2025 SVS临床实践指南：间歇性跛行的管理（更新版）

ABSTRACT

Intermittent claudication(IC) is the most common symptom of peripheral artery disease, which is a growing public health burden in the United States and globally. Patients with IC present with a broad spectrum of risk factors.comorbid conditions, range of disability, and treatment goals. Informed shared decision-making hinges on a comprehensive evaluation of these factors, patient education, and knowledge of the latest available evidence. In 2015, the Society for Vascular Surgery published a clinical practice guideline on the management of asymptomatic peripheral artery disease and IC. An expert writing group was commissioned to provide a focused update to this guideline on the management of IC. Based on the available evidence from published research conducted since the prior guideline. six specific key questions were formulated spanning the areas of antithrombotic management.exercise therapy, and revascularization for IC. A systematic review and evidence synthesis of each question was conducted by a dedicated methodology team. The GRADE approach was employed to describe the strength of each recommendation and level of certainty of evidence. The review identified major gaps in evidence particularly in the arena of comparative effectiveness for interventions(exercise, revascularization) across defined clinical sub-groups and employing meaningful patient-centered outcomes. Twelve recommendations, among which are two best practice statements, are provided in this focused update. They address the use of dual pathway antithrombotic strategies, the role and type of exercise therapy, endovascular interventions for femoropopliteal and infrapopliteal disease, and the identification of specific risk factors that should be incorporated into shared decision-making around revascularization. A comprehensive and individualized approach to the management of patients with IC,relying first on education, risk factor control, optimal medical therapy, and exercise, is emphasized. A rubric for decision-making that includes a thorough assessment of risk, benefits, degree of impairment, and treatment durability, is considered fundamental to a patient-centered approach in IC. Significant unmet research needs in this field are also enumerated.(J Vasc Surg 2025;82:303-26.)

Keywords: Peripheral artery disease: Intermittent claudication; Antithrombotic medication; Exercise therapy; Limb revascularization

From the Division of Vascular and Endovascular Surgery, University of California,San Francisco, San Francisco, the Division of Vascular Surgery and Endovas-cular Therapy, Loyola University Chicago Smith School of Medicine, May-woodb: the Division of Vascular Surgery and Endovascular Therapy, Michael E.DeBakey Department of Surgery, Baylor College of Medicine, Houstonf:the Division of Vascular Surgery and Endovascular Surgery, the Division of Vascular Surgery and Endovascular Surgery, the Mayo Clinic Evidence-based Practice Center, Rochester: the Geisel School of Medicine, Dartmouth-Hitchcock Medical Center, Hanovera: the Medical University of South Carolina, Tidelands Health, Vascular Surgery, Murrell Inletb: the Division of Vascular Surgery, Southern Illinois University School of Medicine, Springfield; and the Division of Vascular and Endovascular Surgery,University of Massachusetts Chan Medical School, Worcester:

Document Oversight Committee Review Statement: Independent peer re-view and oversight has been provided by the members of the Society for Vascular Surgery Document Oversight Committee(Marc Schmerhorn Chair; Britt Tonnessen, Vice Chair; Trissa Babrowski, Allan Conway, Leo

Daab, Brittany Fraser, Peter Henke, Vikram Kashyap,Ahmed Kayssi,Chris Wolek, Steven Maximus,Erika Mitchell, Patrick Muck,Firas Mussa, Kenton Rommens, Palma Shaw, Chris Smolock, Ravi Veeraswamy.Chandu Vemuri,and Grace Wang).

Additional material for this article may be found online at www.jvascurg.org.Correspondence: Michael S. Conte, MD. University of California San Francisco.400 Parnassus Avenue, Suite A 581, San Francisco, CA 94143-0222(e-mail:michaelante2@ucs.fedu).

The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.

©2025 Society for Vascular Surgery. Published by ELSEVIER INC. All rights are reserved, including those for text and data mining. Al training, and similar technologies.

https://doi.org/10.1016/j.jvs.2025.04.041

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TABLE OF CONTENTS

DISCLAIMER 304

# SUMMARY OF RECOMMENDATIONS 304

METHODS 306

Approach to systematic reviews 306

Approach to making recommendations 306

Patient stakeholder involvement of 306

# PICO QUESTIONS, DATA REVIEW, AND

RECOMMENDATIONS 307

PICO question 1 $\quad$ 307

Background and rationale 307

Evidence. 307

Recommendation 308

Patient advisor feedback to PICO question

1 and related recommendations 308

PICO question 2

Background and rationale 308

Evidence $\_$ 309

Recommendation 310

Patient Advisor feedback regarding PICO

<EndOfPara>question 2 and related recommendations

PICO question 3 $\ldots$ 310

Background and rationale 310

Evidence $\_$ 310

Recommendation 310

Patient Advisor feedback regarding PICO

<BeginOfPara>Poi question 3 and related recommendations

PICO question 4 311

Background and rationale $\underline{311}$

Evidence $\_ 312$

Recommendation 313

Patient Advisor feedback regarding PICO

<BeginOfPara>Po question 4 and related recommendations

PICO question 5

Background and rationale $\underline{313}$

Evidence $\_313$

Patient values, preferences, and potential

obstacles 313

Recommendations 314

Patient Advisor feedback regarding PICO

<EndOfPara>question 5 and related recommendations

PICO question 6 $\ldots$ 314

Rationale: revascularization for IC $\_$ 314

Periprocedural MACE $\_$ 316

MALE 316

Reintervention 317

Open revascularization for IC $\boxed{3}$ 1

Long-term mortality

Functional outcomes after intervention 318

Health-related quality of life 319

Patient values, preferences, and potential

obstacles 320

Recommendations regarding

revascularization for IC $\boxed{3}$ 20

Specific considerations 320

Regarding tibial interventions for claudication $\boxed{320}$

Regarding drug-coated devices and

durability $\ldots$ 321

Patient Advisor feedback regarding PICO

<EndOfPara>question 6 and related recommendations $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$ $\ldots$

Major unmet research needs 322

Patient Advisor feedback regarding unmet

needs and future questions $\ldots$ 322

AUTHOR CONTRIBUTIONS $\ldots$ 322

FUNDING 323

DISCLOSURES 323

DISCLAIMER

The Society for Vascular Surgery develops evidenced-based clinical practice guidelines as a resource to assist members in the practice of vascular surgery. The guide-line recommendations contained herein are based on a recent review of published evidence. They reflect the available body of evidence, and their applicability reflects the limitations of that data and are subject to reassess-ment and revision as new knowledge emerges. Given these limitations, clinical practice guidelines do not represent a statement of the standard of care, nor do they substitute for clinician judgment or supplant pa-tient preference or shared decision-making. The Society for Vascular Surgery recognizes that departure from guidelines may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the clinical presentation of the patient,limitations of available resources, advances in knowledge or technology, or patient preference. The reader must rely solely on their own judgment to determine what practices and procedures, whether included in this prac-tice guideline or not, are appropriate for them, their pa-tient, their institution, or their practice.

SUMMARY OF RECOMMENDATIONS

1.In patients with peripheral artery disease (PAD) and intermittent claudication (IC) who have one or more high-risk comorbidities (heart failure, diabetes, kidney insufficiency, or polyvascular disease [lower extremity peripheral artery disease with one or more additional vascular bed affected by atherosclerotic disease]) and who are not at high risk for bleeding, we suggest the vascular bed affective by atherosclerotic disease]) and who are not at high risk for bleeding, we suggest the use of rivaroxaban 2.5 mg twice daily in addition

2.In patients who have undergone surgical or endovas-cular interventions for symptomatic PAD including IC,and who are not at high risk for bleeding, we suggest the use of rivaroxaban 2.5 mg twice daily in addition to low-dose aspirin (81 to 100 mg/d), rather than aspirin alone. to reduce the risk of cardiovascular mor-tality, stroke, Ml, acute limb ischemia (ALI), and major amputation from vascular causes. Level of recom-mendation: grade 2; Level of evidence: B.

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3.In patients with PAD and IC who do not have high-risk comorbidities, are at elevated bleeding risk, or are otherwise intolerant of dual pathway antithrombotic therapy, we recommend the use of single antiplatelet therapy(aspirin 81-100 mg/day, clopidogrel75 mg/day, or ticagrelor 90 mg twice/day) for long-term pre-vention of cardiovascular events. Level of recommen-dation: grade 1; Level of evidence: A.

4. In patients who have undergone endovascular inter-vention for IC, we suggest the use of dual antiplatelet therapy(DAPT) (aspirin 1-100 mg/day, clopidogrel 75 mg/75 mg/day) for at least 1 month, rather than single an-tiplatelet therapy. Level of recommendation: grade 2;Level of evidence: C.

5. In patients with IC who have completed a supervised exercise program and/or refuse or cannot participate in supervised exercise programs, we recommend a home-based walking program. Level of recommen-dation: grade 1; Level of evidence: B.

6. In patients with IC, we recommend a supervised exer-cise program consisting of walking a minimum of three times per week(30-60 min/session) for at least 12 weeks as first-line therapy. Level of recommenda-tion: grade 1; Level of evidence: A.

7. For patients who have undergone revascularization for IC, we suggest the continued use of exercise ther-apy post-intervention(supervised or home-based).Level of recommendation: grade 2; Level of evi-dence:C.

8.In patients who are being considered for revasculari-zation for IC, we recommend that shared decision-making conversations should include each of the following risks and benefits: mortality, major adverse cardiovascular events(MACE), major adverse limb events(MALE)(amputation, reintervention, ALI), func-tional gain, and health-related quality of life(HRQoL)anticipated after revascularization. Best practice statement.

9. In patients who are being considered for revasculari-zation for IC, we recommend that shared decision-making conversations involve an assessment of indi-vidual risk factors known to influence risks and bene-fits. These include key comorbidities(diabetes mellitus[DM], coronary artery disease[CAD], conges-tive heart failure[CHF], chronic obstructive pulmonary disease[COPD]), history of prior limb revasculariza-tion, anatomic complexity of disease(ie, multi-level disease, long segment disease, chronic total occlu-sions), and procedural strategy(ie, open surgery vs endovascular revascularization[ER]). Best practice statement.

10.We recommend against performing revascularization in patients with asymptomatic PAD or IC based solely on hemodynamic measurements or imaging findings.There is no evidence to support the use of revascular-ization for modifying disease progression. Level of recommendation: grade 1; Level of evidence: C.

11. In patients with IC and no signs of chronic limb-threatening ischemia(CLTI), we suggest against the

use of infrapoplite revascularization, either alone or in combination with a more proximal intervention,due to lack of evidence of benefit and potential harm. Level of recommendation: grade 2; Level of evidence: C.

12. In patients with IC who are selected for an endovascu-lar intervention to treat femoropopliteal disease and have lesions exceeding 5 cm in length, we recom-mend the use of either bare metal stents(BMS) or drug-eluting devices(drug-coated balloons[DCB] or drug-eluting works[DES]) over plain balloon angio-plasty(PBA) to reduce the risk of restenosis and need for reintervention. Level of recommendation:grade 1; Level of evidence: B.

In 2015, the Society for Vascular Surgery SVS published a comprehensive clinical practice guideline(CPC) on the management of patients with asymptomatic PAD and claudication.1 IC is the most common symptomatic manifestation of PAD, and one of the most frequent di-agnoses managed by vascular specialists. Patients with IC present with a broad range of symptom severity,from mild to severely disabling. First-line treatment ap-proaches for IC focus on patient education, risk factor reduction, smoking cessation, optimization of medical therapies(OMT), and exercise. Symptomatic PAD is asso-ciated with an increased risk for MACE and related mor-tality; hence, a focus on OMT and risk-reducing strategies is imperative. Revascularization in appropriately selected patients can relieve pain and improve function and HRQOL. However, revascularization has also been associ-ated with risk of downstream disease progression in the limb, including MALE. Decision-making in IC is complex and individualized, based on symptom severity, comor-bid conditions, response to exercise/OMT, anatomic pattern of disease and risk/benefit for the proposed inter-vention. This CPC update was undertaken to provide cli-nicians with the best available contemporary data on OMT, exercise, and interventions to promote an evidence-based framework for the management of IC.

In planning this update, the working group considered the scope of clinical research advances in the treatment of PAD and IC since the prior publication. The areas selected for focus concern the role of therapeutic inter-ventions for patients with IC. Within the domain of med-ical therapies, we focused on antithrombotic management because of important new evidence in this arena directly relevant to the patient with IC. Other sections of the 2015 CPC3 such as those on epidemiology,diagnosis, other forms of medical therapies(eg, silcoa-zol), and post-procedural surveillance were not selected for this update as the prior recommendations were felt to remain relevant. With regard to revascularization stra-tegies, the writing group chose to focus on principal con-siderations in applying best available evidence to clinical decision-making for patients with IC, rather than

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detailed procedural recommendations. In addition to the 2015 SVS guideline document on IC, the reader should refer to other relevant multi-special guidelines on general cardiovascular risk management and preop-erative evaluation for patients with PAD and IC to supple-ment this update.2-4 Comparative effectiveness research studies in IC remain strikingly limited, with few large-scale randomized clinical trials(RCTs) in the domains of exercise and revascularization. Specifically, comparative effectiveness studies of revascularization strategies, with or without exercise, in well-defined patient subgroups with patient-centered endpoints are severely lacking.The majority of new data on peripheral vascular interven-tion(PVI) considered here focuses on the femoral-popliteal segment with relatively little new level 1 evi-dence on aorto-iliac disease. These limitations were high-lighted during the systematic data review undertaken,impacting both the scope and the strength of recom-mendations made.

METHODS

The SVS appointed the chair and invited a representa-tive panel of experts with specific domain expertise in PAD and IC management to form a writing group for this guideline update. Writing group members provided information on relevant conflicts of interest in accor-dance with SVS policies," and these were updated on a regular basis. Two SVS administrative staff members pro-vided ongoing support for the working group including these updates. SVS CPC writing groups, policies, and ac-tivities are overseen by the SVS Document Oversight Committee and subject to Board review and approval.

Methodological support was provided by the Mayo Clinic Evidence-based Practice Center, including facilita-tion of developing structured clinical questions using the PICOS format(population, intervention, comparison, out-comes, subgroups), identification of patient-important outcomes, conducting systematic reviews, and support in the evidence-to-decision process.

The working group developed six key questions to frame the systematic reviews, spanning the therapeutic areas in IC management. These questions were:

1. In patients with IC, what are the comparative out-comes of treatment with a direct oral anticoagulant(DOAC) vs antiplatelet medications alone(aspirin or clopidogrel)?

2. In patients with IC who have undergone limb revascu-larization, what are the comparative outcomes of treatment with a DOAC vs antiplatelet medications alone(aspirin or clopidogrel)?

3. In patients with IC, what are the comparative out-comes of treatment with alternative antiplatelet agents vs aspirin or clopidogrel?

4. In patients with IC, what are the comparative out-comes of supervised exercise therapy(SET) vs home-based exercise therapy(HET)?

5. In patients with IC, what are the outcomes of vascular intervention combined with exercise vs exercise without intervention?

6. In patients with IC who have undergone a limb revas-cularization procedure, what are the clinical.anatomic, and procedural predictors of clinical out-comes(freedom from adverse events and improve-ments in function and HRQoL)?

Approach to systematic reviews. Search strategies were developed by the methodology team in collabora-tion with medical reference librarians. Structured controlled vocabulary and text words were used to search multiple databases. References were selected based on a priori established inclusion criteria. Meta-analysis was conducted when appropriate.The certainty in the estimates was assessed using the Grading of Rec-ommendations, Assessment, Development, and Evalua-tion(GRADE) approach. The GRADE approach assigns an initial high certainty to randomized trials and low cer-tainty to nonrandomized studies, then certainty can be rated down based on risk of bias, imprecision, inconsis-tency, indirectness, and publication bias, and can also be increased in certain scenarios.7.8 SVS assigns the la-bels of A, B, and C to high, moderate, and low/very low certainty.9.10 The detailed findings of the systematic re-view performed for this guideline update are published separately.

Approach to making recommendations. SVS uses the GRADE evidence-to-decision(EtD) framework to trans-form evidence to recommendations based on certainty balance of effects, values and preferences, feasibility,acceptability, impact on health equity, and other contextual factors. Recommendations are either strong or conditional, denoted with the verbs'recommendent' and‘suggest' respectively.

Each recommendation is underpinned with an EtD worksheet. These worksheets were created by a collabo-ration between the writing group and the methodolo-gists and led to assigning a final strength and level of evidence to each recommendation and are provided in the Supplementary Appendix (online only).

Patient stakeholder involvement. An invited panel of patients with personal life experiences relevant to PAD and IC was assembled to provide key stakeholder input to the writing group. The Patient Advisors were engaged to provide a perspective on the research questions. Their perspectives are not intended to be interpreted as evi-dence or generally representative of all patients with claudication. Patient Panel members were nominated by writing group members and by the non-profit Foun-dation to Advance Vascular Cures(Redwood City, CA). Six patients with a personal history of PAD with claudication(two women and four men) participated as Patient

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Advisors for the guideline update. The Patient Advisors were invited to participate in four virtual meetings be-tween April and December 2023. The virtual meetings were facilitated by the authors(M.C.) and two staff members from the Society for Vascular Surgery(Mary Bodach, MLIS; and Reva Bhushan, MA, PhD). Patient Advisors were invited to share video in addition to audio during meetings if they were comfortable doing so, but video sharing was not required. Virtual meetings were recorded, and de-identified transcripts were summa-rized using qualitative software(NVivo 12Plus; QSR International).

The Patient Advisors were provided with email contact information for the facilitator and staff members, and encouraged to reach out with questions before, during,and/or after meetings. Advisors were instructed that their feedback on the guideline questions and recommenda-tions should be based on their personal experiences and opinions, and that their feedback would not be inter-preted as necessarily representative of the perspective of all patients with IC. They were encouraged to offer feedback regarding the research questions, including whether the questions seemed important and relevant to patients with IC, and what related questions patients with IC should ask their health care providers. They were also invited to suggest research questions to consider for future CPCs regardless of whether they were topically related to those under review. Patient Ad-visors were also informed that their contributions would be as advisors, rather than research participants, and could opt out of participation at any time. Patient Advi-sors were compensated$500 each and were given the option to opt into being acknowledged by name in the published guideline.

A glossary of common medical terms within the guide-line was distributed to the Patient Advisors before the first meeting for use as a reference. The first meeting started with a general orientation that included intro-ductions, a review of terminology, and background infor-mation related to the scope of the anticipated work and expected roles and responsibilities for the Patient Advi-sors. The definition and purpose of a CPG was reviewed along with opportunity for questions and answers. Clin-ical topics reviewed during the first meeting included:definitions of PAD and claudication, risk factors for PAD, PAD treatment goals, risk reduction pharmaco-therapy, and symptomatic therapy for claudication(including exercise therapy and revascularization). Termi-nology for endovascular and surgical revascularization procedures, along with synonyms(eg,"intervention" for endovascular procedures) were also reviewed to facilitate understanding of medical terminology commonly used by clinicians.

General feedback from the Patient Advisors regarding their contributions to the guidelines indicated that pa-tients' perspectives are important and not necessarily

understood by clinicians. Patient advisors also recom-mended publication of a lay terminology."patient-friendly" version of the CPG recommendations. They also asked if clinicians who treat IC are permitted to refer patients to other patients for advice regarding treatment options, especially patients who had received the treat-ment(s) being considered.

PICO QUESTIONS, DATA REVIEW, AND RECOMMENDATIONS

PICO question 1

In patients with IC, what are the comparative outcomes of treatment with a DOAC vs antiplatelet medications alone(aspirin or clopidogrel)?

Background and rationale. Data from several sources suggests that progression of lower extremity arterial occlusive disease is more often a result of thromboem-bolic events than previously suspected. Post-mortem histopathologic studies of patients with PAD have iden-tified frequent sequelae of acute thrombotic events,including fragmentation of calcified nodules and plaque rupture, and thrombi in the majority of high-grade infrainguinal lesions.12,13 Vorapaxar, a thrombin receptor antagonist assessed in the TRA2°P-TIMI50 trial, signifi-cantly reduced both ALI and peripheral artery re-vascularizations in patients with PAD.14 This research suggests thrombotic complications are an important modifiable target to reduce PAD progression. As risk factor modification and optimal medical therapy-along with exercise-have long been recognized as essential components of the first-line management for patients with IC, the question of whether newer anti-thrombotic drugs with greater potency or specificity might provide benefit to patients with IC has substantial relevance Recent pharmacologic advances include the DOACs(targeting factor Xu a or thrombin) as well as newer anti-platelet agents(thrombin receptor antagonists and P2Y12 antagonists).

Evidence. Since publication of the 2015 SVS CPCs, a prospective, multi-center, randomized clinical trial re-ported that rivaroxaban, an oral factor Xa inhibitor, pro-vides significant benefits to patients with PAD. Primary results from the Cardiovascular Outcomes for People Using Anticoagulation Strategies(COMPASS) trial15 were published in 2017. This international trial randomized 7470 adults with PAD to low-dose rivaroxaban(2.5 mg orally twice daily) alone, aspirin(100 mg orally once daily)alone, or low-dose rivaroxaban plus aspirin. PAD in this trial was defined by any of the following: IC and either an ankle-brachial index less than 0.9 or sonographic/angio-graphic stenosis of 50% or more of a lower extremity artery; history of prior lower extremity revascularization; a prior leg or foot amputation for PAD; or by sonographic/angiographic stenosis of 50% or more of a carotid artery.Of randomized subjects, 5361(72%) were men, 3287

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(44%) had diabetes, 2052(27%) were active or former users of cigarettes, and 3402(46%) had IC.

The primary outcome, a composite of cardiovascular death, MI, and stroke, occurred in 126(5%) of those ran-domized to rivaroxaban plus aspirin and in 174(7%) of those randomized to aspirin alone(hazard ratio[HR].0.72; 95% confidence interval[CI], 0.57-0.90; P=.0047).Compared with aspirin alone, the combination of rivarox-aban and aspirin was also associated with significant de-creases in several prespecified limb outcomes, including MALE(56[2.2%] vs 30[1.2%]: HR, 0.54; 95% CI, 0.35-0.84;P=.005), ALI(34[1.3%] vs 19[0.8%]: HR, 0.56; 95% CI,0.32-0.99; P=.04), and major amputation(17[0.7%] vs 5[0.2%]: HR, 0.3; 95% CI, 0.11-0.80; P=.01). The combina-tion of low-dose rivaroxaban plus aspirin was associated with increased major bleeding(using a modified Interna-tional Society for Thrombosis and Hemostasis[ISTH]definition)16 above aspirin alone(77[3%] vs 48[2%]: HR,1.6; 95% CI, 1.12-2.31; P=.009) but not fatal bleeding(4[0.2%] vs 3[0.1%]). Rivaroxaban had no significant impact on all-cause mortality.

A secondary analysis17 of the COMPASS trial demon-strated that patients with a prior history of amputation have the highest rate of MACE and MALE, with an inci-dence of 22.6% at 30 months. In addition to those with CLTI presentation(reported as Fontaine classification III or IV), other subjects with PAD with high risk for MACE or MALE included those with renal insufficiency(14.1%incidence at 30 months), CHF(13.5%), DM(13.4%), poly-vascular disease(defined as atherosclerotic disease in two or more vascular beds; 12.8%), or a history of prior leg revascularization(11.8%).

COMPASS trial investigators estimated that treating 1000 trial-eligible patients with low-dose rivaroxaban would avoid 27 MACE or MALE, while leading to one fatal and one critical organ bleed.15 Based on these findings,the investigators have estimated a number needed to treat of 63 patients over 2 years.18 Relevant to interpreting the rate of bleeding complications is the fact that COM-PASS excluded patients who were taking DAPT, patients on therapeutic-dose oral anticoagulant medications, pa-tients who were thought to have an elevated risk of bleeding complications(defined as“high risk of bleeding in COMPASS16), and patients with a recent his-tory of stroke(any stroke within previous 30 days or any prior history of hemorrhagic stroke).16

Recommendation

1. In patients with peripheral artery disease and IC who have one or more high-risk comorbidities(CHF. DM,kidney insufficiency, or polyvascular disease[lower extremity PAD with one or more additional vascular bed affected by atherosclerotic disease]) and who are not at high risk for bleeding, we suggest the use of rivaroxaban 2.5 mg twice daily in addition to aspirin(81 to 100 mg/d), rather than aspirain alone, to reduce the risk of cardiovascular mortality, stroke.

and MI. Level of recommendation: grade 2; Level of evidence: B.

This recommendation is based on a single(albeit large and multinational) randomized trial sponsored by the drug manufacturer. The recommendation is given as grade 2 because of a modest absolute risk reduction in the trial's composite endpoint without a significant reduction in mortality, and the tradeoff of increased bleeding. Until findings are replicated, this recommen-dation has a level of evidence B.

It may be appropriate to consider out-of-pocket patient costs and the incremental cost-effectiveness ratio over aspirin alone. Patients without access to rivaroxaban should be prescribed all other elements of optimal med-ical management previously described in the SVS's 2015 CPG, including antiplatelet therapy(see PICO question 3 below).1 Low-dose rivaroxaban alone had no benefit over aspirin alone in the COMPASS trial. This observation,along with the higher cost compared with aspirin, sug-gests that low-dose rivaroxaban alone should not be used as a substitute for aspirin.

Patient advisor feedback to PICO question 1 and related recommendations. Patient Advisors requested clarification that DOACs would be added to(rather than substituted for) other risk reduction medications(eg, antiplatelet and statin medications), and expressed concerns related to polypharmacy and medication burden. Patient Advisors also raised concerns about the risk of adverse events related to DOACs. Bruising was a significant concern to patients. They also asked for clari-fication related to the outcomes affected by DOAC ther-apy, and several Patient Advisors expressed hesitancy to add DOAC therapy without any anticipated improve-ment of claudication symptoms attributable to taking the additional medication. Additional comments related to decision-making for DOAC initiation focused on clini-cian recommendations rather than a desire for shared decision-making because of the lack of anticipated direct effects on claudication symptoms.

PICO question 2

In patients with IC who have recently undergone limb revascularization, what are the comparative outcomes of treatment with a DOAC vs antiplatelet medications alone(aspirin or clopidogrel)?

Background and rationale. Limb revascularization pro-cedures for symptomatic PAD, whether catheter-based or open surgical, are limited by varying rates of reste-nosis and occlusion. Although a role for antiplatelet therapy is well-established, the question of what consti-tutes optimal anti-thrombotic management, including the duration of therapy following PVls and lower ex-tremity bypass procedures, remains unresolved. The availability of the new oral factor Xa inhibitor rivaroxaban

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has led investigators to question whether it would pro-vide clinical benefit following lower extremity revascu-larization. Patients with PAD undergoing lower extremity revascularization are at increased risk,19 so the question of whether rivaroxaban would lead to significant re-ductions in cardiac events and/or improved limb out-comes in these patients is relevant following COMPASS.

Evidence. The Vascular Outcomes Study of Acetylsali-cylic Acid Along With Rivoxaban in Endovascular or Surgical Limb Revascularization for PAD(VOYAGER-PAD) trial,20 published in 2020, is the second RCT to evaluate the clinical benefit of rivaroxaban in patients with PAD. In contrast to COMPASS, this trial randomized 6564 adults who were planned to undergo revasculari-zation for symptomatic PAD in Europe. Asia, and North and South America to low-dose rivaroxaban or placebo(in addition to background antiplatelet therapy). Symp-tomatic PAD in VOYAGER was defined as IC, rest pain, or ischemic ulceration with both imaging evidence of infrainguinalial arterial disease and appropriate noninvasive hemodynamic testing results(ankle-brachial index of≤0.85 vs≤0.80 or toe-brachial index of≤0.65 vs≤0.60 for those with and without prior limb revascularization).Randomization needed to occur within 10 days of the revascularization procedure. Of randomized subjects,4860(74%) were men, 2629(40%) had diabetes, 2279(35%) currently used cigarettes, and 5052(77%) had IC as the indication for revascularization.

The primary outcome, Kaplan-Meier estimated inci-dence of the composite of cardiovascular death, stroke,MI, major amputation for vascular causes, and ALI at 3 years, occurred in 17.3% of those randomized to rivarox-aban vs 19.9% of those randomized to placebo(HR, 0.85;P=.009).ALI in the first 6 months following revascular-ization was halved(1.7% vs 3.2%; P=.049) with the use of rivaroxaban. There was no significant overall differ-ence in rates of major bleeding as defined by the Thrombolysis in Myocardial Infarction(TIMI) classifica-tion(2.65% vs 1.87%, respectively; HR,1.43; P=.07). In addition, when using the alternative ISTH definition of major bleeding, there was a significant increase seen in the dual therapy-treated patients(4.3% vs 3.08%;HR,1.42;P=.007).Early post-revascularization initiation of rivaroxaban had no significant impact on all-cause mortality.

Based on estimates from the VOYAGER-PAD trial,treat-ing 1000 patients undergoing lower extremity revascu-larization with low-dose rivaroxaban would prevent 18 primary efficacy events(MI, ischemic stroke, death from cardiovascular causes, major amputation for vascular causes, and ALI) and lead to three TIMI major bleeding events.20 Similar to the COMPASS trial, the VOYAGER-PAD trial also excluded patients on anticoagulant medi-cations after revascularization, patients who were thought to have an elevated risk of bleeding complica-tions(any“active or recent”[within 6 months] condition

considered to pose a significant risk of major bleeding ${}^{*21}$ ),and patients with any prior stroke. ${}^{21}$

Secondary analyses of the VOYAGER-PAD trial have re-ported that the degree of benefit in reducing post-revascularization ALI was comparable among all patients undergoing revascularization, irrespective of whether the indication was IC vs CLTI.22 whether the conduit for surgical bypass was prosthetic or vein.23 and whether clopidogrel was also given.24 The reduction in post-revascularization ALI was more pronounced in patients with impaired renal function(estimated glomerular filtration rate of<60 and>15 mL/min/1.73 m2; HR,0.40;95% CI,0.23-0.70).25

Unlike COMPASS, VOYAGER-PAD allowed the use of dual antiplatelet agents for up to 6 months,21 and 3313 participants(50.6%) in the trial used clopidogrel in addi-tion to the assigned treatments after randomization. Pa-tients taking clopidogrel along with rivaroxaban and aspirin did not have significantly reduced incidence rates of any of the endpoints beyond the reduction seen with rivaroxaban and aspirin without clopidogrel. Those tak-ing clopidogrel(in addition to the study regimen[ie“tri-ple therapy”]) for more than 30 days following revascularization had a 3-fold higher rate(2.79% absolute risk increase) of ISTH major bleeding within 1 year of randomization.24

Other investigators have noted that high bleeding risk,pre-existing need for other anticoagulant medications,and other exclusion criteria such as uncontrolled hyper-tension and major tissue loss may limit the use of low-dose rivaroxaban and the generalizability of VOYAGER-PAD trial findings to no more than 20% of patients un-dergoing revascularization for symptomatic PAD.26.27 Furthermore, lack of a direct comparison of this regimen to DAPT, which is commonly used for variable lengths of time following peripheral endovascular interventions (ie recommended in the instructions for use of many pe-ripheral stents and angioplasty balloons, despite a lack of level 1 clinical evidence for benefit), may limit its up-take by some clinicians. Persons categorized as Black comprised only 148 (2.2%) of trial participants; this may further limit generalizability in the United States and other countries with racial diversity.

Although VOYAGER-PAD focused on the management of patients who had recently undergone a limb revascu-larization, the PASS trial, as noted above, demon-strated a net clinical benefit in patients with PAD with a prior history of limb revascularization as a defined high-risk subgroup. However, this subgroup was not parsed further into whether the benefit was specific to those pa-tients whose remote prior revascularization was done for an indication of IC in contrast to CLTI. Thus, the optimal timing of initiation of dual pathway treatment with aspirin and low-dose rivaroxaban, outside of the specific context studied in VOYAGER-PAD, remains unclear in those who have undergone a prior revascularization for IC. An individ-ualized consideration of bleeding risk, as well as

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concomitant indications for other specific anti-thrombotic regimens(eg, DAPT following recent percuta-neous coronary intervention; full anticoagulation for atrial fibrillation, etc), are central to informed shared decision-making conversations with these patients.

Recommendation

2. In patients who have undergone surgical or endovas-cular interventions for symptomatic PAD including IC,and who are not at high risk for bleeding, we suggest the use of rivaroxaban 2.5 mg twice daily in addition to low-dose aspirin (81 to 100 mg/d), rather than aspirin alone, to reduce the risk of cardiovascular mortality, stroke, MI, ALI, and major amputation from vascular causes. Level of recommendation: grade 2;Level of evidence: B.

This recommendation is based on a single, large RCT sponsored by the drug manufacturer and is therefore rated as level of evidence B until findings are replicated.As in patients described in PICO question#1, patients un-dergoing surgical or endovascular intervention for symp-tomatic PAD experienced a modest absolute risk reduction in the trial composite endpoint without a sig-nificant reduction in mortality. A modest increase in bleeding events is also notable as a tradeoff. For this reason, the recommendation has level of evidence B.

It may be appropriate to consider out-of-pocket patient costs and the incremental cost-effectiveness ratio over aspirin alone. Patients without access to rivaroxaban should be prescribed all other elements of optimal med-ical management previously described in the SVS's 2015 CPC, including antiplatelet therapy(see PICO question 3 below). ${}^{1}$ Low-dose rivaroxaban had no benefit over aspirin alone in the COMPASS trial. This observation,along with the higher cost compared with aspirin, sug-gests that low-dose rivaroxaban alone should not be used as a substitute for aspirin. The absence of a direct comparison to DAPT following endovascular intervention is a notable limitation in relation to potentially increased patient costs.

Patient Advisor feedback regarding PICO question 2 and related recommendations. Patient Advisors dis-cussed information overload (ie, becoming overwhelmed with information that they may not completely under-stand or be able to synthesize) as a potential disadvan-tage of shared decision-making. Nonetheless, there was general agreement that patients should understand all the treatment options that are under consideration, even if they prefer to defer to the clinician's recommendation rather than participate in shared decision-making related to treatment selection. When discussing treat-ment options, patients advised that clinicians commu-nicate the "why" behind the recommendation (eg, if there are factors that influence relative acceptability of different options). Contextual and contingent factors mentioned by the Patient Advisors as relevant to their priorities included risks, potential side effects of

<EndOfPara>medications, and whether the treatment intervention under consideration was being considered for preven-tion vs symptomatic therapy.

PICO question 3

In patients with IC, what are the comparative outcomes of treatment with alternative antiplatelet agents vs aspirin or clopidogrel?

Background and rationale. Ticagrelor is a reversible antagonist of the platelet receptor P2Y12. Unlike clopi-dogrel, which is a pro-drug, ticagrelor does not require conversion to an active compound. Ticagrelor produces greater mean percentage platelet inhibition with less variability in individual response than clopidogrel, ${ }^{28}$ and randomized trials have demonstrated superiority of ticagrelor over clopidogrel in patients with acute coro-nary syndromes ${ }^{29}$ and patients with a prior history of M1. ${ }^{30}$ The question of whether these advantages of tica-grelor might benefit patients with PAD and IC is there-fore relevant.

Evidence. Two randomized trials published since the 2015 guideline have assessed the role of ticagrelor. ${ }^{31,32}$ The Examining Use of Ticagrelor in Peripheral Artery Disease(EUCLID) trial randomized 13,885 adults with symptomatic PAD to ticagrelor or to clopidogrel. Sub-jects in this trial did not receive aspirin in addition to the assigned study medication. No difference was seen in the primary endpoint, a composite of cardiovascular death. MI, or ischemic stroke, which occurred in 751(10.8%) assigned to ticagrelor vs 740 (10.6%) assigned to clopidogrel ( $P=.65)$ . Ischemic stroke, however, was significantly lower among those assigned to ticagrelor(131 [1.9%) vs 169 [2.4%]: P=.03). There was no significant difference in major bleeding events as defined by the TIMI classification (1.6% in each group: HR,1.1; P=.4), but bleeding events more often led to medication discon-tinuation among subjects randomized to ticagrelor than to subjects assigned to clopidogrel. ${ }^{31}$

A single-center trial in Italy randomized 40 adults un-dergoing revascularization for symptomatic PAD to tica-grelor plus aspirin or to clopidogrel plus aspirin. Subjects in this trial were all part of the DES arm of a larger trial comparing DES with DCB for symptomatic PAD. No sig-nificant differences were seen in restenosis as assessed by high-resolution frequency-domain optical coherence tomography at 12 months. ${}^{32}$

Recommendation. There is no evidence to support preferential use of ticagrelor over other antiplatelet monotherapy strategies in patients with PAD and IC Accordingly. the recommendation below is similar to that from the 2015 guideline with inclusion of ticagrelor as an equivalent option.

Likewise, there is no new high-quality evidence demon-strating the net benefit of DAPT following endovascular interventions in PAD and IC, although it is widely used based on data from coronary interventional trials and

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has been included in the designs of regulatory trials of peripheral endovascular devices. Observational studies and systematic reviews suggest modest benefit over aspirin alone in reducing MACE and MALE in the early post-procedural period but are inconclusive.33,34 There-fore the prior 2015 recommendation on DAPT use following endovascular interventions is essentially un-changed in this update, and remains based on limited evidence.

3.In patients with PAD and IC who do not have high-risk comorbidities, are at elevated bleeding risk, or are otherwise intolerant of dual pathway antithrombotic therapy, we recommend the use of single antiplatelet therapy(aspirin 81-100 mg/day, clopidogrel 75 mg/day, or ticagrelon 90 mg twice/day) for long-term pre-vention of cardiovascular events. Level of recommen-dation: grade 1; Level of evidence: A.

4.In patients who have undergone endovascular inter-vention for IC, we suggest the use of DAPT(aspirin 81-100 mg/day, clopidogrel 75 mg/day) for at least 1 month, rather than single antiplatelet therapy. Level of recommendation: grade 2; Level of evidence: C.

Patient Advisor feedback regarding PICO question 3 and related recommendations. Patient Advisors emphasized the importance of specific clarification of the risks and the benefits associated with antiplatelet therapy. They expressed concerns that patients may not understand the specific indications for medications that they are taking, and that antiplatelet medications may have multiple indications that are not mutually exclusive. CAD was mentioned as a common indication for DAPT that is also prevalent among patients with clau-dication. The need for a prescription medication with DAPT(as opposed to aspirin monotherapy, which does not require a prescription) was also identified by patient advisors as an important consideration.

PICO question 4

In patients with IC, what are the comparative outcomes of SET vs HET?

Background and rationale. Although exercise therapy is recommended as a first-line treatment for patients with lifestyle-limit cludication, several methods for performing an exercise program exist, with differing ad-vantages and disadvantages. Both SET and HET have been shown to improve several measures of walking performance. SET, consisting of treadmill walking su-pervised by an in-person exercise therapist at a medical facility, is considered the gold standard for improving walking performance in patients with claudication. SET is supported by robust evidence. 1,35,36 It is covered for finite episodes by the Centers for Medicare and Medicaid Services(CMS). 37 Both SET and HET have been demon-strated to improve pain-free and maximum walking distance and/or duration. 35,38,39 It is difficult to provide

specific estimates of the benefits, because there is considerable heterogeneity in outcome measures re-ported(eg,meters vs minutes,treadmill walking vs over-ground walking).

The most striking difference where HET differs is the lack of in-person supervision. The in-person supervision component of therapy has both theoretical advantages and disadvantages. A key rationale for this PICO question is that recent studies have sought to evaluate whether the addition of a cognitive-behavioral therapy element to a home-based exercise program can produce an equal(or superior) effect.39-42 In-person coaching and encouragement from a coach can have cognitive-behavioral advantages above that of home-based pro-grams with virtual coaching. The duration and impact of these theoretical advantages, however, may be limited by costs to the patient because Medicare coverage al-lows up to three sessions per week, lasting 30 to 60 mi-nutes each, for 12 weeks. Other potential disadvantages of in-person supervision include the requirement to coor-dinate the location and timing between the patient and the supervisor. Medicare-covered supervised exercise ses-sions require outpatient or hospital-based facilities that contract with CMS and have personnel(including both physicians and therapists) available for direct physician supervision. Patients in rural or underserved areas may lack access to these resources within their own commu-nity and may also face logistic and financial barriers to participating in SET outside their community. Addition-ally, patients with lifestyle-limiting claudication who are uninsured or younger than 65 may incur out-of-pocket expenses for SET if they are ineligible for Medicare bene-fits. Finally, eligible patients may refuse SET. In a recent systematic review, less than 25% of eligible patients agreed to participate in SET, with lack of interest and inconvenience as the most commonly cited reasons for refusal or non-herence.

Structured HET may overcome some of these limita-tions. Specifically, HET does not require availability of a supervising facility or scheduling that may interfere with work or other commitments. It also does not rely on the use of a treadmill for walking. Many experts have noted that treadmill walking and home-based over-ground walking may have important differences that influence outcomes.44 Although treadmill walking programs may improve outcomes determined using treadmill-based tests, generalizability for over-ground walking should not be assumed. Improvement in mea-sures of over-ground walking have been demonstrated with home-based walking therapy, ${}^{38,45-47}$ suggesting po-tential direct relevance to community walking associ-ated with daily activities.

Home-based exercise programs may be especially valu-able for patients who lack access to supervised exercise programs within their community or face logistical chal-lenges that prevent in-person participation. They can be

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beneficial for patients who have completed supervised exercise program eligibility. Home-based programs that utilize smartphone apps and/or tracking devices allow greater time and location flexibility for walking exercise and also generate tracked output that allows patients to set goals and monitor progress with greater frequency.It is important to note that some patients may lack ac-cess to the devices or sufficient comfort with the technol-ogy to take full advantage of home-based programs.

The rationale for question 4 was to provide guidance regarding how to choose between these exercise ther-apy programs for patients who have access to either one, and whether supervised and structured home-based therapy may have complementary roles when used sequentially.

Evidence. Evidence was mixed regarding the benefit of HET; interpretation requires specific attention to the con-trol intervention. Home-based exercise interventions that included a cognitive-behavioral component were more beneficial than programs lacking a cognitive-behavioral component. The Group Oriented Arterial Leg Study(GOALS) trial investigators compared outcomes for pa-tients who received group-mediated cognitive behavior interventions vs a control group. 39,40 During the first phase (months 1-6), meetings were held in-person,whereas during the second phase (months 7-12), con-tact was via telephone. The benefits of this cognitive behavioral intervention were seen at 6 months, and persisted to 12 months, on outcomes of 6-minute walk test (6MWT) and the speed component of the Walking Impairment Questionnaire. In contrast, the Home-Based Monitored Exercise for PAD (HONOR) trial investigators studied the use of an activity tracker combined with telephone coaching as part of a HET protocol compared with usual care. ${ }^{41}$ There was no significant difference seen at 9 months, which led the authors to conclude that some amount of in-person visits are required for measurable improvement in home-based protocols.

Comparisons between supervised and home-based exercise programs were limited, but outcomes were generally similar. The NEXT Step trial investigators compared SET with structured home-based walking us-ing an activity tracker vs an attention-control group.(The attention control group concept is well-described in the behavioral health literature; the attention control group receives the same dose of interpersonal interac-tion as intervention participants but no other elements of the intervention, to control for the benefits of atten-tion that may come from behavioral interventions.) ${ }^{48}$ Both the SET and HET groups demonstrated improved outcomes at 12 weeks compared with controls: the au-thors did not conclude superiority of one intervention over the other.

<BeginOfPara>The SVS partnered with investigators to study the out-comes of a HET program that made use of a smartphone app for cognitive behavioral techniques and activity

<EndOfPara>monitoring. ${ }^{42}$ They noted significant improvements at 6- and 12-months in the Walking Impairment Question-naire distance metric, and overall, 92% of patients re-ported achieving their self-defined goals. There was not a control group.

The Low Intensity Exercise Intervention (LITE) trial inves-tigators studied several outcomes of home-based struc-tured walking therapy, comparing high-vs low-intensity regimens with a non-exercise control group. 49,50 Key findings included that high-intensity walking (that which induces ischemic leg symptoms) was significantly more effective than low-intensity (comfortable pace) walking;outcomes in the low-intensity walking therapy group were not significantly different than the non-exercise group. High-intensity therapy resulted in the best im-provements on several measures, including change in 6MWT, walking velocity, and Short Physical Performance Battery score, leading the authors to conclude that low-intensity home-based walking therapy should not be recommended.

Undesirable effects of home-based exercise programs were uncommon and generally minor. The HONOR trial4[4] reported difficulty in walking and increased short-ness of breath in both the home-based exercise group and the usual care group. The NEXT Step trial4 did not report any adverse events related to the home-based ex-ercise intervention. A systematic review confirmed these findings and concluded that HET programs have a very favorable safety profile. ${ }^{51}$

Overall, the certainty of available evidence was very low due to precision and study design limitations.Tracking exercise with an activity monitor and use of behavioral change strategies (such as goal-setting, peri-odic check-ins, and coaching) are recommended to support successful implementation of a HET program.44 Effective exercise programs should be followed for at least 12 weeks. These programs should consist of five sessions per week, up to 50 minutes per session, where patients walk at a pace that induces ischemic symp-toms. They should use some sort of activity monitor and set goals for tracking progress. Patients should receive some type of check-in; the optimal frequency and details of this remain unclear, but some in-person visits are advised.

Patient values and preferences for exercise interven-tions have been considered in some fashion with the definition of a "minimal clinically important difference(MCID)". This concept has been widely studied and applied to help with interpretation of measures such as the 6MWT. The key concept is a translation between a number of meters walked that may be statistically sig-nificant and a number of meters that is meaningful to a patient's daily physical function and quality of life. The HONOR trial used an MCID of 20 meters on the 6MWT. A systematic review of MCID across a broader range of medical conditions that impact walking.

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however, suggested that MCID on the 6MWT may range from 14 to 30 meters.52 More recently, the concept of patient-specific self-defined treatment goals has been proposed as an alternative to standardized patient-reported outcome metrics.53 This underscores the importance of counseling to establish shared goals and expectations between patients and clinicians, as well as some of the limitations of outcomes measures that are commonly used in clinical trials among pa-tients with IC.

Recommendation

5. In patients with IC who have completed a supervised exercise program and/or refuse or cannot participate in supervised exercise programs, we recommend a home-based walking program. Level of recommen-dation: grade 1; Level of evidence: B.

Patient Advisor feedback regarding PICO question 4 and related recommendations. The Patient Advisors discussed the importance of other patients with claudi-cation as a resource for questions and advice. The contribution of claudication symptoms to lifestyle limi-tation and the anticipated incremental improvement that would be achieved through the exercise interven-tion were important to patient advisors when consid-ering a walking exercise program. Walking advice was viewed as inferior to SET by some patient advisors, but others considered these alternatives were equally effective.

PICO question 5

In patients with IC, what are the outcomes of vascular intervention combined with exercise vs exercise without intervention?

Background and rationale. Guidelines recommend ex-ercise therapy for appropriate patients prior to consider-ation of revascularization interventions, with selective use of the latter when symptomatic response to exercise therapy is inadequate. We reviewed the evidence that informed the recommendation for the 2015 guideline and have reiterated that recommendation. Limited evi-dence exists, however, regarding the additive or comple-mentary effects of exercise therapy and revascularization used either sequentially or combined. For example,although exercise therapy(either SET or HET) is recom-mended before consideration of revascularization for claudication symptoms, it is possible that either re-attempting or continuing exercise therapy may provide important additional benefits post-revascularization.This topic is worthy of evaluation in future clinical research studies, but available evidence related to these addi-tional questions was inadequate at the time of this up-date. The evidence summary within the current update is therefore limited to interval updates from studies comparing revascularization plus exercise therapy vs exercise therapy alone.

Evidence. There is insufficient evidence to recommend the combination of revascularization and exercise ther-apy as a preferred treatment strategy in patients with claudication compared with exercise alone. Randomized trials of revascularization plus exercise therapy vs exercise therapy alone or vs revascularization alone demon-strated modest improvements favoring combination therapy or no difference in early follow-up.45-56 Impor-tantly, however, these benefits of combination therapy were not sustained at subsequent 2- to 5-year follow-up intervals.56-58 The Invasive Revascularization or Not in Intermittent Claudication (IRONIC) trial investigators found supervised exercise therapy alone resulted in su-perior HRQOL scores on one sub-domain of the SF-36(emotional role) as the only significant difference. Bo et al noted additive benefit of supervised exercise ther-apy after endovascular revascularization vs endovascular revascularization only in 29 patients at 3 months for 6MWT but not HRQOL outcomes. The ERASE trial58 ran-domized 212 patients with IC to either endovascular revascularization plus exercise therapy or exercise ther-apy alone. Although the combination therapy group had superior maximum walking distance (MWD) at 1 year, this was not sustained by 5 years. Cost-effectiveness analyses were only reported for the 12-month endpoint at the time of this guideline.59 A recent network meta-analysis demonstrated that combined exercise and intervention yield improved short- to intermediate-term outcomes of MWD, but the results of all treatments were similar to controls by 2 years of follow-up.60 There is insufficient evidence to guide a recommended duration of exercise therapy post-intervention.

Unanticipated adverse effects of revascularization com-bined with exercise therapy were moderate. Five-year re-sults of the IRONIC study identified increased rates of death and decline in MWD among patients treated with revascularization plus exercise therapy, although neither of these was a primary endpoint.57 The ERASE trial noted a higher total number of procedures for the combination therapy group (including the randomized treatment) compared with the total number of proced-ures in the exercise-only group.

Patient values, preferences, and potential obstacles.

Shared decision-making requires discussion of the find-ings from trials demonstrating no clear benefit of revas-cularization over exercise therapy alone at 2 to 5 years.These studies are notably limited in both size and generalizability. Conversely, patients should be coun-seled that there may be notable short- to mid-term benefits on some metrics after a successful revasculari-zation. Individual patients may find such benefits meaningful; for example, a patient with IC whose occu-pation requires significant walking may be able to maintain job performance even if the effectiveness wanes with time. Patient Advisors were asked to provide

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opinions regarding the minimum durability of a revas-cularization that would make procedural intervention worthwhile for claudication. Responses to this durability probe ranged from a minimum of 3 years to a maximum of 10 years, and some Patient Advisors said they would accept lower durability for revascularization procedures that did not require inpatient hospitalization or pro-longed recovery.

#

6.In patients with IC, we recommend a supervised exer-cise program consisting of walking a minimum of three times per week (30-60 min/session) for at least 12 weeks as first-line therapy. Level of recommenda-tion: grade 1; Level of evidence: A.

<BeginOfPara>7.For patients who have undergone revascularization for IC, we suggest the continued use of exercise ther-apy post-intervention (supervised or home-based).Level of recommendation: grade 2; Level of evi-dence: C.

Patient Advisor feedback regarding PICO question 5 and related recommendations. The Patient Advisors discussed additional benefits of exercise therapy beyond claudication symptoms, including mental health bene-fits such as decreased anxiety.

PICO question 6

In patients with IC who have undergone a limb revascu-larization procedure, what are the clinical, anatomic, and procedural predictors of clinical outcomes (freedom from adverse events, improvements in function, and HRQoL)?

Rationale: revascularization for IC. Current societal practice guidelines as well as Choosing Wisely, an initia-tive of the American Board of Internal Medicine (ABIM)Foundation, recommend lifestyle changes,OMT,and ex-ercise therapy as the initial strategy for the management of IC.1,36,61,62 The benign natural history of IC is well-established, with 70% to 80% of patients remaining stable or improving over time without intervention. ${ }^{63}$ The rate of life-long progression to CLTI is variably low(<5%to 21%), ${ }^{64}$ and the yearly risk of progression to amputa-tion is less than 1% per year. ${ }^{65-67}$ There is no evidence to suggest that intervention on specific atherosclerotic le-sions or arterial segments inhibits progression of atherosclerotic disease in the limb or improves the prognosis of the limb. In fact, failure of intervention may be associated with a natural history for the limb worse than that without intervention. ${ }^{68}$ Guidelines therefore suggest that revascularization should be reserved for those with severe lifestyle-limiting IC symptoms who remain disabled despite OMT and exercise. Nevertheless,given the prevalence of the condition. IC is currently the most common indication for lower extremity arterial revascularization in the United States. Based upon na-tional all-payer claims data from the Nationwide Inpa-tient Sample, the number of lower extremity

revascularization procedures for IC increased dramati-cally during the early 2000s, with the annual volume of procedures for IC overtaking those performed for CLTI in 2006.69 The percentage of revascularization procedures performed for an indication of IC vs those performed for CLTI is slightly lower when sampled within hospitals that participate in available quality improvement registries.Among approximately 250,000 patients treated at North American hospitals reporting to the Vascular Quality Initiative (VQI) between 2010 and 2019,42% were treated for an indication of IC.70 It is notable that most current administrative datasets and clinical registries fail to capture revascularization procedures performed in office-based laboratories or ambulatory surgery centers,which are the site of service for an increasing number of ER procedures.71.72 Therefore, although current data tracking the total volume of revascularization procedures across the United States and globally to treat IC is sparse,revascularization for an indication of IC appears to be increasing.

Practice patterns vary considerably regarding the deci-sion on whether and when to revascularize for IC as well as on the type of revascularization (surgical, endovascu-lar, or hybrid) performed. An analysis of national claims data demonstrates that although early PVI (defined as endovascular treatment within 6 months of initial diag-nosis of IC) is performed in a minority of Medicare bene-ficiaries (3.2%), a small group of physicians (5.6% of those submitting Medicare claims) perform early PVI in greater than 14% of their patients. ${ }^{73}$ Such data may reflect prac-tice at variance with current guidelines, which recom-mend initial medical management, including smoking cessation, and revascularization only for failure of medi-cal therapy to sufficiently improve symptoms. Medical optimization may not be occurring in a significant per-centage of patients with IC who undergo revasculariza-tion. For example, data from VQI demonstrates that greater than 40% of patients undergoing intervention for claudication are still active smokers. ${ }^{74}$

The decision to undertake revascularization in a patient with IC requires individualized assessment of the pre-sumed benefits of revascularization vs potential adverse events. Broadly speaking, the goals of revascularization for IC include improved walking distance and relief of pain with presumed improvement in the ability to perform important activities of daily living (functional sta-tus) and overall HRQOL. Improved walking ability may have the potential to contribute to improved overall car-diovascular health, although data to support this hypoth-esis is lacking. Intervention for asymptomatic PAD or based solely upon hemodynamic parameters or anatomic findings without clinical symptoms is not indi-cated. An exception to this is treatment of a critical lesion within a previously placed bypass graft, even when asymptomatic. Surveillance of bypass grafts and inter-vention on critical bypass graft lesions are considered

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Key Factors for Shared Decision Making in Revascularization for Claudication

 Fig 1. Shared decision-making in revascularization for claudication should include a comprehensive assessment of the patient's individual treatment goals, risk factors, presumed benefits, and estimates of undesirable outcomes.Lifestyle changes such as smoking cessation and healthy diet, optimal medical therapy(OMT), and a trial of ex-ercise therapy should be initial steps in all patients, in addition to education. There are multiple presumed benefits of revascularization, although the likelihood of achieving them and the durability of gain can only be estimated.Undesired outcomes include both short-term complications and more commonly, recurrence of symptoms or need for reintervention. The balance between presumed benefits and undesirable outcomes is influenced by patient-specific risk factors(eg, comorbidities, anatomic complexity) and trade-offs inherent in the mode of revascularization under consideration, taken within the context of the patient's values and preferences.

appropriate for preventing graft failure.1 Other excep-tions may include treatment of an asymptomatic high-grade lesion to provide safe access for another indicated intervention (eg, endovascular aortic procedures).

Adverse events potentially associated with revasculari-zation can be short-term or long-term in nature. Short-

term events include peri-procedural morbidity, including MACE or MALE. Long-term adverse events attributable to revascularization are primarily limb-related. With any intervention, there is the potential for technical compli-cations with important clinical sequelae(such as throm-bosis, distal embolization, or dissection) or future failure

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of the lesion revascularization despite initial technical success. Mid-term or late-term failure can potentially lead to reinterventions, ALI events, or MALE.Treatment failure at any point in time may result in deterioration to CLTI and an associated risk of limb loss greater than that expected for patients with IC treated conservatively.75,76

In addition, the patient's life expectancy and the func-tional limitations imposed by co-existing comorbidities are critically important in considering the potential ben-efits of revascularization for IC. The authors recommend that a full discussion outlining these potential outcomes for each individual patient with IC, based upon their risk factors, anatomy, and the proposed treatment modal-ities, should be made within the context of a shared decision-making process(Fig 1). The decision to revascu-larize should also be informed by expected effectiveness of complementary treatment strategies, and most importantly, the patient's goals, values, and preferences.Such a framework facilitates a comprehensive, patient-oriented discussion that can aid in deciding whether to pursue revascularization. It should be clear that such a discussion requires significant time for patient education and is facilitated by serial engagements without undue time pressure. Shared decision-making has been shown to improve patient satisfaction and, in some cases,reduce health care costs in other medical specialties such as orthopedic surgery. ${}^{77-79}$

Presently, there is significant variability in both the sur-gical and endovascular techniques utilized to treat lower extremity arterial occlusive disease. There is also consid-erable heterogeneity in study designs, patient selection,and endpoints in the literature pertaining to the effec-tiveness of various revascularization strategies for IC,which greatly limits our understanding of the compara-tive effectiveness of revascularization to non-interventional treatments and between various revascu-larization strategies.

Significant practice variation may not be surprising given the dearth of high-quality evidence comparing revascularization with non-interventional treatments for claudication. Further, there is no level I data directly comparing endovascular and surgical revascularization strategies for IC. Given the current state of the clinical sci-ence, we focused on defining the key patient-centered outcomes after revascularization and the predictive fac-tors for these outcomes to provide an evidentiary frame-work for shared decision-making conversations in everyday practice. The authors identified MACE, MALE,target limb reintervention, functional gain, HRQoL and long-term mortality as critical outcomes after revascular-ization for IC.

Periprocedural MACE. Periprocedural MACE are defined as stroke, M l, or death within 30 days of revascu-larization, as previously defined in the SVS's Objective Performance Coals for revascularization in the setting

of CLTI. This measure is also applicable to revasculariza-tion for IC.80 Given that cerebrovascular disease(CVD),CAD, and PAD often coexist, PAD and IC should be regarded as markers for increased risk of fatal and nonfatal cardiovascular events. Approximately 2% to 4%of patients with IC experience a nonfatal cardiovascular event annually. The risk of such events is higher in the first year after onset of IC symptoms than in the patient with longstanding stable claudication symptoms. The patient with IC is more likely to experience a nonfatal MI or stroke than to require a major amputation for leg ischemia.66 MACE is two-fold higher following lower ex-tremity bypass for IC as compared with endovascular intervention for the treatment of IC, primarily attribut-able to an increased rate of cerebrovascular accident(CVA) and MI.80 Independent predictors of MACE following open or endovascular revascularization for IC include age>65 years(HR,3.3; 95% CI,1.7-9.3),CHF(HR,3.042; 95% CI, 0.5-17.9), CAD(HR, 2.7; 95% CI, 1.668-4.3),COPD(HR,2.160;95% CI,1.169-3.991),and DM(HR,1.3;95%CI,1.2-1.4)(Table; Fig.2). Dialysis dependence is also associated with increased likelihood of MACE.80 Notably,the Cls around the risk estimates in this analysis are wide due to limitations in the quality and heterogeneity of reported studies.

MALE. MALE after open or endovascular intervention for IC is a composite outcome that is defined as above-the-ankle amputation or major reintervention(new bypass graft, jump/interposition graft revision, or throm-bectomy/thrombolysis) of the index limb.101-103 MALE has been recommended as one metric of the objective per-formance goals for catheter-based interventions for CLTI and also has relevance for the treatment of IC.101 More recently, a modification of MALE has been defined to include episodes of ALI.104 Because the natural history of IC rarely involves major amputation(estimated 1%-3% 5-year risk). any revascularization for IC should carry a negligible risk for amputation.66,105 MALE should be considered a safety measure for revascularization in the setting of IC. Any major amputation after revasculariza-tion for IC should be considered an absolute failure and is inconsistent with the treatment goals and expected outcomes for lifestyle-limiting claudication.

Factors associated with an increase in MALE following revascularization for LC include age>80 years(HR, 1.7;95% CI, 1.8, 0.3-8.7), poorly controlled DM(HR, 1.7; 95% CI, 1.1-2.5), and prior revascularization(HR, 1.8; 95% CI, 1.2-2.6).(Table: Fig 3). Lesion characteristics and the pattern of occlusive disease also affect the risk for major amputation following peripheral interventions. For example, isolated femoropoplite disease carries a lower risk for major amputation after endovascular intervention compared with more diffuse disease involving both the femoropropli-teal and infrapopliteal segments when the lesion un-dergoes intervention. ${}^{80,89,93}$ The presence of a chronic occlusion(as opposed to stenosis) and lesion length

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Table. Factors associated with increase in major adverse cardiac events(MACE), major adverse limb events(MALE), rein-terventions, mortality, and major amputation following revascularization for intermittent claudication $(IC)^{11}$

||MACE|MALE|Reintervention|Survival|Major amputation| |---|---|---|---|---|---| |Patient factors|Age>65|DM82|Female 83|CAD84-88|CHF89| ||DM80,81,84-86,90||DM83,91|DM84,85,88,90,92|DM89,90,93,94| |||Prior intervention ${}^{80}$||COPD87|| ||CAD81,84,85||||| ||COPD80||||| ||ESRD80||||| |Anatomical factors||Infropapliteal disease ${}^{a,80}$|Infropapliteal disease ${}^{a,93}$|Infropopliteal disease ${}^{93}$|| ||||Longer lesion length (>10cm)a,83,91,95||| ||||Bilateral disease ${}^{a,91}$||| |Procedural factors|Open surgery||PBA9,96,97||| ||||No drug elution ${}^{a,98-100}$||| ||||||| |CAD,Coronary artery disease: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease: PBA, plain balloon angioplasty.|||||| |a Risk factors for outcome after endovascular, but not open, revascular||||||

 Fig 2. Forest plot of factors associated with major adverse cardiac events(MACE) following revascularization for intermittent claudication(IC). BMS. Bare metal stent: CAD. coronary artery disease; CHF, congestive heart failure;CI, confidence interval: COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DM, dia-betes mellitus.

greater than 10 to 20 cm are also associated with down-stream risk of major amputation after PVI.91,95

Reintervention. Given the progressive nature of PAD and the significant incidence of restenosis, repeat inter-vention is relatively common after revascularization. As a matter of principle. open or endovascular revasculari-zation for claudication should not be considered a cure for the underlying disease. This fact should be discussed openly with patients, and the expected durability of the interventions under consideration should be explained.Research indicates that patients with claudication cite expected durability of a procedure as of key importance

in their treatment decision-making. ${}^{106}$ The 2015 SVS CPGs on the management of asymptomatic PAD and IC suggested a minimum threshold of a>50% likelihood of sustained efficacy of intervention for at least 2 years as a benchmark, with anatomic patency a prerequisite for sustained efficacy.1 Although reintervention is depen-dent on a myriad of factors, certain patient,lesion, and device characteristics are associated with higher rates of repeat intervention(Fig 4).These factors include female sex, the presence of bilateral disease, and anatomic complexity(eg,occlusions and longer lesion lengths). ${}^{107}$ Finally,reintervention following endovascular treatment

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  Fig 3. Forest plot of factors associated with major adverse limb events(MALE) following revascularization for intermittent claudication $(IC),{}^{11} C I$ , confidence interval: $C O P D$ , chronic obstructive pulmonary disease; $D M, dia-$

is more common in patients with multilevel disease and for territories more distal in the arterial tree, particularly below the knee. A consistent theme across our literature review was that open or endovascular treatment of infra-popliteal occlusive disease is strongly associated with higher rates of MALE(HR, 2. 2: 95% CI, 1.5-3.2),amputation(HR,4.6;95% CI,3.5-5.9),and reintervention(HR,1.2;95% CI,1.1-1.4).The evidence for primary stenting over PBA with provisional stenting for the treatment of aorto-iliac lesions is limited but is commonly prac-ticed. ${}^{108-110}$

BMS, DCB angioplasty, and DES are associated with improved mid-term patency over PBA in the femoropo-pliteal segment with limited evidence for improved walking performance or quality of life(QoL).11,112 Data on the effectiveness of specialized balloons(eg, intravas-cular lithotripsy) or the adjunctive use if intravascular ul-trasound are limited at present and require future study.Atherectomy has not demonstrated any clear benefits over PBA.112-114 Finally, there is no good evidence to sup-port endovascular reintervention for restenosis after PVI solely based on imaging findings on surveillance in the absence of symptoms. Although there is evidence to support reintervention to maintain a peripheral bypass,no such evidence exists to support repeat intervention,which is not clinically driven. to maintain the patency of endovascular reinterventions in IC. Current evidence,although limited, suggests a benign natural history for asymptomatic restenosis after endovascular intervention and shows no clear benefit to non-clinically driven target lesion revascularization of restenotic lesions in compari-son to observation.115,116

Open revascularization for IC. Because the majority of new data that have emerged since the 2015 SVS CPC has focused on endovascular intervention, much of this up-date related to PICO question 6 lacks specific evidence regarding open surgery outcomes. This is not intended to diminish the role of open revascularization for claudi- cation. Open revascularization for diffuse aorti-iliac dis-ease remains a durable treatment option for properly

selected patients who are fit for the procedure. Femo-ropoliteal bypass, especially when performed with autogenous greater saphenous vein conduit, remains an effective operation for patients with complex or long-segment disease who are deemed acceptable risk.Finally, hybrid operations such as femoral endarterec-tomy combined with proximal and/or distal peripheral interventions have become common procedures for re-lief of caudication in well-selected patients. Comparative studies contrasting open and endovascular interventions for defined patterns of disease are needed.

Long-term mortality. Long-term mortality in patients with PAD and symptoms of IC has been noted to be approximately 30% at 5 years, 50% at 10 years, and 70% at 15 years.66 Mortality17 risk in this population is approximately 2.5 times that of an age-matched cohort in the general population. Factors associated with increased long-term mortality in patients with IC un-dergoing revascularization procedures include COPD,left ventricular dysfunction, DM, CAD, and intervention for infrapopliteal vs femoroploliteal occlusive disease(Table; Fig 5). Given that interventions for IC are primarily targeted at QoL appropriate consideration of estimated survival is paramount to good patient selection.

Functional outcomes after intervention. The impor-tance of functional performance as an outcome measure after revascularization is obvious, as the primary goal of any intervention for IC is improved walking ability. A 2021 network meta-analysis comparing the efficacy of medical optimization, exercise therapy, and endovascular revascularization on MWD within randomized control tri-als, found that ER alone failed to improve MWD at short-(1<1 year), moderate-(1-2 years), or long-term(>2 years)follow-up. At moderate-term follow up, both SET and ER+SET improved MWD compared with controls. None of the treatments demonstrated sustained improvement in MWD after 2 years. The data on functional gain after revascularization for IC remains woefully sparse, and larger long-term studies are needed. Functional status can be measured by a variety of walking tests and walking

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 Fig 4. Forest plot of factors associated with reintervention following revascularization for intermittent claudication(IC).BA,Balloon angioplasty:BMS,bare metal stent:Cl,confidence interval;DCB,drug-coated balloon;DES,drug-eluting stent; DM, diabetes mellitus; FP, femoropoulteal.

 Fig 5. Forest plot of factors associated with long-term mortality following revascularization for intermittent claudication(IC).11 BA Balloon angioplasty; BMS, bare metal stent; CAD, coronary artery disease; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident;DCB, drug-coated balloon; DES, drug-eluting stent; DM, diabetes mellitus.

distance scores as outlined in PICO question 5, including the 6-MWT, MWD,pain-free walking distance(PFWD), and the Walking Distance Score(WDS). The results of this re-view identified adjunctive exercise as a factor associated with improved MWD after revascularization. However,although adjunctive exercise therapy after revasculariza-tion was associated with improved MWD, it was not associated with significant differences in other measures of functional status. The need for better data on expected functional change following interventions for IC is glaring

and paramount to informed decision-making with patients.

Health-related quality of life. The use of QoL measures as key outcomes after revascularization is logical and valuable as the goals of improved physical function, per-formance of daily activities, and pain-free walking are subjective. A variety of general and disease-specific in-struments have been utilized to measure QoL in IC as outlined in PICO question 5. Unfortunately. ${}^{118}$ compara-tive studies employing QoL assessments in IC are

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extremely limited in scope and quality. Therefore, no treatment factors have been definitively identified to meaningfully and durably influence QoL after revascu-larization for IC. The need to assess the impact of revas-cularization on long-term QoL in patients with IC is a glaring deficit that requires well-designed, large-scale clinical trials with adequate follow-up.

Patient values, preferences, and potential obstacles.We have identified several factors associated with adverse short- and long-term outcomes after revascu-larization for IC (Table). These include a variety of patient and anatomical factors associated with MALE and rein-tervention after ER. The range of magnitude of these associations is quite broad. Vascular specialists should be aware of these higher risk conditions, communicate them to patients, and factor them into medical decision-making before revascularization. DM, for example, is a risk factor common to MACE, MALE, major amputation,and long-term mortality. Other factors such as bilateral disease, long segment disease or occlusions, prior revas-cularization, and the presence and treatment of infra-popliteal disease are associated with higher rates of MALE and reintervention after PVI. We suggest that cli-nicians use this information in conversations with pa-tients regarding their individualized risk and presumed benefits. Patients with these risk factors should be well-informed so they can factor them into their decision and also to promote better compliance with OMT and follow-up care.

References regarding revascularization for IC.

8. In patients who are being considered for revasculariza-tion for IC, we recommend that shared decision-making conversations should include each of the following risks and benefits: mortality, MACE, MALE(amputation, reintervention, ALI), functional gain, and HRQOL anticipated after revascularization. Best prac-tice statement.

9. In patients who are being considered for revasculari-zation for IC, we recommend that shared decision-making conversations involve an assessment of indi-vidual risk factors known to influence risks and bene-fits. These include key comorbidities(DM, CAD, CHF,COPD), history of prior limb revascularization,anatomic complexity of disease(ie, multi-level dis-ease, long segment disease, chronic total occlusions),and procedural strategy(ie, open surgery vs ER). Best practice statement.

10.We recommend against performing revascularization in patients with asymptomatic PAD or IC based solely on hemodynamic measurements or imaging find-ings.There is no evidence to support the use of revas-cularization for modifying disease progression. Level of recommendation: grade 1; Level of evidence: C.

Specific considerations

Regarding tibial interventions for claudication. Infra-popliteal interventions for claudication are bereft of data supporting their safety or efficacy yet appear to be increasing in frequency. Analysis of large, contemporary administrative claims databases have found that 10%to 20% of patients with IC undergoing an endovascular intervention include some treatment of infra-popliteal arteries. 93,119,120

In a recent analysis using Medicare claims data from 2017 to 2019, the prevalence of this practice appears to have markedly increased (28% of all index PVI proced-ures for caudication) and was associated with both pa-tient- and provider-specific characteristics. ${ }^{120}$ Despite the frequency of infrapopliteal PVI, evidence supporting tibio-peroneal artery interventions, alone or in combina-tion with aorto-iliac and/or femoropopliteal treatment,is lacking. To date, there are no randomized trials or studies examining the safety and efficacy of infrapopli-teal PVI for claudication. Decisions to treat appear to be based on local and specialty-specific practice patterns or the physician's individual treatment bias or training. ${ }^{120-123}$

Observational studies using registry and claims datasets have raised red flags about the wisdom of this practice.An analysis of the VQI data found that only 20% of com-bined femoropopliteal and tibial interventions were free from claudication at 2 years, which does not meet the 2015 practice guidelines set by the SVS of >50% experi-encing symptom relief. ${}^{123}$ Of more serious concern is that infrapopliteal interventions have been associated with an increased downstream risk of major amputation(Fig. 6) ${}^{80,89,93,124,125}$ Bypass to a tibial artery target for IC has historically undergone scrutiny, with a recent registry-based analysis reporting inferior results for all out-comes in comparison to bypass to a popliteal artery target. ${}^{126}$

The 2015 SVS practice guideline recommended against the use of endovascular intervention for iso-lated infrapopliteal disease in the setting of IC. The combined treatment of infrapopliteal disease down-stream from a more proximal (eg, aorto-iliac or femoro-popliteal) intervention in claudicants should be considered in a similar light. Limiting the procedure extent to treatment of the proximal disease alone leaves the patient with residual isolated infrapopliteal disease. It is recognized that there may be infrequent circumstances where technical success of the up-stream intervention is potentially compromised by distal disease, such as a severe stenosis of the tibiper-oneal trunk; however, this anatomic pattern should be fully considered prior to undertaking any intervention for IC (whether PVI or bypass).

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 Fig 6. Forest plot of factors associated with major amputation following revascularization for intermittent clau-dication(IC).BMS,Bare metal stent;CAD,coronary artery disease; CHF congestive heart failure; Cl, confidence interval; COPD, chronic obstructive pulmonary disease; DES, drug-eluting stent; DM, diabetes mellitus; FP,femoropoliteal.

In summary, comparative effectiveness data for infrain-guinal interventions in IC is limited. and nowhere is this more evident than in the treatment of infrapoliteal dis-ease. We suggest against performing endovascular or open infrapoliteal artery interventions for IC. This recom-mendation is consistent with the recently published SVS appropriate use criteria for management of IC.127

Regarding drug-coated devices and durability. Drug-coated devices, including balloons and stents, have been increasingly used for the treatment of claudica-tion.128 The use of paclitaxel for the treatment of femo-ropoliteal occlusive disease has been scrutinized because of a possible association with increased late mortality in one meta-analysis.129 A full consideration of this controversy is beyond the scope of this publication,but to date, the accumulated evidence, including pa-tient level meta-analysis, the Swedepad prospective trial,and multiple observational studies, does not support a mortality signal.130-135 The United States Food and Drug Administration(FDA) issued a statement that after additional analysis, the accumulated data does not indicate that the use of paclitaxel-coated devices is associated with a late mortality risk.136

In the setting of superficial femoral artery(SFA) inter-ventions for short- to intermediate-length lesions. DCB angioplasty has shown decreased reintervention rates compared with PBA with target lesion revascularization(TLR) rates ranging from 8% to 15% for DCB vs 17% to 28% for percutaneous transluminal angioplasty in ran-domized trials. ${}^{137-140}$ DES has shown decreased reinter-vention in comparison with BMS with comparative TLR rates of 4.5% to 9% for DES vs 17% for percutaneous transluminal angioplasty. ${}^{141,142}$ Two meta-analysis and a Cochrane review have found superiority of paclitaxel

devices for the outcome of TLR, whereas other outcomes have shown no difference.112,140,143 One meta-analysis re-ported comparable rates of freedom from TLR.144

It is important to recognize the limitations of TLR as an efficacy endpoint in claudication studies, as it captures neither anatomic patency nor functional gain for the pa-tient.TLR has been employed as a regulatory endpoint in FDA approval studies but is of limited relevance to clin-ical decision-making. In general, freedom from TLR rates in device trials are notably higher(eg, by 20%-30%) than objectively measured vascular patency. Many patients with IC who experience occlusion or restenosis may choose not to undergo a repeat revascularization pro-cedure. These trials are also largely limited to subjects with short- to intermediate-length SFA lesions(<15 cm).

Finally, conclusive evidence for an optimal ER strategy and device selection for the varying extents of anatom-ical disease is lacking. There is limited evidence that PBA performs as well as BMS for femoropopliteal lesions less than 5 cm in length.145 In contrast, there is a prepon-derance of data demonstrating improved patency for self-expanding stents over PBA and for drug-eluting de-vices(DCB or DES) over PBA and/or BMS.98,146 The major-ity of studies show these therapies to have benefit in femoro-popliteal lesions averaging between 5 and 10 cm in length, although some studies have addressed lesions greater than 10 cm in length.98,112,146-150 Studies have not clearly defined the impact of anatomic charac-teristics such as the presence of occlusion vs stenosis or other morphologic characteristics(eg. vessel size, calcifi-cation) on the effectiveness of these various endovascular therapies. Studies have also not evaluated the cost effec-tiveness of BMS or DES implantation or DCB use relative to the severity of disease treated. The role for newer

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specialized balloons such as intravascular lithotripsy, as well as the use of intravascular ultrasound to improve procedural success, is currently unclear and requires future study. As stated above, current evidence based on observational datasets fails to demonstrate a benefit for use of atherectomy over the other alternatives. Taken as a whole, evidence for the superiority of any one partic-ular endovascular approach based upon lesion length or other anatomic markers of disease severity is largely inconclusive. As a result, significant heterogeneity in practice persists, and future studies should focus on head-to-head randomized comparisons in defined anatomic subsets.

11.In patients with IC and no signs of CLTI, we suggest against the use of infrapopliteal revascularization,either alone or in combination with a more proximal intervention, due to lack of evidence of benefit and potential harm. Level of recommendation: grade 2;Level of evidence: C.

12.In patients with IC who are selected for an endovascu-lar intervention to treat femoropopliteal disease and have lesions exceeding 5 cm in length, we recom-mend the use of either BMS or drug eluting devices(DCB or DES) over PBA to reduce the risk of restenosis and need for reintervention. Level of recommenda-tion: grade 1; Level of evidence: B.

Patient Advisor feedback regarding PICO question 6 and related recommendations

In general, the Patient Advisors agreed that more infor-mation is better than less. Specific kinds information they believed should be included in counseling included a review of the options under consideration, the option recommended by the clinician and why, and the antici-pated incremental benefit achievable through the recom-mended treatment. The Patient Advisors asked about anticipated symptoms and implications of loss of patency following a vascular intervention. They also recommended development of a list of questions that patients should ask their health care providers about claudication treat-ment. The Patient Advisors also discussed QoL as a concept. Specific examples mentioned as elements of QoL included recreation, participating in family or group gatherings, and sex. Golfing and fishing were specific ac-tivities mentioned by Patient Advisors as both examples of QoL and activities that might also be used as treatment goals(ie, becoming able to golf or fish through a claudica-tion treatment intervention). Age was an important contextual element that affected both QoL and treat-ment goals. Some Patient Advisors expressed a strong preference for conservative treatment strategies that avoided revascularization. if possible, whereas others instead favored more aggressive and intensive treatment strategies at an early stage.

Major unmet research needs

<BeginOfPara>1.Comparative effectiveness studies to compare

<EndOfPara>outcomes of treatment strategies(pharmacotherapy,exceednascular interventions) in pa-tients with IC due to femoropopliteal disease

2.Prospective cohort studies to better define the magnitude and duration of symptom relief and func-tional improvement following revascularization for IC, and the critical factors that drive these outcomes

3. Prospective cohort studies to better define the long-term risks of invasive procedures for IC including ac-celeration of natural history of disease, and to opti-mize surveillance strategies to reduce downstream MALE or progression to CLTI

4.Comparative trials to define the relative effectiveness of SET vs HET in IC, and to determine the optimal pro-tocol for HET(coaching, activity tracking, walking to pain.number of minutes)

5.Develop approaches to increase engagement of pa-tients into IC research studies.

6.Better understand the mechanisms of lower limb myopathy in IC and its implications for disease pro-gression, exercise, treatment responses, and new therapeutics

7.Studies to define the role of, and optimal protocol for,post-revascularization exercise therapy for IC.

Patient Advisor feedback regarding unmet needs and future questions

The Patient Advisors suggested that more specific de-scriptions of procedure-related pain (ie, anticipated level and duration of pain that was quantified) would be help-ful when considering treatment options. They also rec-ommended exploration of the heterogeneity of treatment goals and outcomes to support individualized decision-making and outcomes expectations.

The SVS would like to acknowledge the contributions of the patient panelists, Paul A. Carlson, Curt Conrad,Steve Hamburger, Raynard Johnson, Debbie Moore,and Julie Thomson for sharing their valuable feedback and perspective. The authors would also like to acknowl-edge Mary Bodach, MLIS, and Reva Bhushan, PhD, for their invaluable assistance in the development of this manuscript.

AUTHOR CONTRIBUTIONS

Conception and design: MSC,BA,MB,DB,MAC,HM RP,AR,WR,JS

Analysis and interpretation: MSC,BA,MB,DB,MAC,HM RP,RP,WR,JS

Data collection: MSC,NC,BM,MAC,HM

Writing the article: MSC,BA,MB,DB,MAC,HM RP,WR,JS Critical revision of the article: MSC, NB, DB,HM,JS Final approval of the article: MSC,BA,MB,DB,MAC,HM

RP,AR,WR,JS

Statistical analysis: MSC, DB

Obtained funding: Not applicable

Overall responsibility: MSC

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323

FUNDING

None

DISCLOSURES

MHM leads the Mayo Clinic Evidence-based Practice Center, which received funding from the Society for Vascular Surgery to conduct systematic reviews to sup-port their guidelines.

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Submitted Apr 24,2025.

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APPENDIX(online only).

Evidence to Decision Framework Worksheets

Intervention: the addition of low dose irrevoraxaban to baseline aspirin in patients with peripheral artery disease(PAD) and no prior lower extremity intervention.

Alternative strategy: aspirin alone.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|5% vs 7%(HR, 0.72; P=.0047) for composite endpoint of cardiovascular death, stroke, or M1 in the overall COMPASS trial outcomes. There were significant reductions in the rates of pre-specified limb outcomes, including: ALI(1% vs 3%: HR, 0.56; P=.042), MALE(1% vs 2%; P=.0054), vascular amputations(<1% vs 0.1%; P=.0069), and major amputations(<1% vs 1%; P=.0011).[Anand 2018] Most pronounced in patients with high-risk comorbidity (diabetes, heart failure, CKD, or polyvascular disease; 12.4% incidence of MACE or MALE over 30 months) or high-risk limb presentation(rest pain, tissue loss, prior leg amputation, or prior revascularization: 13.7% incidence of MACE or MALE over 30 months) [Kaplovitch 2021].|Moderate| |How substantial are the undesirable anticipated effects?|There is an increased rate(3% vs 2%: HR, 1.61; P=.0089) for major bleeding. No significant increase(1% vs 1%; HR, 113) in "fatal or symptomatic bleeding into a critical organ or surgical site bleeding leading to reoperation."|Small| |Is there important uncertainty or variability about how much people value the main outcomes?|No clear evidence of variability between how patients perceive or value the outcomes|Probably no important uncertainty or variability| |What is the overall certainty of the evidence of effects?|Single randomized clinical trial, albeit large and consistent with VOYAGER|Moderate| |Do the desirable effects outweigh the undesirable effects?|For every 1000 patients treated, 27 MACE or MALE including major amputation would be prevented and one fatal and one critical organ bleed would be caused over a 21-month period.|Probably yes| |How large are the resource requirements associated with the intervention?|Retail price $609/month (as of May 2024)|Moderate cost| |How large is the incremental cost relative to the net benefit?|Not formally studied.|Large ICER| |What would be the impact on health inequities?|Not studied. Would depend on prescribing practices/ access to rivaroxaban.|Unknown| |Is the option acceptable to key stakeholders?|Not queried,though net clinical benefit seems favorable. Would probably be heavily influenced by out-of-pocket costs. Patient acceptability of an additional BID drug, and increase in bruising/minor bleeding, may be limiting.|Unknown| |Is the option feasible to implement?|Yes, medical therapy alone (thus feasible)|Yes| |ALI, Acute limb ischemia: CKD, chronic kidney disease: HR,hazard ratio: ICER, incremental cost-effectiveness ratio: MACE,major adverse cardiovas cular events: MALE,major adverse limb events: M1, myocardial infarction.|||

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Intervention: the addition of low dose rivaroxaban in patients with PAD and claudication symptoms who are undergoing lower extremity intervention (ie, pending/planned/during the index hospitalization)

Alternative strategy: aspirin alone.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|Rivaroxaban was associated with a significant reduction (17.3% vs 19.9%; HR, 0.85; P=.009) for composite endpoint of cardiovascular death, stroke, MI, major amputation for vascular causes, and ALI. [VOYAGER trial, Bonaca 2020]. The benefit in this composite endpoint (26.9% vs 16.7%; P<.05) and net clinical benefit (24.9% vs 19.2%; P=.0457) seem most pronounced in patients with critical limb ischemia [Bonaca MP et al. Symposium presented at: AHA 2020; November 14, 2020; Virtual.] and in patients undergoing recurrent (rather than initial) revascularization (23.8% vs 17.5%; HR, 0.73] [Bonaca MP et al. Symposium presented at: CRISE 2020; September 2020] Decreases in this composite endpoint were not significant in patients with diabetes, however (18.1% vs 20.2%; HR, 0.89; 95% CI, 0.74-1.08). Decreases in the composite endpoint were not affected by age. "fragility" (CKD, elderly or underweight: not the same as frail, or endovascular revascularization. ALI in the first 6 months following revascularization was halved (1.7% vs 3.2%; P=.049) with the use of rivaroxaban. The degree of benefit in reducing ALI seems consistent among all patients undergoing revascularization, irrespective of whether the indication was cludication vs critical limb ischemia, whether the revascularization was surgical or endovascular, whether the conduit for surgical bypass was prosthetic or vein, and whether clipodregl was also given. [Hess CN et al. Symposium presented at: ESC 2020; September 1, 2020; Virtual]. This benefit seems more pronounced in patients with CKD [Hsia J et al. Symposium presented at: AHA 2020; November 2020; Virtual]. Rivoxaban had no impact on all-cause mortality [Bonaca 2020].|| |How substantial are the undesirable anticipated effects?|No significant overall difference (2.65% vs 1.87%; HR, 1.43; P=.07) for TIMI major bleeding. The subgroup with diabetes had higher rates of TIMI major bleeding (3.9% vs 1.2%; HR, 2.45; P=.005). When using the alternative ISTH definition of major bleeding, there was a significant increase seen in the dual-treated patients (4.3% vs 3.08%: HR, 1.42; P=.007).|Small| |Is there important uncertainty or variability about how much people value the main outcomes?|No clear evidence of variability between how patients perceive or value the outcomes|Probably not important| |What is the overall certainty of the evidence of effects?|Two randomized clinical trials: VOYAGER and subgroup analysis of COMPASS.|Moderate| |Do the desirable effects outweigh the undesirable effects?|Yes: "We estimate that for every 10,000 patients who were treated for 1 year,rivaroxaban at a dose of 2.5 mg twice daily added to aspirin would prevent 181 primary efficacy outcome events at the cost of 29 principal safety outcome events." Based on these calculations, the number needed to treat is 55.|Probably yes| |How large are the resource requirements associated with the intervention?|Retail price $609/month (as of May 2024)|Moderate cost|

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Volume 82. Number 2

Continued

|Domain|The effects|Judgment| |---|---|---| |How large is the incremental cost relative to the net benefit?|Not formally studied.|Large ICER| |What would be the impact on health inequities?|Not studied. Would depend on prescribing practices/access to rivaroxaban.|Unknown| |Is the option acceptable to key stakeholders?|Not queried, though net clinical benefit seems favorable. Would probably be heavily influenced by out-of-pocket costs.|Unknown| |Is the option feasible to implement?|Yes, medical therapy alone (thus feasible)|Yes| |ALI, Acute limb ischemia; Cl, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; ICER, incremental cost-effectiveness ratio; ISTH, In-ternational Society on Thrombosis and Haemostasis; M1, myocardial infarction: T/MI, thrombolysis in myocardial infarction.|||

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Strategy/treatment/test/intervention: the addition of rivaroxaban in patients with PAD and WITH a PRIOR his-tory of lower extremity intervention.

Alternative strategy: aspirin alone.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|Trial results of overall COMPASS trial cohort. 35.6% of whom had a prior history of lower extremity revascularization. [Anand 2018]. Specific COMPASS trial subgroup analysis focused on high-risk limb presentation subgroup (which included patients with prior revascularization). The 30-month incidence of the composite primary endpoint was 11.8% (not as high as participants who had prior leg amputation (22.6%) or patients with critical limb ischemia (Fontaine III/IV patients, 17.6%] [Kap/lovitch 2021]|Moderate| |How substantial are the undesirable anticipated effects?|No significant difference (2.65% vs 1.87%; HR.1.43; P=.07) for TIMI major bleeding.|Small| |Is there important uncertainty or variability about how much people value the main outcomes?|No clear evidence of variability between how patients perceive or value the outcomes|Probably not important uncertainty or variability| |What is the overall certainty of the evidence of effects?|Two randomized clinical trials: VOYACER and subgroup analysis of COMPASS.|Moderate| |Do the desirable effects outweigh the undesirable effects?|Yes, the net clinical benefit remains positive in the high-risk limb subgroup of COMPASS (as well as high-risk comorbidity). From Kaplovitch 2021: 'Overall, the net clinical benefit ... remained in favor of rivaroxaban and aspirin compared with aspirin alone (HR. 0.78; 95% CI. 0.63-0.95)... equivalent to an estimated 31 events prevented per 1000 patients treated over 30 months." Based on these calculations, the number needed to treat is 32.|Probably yes| |How large are the resource requirements associated with the intervention?|Retail price $609/month (as of May 2024)|Moderate costs| |How large is the incremental cost relative to the net benefit?|Not formally studied. informal calculation: $751 per composite endpoint avoided|Large ICER| |What would be the impact on health inequities?|Not studied. Would depend on prescribing practices/access to rivaroxaban. Is the option acceptable to key stakeholders?不 queried, though net clinical benefit seems favorable. Would probably be heavily influenced by out-of-pocket costs.|Unknown| |Is the option feasible to implement? CI. Confidence interval: H.R. hazard ratio: lCER. incremental cost-effectiveness ratio: T/1M, thrombolysis in myocardial infarction.||Yes|

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Volume 82, Number 2

Intervention: ticagrelor 90 mg daily as monotherapy or in addition to aspirin in patients with peripheral artery disease.

Alternative strategy: clopidogrel monotherapy; dual antiplatelet therapy with clopidogrel+ aspirin.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|Ticagrelor may consistently reduce platelet reactivity, but this does not result in less neointimal hyperplasia after femoropopliteal stent placement than clopidogrel.[Ducci et al.] Compared with clopidogrel.ticagrelor did not significantly reduce a composite endpoint of adjudicated cardiovascular death, MI, or ischemic stroke(10.8% with ticagrelor.10.6% with clopidogrel.HR,1.02;95% CI,0.92-1.13;P=.65[Hiatt et al]). Compared with clopidogrel.ticagrelor did not significantly reduce rates of hospitalization for AL(1.7% vs 1.7% for ticagrelor vs clopidogrel,respectively;P=.85).rates of lower limb revascularization (12.2% vs 12.8%; P=.30), or combined rates of coronary, limb mesenteric, renal, carotid, and other revascularizations (17.5% vs 18.0%;P=.46).|Trivial| |How substantial are the undesirable anticipated effects?|No significant increase in TIMI major bleeding (1.6% in both the clopidogrel and ticagrelor groups [Haiatt et al.]).|Trivial| |Is there important uncertainty or variability about how much people value the main outcomes?|No clear evidence of variability between how patients perceive or value the outcomes|Probably no important uncertainty or variability| |What is the overall certainty of the evidence of effects?|Findings are from one large (13.885 patients) multi-center randomized controlled clinical trial [Haiatt et al.] and one small (40 patient) single-center RCT.|Low| |Do the desirable effects outweigh the undesirable effects?|No - no significant benefit identified in two clinical trials.|Probably no| |How large are the resource requirements associated with the intervention?|The current retail price of ticagrelor is $471 per month[drugs.com as of 9/30/23]. Now that clopidogrel is available as a generic medication, the price is significantly lower than the price of ticagrelor($4-15/month).|Moderate costs| |How large is the incremental cost relative to the net benefit?|"Dominated" in cost-utility terminology(higher cost,no difference in clinical outcomes).|Large ICER| |What would be the impact on health inequities?|May impose out-of-pocket expenses.|Unknown| |Is the option acceptable to key stakeholders? Is the option feasible to implement?|Possibly acceptable. Some clinicians may feel strongly about more consistent inhibition of platelet reactivity despite higher retail prices.|Unknown| |Is the option feasible to implement?|Yes, feasible - exchange of one antiplatelet medication for another.|Yes| |ALI, Acute limb ischemia: Cl, confidence interval: HR, hazard ratio: ICER, incremental cost-effectiveness ratio: MI, myocardial infarction: RCT, ran-domized controlled trial: T/1M, thrombolysis in myocardial infarction.|||

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Intervention: vorapaxar 2.5 mg daily in addition to aspirin for patients with peripheral artery disease.

Alternative strategy: aspirin alone; aspirin+rivaroxaban.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|A significant (1.6% absolute) reduction in hospitalization for ALI (2.3% vs 3.9%; HR, 0.84; 95% CI, 0.39-0.86; P=.006). A significant (3.6% absolute) reduction in peripheral revascularization (18.4% vs 22.2%; HR, 0.84; 95% CI, 0.73-0.97). A significant (2.2% absolute) reduction in urgent hospitalization for a vascular cause of an ischemic nature (limb as well as coronary and cerebral circulation: 5.8% vs 8.0%; HR, 0.72; 95% CI, 0.56-0.93; P=.01). No significant decrease in the incidence of the composite endpoints of cardiovascular death, MI, or stroke (11.3% vs. 11.9%; HR, 0.94; 95% CI, 0.78-1.14; P=.53) [Bonaca et al.]|Small| |How substantial are the undesirable anticipated effects?|A significant (2.9% absolute) increase in CUSTO moderate or severe bleeding (7.4% vs 4.5%; HR, 1.62; 95% CI, 1.21-2.18; P=.001). No significant difference in rates of intracranial hemorrhage (0.9% vs 0.4%; HR, 2.03, 95% CI, 0.82; 5.0% or 1.02; HR, 0.12; 95% CI, 0.35-2.90; P=.98).|Moderate| |Is there important uncertainty or variability about how much people value the main outcomes?|Bleeding complications of any severity (Bleeding Academic Research Consortium type 1+) are associated with significant decreases in health utility and HRQOL [Amin et al.], whereas revascularization events do not have a significant impact on quality of life [Neuwah et al.]. No clear evidence of variability between how patients perceive or value the outcomes.|Probably no important uncertainty or variability| |What is the overall certainty of the evidence of effects?|Evidence from a single large clinical trial.|Low| |Do the desirable effects outweigh the undesirable effects?|Significant increase in moderate or severe bleeding is not outweighed by the small absolute decrease in "urgent hospitalization for a vascular cause" without a significant reduction in cardiovascular death, MI, or stroke.|No| |How large are the resource requirements associated with the intervention?|$309 for a 30 -day supply of vorapaxar [Drugs.com, 9/29/$ 2023]|Moderate costs| |How large is the incremental cost relative to the net benefit?|"Dominated" in cost-utility terminology (ie.higher costs with poorer health outcomes).|Large ICER| |What would be the impact on health inequities?|With high cost and clinical benefit outweighed by clinical harms, it is unlikely to impact health inequities.|Unknown| |Is the option acceptable to key stakeholders?|No literature.|Unknown| |Is the option feasible to implement?|Yes, as it is a single medication and "annualized treatment discontinuation was similar to other trials of antiplatelet therapies in stable populations" [Bonacata et al.]|Probably yes| |ALI,Acute limb ischemia: CI,confidence interval: CUSTO,global use of streptokinase in myocardial infarction trial:HR,hazard ratio:HRQoL.health-related quality of life:ICER,incremental cost-effectiveness ratio:MI,myocardial infarction.|||

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Volume 82, Number 2

Intervention: HET.

Alternative strategy: SET.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|Results are mixed between studies, but generally indicate none-to-small benefit to HET as compared with SET. Home-based exercise trials that included a cognitive-behavioral component were more beneficial than home-based exercise without this. HET demonstrated benefit over no exercise therapy.|Small| |How substantial are the undesirable anticipated effects?|The HONOR trial reported difficulty in walking and increased shortness of breath in both the home-based exercise group and the usual care group. The NEXT Step trial did not report any adverse events related to the study.|Trivial| |Is there important uncertainty or variability about how much people value the main outcomes?|Possibly yes, with prior studies(not included in this syst. rev.) defining thresholds of clinical significance for both walking distance and HR-QoL scores|Possibly important uncertainty or variability| |What is the overall certainty of the evidence of effects?|Low due to imprecision and other study limitations|Low| |Do the desirable effects outweigh the undesirable effects?||Probably yes| |How large are the resource requirements associated with the intervention?|Porily defined/not reported|Unknown| |How large is the incremental cost relative to the net benefit?|Porily defined/not reported|Unknown| |What would be the impact on health inequities?|Probably improved: potential benefits in terms of increased access to exercise therapy, no copays, flexible scheduling that limits intrusion on employment. Potential drawbacks when smart phones/wearable technology is required|Probably you improved| |Is the option acceptable to key stakeholders?|In the HONOR trial, follow up rates were high in both groups at 9 months. However, the increase in walking episodes per week was not maintained at 9-month follow-up, suggesting that acceptability may decline over time. The NEXT Step trial only had follow-up out to 3 months and used a lead-in phase for enrollment.|Probably yes| |Is the option feasible to implement?|Yes, although with notable limitations when smart phones± wearable technology is required. It is also unclear how extensive the check-ins must be, so that feasibility cannot be assessed.|Probably yes| |HET.Home-based exercise therapy: HRQoL health-related quality of life: SET, supervised exercise therapy.|||

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Intervention: Vascular intervention plus exercise therapy.

Alternative strategy: Exercise therapy without proce-dural intervention.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|Desirable effects among RCTs limited to single SF-36 domain, role emotional domain score, that demonstrated superiority of exercise alone at 5 years (Djerf, Millinger et al [IRONIC]. 2020). Bo et al noted additive benefit of angioplasty + SET over angioplasty alone (no exercise alone group) in 29 patients at 3 months for 6MWT, MWD, and PFWD but not HRQoL.|Small| |How substantial are the undesirable anticipated effects?|5-year results of the IRONIC study identified increased rates of death and decline in MWD among patients treated with revascularization plus exercise therapy, although neither of these was a primary endpoint.|Moderate| |Is there important uncertainty or variability about how much people value the main outcomes?|No clear evidence of variability between how patients perceive or value the outcomes. Combined intervention at early time points, which degrades over time.|Probably important uncertainty or variability| |What is the overall certainty of the evidence of effects?|Results of the IRONIC trial are relevant to this question but should be interpreted with the following appropriate perspectives. First, most participants in both randomization groups were active smokers and patients with severe, lifestyle-limiting claudication were excluded. The study inclusion criteria therefore are inconsistent with what most vascular surgeons and clinical practice guidelines would consider appropriate for revascularization in claudication. Second, the study used structured (not supervised) exercise therapy. Third, 25% of patients randomized to exercise had at least one revascularization post-randomization during the 5-year study period. Results of the ERASE study, which utilized supervised exercise, showed incremental benefit of exercise + revascularization over exercise alone at 1 year, but IRONIC results also showed early benefit of revascularization at 1 and 2 years that subsequently was lost.|| |Do the desirable effects outweigh the undesirable effects?|No adverse events associated with SET were identified. Adding revascularization adds cost and risk without clear benefit. Tradeoff therefore negligible for use of SET in addition to revascularization - trivial benefit but no risk of adding exercise to revascularization.|Probably no| |How large are the resource requirements associated with the intervention?|Djerf et al showed that revascularization was $5480-$6133 more expensive per patient over 5 years (P=.02).|Moderate costs| |How large is the incremental cost relative to the net benefit?|Djerf et al observed that revascularization was more expensive and associated with worse health outcomes; $5,503,448 per QALY|Large ICER| |What would be the impact on health inequities?|Unknown. This was not discussed in the studies; however, the high cost of revascularization would potentially suggest worsening of health inequities.|Unknown| |Is the option acceptable to key stakeholders?|Crossovers to revascularization were common, suggesting that the exercise option was not acceptable to all patients in the long-term as monotherapy|Probably yes yes| |Is the option feasible to implement?|Some studies relied upon unsupervised exercise programs. which are likely less effective, although also less expensive than unsupervised programs. Cost challenges limit implementation of supervised exercise in the United States, especially beyond 12 weeks.|Unknown| |6MWT,6-minute walk test: HRQoL health-related quality of life; ICER, incremental cost-effectiveness ratio; MWD, maximum walking distance; PFWD pain-free walking distance: QALY, quality-adjusted life year; RCT, randomized controlled trial: SET, supervised exercise therapy.|||

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Volume 82, Number 2

Intervention: Revascularization on patients with asymptomatic PAD or in IC based solely on hemody-namic measurements, imaging findings, or to modify dis-ease progression.

Alternative strategy:Management without revascularization.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|The desirable effect of avoiding potential MACE and MALE related to revascularization would be perceived as substantial, although evidence supporting this benefit when the indication is only based on hemodynamics is unclear.|Unknown| |How substantial are the undesirable anticipated effects?|The undesirable effects of unnecessary revascularization in asymptomatic patients or those with mild IC are important.|Moderate| |Is there important uncertainty or variability about how much people value the main outcomes?|Little data specifically demonstrates how much patients value avoiding unnecessary procedures or fear disease progression. Patients value avoiding unnecessary procedures defined as ones which are not shown to improve duration or QoL. When properly educated on the natural history of asymptomatic PAD, as well as the risks of intervention. patients uniformly choose medical management and do not desire intervention.|Possibly important uncertainty or variability| |What is the overall certainty of the evidence of effects?|The potential risk of MACE and MALE with lower extremity PAD are well described. The natural history of the limb as well as systemic cardiovascular risk in patients with asymptomatic PAD are also well-described.|Low| |Do the desirable effects outweigh the undesirable effects?||Probably no Large costs| |How large are the resource requirements associated with the intervention?||| |How large is the incremental cost relative to the net benefit?|Savings would be anticipated with the nonoperative approach due to avoidance of initial revascularization procedures and follow-up care, including potential for reinterventions.|Unknown| |What would be the impact on health inequities?|Would mitigate health inequities as some data suggests minority populations more often undergo revascularization for IC, although the rates of revascularization for asymptomatic disease are not known as payment for these procedures would not be covered. Documentation for some patients with asymptomatic disease undergoing intervention may not be accurate.|Unknown| |Is the option acceptable to key stakeholders?|Physicians will likely oppose broad limitations on care that do not allow for physician and patient discretion but should support education for evidence-based care in order to avoid unnecessary procedures.|Unknown| |Is the option feasible to implement?|Patient education is required to dispel misguided patient concerns which may contribute to the expectation of revascularization in the setting of asymptomatic or mild PAD.|Probably yes| |/C,Intermittent claudication;MACE,major adverse cardiovascular events;MALE,major adverse limb events;PAD,peripheral artery disease;QoL.quality of life.|||

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Intervention: Revascularization for tibial-peroneal occlusive disease in patients with IC.

Alternative strategy: Confine revascularization to the aorto-iliac and/or femoral-popliteal segment in

<EndOfPara>patients with intermittent claudication. Maximize ex-ercise, smoking cessation, and cardiovascular medica-tions for patients with IC and tibial-peroneal occlusive disease.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|Benefit is trivial or unknown. In fact, harms are likely. Treatment of tibial-peroneal arteries is associated with an increase in MALE (OR.2.16), major amputations (OR. 4.57), and reinterventions (OR.1.24)|Trivial| |How substantial are the undesirable anticipated effects?|Bypass to a tibial artery is associated with $\sim 60\%$ increase in occlusion/death, major amputation/death and reintervention/amputation/death (Levin 2020) Isolated infropapliteal PVI is associated with an increased risk of major amputation (OR.6.47; 95% CI. 6.45-6.49; P <.0001)|Large| |Is there important uncertainty or variability about how much people value the main outcomes?|No clear evidence of variability between how patients perceive or value the outcomes|Probably no uncertainty or variability| |What is the overall certainty of the evidence of effects?|Very low secondary to study limitation.|Very low| |Do the desirable effects outweigh the undesirable effects?|Undesired effects include potential for undertreatment of select patients with severe claudication and anatomy conducive to a favorable long-term result|Probably no| |How large are the resource requirements associated with the intervention?|Bose et al report that 27% of Medicare patients undergo tibial PVI for claudication Potential exists for the wasteful use of available resources|Large costs| |How large is the incremental cost relative to the net benefit?|Bose et al report the average Medicare reimbursement per patient was dramatically higher for physicians performing high rates of tibial PVI We are unable to estimate the potential cost benefit.|Unknown| |What would be the impact on health inequities?|No likely impact on health inequities|Unknown| |Is the option acceptable to key stakeholders?|We understand some vascular specialists may offer infropapliteal revascularization for claudication.|Probably yes| |Is the option feasible to implement?|From our practice, it is feasible to limit tibial-peroneal interventions for the indication of claudication.|Yes|

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Volume 82, Number 2

Intervention: BMS or drug-eluting devices (DCB or DES)for intermediate length lesions of the superficial femoral-popliteal artery.

Alternative strategy: PBA as a stand-alone therapy for superficial femoral-popliteal artery lesions>5 cm.

|Domain|The effects|Judgment| |---|---|---| |How substantial are the desirable anticipated effects of the strategy?|DCB are superior to PBA with a decrease in target lesion revascularization out to 5 years (OR, 0.28: 95% CI, 0.17-0.47 at 6 months: OR,0.40; 95% CI, 0.31-0.51 at 12 months: OR. 0.28; 95% CI, 0.18-0.44 at 2 years; OR, 0.21; 95% CI, 0.09-0.51 at 5 years) (Kayssi et al)|Moderate| |How substantial are the undesirable anticipated effects?|The association of paclitaxel with an increase in late mortality remains unresolved but the totality of evidence has not supported a mortality signal.|Unknown| |Is there important uncertainty or variability about how much people value the main outcomes?|Patients value different aspects of treatment but durability is an important consideration. Patients and vascular specialists alike recognize the value of limiting reinterventions for patients with claudication. No clear evidence of variability between how patients perceive or value the outcomes|Probably no important uncertainty or variability| |What is the overall certainty of the evidence of effects?|Randomized trials, systemic reviews and meta-analysis have consistently reported a decrease in target lesion revascularization with the use of paclitaxel devices for the femoral-popliteal segment.|Moderate| |Do the desirable effects outweigh the undesirable effects?|Reduction in reintervention likely outweighs the uncertain impact on late survival.|Probably yes| |How large are the resource requirements associated with the intervention?|Moderate increased cost for the use of drug-coated devices.|Moderate costs| |How large is the incremental cost relative to the net benefit?|The potential cost savings from the reduction in repeat procedures likely outweighs the increased cost of drug coating balloons and stents.|Unknown| |What would be the impact on health ineqituities?|No likely impact on health inequities|Unknown| |Is the option acceptable to key stakeholders?|One specialty organization, the Society for Cardiovascular Angiography and Interventions has recommended DCB/ DES assigning a Class 1 recommendation for most anatomical scenarios. We anticipate other stakeholders(patients, specialist and payors) would find this recommendation acceptable.|Probably yes| |Is the option feasible to implement? BMS,Bare metal stent; CI,confidence interval; DCB,drug-coated balloon; DES,drug-eluting stent; OR odds ratio; PBA, plain balloon angioplasty.|Yes||