risk stratification tools can identify patients with PAD who will have the greatest benefit from specific therapies? • What risk stratification measures can identify patients with PAD at highest risk (such as risk of bleeding) from specific therapies?	• Validated risk stratification tools for specific outcomes in PAD (MACE, heart failure, kidney disease, etc.) should be developed. • Validated risk stratification tools are needed for MALE prediction to inform therapeutic decision making. • Validated risk stratification tools to assess bleeding risk in PAD are needed.
6. Prospective collection and categorization of MALE in large randomized clinical trials	• There is heterogeneity in severity and factors associated with each component of MALE. • MALE are rarely included in primary and key secondary outcomes in cardiovascular trials.	• What is the optimal definition of MALE? • What are the optimal variables for categorization of MALE outcomes? • Which secondary preventive therapies are most effective at preventing MALE?	• Consensus definitions of MALE outcomes should be developed. • Large randomized clinical trials should collect data to adjudicate MALE.
7. Surrogate outcomes	• MALE is associated with biological processes such as calcification, lipid-rich plaque deposition, and thrombosis. • Validated surrogate outcomes may enable early-phase exploration of novel therapies to reduce MALE.	• What is the relationship between the imaging characteristics of limb disease (e.g., plaque, stenosis, calcification) and outcomes? • What are the ideal and validated perfusion measurements to predict wound healing and prevent amputation? • Are there unique blood biomarkers (e.g., inflammatory pathways) that predict MALE outcomes?	• Use angiography to show imaging characteristics and their relationship to MALE outcomes. • Define angiographic characteristics that are associated with adverse outcomes (e.g., noncalcified plaque) and whether these can be modified. • Validated perfusion assessments that correlate with MALE outcomes and wound healing are needed. • Biomarker studies should investigate independent associations with MALE.

CAD, coronary artery disease; MACE, major adverse cardiovascular events; MALE, major adverse limb effects.

Implementation science

Implementation science is the scientific study of strategies to promote uptake of evidence-based interventions into clinical practice or policy. Implementation science is a particularly important discipline for PAD because most people with PAD do not receive evidence-based care, such as exercise interventions, statins, or antiplatelet therapy to prevent cardiovascular events.^9,11,66 For example, among 129,699 patients with PAD and Medicare insurance, just 1735 (1.3%) were enrolled in SET between 2017 and 2018, and only 89 (0.068%) completed all supervised exercise sessions.¹¹ In a cohort of people with PAD from five cities enrolled in a clinical trial for walking performance in 2019–2021, approximately 71% were taking statins and approximately 69% were taking antiplatelet drugs.⁶⁶ Among patients enrolled in the BEST-CLI trial, only 25% were receiving comprehensive optimal medical therapy, including absence of cigarette smoking.⁶⁷ Factors likely contributing to undertreatment of PAD include underdiagnosis of PAD and poor knowledge among clinicians and patients about the clinical significance and optimal treatment of PAD.^8,9,68 Patients with PAD typically have multiple comorbidities, such as diabetes, chronic obstructive pulmonary disease (COPD), and cardiac diseases, which may distract from optimal care for PAD.⁶⁹ Other potential barriers to optimal care include the costs of treatment and lack of availability of therapies such as supervised exercise.

Challenges to implementation science in PAD

First, funding opportunities are needed to increase implementation science to improve diagnosis and treatment of PAD. Second, investigators trained in implementation and focused on PAD are needed to increase high-quality scientific investigation of this disease. Third, changing clinician behavior is difficult. Although suboptimal treatment of patients with PAD was first documented more than 20 years ago, those with PAD continue to be undertreated to prevent cardiovascular events, MALE, or to improve walking performance.^11,67,68

Priorities for implementation science in PAD

First, methods should be developed to increase the implementation of guideline-directed therapies for people with PAD (Table 6). This will likely require interventions to improve awareness and knowledge of PAD and its optimal treatment among patients and clinicians. These interventions should consider that underdiagnosis of PAD contributes to suboptimal therapy for people with PAD. Second, implementation science for PAD should include studying the role of structural racism as a contributor to adverse outcomes in people with PAD. Third, studies should incorporate community-based participatory research and stakeholder engagement. Fourth, studies are needed to evaluate optimal use of multidisciplinary healthcare teams to improve the diagnosis and treatment of PAD.

Table 6.

Implementation science priorities for peripheral artery disease (PAD).

Category	What is known	What is unclear	Examples of proposed science
1. Increase implementation of guideline-directed therapies for PAD	• Most people with PAD do not receive optimal medical therapy to prevent MACE or MALE. • Most people with PAD do not take part in SET covered by the Center for Medicare and Medicaid Services. • Most people with PAD do not participate in structured community-based exercise as recommended by guidelines.	• What medical therapy is optimal for preventing MACE and MALE? • What are the optimal methods to overcome barriers to participation in SET? • What are the most efficient methods to help patients with PAD take part in guideline-recommended home-based exercise?	• Interventions to improve knowledge and awareness of PAD among patients and clinicians are needed. • Methods to improve PAD diagnosis are required to improve implementation of optimal therapy for people with PAD.
2. Define the roles of structural racism, discrimination, bias, and poor access to care in preventing optimal treatment of PAD	• People who live in poverty or rural areas and Black individuals are less likely to receive optimal treatment for PAD.	• How do discrimination and racism specifically impair quality of care for people with PAD? • What role does poor access to care play regarding suboptimal treatment of people with PAD, and how can this problem be corrected?	• Qualitative research that involves community-based participatory research and all stakeholders may identify how structural racism, discrimination, and bias contribute to underdiagnosis and suboptimal treatment of PAD.

MACE, major adverse cardiovascular events; MALE, major adverse limb effects; PAD, peripheral artery disease; SET, supervised exercise therapy.

Summary

This document proposes priorities for scientific investigation to reduce the incidence of PAD, improve health outcomes among people with PAD, and increase rates of diagnosis and treatment of PAD (Figure 1). These priorities should help inform funding agencies, policymakers, and other leaders in scientific investigation. Improving the diagnosis and treatment of PAD are among the highest priority areas for future scientific investigation. Developing animal models that accurately represent the complexity of PAD pathophysiology in humans, identifying new effective therapies for impaired walking performance in PAD, and delineating the biologic pathway by which exercise improves walking performance in PAD are also high-priority areas for future investigation. Although testing whether screening high-risk groups with the ABI may improve rates of PAD diagnosis, future investigation is needed to determine whether blood or genetic testing or a combination of tests could be a more efficient and effective method.

Figure 1.

Summary of priorities for scientific investigation of peripheral artery disease.

Potential challenges to carrying out scientific investigation in these high-priority areas have been identified. First, more scientists studying PAD, across all disciplines, are needed. Dedicated training programs to increase the number of people focused on the scientific investigation of PAD are lacking. Second, greater funding for scientific investigation dedicated to PAD is needed. As of September 1, 2024, a search on ClinicalTrials.gov yielded 11,109 studies focused on CAD, 9652 focused on cerebrovascular disease, and only 1975 focused on PAD. Third, enrolling people with PAD in randomized clinical trials is challenging and may have discouraged some scientists from conducting clinical trials in people with PAD. Multicentered clinical trial networks may facilitate enrollment of people with PAD and speed completion of randomized clinical trials. Fourth, conducting clinical trials and large high-quality epidemiologic studies is expensive and can take years to complete. Registries such as the National Vascular Quality Initiative (VQI) can collect data on patients during routine medical care and inform scientific investigation of PAD at a lower cost than clinical trials, for example. However, missing data and inter-rater reliability of endpoint methods limit the effectiveness of registries as a high-quality method of scientific investigation.⁷⁰

Limitations of this review include the following. First, these recommendations are not all-encompassing and are not meant to exclude other important and innovative topics of investigation in PAD. Second, it was not possible to cover all high-priority areas of scientific investigation of PAD; the scope of this document focused on domains of basic science, translational science, epidemiology, clinical science, and implementation. Third, priorities for scientific investigation were based on voting by co-authors, but there was no unanimity in selecting the highest priorities for investigation.

In summary, substantial scientific investigation is needed to improve the diagnosis, treatment, and health outcomes for people with PAD. To implement these recommendations, additional scientists and increased funding dedicated to PAD are essential.

Footnotes

Acknowledgements

The authors thank Corinne H Miller, MLS of Northwestern University for performing a literature search for the manuscript.

Declaration of conflicting interests

The authors disclosed the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Mary M McDermott: research support from Mars and ACI Medical. Daniella Kadian-Dodov: honoraria and consultant fees from Boston Scientific and Abbott Laboratories; honoraria from Medscape (via grant from Janssen) and McGraw Hill. Herbert Aronow: consulting fees from Amplitude Vascular Systems, Philips, Recor, Medtronic, RapidAI, Silk Road Medical, and Novartis. Joshua Beckman: consulting fees from Cook, JanOne, Merck, Novartis, and Tourmaline. Yulanka Castro-Dominguez: consulting fees from Boston Scientific and Medtronic. Heather L Gornik: holds a patent related to oscillometric techniques for determination of the ankle–brachial index (receives no compensation related to this). Naomi Hamburg: consulting fees from Boston Scientific. Nicholas J Leeper: consulting fees from Bitterroot Bio, Arrowhead Pharmaceuticals, Janssen Pharmaceuticals, and Regeneron Pharmaceuticals. Jeffrey Olin: consulting fees from Boston Scientific, Antidote Therapeutics, and Akros Pharma. Elsie Ross: consulting fees from Cook Medical and Novartis; honoraria from Egg Medical and Medscape. Marc Bonaca: consulting fees from Audentes and modest stock holdings in Medtronic and Pfizer. Dr Bonaca also serves as Executive Director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between February 2021 and present from the following: Abbott Laboratories, Adamis Pharmaceuticals Corporation, Agios Pharmaceuticals, Inc., Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., ARCA Biopharma, Inc., Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc., Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc., BIDMC, Boston Clinical Research Institute, Bristol-Meyers Squibb Company, Cambrian Biopharma, Inc., Cardiol Therapeutics Inc., CellResearch Corp., Cook Medical Incorporated, Covance, CSL Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd, EPG Communication Holdings Ltd, Epizon Pharma, Inc., Esperion Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt. Ltd, Faraday Pharmaceuticals, Inc., Foresee Pharmaceuticals Co. Ltd, Fortress Biotech, Inc., HDL Therapeutics Inc., HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, IQVIA Inc., JanOne Biotech Holdings Inc., Janssen and Affiliates, Kaneka, Kowa Research Institute, Inc., Kyushu University, Lexicon Pharmaceuticals, Inc., LSG Kyushu University, Medimmune Ltd, Medpace, Merck & Affiliates, Novartis Pharmaceuticals Corp., Novate Medical, Ltd, Novo Nordisk, Inc., Pan Industry Group, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio Biosciences, Inc., Rexgenero, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics plc, Smith & Nephew plc, Stealth BioTherapeutics, Inc., State of Colorado CCPD Grant, The Brigham & Women’s Hospital, Inc., The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, WCT Atlas, Worldwide Clinical Trials Inc., WraSer, LLC, and Yale Cardiovascular Research Group. The remaining authors have no conflicting interests.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Mary M McDermott

Daniella Kadian-Dodov

Herbert D Aronow

Joshua A Beckman

Yulanka S Castro-Dominguez

Mark A Creager

Philip P Goodney

Heather L Gornik

Marc P Bonaca

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