2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease

PreambleSince 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, based on systematic methods to evaluate and classify evidence, provide a cornerstone of quality cardiovascular care.In response to reports from the Institute of Medicine 1,2 and a mandate to evaluate new knowledge and maintain relevance at the point of care, the ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) modified its methodology.[3][4][5]The relationships among guidelines, data standards, appropriate use criteria, and performance measures are addressed elsewhere. 5Intended Use-Practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease. The focus is on medical practice in the United States, but guidelines developed in collaboration with other organizations may have a broader target. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients' interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. Guidelines are reviewed annually by the Task Force and are official policy of the ACC and AHA. Each guideline is considered current until it is updated, revised, or superseded by published addenda, statements of clarification, focused updates, or revised full-text guidelines. To ensure that guidelines remain current, new data are reviewed biannually to determine whether recommendations should be modified. In general, full revisions are posted in 5-year cycles.[3][4][5][6]Modernization-Processes have evolved to support the evolution of guidelines as "living documents" that can be dynamically updated. This process delineates a recommendation to address a specific clinical question, followed by concise text (ideally <250 words) and hyperlinked to supportive evidence. This approach accommodates time constraints on busy clinicians and facilitates easier access to recommendations via electronic search engines and other evolving technology.Evidence Review-Writing committee members review the literature; weigh the quality of evidence for or against particular tests, treatments, or procedures; and estimate expected health outcomes. In developing recommendations, the writing committee uses evidence-based methodologies that are based on all available data. 3-7 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only selected references are cited.The Task Force recognizes the need for objective, independent Evidence Review Committees (ERCs) that include methodologists, epidemiologists, clinicians, and biostatisticians who systematically survey, abstract, and assess the evidence to address systematic review questions posed in the PICOTS format (P=population, I=intervention, C=comparator, O=outcome, T=timing, S=setting). 2,4-6 Practical considerations, including time and resource constraints, limit et al.the ERCs to evidence that is relevant to key clinical questions and lends itself to systematic review and analysis that could affect the strength of corresponding recommendations.Guideline-Directed Management and Treatment-The term "guideline-directed management and therapy" (GDMT) refers to care defined mainly by ACC/AHA Class I recommendations. For these and all recommended drug treatment regimens, the reader should confirm dosage with product insert material and carefully evaluate for contraindications and interactions. Recommendations are limited to treatments, drugs, and devices approved for clinical use in the United States.Class of Recommendation and Level of Evidence-TheClass of Recommendation (COR; ie, the strength of the recommendation) encompasses the anticipated magnitude and certainty of benefit in proportion to risk. The Level of Evidence (LOE) rates evidence supporting the effect of the intervention on the basis of the type, quality, quantity, and consistency of data from clinical trials and other reports(Table 1). 3-5 Unless otherwise stated, recommendations are sequenced by COR and then by LOE. Where comparative data exist, preferred strategies take precedence. When >1 drug, strategy, or therapy exists within the same COR and LOE and no comparative data are available, options are listed alphabetically.Relationships With Industry and Other Entities-The ACC and AHA sponsor the guidelines without commercial support, and members volunteer their time. The Task Force zealously avoids actual, potential, or perceived conflicts of interest that might arise through relationships with industry or other entities (RWI). All writing committee members and reviewers are required to disclose current industry relationships or personal interests, from 12 months before initiation of the writing effort. Management of RWI involves selecting a balanced writing committee and assuring that the chair and a majority of committee members have no relevant RWI (Appendix 1). Members are restricted with regard to writing or voting on sections to which their RWI apply. For transparency, members' comprehensive disclosure information is available online. Comprehensive disclosure information for the Task Force is also available online.The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds representing different geographic regions, sexes, ethnicities, intellectual perspectives/biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators.Individualizing Care in Patients With Associated Conditions and Comorbidities-Managing patients with multiple conditions can be complex, especially when recommendations applicable to coexisting illnesses are discordant or interacting. 8 The guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances. The recommendations should not replace clinical judgment.Clinical Implementation-Management in accordance with guideline recommendations is effective only when followed. Adherence to recommendations can be enhanced by shared decision making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities. Consequently, circumstances may arise in which deviations from these guidelines are appropriate. et al.the literature searches used for the existing evidence reviews, so the ERC concluded that no additional systematic review was necessary to address either of these critical questions.A third systematic review question was then identified: 3) Is one revascularization strategy (endovascular or surgical) associated with improved cardiovascular and limb-related outcomes in patients with critical limb ischemia (CLI)? This question had also been the subject of a high-quality systematic review that synthesized evidence from observational data and an RCT 14 ; additional RCTs addressing this question are ongoing. [15][16][17] The writing committee and the Task Force decided to expand the survey to include more relevant randomized and observational studies. Based on evaluation of this additional evidence the ERC decided that further systematic review was not needed to inform the writing committee on this question. Hence, the ERC and writing committee concluded that available systematic reviews could be used to inform the development of recommendations addressing each of the 3 systematic review questions specified above. The members of the Task Force and writing committee thank the members of the ERC that began this process and their willingness to participate in this volunteer effort. They include Aruna Pradhan, MD, MPH (ERC Chair);

# Introduction

## Methodology and evidence review
The recommendations listed in this guideline are, whenever possible, evidence based. An initial extensive evidence review, which included literature derived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline, was conducted from January through September 2015. Key search words included but were not limited to the following: acute limb ischemia, angioplasty, ankle-brachial index, anticoagulation, antiplatelet therapy, atypical leg symptoms, blood pressure lowering/hypertension, bypass graft/bypass grafting/ surgical bypass, cilostazol, claudication/intermittent claudication, critical limb ischemia/ severe limb ischemia, diabetes, diagnostic testing, endovascular therapy, exercise rehabilitation/exercise therapy/exercise training/supervised exercise, lower extremity/foot wound/ulcer, peripheral artery disease/peripheral arterial disease/peripheral vascular disease/ lower extremity arterial disease, smoking/smoking cessation, statin, stenting, and vascular surgery. Additional relevant studies published through September 2016, during the guideline writing process, were also considered by the writing committee, and added to the evidence tables when appropriate. The final evidence tables included in the Online Data Supplement summarize the evidence utilized by the writing committee to formulate recommendations.
Additionally, the writing committee reviewed documents related to lower extremity peripheral artery disease (PAD) previously published by the ACC and AHA. 9,10 References selected and published in this document are representative and not all-inclusive.
As stated in the Preamble, the ACC/AHA guideline methodology provides for commissioning an independent ERC to address systematic review questions (PI-COTS format) to inform recommendations developed by the writing committee. All other guideline recommendations (not based on the systematic review questions) were also subjected to an extensive evidence review process. For this guideline, the writing committee in conjunction with the Task Force and ERC Chair identified the following systematic review questions: 1) Is antiplatelet therapy beneficial for prevention of cardiovascular events in the patient with symptomatic or asymptomatic lower extremity PAD? 2) What is the effect of revascularization, compared with optimal medical therapy and exercise training, on functional outcome and quality of life (QoL) among patients with claudication? Each question has been the subject of recently published, systematic evidence reviews. The quality of these evidence reviews was appraised by the ACC/AHA methodologist and a vendor contracted to support this process (Doctor Evidence [Santa Monica, CA]). Few substantive randomized or nonrandomized studies had been published after the end date of The symptoms and signs of PAD are variable. Patients with PAD may experience the classic symptom of claudication or may present with advanced disease, including CLI. Studies have demonstrated that the majority of patients with confirmed PAD do not have typical claudication but have other non-joint-related limb symptoms or are asymptomatic. 53,55 Atypical lower extremity symptoms related to PAD may include pain or discomfort that begins at rest but et al. Circulation. Author manuscript; available in PMC 2017 September 21.

## Va author manuscript
VA Author Manuscript VA Author Manuscript worsens with exertion, pain or discomfort that does not stop an individual from walking, and pain or discomfort that begins with exertion but is not alleviated within 10 minutes of rest. Patients with PAD who do not have typical claudication but have other leg symptoms, or who are asymptomatic, have been shown to have functional impairment comparable to patients with claudication. Thus, all patients at increased risk of PAD should be asked not only about claudication but also about other exertional non-joint-related limb symptoms and perceived walking impairment.

## I b-nr
Patients at increased risk of PAD [fig_ref] Table 4: Patients at Increased Risk of PADAge 65 y Age 50-64 y, with... [/fig_ref] should undergo vascular examination, including palpation of lower extremity pulses (ie, femoral, popliteal, dorsalis pedis, and posterior tibial), auscultation for femoral bruits, and inspection of the legs and feet. See Online Data Supplements.
A thorough lower extremity vascular examination and careful inspection of the legs and feet are important components of the clinical assessment for PAD. To perform a thorough examination, legs and feet are examined with lower garments (pants/skirt, shoes, and socks) removed. Examination findings suggestive of PAD are shown in [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref]. Lower extremity pulses should be assessed and rated as follows: 0, absent; 1, diminished; 2, normal; or 3, bounding. Reproducibility of pulse assessment is better for detection of normal versus absent pulse than for normal versus diminished pulse. Absence of the dorsalis pedis pulse is less accurate for diagnosis of PAD than is absence of the posterior tibial pulse because the dorsalis pedis pulse can be absent on examination in a significant percentage of healthy patients. The presence of multiple abnormal physical findings (ie, multiple pulse abnormalities, bruits) increases the likelihood of confirmed PAD. Abnormal physical findings, such as a pulse abnormality, require confirmation with the ankle-brachial index (ABI) to establish the diagnosis of PAD. Similarly, an entirely normal pulse examination and absence of bruits decreases the likelihood of confirmed PAD. The presence of nonhealing lower extremity wounds may be a sign of CLI. Findings of cool or discolored skin and delayed capillary refill are not reliable for PAD diagnosis. To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing (Section 3), generally with the ABI as the initial test.

## I b-nr
Patients with PAD should undergo noninvasive blood pressure measurement in both arms at least once during the initial assessment. See Online Data Supplement 1.
An inter-arm blood pressure difference of >15 to 20 mm Hg is abnormal and suggestive of subclavian (or innominate) artery stenosis. Patients with PAD are at increased risk of subclavian artery stenosis. Measuring blood pressure in both arms identifies the arm with the highest systolic pressure, a requirement for accurate measurement of the ABI. Identification of unequal blood pressures in the arms also allows for more accurate measurement of blood pressure in the treatment of hypertension (ie, blood pressure is taken at the arm with higher measurements). Although a difference in arm systolic pressures of >15 to 20 mm Hg suggests subclavian (or innominate) artery stenosis, in the absence of symptoms (eg, arm claudication or symptoms of vertebral artery steal), no further imaging or intervention is warranted.

## Diagnostic testing for the patient with suspected lower extremity pad
(Claudication or CLI) [bib_ref] Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines, Accf/Aha Task Force On Practice [/bib_ref] 

## .1. resting abi for diagnosing pad: recommendations
Recommendations for Resting ABI for Diagnosing PAD

## Cor loe recommendations

## I b-nr
In patients with history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref] , the resting ABI, with or without segmental pressures and waveforms, is recommended to establish the diagnosis. [bib_ref] Comparison of lower limb arterial assessments using colorduplex ultrasound and ankle/brachial pressure..., Allen [/bib_ref] [bib_ref] ROC analysis of noninvasive tests for peripheral arterial disease, Lijmer [/bib_ref] [bib_ref] Sensitivity and specificity of ankle-brachial index for detecting angiographic stenosis of peripheral..., Guo [/bib_ref] [bib_ref] Diagnostic utility of the two methods of ankle brachial index in the..., Niazi [/bib_ref] See Online Data Supplement 4.
The resting ABI is obtained by measuring systolic blood pressures at the arms (brachial arteries) and ankles (dorsalis pedis and posterior tibial arteries) in the supine position by using a Doppler device. The ABI of each leg is calculated by dividing the higher of the dorsalis pedis or posterior tibial pressure by the higher of the right or left arm blood pressure. In patients with a history or physical examination suggestive of PAD, the ABI has good validity as a first-line test in the diagnosis of PAD, as shown by vascular imaging, with sensitivities ranging from 68% to 84% and specificities from 84% to 99%. [bib_ref] ROC analysis of noninvasive tests for peripheral arterial disease, Lijmer [/bib_ref] [bib_ref] Sensitivity and specificity of ankle-brachial index for detecting angiographic stenosis of peripheral..., Guo [/bib_ref] [bib_ref] Diagnostic utility of the two methods of ankle brachial index in the..., Niazi [/bib_ref] Those with ABI 0.91 to 0.99 may possibly have PAD and should undergo exercise ABI, if the clinical suspicion of PAD is significant [fig_ref] Table 4: Patients at Increased Risk of PADAge 65 y Age 50-64 y, with... [/fig_ref]. [bib_ref] Critical evaluation of stress testing in the diagnosis of peripheral vascular disease, Ouriel [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] Values >1.40 indicate that the arteries were not able to be compressed, which is more common among individuals with diabetes mellitus and/or advanced chronic kidney disease. In the setting of noncompressible ABI values, additional imaging can be used to diagnose PAD if the clinical suspicion is significant [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref]. [bib_ref] The association between elevated ankle systolic pressures and peripheral occlusive arterial disease..., Aboyans [/bib_ref] These cutpoints for ABI interpretation have been previously proposed and represent a reasonable standardized categorization. 27

## Iia b-nr
In patients at increased risk of PAD [fig_ref] Table 4: Patients at Increased Risk of PADAge 65 y Age 50-64 y, with... [/fig_ref] but without history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref] , measurement of the resting ABI is reasonable. 54,55, See Online Data Supplements 3 and 4.
The ABI test is noninvasive, is simple to perform, and has minimal risks, making it suitable for use in asymptomatic individuals. Previous studies have demonstrated a significant prevalence of abnormal resting ABI among asymptomatic patients with risk factors for PAD. 55,79,95 A significant body of evidence demonstrates that patients with an abnormal ABI who are asymptomatic have poorer cardiovascular morbidity and mortality outcomes than do patients with normal ABI. [bib_ref] Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral..., Diehm [/bib_ref] [bib_ref] Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events..., Flowkes [/bib_ref] [bib_ref] Prevalence and association between risk factors, stroke subtypes, and abnormal ankle brachial..., Ratanakorn [/bib_ref] [bib_ref] Association of asymptomatic peripheral arterial disease with vascular events in patients with..., Sen [/bib_ref] [bib_ref] Asymptomatic peripheral arterial disease in type 2 diabetes patients: a 10-year follow-up..., Bundo [/bib_ref] [bib_ref] Prognostic usefulness of clinical and subclinical peripheral arterial disease in men with..., Bouisset [/bib_ref] While there is no conclusive evidence that aspirin treatment changes cardiovascular or limb outcomes in this population, in 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes. [bib_ref] The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial..., Belch [/bib_ref] [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] [bib_ref] A systematic review for the screening for peripheral arterial disease in asymptomatic..., Alahdab [/bib_ref] [bib_ref] The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction..., Lin [/bib_ref] There is also evidence that asymptomatic patients with a low resting ABI have a poorer functional status and a more rapid rate of functional decline than do patients with a normal ABI. 54,88-92 Although physical activity has been shown to be associated with improvement in functional status in patients with asymptomatic PAD, 93,94 the benefit of resting ABI testing to identify asymptomatic patients who are at increased risk of functional decline and may benefit from structured exercise programs remains to be determined.

## Iii: no benefit b-nr
In patients not at increased risk of PAD [fig_ref] Table 4: Patients at Increased Risk of PADAge 65 y Age 50-64 y, with... [/fig_ref] and without history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref] , the ABI is not recommended. See Online Data Supplement 4.
The prevalence of PAD among individuals without risk factors for atherosclerosis and who are <50 years of age is low. Data from population-based cohort studies have demonstrated a low prevalence (approximately 1%) of abnormal resting ABI among individuals <50 years of age. In the NHANES (National Health and Nutrition Study), approximately 95% of participants with an abnormal resting ABI had at least 1 risk factor for atherosclerosis. The yield of ABI testing among younger, asymptomatic individuals without risk factors for atherosclerosis is low, and these patients should not be routinely tested for PAD. 95,98

## Physiological testing: recommendations
Recommendations for Physiological Testing COR LOE Recommendations I B-NR Toe-brachial index (TBI) should be measured to diagnose patients with suspected PAD when the ABI is greater than 1.40. [bib_ref] The association between elevated ankle systolic pressures and peripheral occlusive arterial disease..., Aboyans [/bib_ref] See Online Data Supplement 5.
TBI is a noninvasive test that is useful to evaluate for PAD in patents with noncompressible arteries, which cause an artificial elevation of the ABI. 99,100,102,103 A TBI 0.70 is abnormal and diagnostic of PAD because the digital arteries are rarely noncompressible. 99-102,104, [bib_ref] Utility of toe-brachial index for diagnosis of peripheral artery disease, Park [/bib_ref] Patients with longstanding diabetes mellitus [bib_ref] The association between elevated ankle systolic pressures and peripheral occlusive arterial disease..., Aboyans [/bib_ref] or advanced chronic kidney disease [bib_ref] Vascular calcification in chronic kidney disease, Covic [/bib_ref] 

## Va author manuscript
VA Author Manuscript PAD in these patients with noncompressible arteries who have history or physical examination findings suggestive of PAD [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref].

## I b-nr
Patients with exertional non-joint-related leg symptoms and normal or borderline resting ABI (>0.90 and 1.40) should undergo exercise treadmill ABI testing to evaluate for PAD. [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolai [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] See Online Data Supplement 5.
Exercise treadmill ABI testing is important to objectively measure symptom limitations and diagnose PAD. [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolai [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] It is useful in establishing the diagnosis of lower extremity PAD in the symptomatic patient when resting ABIs are normal or borderline and to differentiate claudication from pseudoclaudication in individuals with exertional leg symptoms. If the postexercise treadmill ABI is normal, alternative causes of leg pain are considered [fig_ref] Table 6: Alternative Diagnoses for Leg Pain or Claudication With Normal Physiological Testing [/fig_ref]. If a treadmill is not available, the pedal plantarflexion ABI test is a reasonable alternative because the results correlate well with treadmill ABIs [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref]. 111

## Iia b-nr
In patients with PAD and an abnormal resting ABI (0.90), exercise treadmill ABI testing can be useful to objectively assess functional status. [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolai [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] See Online Data Supplement 5.
In patients with PAD, exercise treadmill ABI testing can objectively assess symptoms, measure change in ABI in response to exercise, and assess functional status [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolai [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref]. It can be useful to correlate exertional lower extremity symptoms to a decline in ABI after treadmill exercise. Exercise treadmill ABI testing can document the magnitude of symptom limitation in patients with PAD and provide objective data that can demonstrate the safety of exercise and help to individualize exercise prescriptions in patients with PAD before initiation of a formal program of structured exercise training. Exercise ABI may also be used to objectively measure the functional improvement obtained in response to claudication treatment (eg, structured exercise program or revascularization). Administration of a 6-minute walk test in a corridor is a reasonable alternative to treadmill ABI testing for assessment of functional status. 54

## Iia b-nr
In patients with normal (1.00-1.40) or borderline (0.91-0.99) ABI in the setting of nonhealing wounds or gangrene, it is reasonable to diagnose CLI by using TBI with waveforms, transcutaneous oxygen pressure (TcPO 2 ), or skin perfusion pressure (SPP). [bib_ref] Transcutaneous oxygen pressure measurements in diabetic and non-diabetic patients clinically suspected of..., Biotteau [/bib_ref] [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] [bib_ref] Skin perfusion pressure measurement is valuable in the diagnosis of critical limb..., Castronuovo [/bib_ref] [bib_ref] Validation of the relationship between ankle-brachial and toe-brachial indices and infra-genicular arterial..., Bunte [/bib_ref] [bib_ref] An analysis of IN.PACT DEEP randomized trial on the limitations of the..., Shishehbor [/bib_ref] See Online Data Supplement 5.
The toe pressure and TBI may be discordant with the ABI 0.90 to 1.40 in some patients with diabetes mellitus and a nonhealing wound . [bib_ref] Validation of the relationship between ankle-brachial and toe-brachial indices and infra-genicular arterial..., Bunte [/bib_ref] [bib_ref] An analysis of IN.PACT DEEP randomized trial on the limitations of the..., Shishehbor [/bib_ref] A TBI 0.70 is considered diagnostic of PAD. 101,104,105 Doppler or plethysmographic waveforms taken at the toe supplement the toe pressure and TBI measurement and may be severely dampened in the setting of CLI. The likelihood of wound healing decreases with toe pressure <30 mm Hg. 100 Perfusion assessment measures (ie, TBI with waveforms, TcPO 2 , SPP) are obtained in a warm room to prevent arterial vasoconstriction in response to the cold. TcPO 2 measurements are performed with a standardized protocol and are taken at multiple sites. [bib_ref] Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based..., Fife [/bib_ref] Correlation between TBI, TcPO 2 , and SPP has been reported. [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] TcPO 2 >30 mm Hg has been used to predict ulcer healing. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] SPP 30 to 50 mm Hg is associated with increased likelihood of wound healing. [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] If perfusion measures are normal or only mildly impaired, alternative causes of the nonhealing wounds are considered [fig_ref] Table 7: Alternative Diagnoses for Nonhealing Wounds With Normal Physiological Testing [/fig_ref]. TcPO 2 and SPP can be used in angiosome-targeted assessment for revascularization. 119

## Iia b-nr
In patients with PAD with an abnormal ABI (0.90) or with noncompressible arteries (ABI >1.40 and TBI 0.70) in the setting of nonhealing wounds or gangrene, TBI with waveforms, TcPO 2 , or SPP can be useful to evaluate local perfusion. [bib_ref] Transcutaneous oxygen pressure measurements in diabetic and non-diabetic patients clinically suspected of..., Biotteau [/bib_ref] [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] [bib_ref] Skin perfusion pressure measurement is valuable in the diagnosis of critical limb..., Castronuovo [/bib_ref] [bib_ref] Validation of the relationship between ankle-brachial and toe-brachial indices and infra-genicular arterial..., Bunte [/bib_ref] [bib_ref] An analysis of IN.PACT DEEP randomized trial on the limitations of the..., Shishehbor [/bib_ref] See Online Data Supplement 5.
Perfusion assessment measures (eg, TBI with waveforms, TcPO 2 , SPP) can be useful when the ABI is only mildly reduced (eg, ABI 0.70-0.90) to determine whether factors other than PAD may be contributing to impaired wound healing . These perfusion assessment measures are obtained in a warm room to prevent arterial vasoconstriction in response to the cold. TcPO 2 measurements are performed with a standardized protocol and are taken at multiple sites. [bib_ref] Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based..., Fife [/bib_ref] The likelihood of wound healing decreases with toe pressure <30 mm Hg. There is correlation between TBI, TcPO 2 , and SPP. TcPO 2 >30 mm Hg has been used to predict ulcer healing. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] SPP 30 to 50 mm Hg is associated with increased likelihood of wound healing. [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] TcPO 2 and SPP can be used in angiosome-targeted assessment for revascularization. [bib_ref] Angiosome-targeted infrapopliteal endovascular revascularization for treatment of diabetic foot ulcers, Soderstrom [/bib_ref] Additional perfusion assessment may also be useful for patients with nonhealing wounds or gangrene who have noncompressible arteries (ABI >1.40) but who have a diagnosis of PAD that is based on an abnormal TBI (ABI 0.70).

## I b-nr
Duplex ultrasound, computed tomography angiography (CTA), or magnetic resonance angiography (MRA) of the lower extremities is useful to diagnose anatomic location and severity of stenosis for patients with symptomatic PAD in whom revascularization is considered. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] [bib_ref] Diagnostic accuracy of 64 multidetector computed tomographic angiography in peripheral vascular disease, Shareghi [/bib_ref] [bib_ref] MDCT compared with digital subtraction angiography for assessment of lower extremity arterial..., Ota [/bib_ref] [bib_ref] Summary receiver operating characteristic curves as a technique for meta-analysis of the..., De Vries [/bib_ref] See Online Data Supplement 6.
For symptomatic patients in whom ABI/TBI confirms PAD and in whom revascularization is considered, additional imaging with duplex ultrasonography, CTA, or MRA is useful to develop an individualized treatment plan, including assistance in selection of vascular access sites, identification of significant lesions, and determination of the feasibility of and modality for invasive treatment. All 3 of these noninvasive imaging methods have good sensitivity and specificity as compared with invasive angiography. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] [bib_ref] Diagnostic accuracy of 64 multidetector computed tomographic angiography in peripheral vascular disease, Shareghi [/bib_ref] [bib_ref] MDCT compared with digital subtraction angiography for assessment of lower extremity arterial..., Ota [/bib_ref] [bib_ref] Summary receiver operating characteristic curves as a technique for meta-analysis of the..., De Vries [/bib_ref] Renal function does not affect the safety of duplex ultrasonography, although duplex offers lower spatial resolution than CTA and MRA in the setting of arterial calcification. The tomographic data from CTA and MRA afford 3dimensional reconstruction of the vessels examined. The iodinated contrast used in CTA confers risk of contrast-induced nephropathy and (rarely) severe allergic reaction [bib_ref] Side effects of radiographic contrast media: pathogenesis, risk factors, and prevention, Andreucci [/bib_ref] [bib_ref] Contrast induced nephropathy: updated ESUR Contrast Media Safety Committee guidelines, Stacul [/bib_ref] ; CTA uses ionizing radiation. MRA does not use ionizing radiation; however, gadolinium contrast used frequently in MRA studies confers risk of nephrogenic systemic sclerosis for patients with advanced renal dysfunction and is therefore contraindicated in this population. The choice of the examination should be determined in an individualized approach to the anatomic assessment for each patient, including risk-benefit assessment of each study type. If these noninvasive tests are nondiagnostic, then invasive angiography may be required to delineate anatomy and plan revascularization.

## I c-eo
Invasive angiography is useful for patients with CLI in whom revascularization is considered.

## N/a
By definition, CLI results from extensive PAD that limits tissue perfusion. Because timely diagnosis and treatment are essential to preserve tissue viability in CLI, it is often most effective and expeditious to pursue invasive angiography with endovascular revascularization directly, without delay and potential risk of additional noninvasive imaging.

## Iia c-eo
Invasive angiography is reasonable for patients with lifestyle-limiting claudication with an inadequate response to GDMT for whom revascularization is considered.

## N/a
For patients with lifestyle-limiting claudication despite GDMT (including structured exercise therapy) for whom revascularization is being considered, proceeding directly to invasive angiography for anatomic assessment and to determine revascularization strategy is reasonable. In certain clinical settings, noninvasive imaging studies for anatomic assessment (ie, duplex ultrasound, CTA, or MRA) may not be available because of lack of local resources or expertise. In addition, there are clinical scenarios in which noninvasive studies for anatomic assessment may be perceived to confer greater risk to the patient than invasive angiography (eg, patient with advanced chronic kidney disease for whom contrast dose for invasive angiography would be lower than that required for CTA).

## Iia

## B-nr
A screening duplex ultrasound for abdominal aortic aneurysm (AAA) is reasonable in patients with symptomatic PAD. See Online Data Supplement 8.
PAD has been recognized as a risk factor for AAA. In observational studies, the prevalence of AAA (aortic diameter 3 cm) was higher in patients with symptomatic PAD than in the general population 127,129 and in a population of patients with atherosclerotic risk factors. The prevalence of AAA among patients with PAD increased with age, beginning in patients 55 years of age, and was highest in patients 75 years of age. There are no data on AAA screening in patients with asymptomatic PAD. This recommendation refers to screening patients with symptomatic PAD for AAA regardless of patient age, sex, smoking history, or family history of AAA. Recommendations for screening the general population with risk factors for AAA (based on age, sex, smoking history, and family history) have been previously published. 9

## Screening for asymptomatic atherosclerosis in other arterial beds (coronary, carotid, and renal arteries)
The prevalence of atherosclerosis in the coronary, carotid, and renal arteries is higher in patients with PAD than in those without pad. 128,130-135 However, intensive atherosclerosis risk factor modification in patients with PAD is justified regardless of the presence of disease in other arterial beds. Thus, the only justification for screening for disease in other arterial beds is if revascularization results in a reduced risk of myocardial infarction (MI), stroke, or death, and this has never been shown. Currently, there is no evidence to demonstrate that screening all patients with PAD for asymptomatic atherosclerosis in other arterial beds improves clinical outcome. Intensive treatment of risk factors through GDMT is the principle method for preventing adverse cardiovascular ischemic events from asymptomatic disease in other arterial beds. Patients with PAD (ie, ABI 0.90) who do not have claudication may have leg symptoms atypical for claudication or may be too functionally limited to allow for adequate leg symptom assessment. Patients with PAD without claudication are at increased cardiovascular risk. [bib_ref] Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral..., Diehm [/bib_ref] Subgroup analysis in a trial evaluating asymptomatic patients did not show an effect of aspirin in patients with an abnormally low ABI (<0.80 or 0.90). [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] However, the trial was not powered to analyze subgroups, and the uncertainty of the result does not rule out the possibility that aspirin could provide benefit in such patients, especially in those at increased risk of cardiovascular events. Another trial that included asymptomatic patients was too small to derive meaningful conclusions. 140

## Medical therapy for the patient with pad
IIb B-R In asymptomatic patients with borderline ABI (0.91-0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain. [bib_ref] The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial..., Belch [/bib_ref] [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] See Online Data Supplement 13.
In asymptomatic patients with an abnormal or borderline ABI, 2 RCTs found that aspirin had no effect in reducing cardiovascular events [bib_ref] The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial..., Belch [/bib_ref] [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] and might increase bleeding. [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] However, the trials were not powered to examine patients with borderline ABI separately. Given that cardiovascular risk is lower in patients with borderline ABI than in those with abnormal ABI, [bib_ref] Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events..., Flowkes [/bib_ref] it would be unlikely that aspirin would have a meaningful effect in this subgroup when there was no evidence of an effect in the total trial populations.

## Iib b-r
The effectiveness of dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established. [bib_ref] Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in..., Bhatt [/bib_ref] See Online Data Supplement 13.
Based on findings from a subset of patients with PAD in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, DAPT with aspirin plus clopidogrel may be considered for patients with PAD at particularly high risk of cardiovascular ischemic events who are not at high risk of bleeding. 143, [bib_ref] Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in..., Bhatt [/bib_ref] Currently, there are sparse data on newer P2Y 12 antagonists for PAD. There is uncertainty about the net benefit of long-term DAPT for patients with PAD-specifically the balance of risks of cardiovascular ischemic events versus major bleeding. Additional clinical trials are needed in the population with PAD. Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD. 20
IIb C-LD DAPT (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization. [bib_ref] Management of peripheral arterial interventions with mono or dual antiplatelet therapy-the MIRROR..., Tepe [/bib_ref] [bib_ref] Association of dual-antiplatelet therapy with reduced major adverse cardiovascular events in patients..., Armstrong [/bib_ref] [bib_ref] Twelve-month results of a randomized trial comparing mono with dual antiplatelet therapy..., Strobl [/bib_ref] [bib_ref] CASPAR Writing Committee. Results of the randomized, placebocontrolled Clopidogrel and Acetylsalicylic Acid..., Belch [/bib_ref] See Online Data Supplements 13 and 14.
There are sparse data on DAPT after lower extremity revascularization. Still, DAPT is prescribed in up to 55% of patients after endovascular revascularization for CLI. [bib_ref] Association of dual-antiplatelet therapy with reduced major adverse cardiovascular events in patients..., Armstrong [/bib_ref] One small RCT of aspirin or aspirin plus clopidogrel in patients undergoing endovascular revascularization demonstrated that patients with DAPT had fewer repeat revascularization procedures for clinical symptoms. [bib_ref] Management of peripheral arterial interventions with mono or dual antiplatelet therapy-the MIRROR..., Tepe [/bib_ref] A subsequent small RCT of aspirin plus placebo or aspirin plus clopidogrel in patients after endovascular revascularization also showed a decrease in the need for repeat revascularization at 6 months in patients receiving clopidogrel. [bib_ref] Twelve-month results of a randomized trial comparing mono with dual antiplatelet therapy..., Strobl [/bib_ref] An RCT of aspirin plus placebo or aspirin plus clopidogrel in patients who underwent below-knee bypass graft showed a decrease in limb-related events only in the prespecified subgroup of patients with prosthetic bypass grafts. [bib_ref] CASPAR Writing Committee. Results of the randomized, placebocontrolled Clopidogrel and Acetylsalicylic Acid..., Belch [/bib_ref] Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD. 20
IIb B-R The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] This novel antagonist of protease-activated receptor-1 added to existing antiplatelet therapy reduced the risk of cardiovascular ischemic events in patients with atherosclerosis who were receiving standard therapy in an RCT. [bib_ref] Vorapaxar in the secondary prevention of atherothrombotic events, Morrow [/bib_ref] [bib_ref] Efficacy and safety of vorapaxar with and without a thienopyridine for secondary..., Bohula [/bib_ref] However, it also increased the risk of moderate or severe bleeding. Although the cardiovascular benefit was not demonstrated in the subgroup with symptomatic PAD, there was a reduction in limb-related events with vorapaxar, specifically in acute limb ischemia (ALI) and peripheral revascularization. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] [bib_ref] Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery..., Bonaca [/bib_ref] More than half of ALI events in the PAD subset were due to thrombosis of lower extremity bypass grafts. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] Unfortunately, the benefit in limb events in patients with PAD was accompanied by an increased risk of bleeding. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] [bib_ref] Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery..., Bonaca [/bib_ref] Therefore, the overall clinical benefit of vorapaxar in patients with PAD is uncertain. Statin therapy improves both cardiovascular and limb outcomes in patients with PAD.In a subgroup of 6748 patients with PAD in the HPS (Heart Protection Study), simvastatin 40 mg daily reduced the rate of first major vascular event by 22% relative to placebo.In a multinational registry, statin use among patients with PAD reduced 4-year adverse limb-related events (ie, worsening claudication, new CLI, new lower extremity revascularization, new ischemic amputation) compared with no statin. [bib_ref] Statin therapy and long-term adverse limb outcomes in patients with peripheral artery..., Kumbhani [/bib_ref] Use of simvastatin in the HPS reduced relative risk of peripheral vascular events (including noncoronary revascularization, aneurysm repair, major amputation, or PAD death) compared with placebo.In Medicare patients undergoing lower extremity revascularization, 1-year limb salvage rates were improved among those receiving statin medication. [bib_ref] Preoperative statins and limb salvage after lower extremity revascularization in the Medicare..., Vogel [/bib_ref] In a multicenter RCT, use of atorvastatin 80 mg daily improved pain-free walking time and community-based walking at 12 months compared with placebo. [bib_ref] Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial..., Mohler [/bib_ref] In 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes. Guidelines for dosing of statin medications have been previously published. 24

## Statin agents: recommendation

## Antihypertensive agents: recommendations

## Recommendations for antihypertensive agents

## Cor loe recommendations
I A Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death. [bib_ref] Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings..., Bavry [/bib_ref] [bib_ref] Cardioprotective medication is associated with improved survival in patients with peripheral arterial..., Feringa [/bib_ref] [bib_ref] The HOPE Study (Heart Outcomes Prevention Evaluation), Sleight [/bib_ref] [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] See Online Data Supplements 17 and 18.
Treatment of elevated blood pressure is indicated to lower the risk of cardiovascular events.Target blood pressure and selection of antihypertensive therapy should be consistent with current published guidelines for hypertension management. Concerns have been raised that antihypertensive therapy may reduce limb perfusion. However, multiple studies have demonstrated that blood pressure treatment, including the use of beta blockers, does not worsen claudication symptoms or impair functional status in patients with PAD. [bib_ref] Effect of nebivolol vs. hydrochlorothiazide on the walking capacity in hypertensive patients..., Diehm [/bib_ref] [bib_ref] Beta blockers for peripheral arterial disease, Paravastu [/bib_ref] [bib_ref] -Blockers in patients with intermittent claudication and arterial hypertension: results from the..., Espinola-Klein [/bib_ref] There is no evidence that one class of antihypertensive medication or strategy is superior for blood pressure lowering in PAD. [bib_ref] Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings..., Bavry [/bib_ref] [bib_ref] Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT, Piller [/bib_ref] [bib_ref] Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan..., Zanchetti [/bib_ref] An updated multisocietal guideline on the management of high blood pressure is anticipated in 2017.

## Iia a
The use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD. [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] [bib_ref] Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients...., Yusuf [/bib_ref] See Online Data Supplement 17.
The effect of ramipril versus placebo on cardiovascular events was studied in high-risk patients free of heart failure in the HOPE (Heart Outcomes Prevention Evaluation) trial. [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] [bib_ref] Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients...., Yusuf [/bib_ref] Patients were normotensive on average at the time of enrollment. In a subgroup of 4051 patients with PAD, ramipril reduced the risk of MI, stroke, or vascular death by 25%, similar to the efficacy in the entire study population. [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] [bib_ref] Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients...., Yusuf [/bib_ref] The efficacy was similar in patients with PAD with symptomatic disease and asymptomatic low ABI. [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial) compared telmisartan, ramipril, and combination therapy in patients with cardiovascular disease, including PAD, and/or diabetes mellitus. [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] All 3 treatments had similar cardiovascular event rates with higher rates of adverse events (including hypotension, syncope, and renal failure) in the combination-therapy group. The efficacy of telmisartan was similar in the subgroup of 3468 patients with PAD, which supports the use of angiotensin-receptor blockers as an alternative to angiotensin-converting enzyme inhibitors. [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] The effect of angiotensin-receptor blockers in asymptomatic PAD has not been studied.

## Smoking cessation: recommendations

## Recommendations for smoking cessation

## Cor loe recommendations
I A Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit. [bib_ref] Effectiveness of a smoking cessation program for peripheral artery disease patients: a..., Hennrikus [/bib_ref] [bib_ref] Physician advice for smoking cessation, Stead [/bib_ref] [bib_ref] Variation in smoking cessation after vascular operations, Hoel [/bib_ref] See Online Data Supplements 19 and 20.
Tobacco use is a strong risk factor for the development and progression of PAD. [bib_ref] Influence of smoking on incidence and prevalence of peripheral arterial disease, Willigendael [/bib_ref] [bib_ref] The contribution of tobacco use to high health care utilization and medical..., Duval [/bib_ref] Sparse evidence exists with regard to the association of novel tobacco product use, including electronic cigarettes, and PAD. [bib_ref] Electronic cigarettes: a policy statement from the, Bhatnagar [/bib_ref] Observational studies suggest that smoking cessation is associated with lower rates of cardiovascular ischemic events, limb-related events, bypass graft failure, amputation, and death in patients with PAD. [bib_ref] Variation in smoking cessation after vascular operations, Hoel [/bib_ref] [bib_ref] Smoking cessation is associated with decreased mortality and improved amputation-free survival among..., Armstrong [/bib_ref] [bib_ref] Association of smoking cessation and weight change with cardiovascular disease among adults..., Clair [/bib_ref] [bib_ref] Preoperative smoking is associated with early graft failure after infrainguinal bypass surgery, Selvarajah [/bib_ref] Clinician advice increases quit rates, which supports simple provider-based measures as a component of smoking cessation programs. 22,171,179

## I a
Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (ie, varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program. [bib_ref] Effectiveness of a smoking cessation program for peripheral artery disease patients: a..., Hennrikus [/bib_ref] [bib_ref] Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular..., Rigotti [/bib_ref] [bib_ref] Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized..., Rigotti [/bib_ref] [bib_ref] Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre,..., Tonstad [/bib_ref] See Online Data Supplements 19 and 20.
Coordinated smoking cessation interventions that include nonpharmacological and pharmacological approaches have the greatest efficacy. An RCT of a follow-up program and smoking cessation medications provided to hospitalized patients, including those with PAD, demonstrated a modest increase in quit rates. [bib_ref] Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized..., Rigotti [/bib_ref] In an RCT of patients with PAD specifically, a comprehensive smoking cessation program combining counseling and pharmacological agents increased the rates of smoking cessation to 21.3%, compared with 6.8% with standard advice. [bib_ref] Effectiveness of a smoking cessation program for peripheral artery disease patients: a..., Hennrikus [/bib_ref] Three pharmacological approaches (ie, varenicline, bupropion, and nicotine replacement therapy) used alone or in combination all increase smoking cessation rates. [bib_ref] Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular..., Rigotti [/bib_ref] [bib_ref] Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre,..., Tonstad [/bib_ref] Two meta-analyses of RCTs of smoking cessation medications showed no evidence of increased cardiovascular event rates with nicotine replacement, bupropion, or varenicline. [bib_ref] Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis, Mills [/bib_ref] [bib_ref] Risk of cardiovascular serious adverse events associated with varenicline use for tobacco..., Prochaska [/bib_ref] Sparse data suggest that electronic cigarettes have no benefit on smoking cessation rates. 179

## I b-nr
Patients with PAD should avoid exposure to environmental tobacco smoke at work, at home, and in public places. [bib_ref] Association between smoke-free legislation and hospitalizations for cardiac, cerebrovascular, and respiratory diseases:..., Tan [/bib_ref] [bib_ref] Association between level of exposure to secondhand smoke and peripheral arterial disease:..., Lu [/bib_ref] See Online Data Supplement 20.
Passive smoke exposure has been associated with the development of PAD. [bib_ref] Association between level of exposure to secondhand smoke and peripheral arterial disease:..., Lu [/bib_ref] Observational studies have shown lower cardiovascular and cerebrovascular event rates in the general population after enactment of smoke-free legislation. [bib_ref] Association between smoke-free legislation and hospitalizations for cardiac, cerebrovascular, and respiratory diseases:..., Tan [/bib_ref] The effects of avoidance of passive smoke exposure on limb-related events are not known. [bib_ref] Association of elevated fasting glucose with lower patency and increased major adverse..., Singh [/bib_ref] [bib_ref] The influence of glycemic control on the prognosis of Japanese patients undergoing..., Takahara [/bib_ref] See Online Data Supplement 22.

## Glycemic control: recommendations
In a cohort of 1974 participants with diabetes mellitus from the Strong Heart Study, compared with patients without PAD, patients with PAD and a Hg A1c level <6.5% had lower ageadjusted odds of major amputation compared to patients with PAD and hemoglobin A1c 6.5% to 9.5% and hemoglobin A1c >9.5%. [bib_ref] Relationship of high and low ankle brachial index to all-cause and cardiovascular..., Resnick [/bib_ref] Glycemic control is particularly important for patients with PAD and diabetes mellitus who have CLI. Single-center observational studies have demonstrated improved limb-related outcomes, including lower rates of major amputation and improved patency after infrapopliteal intervention, among patients with CLI who have more optimized glycemic control parameters compared with patients with inferior glycemic control. [bib_ref] Association of elevated fasting glucose with lower patency and increased major adverse..., Singh [/bib_ref] [bib_ref] The influence of glycemic control on the prognosis of Japanese patients undergoing..., Takahara [/bib_ref] 

## Oral anticoagulation: recommendations

## Recommendations for oral anticoagulation

## Cor loe recommendations
IIb B-R The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain. [bib_ref] Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk..., Sarac [/bib_ref] [bib_ref] Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery, Bedenis [/bib_ref] See Online Data Supplements 23 and 24.
Two RCTs evaluating the effectiveness of oral anticoagulation (warfarin) in improving lower extremity bypass patency demonstrated improved patency among the subgroup of patients with autogenous vein bypass grafts. [bib_ref] Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk..., Sarac [/bib_ref] However, a Cochrane systematic review showed no patency benefit with the use of anticoagulation compared with antiplatelet therapy. [bib_ref] Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery, Bedenis [/bib_ref] All RCTs and observational studies evaluating the effect of anticoagulants on bypass patency demonstrated increased bleeding complications associated with anticoagulant use. One RCT evaluating the effectiveness of oral anticoagulation (warfarin) in addition to aspirin in improving lower extremity bypass patency demonstrated improved patency in a subgroup of patients with 6-mm polytetrafluoroethylene (known as PTFE) bypass graft. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref] Randomization to anticoagulation plus aspirin was associated with increased risk of death and major hemorrhage versus aspirin alone.

## Iii: harm
A Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref] [bib_ref] Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, Alonso-Coello [/bib_ref] [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] See Online Data Supplements 23 and 24
RCTs and observational studies have uniformly demonstrated that oral anticoagulation therapy aimed at decreasing major cardiovascular ischemic events provided no benefit and resulted in increased morbidity. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref] [bib_ref] Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, Alonso-Coello [/bib_ref] [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] In the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial of patients with atherosclerotic vascular disease, including PAD, there was no difference in cardiovascular ischemic events among patients randomized to oral anticoagulation and antiplatelet therapy versus antiplatelet therapy alone. [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] In addition, there was an increase in bleeding endpoints including lifethreatening and intracranial bleeding. [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] One RCT demonstrated increased death rate among patients randomized to warfarin plus aspirin versus aspirin alone after lower extremity bypass grafting. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref] 

## Cilostazol: recommendation
Recommendation for Cilostazol COR LOE Recommendation I A Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication. [bib_ref] Cilostazol for intermittent claudication, Bedenis [/bib_ref] [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] See Online Data Supplement 25.
In a Cochrane review including 15 double-blind RCTs with a total of 3718 participants, cilostazol was associated with improvement in claudication symptoms but no changes in et al.

## Page 15
Circulation. Author manuscript; available in PMC 2017 September 21. cardiovascular deaths or QoL when compared with placebo. [bib_ref] Cilostazol for intermittent claudication, Bedenis [/bib_ref] In 1 RCT, cilostazol was more effective than pentoxifylline or placebo. [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] Side effects include headache, abnormal stool (diarrhea), dizziness, and palpitations. Cilostazol is contraindicated in patients with congestive heart failure.In 1 trial, 20% of patients discontinued cilostazol within 3 months. 202

## Pentoxifylline: recommendation
Recommendation for Pentoxifylline COR LOE Recommendation III: No Benefit B-R Pentoxifylline is not effective for treatment of claudication. [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] [bib_ref] Pentoxifylline for intermittent claudication, Salhiyyah [/bib_ref] See Online Data Supplement 26.
In a Cochrane review of 24 studies with 3377 participants, there was large variability in study design and results between individual studies, and therefore the review's effectiveness was unclear. [bib_ref] Pentoxifylline for intermittent claudication, Salhiyyah [/bib_ref] Pentoxifylline was shown to be generally well tolerated. [bib_ref] Pentoxifylline for intermittent claudication, Salhiyyah [/bib_ref] In a multicenter RCT of pentoxifylline, cilostazol, or placebo for patients with moderate-to-severe claudication, there was no difference between pentoxifylline and placebo in the primary endpoint of maximal walking distance. [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] Therefore, pentoxifylline is not recommended as treatment for claudication.

## Chelation therapy: recommendation
Recommendation for Chelation Therapy

## Cor loe recommendation

## Iii: no benefit b-r chelation therapy (eg, ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication. 204
See Online Data Supplement 27.
In a Cochrane review of 5 studies with 260 participants, chelation therapy showed no significant difference in symptoms (maximal and pain-free walking distance) compared with placebo. 204

## Homocysteine lowering: recommendation

## Recommendation for homocysteine lowering

## Cor loe recommendation

## Iii: no benefit b-r
B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended. [bib_ref] Rationale, design and baseline characteristics of a large, simple, randomized trial of..., Lonn [/bib_ref] [bib_ref] Homocysteine lowering with folic acid and B vitamins in vascular disease, Lonn [/bib_ref] [bib_ref] Homocysteine and peripheral arterial disease: systematic review and meta-analysis, Khandanpour [/bib_ref] See Online Data Supplements 28 and 29.
Although patients with PAD have been shown to have increased plasma homocysteine levels compared with patients without PAD, there is no evidence that B-complex vitamin supplementation improves clinical outcomes in patients with PAD. [bib_ref] Homocysteine and peripheral arterial disease: systematic review and meta-analysis, Khandanpour [/bib_ref] The HOPE-2 trial randomized 5522 patients with atherosclerotic vascular disease, including symptomatic PAD, or diabetes mellitus with additional risk factors to receive folic acid/vitamin B6/vitamin B12 or placebo. [bib_ref] Rationale, design and baseline characteristics of a large, simple, randomized trial of..., Lonn [/bib_ref] [bib_ref] Homocysteine lowering with folic acid and B vitamins in vascular disease, Lonn [/bib_ref] Despite lowering of homocysteine levels in the vitamin supplementation arm, there was no improvement in the primary endpoint of cardiovascular death, MI, or stroke. Observational studies have demonstrated reduced cardiovascular event rates among patients with cardiovascular disease who have received an influenza vaccination. Two RCTs that enrolled patients with CAD demonstrated a benefit of an influenza vaccination on the prevention of cardiovascular events, particularly coronary ischemic events. [bib_ref] Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS)..., Gurfinkel [/bib_ref] [bib_ref] Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery..., Ciszewski [/bib_ref] Although these trials did not specifically enroll participants with PAD, a majority of patients with PAD also have CAD. On the basis of this evidence, an annual influenza vaccination is recommended as a component of medical therapy for patients with PAD.

## Influenza vaccination: recommendation

## Structured exercise therapy: recommendations
Structured exercise therapy is an important element of care for the patient with PAD. Components of structured exercise programs for PAD are outlined in . The data supporting the efficacy of supervised exercise training as an initial treatment for claudication continue to develop and remain convincing, building on many earlier RCTs. 40-46,48,210,211 Trials with long-term follow-up from 18 months 37,38 to 7 years 36 have demonstrated a persistent benefit of supervised exercise in patients with claudication. Data also support a benefit of supervised exercise for patients with symptomatic PAD and diabetes mellitus. [bib_ref] Diabetes status differentiates endothelial function and plasma nitrite response to exercise stress..., Allen [/bib_ref] The risk-benefit ratio for supervised exercise in PAD is favorable, with an excellent safety profile in patients screened for absolute contraindications to exercise such as exercise-limiting cardiovascular disease, amputation or wheelchair confinement, and other major comorbidities that would preclude exercise. 36,39,49,213-216 Despite the health benefits associated with supervised exercise in patients with PAD, initiating and maintaining a high level of adherence remain challenging. Frequent contact with patients both when performing exercise in the supervised setting and at home has been somewhat effective in promoting retention. 37,38 I B-R A supervised exercise program should be discussed as a treatment option for claudication before possible revascularization. See Online Data Supplement 32.

## Recommendations for structured exercise
The CLEVER (Claudication: Exercise Versus Endoluminal Revascularization) trial randomized patients with symptomatic aortoiliac PAD and showed comparable benefits for supervised exercise and stent revascularization at 6 and 18 months, with each therapy being superior to optimal medical care. 37,38 Overall, the safety profile for supervised exercise was excellent. An RCT that compared 7-year effectiveness of supervised exercise or endovascular revascularization in patients with stable claudication with iliac or femoropopliteal disease found no differences in improved walking and QoL outcomes. Although more secondary interventions occurred in the exercise group, the total number of interventions was greater in the endovascular revascularization group. Collectively, these studies provide strong support for offering patients a supervised exercise program for reducing claudication symptoms and for improving functional status and QoL.
A 3-month RCT that compared percutaneous transluminal angioplasty (PTA), supervised exercise, and combined treatment for claudication found that both supervised exercise and PTA improved clinical and QoL outcomes, whereas PTA plus supervised exercise produced greater benefits than either therapy alone. [bib_ref] Early outcomes from a randomized, controlled trial of supervised exercise, angioplasty, and..., Mazari [/bib_ref] The ERASE (Endovascular Revascularization and Supervised Exercise) study randomized participants with claudication to endovascular revascularization plus supervised exercise or supervised exercise alone. After 1 year, patients in both groups had significant improvements in walking distances and health-related QoL, with greater improvements in the combined-therapy group. [bib_ref] Endovascular revascularization and supervised exercise for peripheral artery disease and intermittent claudication:..., Fakhry [/bib_ref] Collectively, these studies support the continued provision of supervised exercise to patients with claudication, whether as a monotherapy or combined with revascularization. Unstructured community-based or home-based walking programs that consist of providing general recommendations to patients with claudication to simply walk more are not efficacious. 50 Studies supporting structured community-or home-based programs for patients with symptomatic PAD (claudication and/or leg symptoms atypical for claudication) are more recent than studies supporting supervised exercise programs, and have provided strong evidence in support of the community-or home-based approach. 47,49,51,88,94,213 For example, the GOALS (Group Oriented Arterial Leg Study) trial 94 included patients with confirmed PAD with and without claudication (atypical lower extremity symptoms or no symptoms) and showed increases in several parameters of functional status for both of these patient cohort subgroups, versus nonexercising controls, after 6 months, 88 with improvement maintained at 12 months. 94
As with supervised exercise programs, despite proven benefit, initiating and maintaining a high level of adherence to community-or home-based exercise programs remains challenging. Studies that have incorporated behavioral change techniques, such as health coaching and activity tracking used in supervised settings, appear to reduce attrition and promote higher levels of adherence, thereby improving functional and QoL outcomes, both short term and long term. Hg, white blood cell count >12 000 or <4000/mcL or >10% immature forms). 226 Probe-tobone test is moderately predictive for osteomyelitis but is not pathognomonic. 227

## Iia c-ld in patients with pad and signs of foot infection, prompt referral to an interdisciplinary care team (

## N/a
A history of foot ulcers, foot infections, or amputation identifies patients with a very high (>10%) yearly incidence of recurrent ulcers. 231 Examination includes a visual inspection for foot ulcers (full-thickness epithelial defects) and structural (bony) deformities, monofilament testing for sensory neuropathy, and palpation for pedal pulses.

## Revascularization for claudication
An individualized approach to revascularization for claudication is recommended for each patient to optimize outcome. Revascularization is but one component of care for the patient with claudication, as each patient should have a customized care plan that also includes medical therapy (Section 5), structured exercise therapy (Section 6), and care to minimize tissue loss (Section 7). If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both.
Because of the variability of ischemic limb symptoms and impact of these symptoms on functional status and QoL, patients should be selected for revascularization on the basis of severity of their symptoms. Factors to consider include a significant disability as assessed by the patient, adequacy of response to medical and structured exercise therapy, status of comorbid conditions, and a favorable risk-benefit ratio. Patient preferences and goals of care are important considerations in the evaluation for revascularization. The revascularization strategy should have a reasonable likelihood of providing durable relief of symptoms. A general recommendation for revascularization as a treatment option for claudication is provided below followed by specific recommendations for endovascular (Section 8. A minority of patients with claudication (estimated at <10% to 15% over 5 years or more) will progress to CLI. 234-237 Therefore, the role of revascularization in claudication is improvement in claudication symptoms and functional status, and consequently in QoL, rather than limb salvage. Revascularization is reasonable when the patient who is being treated with GDMT (including structured exercise therapy) presents with persistent lifestyle-limiting claudication. 12,37,38,232,233 Lifestyle-limiting claudication is defined by the patient rather than by any test. It includes impairment of activities of daily living and/ or vocational and/or recreational activities due to claudication. There should be clear discussion with the patient about expected risks and benefits of revascularization, as well as discussion of the durability of proposed procedures.

## Endovascular revascularization for claudication: recommendations-
Endovascular techniques to treat claudication include balloon dilation (angioplasty), stents, and atherectomy. These techniques continue to involve and now include covered stents, drug-eluting stents (DES), cutting balloons, and drug-coated balloons. The technique chosen for endovascular treatment is related to lesion characteristics (eg, anatomic location, lesion length, degree of calcification) and operator experience. Assessment of the appropriateness of specific endovascular techniques for specific lesions for the treatment of claudication is beyond the scope of this document.
Revascularization is performed on lesions that are deemed to be hemodynamically significant, and stenoses selected for endovascular treatment should have a reasonable likelihood of limiting perfusion to the distal limb. Stenoses of 50% to 75% diameter by angiography may not be hemodynamically significant, and resting or provoked intravascular pressure measurements may be used to determine whether lesions are significant. The durability of endovascular treatment for claudication is directly related to vessel patency. Long-term patency is greater in the iliac artery than in the femoropopliteal segment. Furthermore, durability is diminished with greater lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poorquality runoff, diabetes mellitus, chronic kidney disease, renal failure, and smoking. The choice of endovascular therapy as a revascularization approach for claudication due to femoropopliteal disease therefore should include a discussion of outcomes, addressing the risk of restenosis and repeat intervention, particularly for lesions with poor likelihood of long-term durability.

## Iib c-ld
The usefulness of endovascular procedures as a revascularization option for patients with claudication due to isolated infrapopliteal artery disease is unknown. [bib_ref] Paclitaxel-coated balloon angioplasty versus drugeluting stenting for the treatment of infrapopliteal long-segment..., Siablis [/bib_ref] See Online Data Supplement 35.
Isolated infrapopliteal disease is unlikely to cause claudication. Incidence of in-stent restenosis is high and long-term benefit lacking with bare-metal stenting of the infrapopliteal arteries. Studies that have enrolled patients with claudication as well as CLI have demonstrated a benefit of DES versus bare-metal stents or versus drug-coated balloons for revascularization of infrapopliteal lesions. 257,258 However, these differences were mainly for patency and restenosis endpoints, and neither of these studies included patient-oriented outcomes, such as walking function or QoL parameters. Additional efficacy data on the use of infrapopliteal drug-coated balloon or DES for the treatment of claudication are likely to be published in the near future. There are no data to support a practice paradigm of performing endovascular procedures on patients with PAD for the purpose of preventing progression of claudication symptoms to CLI. Reported rates of amputation or progression to CLI from prospective cohort studies of patients with claudication are <10% to 15% over 5 years or more, and increased mortality rate associated with claudication is usually the result of cardiovascular events rather than limb-related events. [bib_ref] Intermittent claudication. Incidence in the Framingham Study, Kannel [/bib_ref] Similarly, there are no data to support revascularization in patients with asymptomatic PAD. Procedural risks include bleeding, renal failure from contrast-induced nephropathy, and the possibility of adverse limb outcomes. [bib_ref] Trends in the national outcomes and costs for claudication and limb threatening..., Sachs [/bib_ref] [bib_ref] Predictors of distal embolization in peripheral percutaneous interventions: a report from a..., Shammas [/bib_ref] [bib_ref] Complications of lower-limb percutaneous transluminal angioplasty: a prospective analysis of 410 procedures..., Matsi [/bib_ref] Therefore, the known risks of endovascular procedures outweigh any hypothetical benefit of preventing progression from asymptomatic PAD or claudication to CLI.

## Surgical revascularization for claudication: recommendations

## Recommendations for surgical revascularization for claudication

## Cor loe recommendations
I A When surgical revascularization is performed, bypass to the popliteal artery with autogenous vein is recommended in preference to prosthetic graft material. [bib_ref] Prospective controlled study of polytetrafluoroethylene versus saphenous vein in claudicant patients with..., Aburahma [/bib_ref] [bib_ref] Femoropopliteal bypass with either adequate ipsilater-al reversed saphenous vein or obligatory polytetrafluoroethylene, Archie [/bib_ref] [bib_ref] Ten years after arterial bypass surgery for claudication: venous bypass is the..., Eugster [/bib_ref] [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] [bib_ref] Patency results of percutaneous and surgical revascularization for femoropopliteal arterial disease, Hunink [/bib_ref] [bib_ref] Comparative evaluation of externally supported Dacron and polytetrafluoroethylene prosthetic bypasses for femorofemoral..., Johnson [/bib_ref] [bib_ref] Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a..., Klinkert [/bib_ref] [bib_ref] Graft type for femoro-popliteal bypass surgery, Twine [/bib_ref] [bib_ref] Meta-analysis of femoropopliteal bypass grafts for lower extremity arterial insufficiency, Pereira [/bib_ref] See Online Data Supplements 37 and 38.
The superficial femoral and proximal popliteal arteries are the most common anatomic sites of stenosis or occlusion among individuals with claudication. Femoral-popliteal bypass is therefore one of the most common surgical procedures for claudication and may be performed under general or regional anesthesia. The type of conduit and site of et al.

## Page 21
Circulation. Author manuscript; available in PMC 2017 September 21.
popliteal artery anastomosis (above versus below knee) are major determinants of outcomes associated with femoral-popliteal bypass. Systematic reviews and metaanalyses have identified a clear and consistent primary patency benefit for autogenous vein versus to prosthetic grafts for popliteal artery bypass. [bib_ref] Graft type for femoro-popliteal bypass surgery, Twine [/bib_ref] [bib_ref] Meta-analysis of femoropopliteal bypass grafts for lower extremity arterial insufficiency, Pereira [/bib_ref] Prosthetic grafts to the popliteal artery above the knee have reduced patency rates and increased rates of repeat intervention. [bib_ref] Prospective controlled study of polytetrafluoroethylene versus saphenous vein in claudicant patients with..., Aburahma [/bib_ref] [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] [bib_ref] Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a..., Klinkert [/bib_ref] [bib_ref] A comparative evaluation of polytetrafluoroethylene, umbilical vein, and saphenous vein bypass grafts..., Johnson [/bib_ref] Sparse evidence suggests a long-term patency advantage for Dacron over polytetrafluoroethylene (known as PTFE) graft for above-knee bypass, [bib_ref] Graft type for femoro-popliteal bypass surgery, Twine [/bib_ref] although this finding has not been consistently demonstrated in all RCTs. [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] Claudication does not commonly progress to CLI. Reported rates of amputation or progression to CLI from prospective cohort studies of patients with claudication are <10% to 15% for 5 years or more, and increased mortality rate associated with claudication is usually the result of cardiovascular events rather than limb-related events. 234-237, [bib_ref] Intermittent claudication. Incidence in the Framingham Study, Kannel [/bib_ref] Surgical intervention should not be performed primarily to prevent disease progression, given the risk of adverse perioperative events without potential for significant benefit. Similarly, there are no data to support surgical revascularization in patients with asymptomatic PAD to prevent progression to CLI.

## Management of cli
Patients with CLI are at increased risk of amputation and major cardiovascular ischemic events. Care of the patient with CLI includes evaluation for revascularization and wound healing therapies, with the objective to minimize tissue loss, completely heal wounds, and preserve a functional foot. Medical therapy to prevent cardiovascular ischemic events is also an important component of care for the patient with CLI (Section 5). Patients with CLI are at high risk of major cardiovascular ischemic events, as well as nonhealing wounds and major amputation. In a systematic review of 13 studies of patients with CLI who did not receive revascularization, which included patients enrolled in medical and angiogenic therapy trials, there was a 22% all-cause mortality rate and a 22% rate of major amputation at a median follow-up of 12 months. [bib_ref] The natural history of untreated severe or critical limb ischemia, Dabrh [/bib_ref] The goal of surgical or endovascular revascularization is to provide in-line blood flow to the foot through at least 1 patent artery, which will help decrease ischemic pain and allow healing of any wounds, while preserving a functional limb. Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing. 15-17 Revascularization is not warranted in the setting of a nonviable limb.

## Revascularization for cli: recommendations

## I c-eo
An evaluation for revascularization options should be performed by an interdisciplinary care team [fig_ref] Table 9: can be beneficial [/fig_ref] before amputation in the patient with CLI.

## N/a
Patients with CLI should be evaluated by an interdisciplinary care team. Before amputation, evaluation generally includes imaging for assessment of revascularization options (eg, duplex ultrasound, CTA, MRA, or catheter-based angiogram). The objective of this strategy is to minimize tissue loss and preserve a functional limb with revascularization.

## Endovascular revascularization for cli: recommendations

## Iia c-ld
A staged approach to endovascular procedures is reasonable in patients with ischemic rest pain. [bib_ref] Complex endovascular treatment for critical limb ischemia in poor surgical candidates: a..., Gray [/bib_ref] [bib_ref] Analysis of outcomes following failed endovascular treatment of chronic limb ischemia, Ryer [/bib_ref] N/A For patients with multilevel disease who suffer from ischemic rest pain, in-flow lesions are generally addressed first. [bib_ref] Complex endovascular treatment for critical limb ischemia in poor surgical candidates: a..., Gray [/bib_ref] [bib_ref] Analysis of outcomes following failed endovascular treatment of chronic limb ischemia, Ryer [/bib_ref] Depending on procedural characteristics, including contrast volume used, radiation exposure, and procedure time, out-flow lesions can be addressed in the same setting or at a later time if symptoms persist. This strategy for ischemic rest pain is distinct from the strategy recommended for CLI in the patient with a nonhealing wound or gangrene. In that scenario, restoration of direct in-line flow to the foot is essential for wound healing.
IIa B-R Evaluation of lesion characteristics can be useful in selecting the endovascular approach for CLI. [bib_ref] Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon..., Schillinger [/bib_ref] See Online Data Supplement 39.
The lesion characteristics to consider include length, anatomic location, and extent of occlusive disease. For example, if an adequate angioplasty result can be achieved with PTA alone for short (<10 cm) stenoses in the femoropopliteal segment, then stent placement is not necessary. [bib_ref] Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon..., Schillinger [/bib_ref] Presence of thrombosis or calcification at the lesion site will also affect the endovascular approach. In general, the advantages of DES and drug-coated balloons over PTA alone or bare-metal stents are more consistent in the femoropopliteal segment than for infrapopliteal interventions. 257,258,299-309 However, these differences are mainly for patency, restenosis, and repeat-revascularization endpoints. Most studies were underpowered or did not examine other patient-oriented outcomes, such as amputation or wound healing in CLI. Endovascular techniques continue to evolve rapidly, and there has been limited literature comparing techniques with regard to clinically significant outcomes, such as amputation or wound healing. During the past decade, the goal of care with regard to endovascular therapy for the treatment of nonhealing wounds due to CLI has been establishment of direct in-line blood flow to the affected limb. The angiosome concept has also been described in the literature in relation to the treatment of nonhealing wounds. Angiosome-directed treatment entails establishing direct blood flow to the infrapopliteal artery directly responsible for perfusing the region of the leg or foot with the nonhealing wound. Multiple retrospective studies and 1 small nonrandomized prospective study assessing the efficacy of this concept have been published. [bib_ref] Angiosome-targeted infrapopliteal endovascular revascularization for treatment of diabetic foot ulcers, Soderstrom [/bib_ref] [bib_ref] Results of infrapopliteal endovascular procedures performed in diabetic patients with critical limb..., Acin [/bib_ref] [bib_ref] Selective primary angioplasty following an angiosome model of reperfusion in the treatment..., Alexandrescu [/bib_ref] [bib_ref] Factors influencing wound healing of critical ischaemic foot after bypass surgery: is..., Azuma [/bib_ref] [bib_ref] Endovascular treatment of diabetic foot in a selected population of patients with..., Fossaceca [/bib_ref] [bib_ref] Long-term results of direct and indirect endovascular revascularization based on the angiosome..., Iida [/bib_ref] [bib_ref] Outcomes of angiosome and non-angiosome targeted revascularization in critical lower limb ischemia, Kabra [/bib_ref] [bib_ref] Utility of direct angiosome revascularization and runoff scores in predicting outcomes in..., Kret [/bib_ref] [bib_ref] Long-term outcomes of direct and indirect below-the-knee open revascularization based on the..., Lejay [/bib_ref] [bib_ref] Revascularization of a specific angiosome for limb salvage: does the target artery..., Neville [/bib_ref] [bib_ref] Importance of the six angio-somes concept through arterialarterial connections in CLI, Osawa [/bib_ref] [bib_ref] The impact of arterial pedal arch quality and angiosome revascularization on foot..., Rashid [/bib_ref] [bib_ref] The role of foot collateral vessels on ulcer healing and limb salvage..., Varela [/bib_ref] Metaanalyses of these studies found improved wound healing and limb salvage with angiosomeguided therapy but cautioned that the quality of the evidence was low. [bib_ref] Systematic review and meta-analysis of direct versus indirect angiosomal revascularisation of infrapopliteal..., Bosanquet [/bib_ref] [bib_ref] Angiosome-targeted lower limb revascularization for ischemic foot wounds: systematic review and metaanalysis, Biancari [/bib_ref] Although the angiosome concept is theoretically satisfying, randomized data comparing the establishment of in-line flow versus angiosome-guided therapy have yet to be published. Furthermore, there is no evidence yet to demonstrate the potential benefit of treating additional infrapopliteal arteries once in-line flow has been established in one artery, regardless of angiosome. Important considerations with regard to angiosome-guided therapy include the potential for longer procedural times, more contrast exposure, and more technically complex procedures. The impact of all these factors needs to be weighed against the likelihood of a technically successful procedure providing hypothetical added benefit over the establishment of in-line blood flow. Many large RCTs have demonstrated that bypasses above the knee should be autogenous vein either reversed or in situ vein. [bib_ref] Prospective controlled study of polytetrafluoroethylene versus saphenous vein in claudicant patients with..., Aburahma [/bib_ref] [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] [bib_ref] Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a..., Klinkert [/bib_ref] [bib_ref] A comparative evaluation of polytetrafluoroethylene, umbilical vein, and saphenous vein bypass grafts..., Johnson [/bib_ref] There are large single-center trials showing the efficacy of autogenous vein to distal tibial vessels. [bib_ref] Present status of infrainguinal arterial bypass procedures following an all autogenous policy-long-term..., Eugster [/bib_ref] [bib_ref] Contemporary outcomes for open infrainguinal bypass in the endovascular era, Reifsnyder [/bib_ref] In addition, composite sequential femoropopliteal-tibial bypass and bypass to an isolated popliteal arterial segment that has collateral out flow to the foot are both acceptable methods of revascularization and should be considered when no other form of bypass with adequate autogenous conduit is possible. [bib_ref] Autogenous composite vein bypass graft for infrainguinal arterial reconstruction, Chew [/bib_ref] [bib_ref] Preferred strategies for secondary infrainguinal bypass: lessons learned from 300 consecutive reoperations, Belkin [/bib_ref] I C-LD Surgical procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene. [bib_ref] A comparison of in situ and reversed saphenous vein grafts for infrainguinal..., Fogle [/bib_ref] [bib_ref] In-situ saphenous vein arterial bypass for the treatment of limb ischemia, Leather [/bib_ref] [bib_ref] Present status of reversed vein bypass grafting: five-year results of a modern..., Taylor [/bib_ref] See Online Data Supplement 42.

## Surgical revascularization for cli: recommendations
In patients presenting with nonhealing ulcers or gangrene, surgical procedures should be performed to establish in-line blood flow to the foot. [bib_ref] A comparison of in situ and reversed saphenous vein grafts for infrainguinal..., Fogle [/bib_ref] [bib_ref] In-situ saphenous vein arterial bypass for the treatment of limb ischemia, Leather [/bib_ref] [bib_ref] Present status of reversed vein bypass grafting: five-year results of a modern..., Taylor [/bib_ref] Table 10 addresses factors that may prompt a surgical approach to the patient with CLI.

## Iia b-nr
In patients with CLI for whom endovascular revascularization has failed and a suitable autogenous vein is not available, prosthetic material can be effective for bypass to the below-knee popliteal and tibial arteries. [bib_ref] Prior failed ipsilateral percutaneous endovascular intervention in patients with critical limb ischemia..., Nolan [/bib_ref] [bib_ref] Lower extremity autologous vein bypass for critical limb ischemia is not adversely..., Santo [/bib_ref] [bib_ref] Pedal bypass surgery after crural endovascular intervention, Uhl [/bib_ref] See Online Data Supplement 42.
There are studies demonstrating that patients for whom endovascular treatment for CLI has failed can be treated successfully with autogenous vein bypass graft 332,333 or prosthetic material. [bib_ref] Prior failed ipsilateral percutaneous endovascular intervention in patients with critical limb ischemia..., Nolan [/bib_ref] Although autogenous vein is the preferred conduit for surgical revascularization, prosthetic conduit is a secondary option for patients with CLI without suitable saphenous vein who require surgical revascularization.

## Iia c-ld
A staged approach to surgical procedures is reasonable in patients with ischemic rest pain. [bib_ref] The role of common femoral artery endarterectomy in the endovascular era, Nishibe [/bib_ref] [bib_ref] Long-term results of a hybrid revascularization procedure for peripheral arterial disease, Okadome [/bib_ref] [bib_ref] Hybrid and open surgery of Trans-Atlantic Inter-Society II type C and D..., Starodubtsev [/bib_ref] N/A It is reasonable to perform a staged approach to revascularization in patients with ischemic rest pain with multilevel disease. For example, aortoiliac (inflow) disease may be treated first with endovascular treatment or by surgical reconstruction, depending on lesion characteristics, patient comorbidities, and patient preference. [bib_ref] Seven-year approach evolution of the aortoiliac occlusive disease endovascular treatment, Kasemi [/bib_ref] The management of patients with CLI and nonhealing wounds should include coordinated efforts for both revascularization and wound healing, because the risk of limb-threatening infections remains until complete wound healing is achieved. The structure and activities of interdisciplinary care teams for CLI may vary according to several factors, including the local availability of resources. Previous groups have described various combinations of activities of this team, which are in addition to revascularization and include functions such as wound care, infection management, orthotics, and prosthetics (see Online Data Supplement 34a for a complete list of functions). Coordination of these activities and some degree of organized team structure are recommended, as opposed to ad hoc or unstructured referrals among various specialty clinicians not involved in interdisciplinary care.
Ambulatory patients with PAD and nonhealing foot ulcers should be considered for efforts to prevent amputation. The components of this effort may include revascularization, offloading, treatment of infection, and wound care. The long-term outcome of the limb is excellent when complete wound healing can be achieved. [bib_ref] Prognosis of critical limb ischemia patients with tissue loss after achievement of..., Kobayashi [/bib_ref] Revascularization should be coordinated with the efforts of clinicians who manage foot infections, provide offloading, and achieve complete wound healing, either through medical therapy, surgical options, or a combination thereof. Coordinated and timely interdisciplinary care can achieve excellent limb outcomes for patients with PAD and nonhealing foot wounds. 229,339-341

## I c-ld
In patients with CLI, wound care after revascularization should be performed with the goal of complete wound healing. [bib_ref] Prognosis of critical limb ischemia patients with tissue loss after achievement of..., Kobayashi [/bib_ref] See Online Data Supplement 44.
A comprehensive plan for treatment of CLI must include a plan for achieving an intact skin surface on a functional foot. One study demonstrated a limb salvage rate of 100% at 3 years in a cohort of patients with CLI who achieved complete wound healing with endovascular revascularization and dedicated wound care. [bib_ref] Prognosis of critical limb ischemia patients with tissue loss after achievement of..., Kobayashi [/bib_ref] Before revascularization, the interdisciplinary care team should devise a plan to achieve the goal of complete wound healing. After successful revascularization, most patients with gangrene of the foot are evaluated for minor amputation with staged/delayed primary closure or surgical reconstruction when feasible. [bib_ref] Surgical complications associated with primary closure in patients with diabetic foot osteomyelitis, Garcia-Morales [/bib_ref] [bib_ref] Clinical outcomes after closed, staged, and open forefoot amputations, Berceli [/bib_ref] [bib_ref] Outcome of limited forefoot amputation with primary closure in patients with diabetes, Shaikh [/bib_ref] Negative-pressure wound therapy dressings are helpful to achieve wound healing after revascularization and minor (ie, digit or partial foot) amputation when primary or delayed secondary closure is not feasible. [bib_ref] Diabetic Foot Study ConsortiumNegative pressure wound therapy after partial diabetic foot amputation:..., Armstrong [/bib_ref] [bib_ref] Negative-pressure wound therapy versus standard wound dressing in the treatment of diabetic..., Sepulveda [/bib_ref] Spontaneous amputation, or autoamputation, of gangrenous digits should be reserved for palliation in patients without options for revascularization. [bib_ref] Diabetic Foot Study ConsortiumNegative pressure wound therapy after partial diabetic foot amputation:..., Armstrong [/bib_ref] [bib_ref] Minor amputation and palliative wound care as a strategy to avoid major..., Barshes [/bib_ref] [bib_ref] Awaiting autoamputation: a primary management strategy for toe gangrene in diabetic foot..., Fikri [/bib_ref] Other evidence-based guidelines relevant to those with nonhealing foot wounds following revascularization cover the full spectrum of diabetic foot problems 349 or separately consider the management of infection, 225,350 offloading, [bib_ref] Footwear and offloading interventions to prevent and heal foot ulcers and reduce..., Bus [/bib_ref] and wound care. [bib_ref] IWGDF guidance on use of interventions to enhance the healing of chronic..., Game [/bib_ref] To date, there are no RCTs or high-quality studies that have focused on wound healing adjuncts in limbs with severe PAD (eg, topical cytokine ointments, skin substitutes, cell-based therapies intended to optimize wound healing).

## Iib b-nr
In patients with CLI, intermittent pneumatic compression (arterial pump) devices may be considered to augment wound healing and/or ameliorate severe ischemic rest pain. [bib_ref] A systematic review of intermittent pneumatic compression for critical limb ischaemia, Moran [/bib_ref] See Online Data Supplement 44.
A systematic review of studies that used intermittent pneumatic compression devices specifically designed to augment arterial perfusion of the lower extremities suggests that these may provide modest clinical benefit (specifically, decreased amputation rates and improved QoL) in patients with CLI who were ineligible for revascularization. [bib_ref] A systematic review of intermittent pneumatic compression for critical limb ischaemia, Moran [/bib_ref] The potential benefit appears to outweigh the low risk associated with the use of these devices. The literature evaluating the utility of hyperbaric oxygen therapy has focused on patients without severe PAD and has not demonstrated a long-term benefit on wound healing or improving amputation-free survival when compared with sham treatment. [bib_ref] Hyperbaric oxygen therapy for chronic wounds, Kranke [/bib_ref] There are no published studies evaluating the role of hyperbaric oxygen therapy for patients with nonreconstructible PAD. One small RCT that focused on patients with foot ulcers and PAD (ABI <0.80 or TBI <0.70) for whom no revascularization was planned demonstrated a significant decrease in ulcer area at 6 weeks, but no significant differences in ulcer size at 6 months, complete ulcer healing at 6 weeks or 6 months, and major or minor amputations. [bib_ref] The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers:..., Abidia [/bib_ref] Further research on the utility of hyperbaric oxygen therapy in this context is needed.

## Iib c-ld

## Iii: no benefit b-r prostanoids are not indicated in patients with cli. 356
See Online Data Supplement 43.
A systematic review and meta-analysis concluded that RCTs have not demonstrated meaningful long-term clinical benefit from the administration of prostanoids to patients with CLI attributable to nonreconstructible PAD. 356

## Management of ali
ALI is one of the most treatable and potentially devastating presentations of PAD. Timely recognition of arterial occlusion as the cause of an ischemic, cold, painful leg is crucial to successful treatment. The writing committee has used a standard definition of ALI in which symptom duration is <2 weeks (

## Clinical presentation of ali: recommendations

## Recommendations for clinical presentation of ali

## Cor loe recommendations

## I c-eo
Patients with ALI should be emergently evaluated by a clinician with sufficient experience to assess limb viability and implement appropriate therapy.

## N/a
Patients with ALI should be rapidly evaluated by a vascular specialist if one is available. Depending on local clinical expertise, the vascular specialist may be a vascular surgeon, interventional radiologist, cardiologist, or a general surgeon with specialized training and experience in treating PAD. If such expertise is not locally or rapidly available, there should be strong consideration of transfer of the patient to a facility with such resources. The more advanced the degree of ischemia, the more rapidly the communication (including communication about potential patient transfer) needs to occur.

## I c-ld
In patients with suspected ALI, initial clinical evaluation should rapidly assess limb viability and potential for salvage and does not require imaging. [bib_ref] Outcomes of lower extremity bypass performed for acute limb ischemia, Baril [/bib_ref] [bib_ref] Patient delay is the main cause of treatment delay in acute limb..., Londero [/bib_ref] [bib_ref] Analysis of associated diseases in patients with acute critical lower limb ischemia, Manojlovic [/bib_ref] [bib_ref] The impact of prolonged lower limb ischemia on amputation, mortality, and functional..., Duval [/bib_ref] [bib_ref] Update experience of surgery for acute limb ischaemia in a district general..., Morris-Stiff [/bib_ref] See Online Data Supplements 45 and 46.
ALI is a medical emergency and must be recognized rapidly. The time constraint is due to the period that skeletal muscle will tolerate ischemia-roughly 4 to 6 hours. [bib_ref] The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review, Blaisdell [/bib_ref] A rapid assessment of limb viability and ability to restore arterial blood flow should be performed by a clinician able to either complete the revascularization or triage the patient. [bib_ref] Patient delay is the main cause of treatment delay in acute limb..., Londero [/bib_ref] Lower extremity symptoms in ALI can include both pain and loss of function. The longer these symptoms are present, the less likely the possibility of limb salvage. [bib_ref] The impact of prolonged lower limb ischemia on amputation, mortality, and functional..., Duval [/bib_ref] [bib_ref] Update experience of surgery for acute limb ischaemia in a district general..., Morris-Stiff [/bib_ref] Clinical assessment must include symptom duration, pain intensity, and motor and sensory deficit severity to distinguish a threatened from a nonviable extremity [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref]. The bedside assessment should include arterial and venous examination with a handheld continuous-wave Doppler because of the inaccuracy of pulse palpation. The loss of dopplerable arterial signal indicates that the limb is threatened. [bib_ref] Heparin-induced thrombocytopenia causing graft thrombosis and bowel ischemia postendovascular aneurysm repair, Altoijry [/bib_ref] [bib_ref] Catheter-directed thrombolysis of acute lower extremity arterial thrombosis in a patient with..., Turba [/bib_ref] In this situation, a direct thrombin inhibitor is given, rather than heparin, if heparin-induced thrombocytopenia with thrombosis is suspected.

## Revascularization for ali: recommendations

## Recommendations for revascularization for ali

## Cor loe recommendations

## I c-ld in patients with ali, the revascularization strategy should be determined by local resources and patient factors (eg, etiology and degree of ischemia). 367-369
See Online Data Supplement 47.
For marginally or immediately threatened limbs (Category IIa and IIb ALI [ [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref] , revascularization should be performed emergently (within 6 hours). For viable limbs (Category I ALI [ [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref] , revascularization should be performed an on urgent basis (within 6-24 hours). The revascularization strategy can range from catheter-directed thrombolysis to surgical thromboembolectomy. Available facilities and clinical expertise are factors that should be considered when determining the revascularization strategy. The technique that will provide the most rapid restoration of arterial flow with the least risk to the patient should be selected. For example, catheter-directed thrombolysis can provide rapid restoration of arterial flow to a viable or marginally threatened limb, particularly in the setting of recent occlusion, thrombosis of synthetic grafts, and stent thrombosis. [bib_ref] Results of a prospective, randomized trial of surgery versus thrombolysis for occluded..., Comerota [/bib_ref] If this is not available locally, surgical options for timely revascularization should be considered, along with the feasibility of timely transfer to a facility with the necessary expertise.
I A Catheter-based thrombolysis is effective for patients with ALI and a salvageable limb. [bib_ref] Results of a prospective, randomized trial of surgery versus thrombolysis for occluded..., Comerota [/bib_ref] [bib_ref] Assessment of peripheral intraarterial thrombolysis versus surgical revascularization in acute lower-limb ischemia:..., Diffin [/bib_ref] have demonstrated similar limb salvage rates between the 2 approaches but better survival with catheter-based therapy. The survival advantage of catheter-based therapy may be at least in part attributable to multiple comorbidities found among the population of patients who present with ALI. Increased comorbidities are likely to contribute to increased perioperative risk. Several of the RCTs included patients with relatively chronic ischemia. Acuity and severity are both factors in the decision to consider thrombolysis. 367,369-371 I C-LD Amputation should be performed as the first procedure in patients with a nonsalvageable limb. [bib_ref] Metabolic consequences of acute limb ischemia and their clinical implications, Eliason [/bib_ref] [bib_ref] Contemporary management of acute limb ischemia: factors associated with amputation and in-hospital..., Henke [/bib_ref] See Online Data Supplement 48.
For patients with Category III ALI [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref] , amputation should be performed as the index procedure. Prolonged duration of ischemia is the most common factor in patients requiring amputation for treatment of ALI. The risks associated with reconstruction outweigh the potential benefit in a limb that is already insensate or immobile because of prolonged ischemia. The lower extremity muscles reside in compartments, surrounded by fascia and bones. Reperfusion to ischemic muscles can cause cellular edema, resulting in increased compartment pressure. When compartment pressure is >30 mm Hg, there is capillary and venule compression that leads to malperfusion of the muscle; this is compartment syndrome. Fasciotomy is indicated when the compartment pressure increases. Measurement of intracompartment pressure is not always easily accessible. In such cases, evaluation for fasciotomy is prompted by development of increased pain, tense muscle, or nerve injury. Fasciotomy should be considered for patients with Category IIb ischemia for whom the time to revascularization is >4 hours.

## Iia b-nr
In patients with ALI with a salvageable limb, percutaneous mechanical thrombectomy can be useful as adjunctive therapy to thrombolysis. [bib_ref] Treatment of acute limb ischemia with a percutaneous mechanical thrombectomy-based endovascular approach:..., Ansel [/bib_ref] [bib_ref] Percutaneous isolated pharmaco-mechanical thrombolysis-thrombectomy system for the management of acute arterial limb..., Gupta [/bib_ref] [bib_ref] Rheolytic thrombectomy in the treatment of acute limbthreatening ischemia: immediate results and..., Silva [/bib_ref] [bib_ref] Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia, Taha [/bib_ref] [bib_ref] Rheolytic pharmacom-echanical thrombectomy for the management of acute limb ischemia: results from..., Leung [/bib_ref] See Online Data Supplements 49 and 50.
Multiple nonrandomized studies have suggested that percutaneous mechanical thrombectomy in combination with pharmacological therapy can be beneficial in the treatment of threatened limbs. [bib_ref] Treatment of acute limb ischemia with a percutaneous mechanical thrombectomy-based endovascular approach:..., Ansel [/bib_ref] [bib_ref] Percutaneous isolated pharmaco-mechanical thrombolysis-thrombectomy system for the management of acute arterial limb..., Gupta [/bib_ref] [bib_ref] Rheolytic thrombectomy in the treatment of acute limbthreatening ischemia: immediate results and..., Silva [/bib_ref] [bib_ref] Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia, Taha [/bib_ref] [bib_ref] Rheolytic pharmacom-echanical thrombectomy for the management of acute limb ischemia: results from..., Leung [/bib_ref] IIa C-LD In patients with ALI due to embolism and with a salvageable limb, surgical thromboembolectomy can be effective. [bib_ref] Factors affecting long-term outcomes after thromboembolectomy for acute lower limb ischemia, Zaraca [/bib_ref] [bib_ref] Management of non-traumatic acute limb ischemia and predictors of outcome in 270..., Topal [/bib_ref] [bib_ref] A method for extraction of arterial emboli and thrombi, Fogarty [/bib_ref] See Online Data Supplements 49 and 50.
Patients with arterial embolism and an absent pulse ipsilateral to the ischemic limb can be treated by exposure of an artery in the affected limb and balloon-catheter thromboembolectomy. These patients may benefit from adjunctive intraoperative fibrinolytics. In the event that thromboembolectomy does not restore arterial flow, bypass can be performed. [bib_ref] A method for extraction of arterial emboli and thrombi, Fogarty [/bib_ref] [bib_ref] Clinical practice. Acute limb ischemia, Creager [/bib_ref] [bib_ref] Proper evaluation and management of acute embolic versus thrombotic limb ischemia, O&apos;connell [/bib_ref] IIb C-LD The usefulness of ultrasound-accelerated catheter-based thrombolysis for patients with ALI with a salvageable limb is unknown. [bib_ref] Initial results of catheter-directed ultrasoundaccelerated thrombolysis for thromboembolic obstructions of the aortofemoral..., Schrijver [/bib_ref] [bib_ref] Ultrasound-accelerated thrombolysis for lower extremity ischemia: multicenter experience and literature review, Schrijver [/bib_ref] [bib_ref] Dutch randomized trial comparing standard catheter-directed thrombolysis versus ultrasound-accelerated thrombolysis for thromboembolic..., Schrijver [/bib_ref] See Online Data Supplements 47 and 50.
The use of ultrasound-accelerated catheter delivery of thrombolytic agents has been published in case series [bib_ref] Initial results of catheter-directed ultrasoundaccelerated thrombolysis for thromboembolic obstructions of the aortofemoral..., Schrijver [/bib_ref] and retrospective analyses. [bib_ref] Ultrasound-accelerated thrombolysis for lower extremity ischemia: multicenter experience and literature review, Schrijver [/bib_ref] However, the single RCT comparing this technique to standard catheter-based thrombolytic therapy failed to demonstrate a difference in outcomes, including bleeding, despite a lower total amount of lytic delivered. 386

## Diagnostic evaluation of the cause of ali: recommendations

## I c-eo
Patients with PAD who have undergone lower extremity revascularization (surgical and/or endovascular) should be followed up with periodic clinical evaluation and ABI measurement.

## N/a
In addition to the clinical evaluation of cardiovascular risk factors, functional status, and adherence to medical therapy and smoking cessation, patients with PAD who have previously undergone lower extremity revascularization (surgical and/or endovascular) require additional ongoing assessment and care. Follow-up visits after revascularization should include reassessment of the patient's limb symptoms and interval change in functional status, as well as participation in a structured exercise program. Pulse examination and ABI are included in the assessment. A change in ABI of 0.15 is considered clinically significant. 388 [bib_ref] Secondary interventions in patients with autologous infrainguinal bypass grafts strongly improve patency..., Jongsma [/bib_ref] [bib_ref] The natural history of stenoses within lower limb arterial bypass grafts using..., Carter [/bib_ref] [bib_ref] Does a completely accomplished duplex-based surveillance prevent vein-graft failure?, Ihlberg [/bib_ref] [bib_ref] Prospective validation of threshold criteria for intervention in infrainguinal vein grafts undergoing..., Westerband [/bib_ref] [bib_ref] Femoropopliteal-crural graft patency is improved by an intensive surveillance program: a prospective..., Lundell [/bib_ref] [bib_ref] The importance of routine surveillance of distal bypass grafts with duplex scanning:..., Mills [/bib_ref] [bib_ref] A low flow velocity predicts failure of femoropopliteal and femorotibial bypass grafts, Bandyk [/bib_ref] See Online Data Supplements 51 and 52.

## Iia b-r duplex ultrasound can be beneficial for routine surveillance of infrainguinal, autogenous vein bypass grafts in patients with pad.
A general surveillance schedule may be at 4 to 6 weeks, 6 months, and 12 months in the first year and yearly thereafter. It is important that testing frequency is individualized to the patient, type of arterial bypass, and any prior duplex scan findings. Duplex graft surveillance focuses on the identification of high-grade stenosis (eg, peak systolic velocity >300 cm/s and peak systolic velocity ratio across the stenosis >3.5) or impending graft failure (eg, PSV <40 cm/s). [bib_ref] Prospective validation of threshold criteria for intervention in infrainguinal vein grafts undergoing..., Westerband [/bib_ref] [bib_ref] A low flow velocity predicts failure of femoropopliteal and femorotibial bypass grafts, Bandyk [/bib_ref] Detection of a graft stenosis prompts the consideration of further revascularization to treat the stenosis and maintain graft patency. Duplex may detect significant stenoses that may not be detected by a decline in ABI. [bib_ref] The importance of routine surveillance of distal bypass grafts with duplex scanning:..., Mills [/bib_ref] Although case series have demonstrated high rates of primary assisted patency with a duplex ultrasoundsurveillance strategy, RCTs of duplex surveillance versus clinical surveillance with the ABI have demonstrated mixed results in terms of a benefit on patency and limb outcomes. [bib_ref] Does a completely accomplished duplex-based surveillance prevent vein-graft failure?, Ihlberg [/bib_ref] [bib_ref] Femoropopliteal-crural graft patency is improved by an intensive surveillance program: a prospective..., Lundell [/bib_ref] [bib_ref] Is duplex surveillance of value after leg vein bypass grafting? Principal results..., Davies [/bib_ref] IIa C-LD Duplex ultrasound is reasonable for routine surveillance after endovascular procedures in patients with PAD. [bib_ref] Utility of duplex surveillance following iliac artery angioplasty and primary stenting, Back [/bib_ref] [bib_ref] Duplex evaluation following femoropopliteal angioplasty and stenting: criteria and utility of surveillance, Baril [/bib_ref] [bib_ref] Duplex ultrasound diagnosis of failing stent grafts placed for occlusive disease, Troutman [/bib_ref] See Online Data Supplement 52.
Studies have developed duplex ultrasound diagnostic criteria for diagnosing restenosis at the site of endovascular revascularization. Diagnostic criteria need to be customized to the location (eg, iliac or superficial femoral artery) and type of intervention (eg, angioplasty, uncovered stent, or covered stent). The optimal timing for surveillance after endovascular procedures is unclear. [bib_ref] Utility of duplex surveillance following iliac artery angioplasty and primary stenting, Back [/bib_ref] [bib_ref] Duplex evaluation following femoropopliteal angioplasty and stenting: criteria and utility of surveillance, Baril [/bib_ref] [bib_ref] Duplex ultrasound diagnosis of failing stent grafts placed for occlusive disease, Troutman [/bib_ref] There are limited outcome data on routine duplex surveillance versus clinical surveillance plus the ABI after endovascular revascularization. [bib_ref] Utility of duplex surveillance following iliac artery angioplasty and primary stenting, Back [/bib_ref] [bib_ref] Duplex evaluation following femoropopliteal angioplasty and stenting: criteria and utility of surveillance, Baril [/bib_ref] [bib_ref] Duplex ultrasound diagnosis of failing stent grafts placed for occlusive disease, Troutman [/bib_ref] The value of duplex ultrasound may be greater in cases with higher rates of restenosis, such as after interventions to treat very long lesions or occlusions. 400 Duplex ultrasound of prosthetic bypass grafts may be used to characterize mid-graft velocity, because low velocities can predict impending graft failure. [bib_ref] The relative importance of graft surveillance and warfarin therapy in infrainguinal prosthetic..., Brumberg [/bib_ref] [bib_ref] Should duplex ultrasonography be performed for surveillance of femoropopliteal and femorotibial arterial..., Calligaro [/bib_ref] [bib_ref] Duplex ultrasound criteria for femorofemoral bypass revision, Stone [/bib_ref] Outcome studies of duplex surveillance of prosthetic grafts have not shown consistent benefit. [bib_ref] Femoropopliteal-crural graft patency is improved by an intensive surveillance program: a prospective..., Lundell [/bib_ref] [bib_ref] The relative importance of graft surveillance and warfarin therapy in infrainguinal prosthetic..., Brumberg [/bib_ref] [bib_ref] Should duplex ultrasonography be performed for surveillance of femoropopliteal and femorotibial arterial..., Calligaro [/bib_ref] [bib_ref] Duplex ultrasound criteria for femorofemoral bypass revision, Stone [/bib_ref] One RCT of duplex versus clinical surveillance with the ABI for femoropopliteal grafts did not show a benefit of duplex on outcome in the subset of patients with prosthetic grafts, though there was a benefit of duplex surveillance for vein bypass grafts. 393

## Iib b-r the effectiveness of duplex ultrasound for routine surveillance of infrainguinal prosthetic bypass grafts in patients with

## Evidence gaps and future research directions
In performing the evidence review and in developing the present guidelines, the writing committee identified the following critical evidence gaps and future directions for PADrelated research:
- Basic science and translational studies to better understand the vascular biology of endovascular therapies and bypass grafting and to develop new methods for preventing restenosis after revascularization.
- Determination of risk factors for progression from asymptomatic PAD to symptomatic disease, including CLI.
- RCTs needed to determine the value of using the ABI to identify asymptomatic patients with PAD for therapies to reduce cardiovascular risk (eg, antiplatelet agents, statins, and other therapies).
- Advancement in PAD diagnostics, such as technologies for simplified yet highly accurate measurement of the ABI and tools for more reliable noninvasive perfusion assessment in CLI.
- Comparative-effectiveness studies to determine the optimal antiplatelet therapy (drug or drugs and dosage) for prevention of cardiovascular and limb-related events in patients with PAD.
- Development of additional medical therapies for claudication-an area of unmet medical need with a currently limited research pipeline. [bib_ref] Clinical trials in peripheral vascular disease: pipeline and trial designs: an evaluation..., Subherwal [/bib_ref] - Studies to investigate the role of dietary intervention, in addition to statin therapy, to improve outcome and modify the natural history of PAD.
- Additional research to identify the best community-or home-based exercise programs for patients with PAD to maximize functional status and improve QoL, as well as the role of such exercise programs before or in addition to revascularization.
- Development and validation of improved clinical classification systems for PAD that incorporate symptoms, anatomic factors, and patient-specific risk factors and can be used to predict clinical outcome and optimize treatment approach. An example of a recently developed classification system is the Society for Vascular Surgery limb classification system, based on wound, ischemia, and foot infection (WIfI), which has been validated in different populations and may permit more meaningful prognosis in patients with CLI. [bib_ref] Predictive ability of the Society for Vascular Surgery Wound, Ischemia, and foot..., Darling [/bib_ref] balloons and DES. Studies should include patient-centered end-points, such as functional parameters, time to wound healing, and QoL, in addition to standard patency-focused outcomes. These studies could then be incorporated into valuebased clinical algorithms for approach to revascularization for claudication and CLI.
- Additional studies to demonstrate the impact of multisocietal registries on clinical outcomes and appropriate use. At present, these include the Vascular Quality Initiative (VQI), the National Cardiovascular Data Registry Peripheral Vascular Intervention RegistryTM (PVI RegistryTM), and the National Radiology Data Registry for Interventional Radiology (NRDR). These registries provide an opportunity to obtain "real-world" data on surgical and endovascular procedures for PAD and to improve quality by providing feedback to participating centers. Future efforts should incorporate these registries into interventional RCTs and postmarketing studies of PAD-related devices.

## Advocacy priorities
The writing committee identified 3 priorities for multi-societal advocacy initiatives to improve health care for patients with PAD. First, the writing committee supports the availability of the ABI as the initial diagnostic test to establish the diagnosis of PAD in patients with history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref].
Although the ABI test is generally reimbursed by third-party payers for patients with classic claudication or lower extremity wounds, payers may not provide reimbursement for the ABI with other findings suggestive of PAD, such as lower extremity pulse abnormalities or femoral bruits. The writing committee affirms the importance of confirming the diagnosis of PAD in such patients to allow for GDMT as delineated in this document. Second, the writing committee supports the vital importance of insuring access to supervised exercise programs for patients with PAD. Although extensive high-quality evidence supports supervised exercise programs to improve functional status and QoL, only a minority of patients with PAD participate in such programs because of lack of reimbursement by third-party payers. Third, the writing committee recognizes the need for incorporation of patient-centered outcomes into the process of regulatory approval of new medical therapies and revascularization technologies. For revascularization technologies, regulatory approval is driven primarily by data on angiographic efficacy (ie, target lesion patency) and safety endpoints. The nature of the functional limitation associated with PAD warrants the incorporation of patient-centered outcomes, such as functional parameters and QoL, into the efficacy outcomes for the approval process.

# Supplementary material
Refer to Web version on PubMed Central for supplementary material.Definition of PAD Key Terms

## Term definition
Claudication Fatigue, discomfort, cramping, or pain of vascular origin in the muscles of the lower extremities that is consistently induced by exercise and consistently relieved by rest (within 10 min).
Acute limb ischemia (ALI) Acute (<2 wk), severe hypoperfusion of the limb characterized by these features: pain, pallor, pulselessness, poikilothermia (cold), paresthesias, and paralysis.
One of these categories of ALI is assigned (Section 10):

## I.
Viable-Limb is not immediately threatened; no sensory loss; no muscle weakness; audible arterial and venous Doppler.

## Ii.
Threatened-Mild-to-moderate sensory or motor loss; inaudible arterial Doppler; audible venous Doppler; may be further divided into IIa (marginally threatened) or IIb (immediately threatened).

## Iii.
Irreversible-Major tissue loss or permanent nerve damage inevitable; profound sensory loss, anesthetic; profound muscle weakness or paralysis (rigor); inaudible arterial and venous Doppler. Tissue loss Type of tissue loss:
Minor-nonhealing ulcer, focal gangrene with diffuse pedal ischemia. Major-extending above transmetatarsal level; functional foot no longer salvageable. 33
Critical limb ischemia (CLI) A condition characterized by chronic (2 wk) ischemic rest pain, nonhealing wound/ulcers, or gangrene in 1 or both legs attributable to objectively proven arterial occlusive disease.
The diagnosis of CLI is a constellation of both symptoms and signs. Arterial disease can be proved objectively with ABI, TBI, TcPO 2 , or skin perfusion pressure. Supplementary parameters, such as absolute ankle and toe pressures and pulse volume recordings, may also be used to assess for significant arterial occlusive disease. However, a very low ABI or TBI does not necessarily mean the patient has CLI. The term CLI implies chronicity and is to be distinguished from ALI. 35
In-line blood flow Direct arterial flow to the foot, excluding collaterals.
Functional status Patient's ability to perform normal daily activities required to meet basic needs, fulfill usual roles, and maintain health and well-being. Walking ability is a component of functional status.
Nonviable limb Condition of extremity (or portion of extremity) in which loss of motor function, neurological function, and tissue integrity cannot be restored with treatment.
Salvageable limb Condition of extremity with potential to secure viability and preserve motor function to the weight-bearing portion of the foot if treated.
Structured exercise program Planned program that provides individualized recommendations for type, frequency, intensity, and duration of exercise.
Program provides recommendations for exercise progression to assure that the body is consistently challenged to increase exercise intensity and levels as functional status improves over time.
There are 2 types of structured exercise program for patients with PAD:

## 1.
Supervised exercise program

## 2.
Structured community-or home-based exercise program Supervised exercise program Structured exercise program that takes place in a hospital or outpatient facility in which intermittent walking exercise is used as the treatment modality.
Program can be standalone or can be made available within a cardiac rehabilitation program.
Program is directly supervised by qualified healthcare provider(s).
Training is performed for a minimum of 30 to 45 min per session, in sessions performed at least 3 times/wk for a minimum of 12 wk. 36-46 Patients may not initially achieve these targets, and a treatment goal is to progress to these levels over time.
Circulation. Author manuscript; available in PMC 2017 September 21. et al.

## Page 63

## Term definition
Training involves intermittent bouts of walking to moderate-to-maximum claudication, alternating with periods of rest.
Warm-up and cool-down periods precede and follow each session of walking.
Structured community-or homebased exercise program Structured exercise program that takes place in the personal setting of the patient rather than in a clinical setting. 41,47-51
Program is self-directed with the guidance of healthcare providers who prescribe an exercise regimen similar to that of a supervised program.
Patient counseling ensures that patients understand how to begin the program, how to maintain the program, and how to progress the difficulty of the walking (by increasing distance or speed).
Program may incorporate behavioral change techniques, such as health coaching and/or use of activity monitors.

## Emergency versus urgent
An emergency procedure is one in which life or limb is threatened if the patient is not in the operating room or interventional suite and/or where there is time for no or very limited clinical evaluation, typically within <6 h.
An urgent procedure is one in which there may be time for a limited clinical evaluation, usually when life or limb is threatened if the patient is not in the operating room or interventional suite, typically between 6 and 24 h.
Interdisciplinary care team A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD.
For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care. [fig_ref] Table 9: can be beneficial [/fig_ref] Interdisciplinary Care Team for PAD A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD. For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care.
Interdisciplinary care team members may include:

## Examples
Factors associated with technical failure or poor durability with endovascular treatment Lesion involving common femoral artery, including origin of deep femoral artery Long segment lesion involving the below-knee popliteal and/or infrapopliteal arteries in a patient with suitable single-segment autogenous vein conduit Diffuse multilevel disease that would require endovascular revascularization at multiple anatomic levels Small-diameter target artery proximal to site of stenosis or densely calcified lesion at location of endovascular treatment Endovascular treatment likely to preclude or complicate subsequent achievement of in-line blood flow through surgical revascularization Single-vessel runoff distal to ankle

## Findings that favor consideration of endovascular revascularization

## Examples
The presence of patient comorbidities may place patients at increased risk of perioperative complications from surgical revascularization. In these patients, an endovascular-first approach should be used regardless of anatomy Patient comorbidities, including coronary ischemia, cardiomyopathy, congestive heart failure, severe lung disease, and chronic kidney disease Patients with rest pain and disease at multiple levels may undergo a staged approach as part of endovascular-first approach
In-flow disease can be addressed first, and out-flow disease can be addressed in a staged manner, when required, if clinical factors or patient safety prevent addressing all diseased segments at one setting
[fig] Figure 1: Diagnostic Testing for Suspected PAD [/fig]
[fig] Figure 3: Diagnosis and Management of ALI [/fig]
[table] Table 9: can be beneficial.[228][229][230] The EuroDIALE (European Study Group on Diabetes and the Lower Extremity) study demonstrated that the presence of both PAD and foot infection conferred a nearly 3-fold higher risk of leg amputation than either infection or PAD alone.228 The treatment of deep soft-tissue infection typically requires prompt surgical drainage; vascular imaging and expeditious revascularization generally follow. Experienced clinical teams have reported very good outcomes when this is performed in a coordinated and timely fashion. 229,230 Previous groups have described various combinations of functions of interdisciplinary care teams (See Online Data Supplement 34a for a complete list of functions). See Section 9.2 for recommendations related to the role of the interdisciplinary care team in wound healing therapies for CLI.Although there are limited data to support patient education about self-foot examination and foot care for patients with diabetes mellitus, there are no data that have evaluated this practice in a population of patients with PAD but without diabetes mellitus. Nonetheless, this is a very low-risk intervention with potential for benefit. Educational efforts generally include teaching patients about healthy foot behaviors (eg, daily inspection of feet; foot care and hygiene, including appropriate toenail cutting strategies; avoidance of barefoot walking), the selection of appropriately fitting shoes, and the importance of seeking medical attention for new foot problems. 223IIaC-EO Biannual foot examination by a clinician is reasonable for patients with PAD and diabetes mellitus. [/table]
[table] Table 3: 33,34 Category I refers to viable limbs that are not immediately threatened. Category II refers to threatened limbs. Category IIa limbs are marginally threatened and salvageable, if promptly treated. Category IIb are immediately threatened limbs that require immediate revascularization if salvage is to be accomplished. Category III are irreversibly damaged limbs, in which case resultant major tissue loss or permanent nerve damage is inevitable.34 [/table]
[table] Table 2: Important Guideline PolicyACC/AHA Guideline policy relevant to the management of lower extremity PAD [/table]
[table] Table 4: Patients at Increased Risk of PADAge 65 y Age 50-64 y, with risk factors for atherosclerosis (eg, diabetes mellitus, history of smoking, hyperlipidemia, hypertension) or family history of PAD 63Age <50 y, with diabetes mellitus and 1 additional risk factor for atherosclerosis Individuals with known atherosclerotic disease in another vascular bed (eg, coronary, carotid, subclavian, renal, mesenteric artery stenosis, or AAA) AAA indicates abdominal aortic aneurysm; PAD, peripheral artery disease.Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity symptoms (not typical of claudication)Other suggestive lower extremity physical findings (eg, elevation pallor/dependent rubor) PAD indicates peripheral artery disease.Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 6: Alternative Diagnoses for Leg Pain or Claudication With Normal Physiological Testing (Not PAD-Related)Modified from Norgren L et al. 35 PAD indicates peripheral artery disease. Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 7: Alternative Diagnoses for Nonhealing Wounds With Normal Physiological Testing (Not PAD-Related)Develops in regions of skin changes due to chronic venous disease and local venous hypertension Typically wet (ie, wound drainage) rather than dry lesion Thrombotic (eg, antiphospholipid antibody syndrome, Sneddon's syndrome, warfarin skin necrosis, disseminated intravascular coagulation, livedoid vasculitis, protein C or S deficiency, prolonged vasospasm) Medication direct toxicity (eg, doxorubicin, hydroxyurea, some tyrosine kinase inhibitors)NeuropathicPressure zones of footHyperkeratosis surrounds the ulcer Diabetes mellitus with peripheral neuropathy Peripheral neuropathy without diabetes mellitus Leprosy Autoimmune injury Toes, foot, leg With blisters (eg, pemphigoid, pemphigus, epidermolysis bullosa) Without blisters (eg, dermatomyositis, lupus, scleroderma) PAD indicates peripheral artery disease. Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 10: Therapy for CLI: Findings That Prompt Consideration of Surgical or Endovascular Revascularization Findings That Favor Consideration of Surgical Revascularization [/table]