SOCIETY FOR VASCULAR SURGERY DOCUMENT

Society for Vascular Surgery Clinical Practice Guideline

on the management of intermittent claudication:

Focused update

Michael S. Conte, MD,

Bernadette Aulivola, MD, MS,

Neal R. Barshes, MD, MPH,

Daniel J. Bertges, MD,

Matthew A. Corriere, MD, MS,

M. Hassan Murad, MD, MPH,

Richard J. Powell, MD,

Amy B. Reed, MD,

William P. Robinson III, MD,

and

Jessica P. Simons, MD, MPH,

San Francisco, CA; Maywood, Springﬁeld, IL;

Houston, TX; Burlington, VT; Columbus, OH; Rochester, MN; Hanover, NH; Murrells Inlet, SC; and Worcester, MA

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 spe ctrum 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,theSocietyforVascularSurgerypublished a clinical practice g uideline on the management of asymptomatic

peripheral artery disea se and IC. An e xpert writing g roup was commissioned to provide a focused update to this

guideline on the management of IC. Bas ed on th e avail able evidence from published research conducted since the

prior guideline, six speciﬁc key questions were formulated spanning the areas of antithrombotic management,

exercise t herapy, and revas cularizati on for IC. A systematic r eview 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 cert ainty of evidence. The review identiﬁed major gaps in evidence particularly in

the arena of compar ative eff ectiveness for interventions (exercise, revascularization) across deﬁned clinical sub-

groups and employing meaningful patient-centered outcomes. Twelve recommendations, among which are two

best practice stat ements, are provided in this focused update. They address the use of dual p athway 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 o n education, risk factor control, optima l medical therapy, a nd exer cise, is emphasized. A rubric for

decision-making that includes a thorough assessment of risk, beneﬁ ts, 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 Stritch School of Medicine, May-

wood

; the Division of Vascular Surgery and Endovascular Therapy, Michael

E. DeBakey Department of Surgery, Baylor College of Medicine, Houston

;

the Division of Vascular Surgery and Endovascular Therapy, University of Ver-

mont Medical Center, Burlington

; the Division of Vascular Surgery and Dis-

eases, The Ohio State University Wexner Medical Center, Columbus

; the

Mayo Clinic Evidence-based Practice Center, Rochester

; the Geisel School

of Medicine, Dartmouth-Hitchcock Medical Center, Hanover

; the Medical

University of South Carolina, Tidelands Health, Vascular Surgery, Murrells

Inlet

; 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: Independe nt peer re-

view and oversig ht ha s bee n pr ov ided by the members of t he Society for

Vascular Surgery Document Ov ersight Committee (Marc Schermerhorn,

Chair; Britt Tonness en, Vice Chair; Trissa Ba browski, A llan Conway, Leo

Daab, Brittany Fraser, Peter Henke, Vikram Kashyap, Ahmed Kayss i, Chris

Kwolek, Steven Maximus, Erika Mitchell, Pa trick Muck, Fira s 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.jvascsurg.org.

Correspondence: Michael S. Conte, MD, University of California San Francisco,

400 Parnassus Avenue, Suite A 581, San Francisco, CA 94143-0222 (e-mail:

michael.conte2@ucsf.edu).

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.

0741-5214

Ó 2025 Society for Vascular Surgery. Published by ELSEVIER INC. All rights are

reserved, including those for text and data mining, AI training, and similar

technologies.

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

303

TABLE OF CONTENTS

DISCLAIMER ................................................................................

304

SUMMARY OF RECOMMENDATIONS ............................ 304

METHODS ..................................................................................... 306

Approach to systematic reviews ................................ 306

Approach to making recommendations ............ 306

Patient stakeholder involvement .............................. 306

PICO QUESTIONS, DATA REVIEW, AND

RECOMMENDATIONS ............................................................

307

PICO question 1 ........................................................................ 307

Background and rationale ...................................... 307

Evidence ................................................................................. 307

Recommendation .......................................................... 308

Patient advisor feedback to PICO question

1 and related recommendations .......................

308

PICO question 2 ....................................................................... 308

Background and rationale ...................................... 308

Evidence ................................................................................. 309

Recommendation .......................................................... 310

Patient Advisor feedback regarding PICO

question 2 and related recommendations

310

PICO question 3 ....................................................................... 310

Background and rationale ...................................... 310

Evidence ................................................................................. 310

Recommendation .......................................................... 310

Patient Advisor feedback regarding PICO

question 3 and related recommendations

311

PICO question 4 ....................................................................... 311

Background and rationale ...................................... 311

Evidence ................................................................................. 312

Recommendation .......................................................... 313

Patient Advisor feedback regarding PICO

question 4 and related recommendations

313

PICO question 5 ....................................................................... 313

Background and rationale ...................................... 313

Evidence ................................................................................. 313

Patient values, preferences, and potential

obstacles ................................................................................

313

Recommendations ........................................................ 314

Patient Advisor feedback regarding PICO

question 5 and related recommendations

314

PICO question 6 ...................................................................... 314

Rationale: revascularization for IC ..................... 314

Periprocedural MACE .................................................. 316

MALE ......................................................................................... 316

Reintervention ................................................................... 317

Open revascularization for IC ................................ 318

Long-term mortality ..................................................... 318

Functional outcomes after intervention 318

Health-related quality of life .......................... 319

Patient values, preferences, and potential

obstacles ................................................................................

320

Recommendations regarding

revascularization for IC ...............................................

320

Speciﬁc considerations .............................................. 320

Regarding tibial interventions for

claudication .................................................................

320

Regarding drug-coated devices and

durability ........................................................................

321

Patient Advisor feedback regarding PICO

question 6 and related recommendations .......

322

Major unmet research needs ................................ 322

Patient Advisor feedback regarding unmet

needs and future questions ...........................................

322

AUTHOR CONTRIBUTIONS ................................................. 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

use of rivaroxaban 2.5 mg twice daily in addition to

aspirin (81 to 100 mg/d), rather than aspirin alone, to

reduce the risk of cardiovascular mortality, stroke,

and myocardial infarction (MI). Level of recommen-

dation: grade 2; Level of evidence: B.

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, MI, 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, clopidogrel 75 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 81-100 mg/day, clopidogrel

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 bene ﬁts: 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 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 bare metal stents (BMS) or

drug-eluting devices (drug-coated balloons [DCB] or

drug-eluting stents [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 (CPG) on the

management of patients with asymptomatic PAD and

claudication.

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 CPG 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 CPG

such as those on epidemiology,

diagnosis, other forms of medical therapies (eg, cilosta-

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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Conte et al

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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-specialty 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 CPG 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 ‘recommend’ 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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Journal of Vascular Surgery

August 2025

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 CPGs 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.

This research

suggests thrombotic complications are an important

modiﬁable target to reduce PAD progression. As risk

factor modiﬁcation and optimal medical therapydalong

with exercisedhave 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 Xa or thrombin) as well as newer anti-

platelet agents (thrombin receptor antagonists and

P2Y12 antagonists).

Evidence. Since publication of the 2015 SVS CPGs,

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) trial

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

Journal of Vascular Surgery

Conte et al

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Volume 82, Number 2

(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;

¼ .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;

¼ .005), ALI (34 [1.3%] vs 19 [0.8%]; HR, 0.56; 95% CI,

0.32-0.99;

¼ .04), and major amputation (17 [0.7%] vs

5 [0.2%]; HR, 0.3; 95% CI, 0.11-0.80;

¼ .01). The combina-

tion of low-dose rivaroxaban plus aspirin was associated

with increased major bleeding (using a modi ﬁed Interna-

tional Society for Thrombosis and Hemostasis [ISTH]

deﬁnition)

above aspirin alone (77 [3%] vs 48 [2%]; HR,

1.6; 95% CI, 1.12-2.31;

¼ .009) but not fatal bleeding (4

[0.2%] vs 3 [0.1%]). Rivaroxaban had no signiﬁcant

impact on all-cause mortality.

A secondary analysis

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.

Based on these ﬁndings,

the investigators have estimated a number needed to

treat of 63 patients over 2 years.

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 COMPASS

), and patients with a recent his-

tory of stroke (any stroke within previous 30 days or any

prior history of hemorrhagic stroke).

Recommendation

1. In patients with peripheral artery disease and IC who

have one or more high-risk comorbidities (CHF, DM,

kidney insufﬁciency,orpolyvasculardisease[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 riv aroxaban 2.5 mg twice daily in addition to

aspirin (81 to 100 mg/d), rather than aspirin alone, to

reduce the risk of cardiovascular mortality, stroke,

and MI. Level o f 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).

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 PVIs 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,

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 Rivaroxaban in Endovascular or

Surgical Limb Revascularization for PAD (VOYAGER-

PAD) trial,

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

infrainguinal 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 amputa tion for vascular causes, and ALI at 3

years, occurred in 17.3% of those randomized to rivarox-

aban vs 19.9% o f those randomized to placebo (HR, 0.85;

¼ .009). ALI in the ﬁrst 6 months following reva scular-

ization was halved (1.7% vs 3.2%;

¼ .0 49) with the use

of rivaroxaban. Ther e was no signiﬁcant overall differ-

ence in rates of major bleeding as deﬁnedbythe

Thrombolysis in Myocardial Infarction (TIMI) classiﬁca-

tion (2.65% vs 1.87%, respectively; HR, 1.43;

¼ .07). In

addition, when using the alterna tive ISTH deﬁnition of

major bleeding, there was a signiﬁcant incr ease seen

in the dual therapy-treated patients (4.3% vs 3.08%;

HR, 1.42;

¼ .007). Early post-revascularization initiation

of rivaroxaba n 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.

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”

and patients with any prior stroke.

Secondary analyses of the VOYAGER-PAD trial have re-

ported that the degree of beneﬁtinreducingpost-

revascularization ALI was comparable among all patients

undergoing revascularization, irrespective of whether the

indication was IC vs CLTI,

whether the conduit for surgical

bypass was prosthetic or vein,

and whether clopidogrel

was also given.

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 m

; HR, 0.40; 95% CI, 0.23-0.70).

Unlike COMPASS, VOYAGER-PAD allowed the use of

dual antiplatelet agents for up to 6 months,

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.

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 COMPASS 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 speciﬁcanti-

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

CPG, including antiplatelet therapy (see PICO question 3

below).

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

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 P2Y

. 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,

and

randomized trials have demonstrated superiority of

ticagrelor over clopidogrel in patients with acute coro-

nary syndromes

and patients with a prior history of

MI.

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 (

¼ .65). Ischemic stroke, however, was

signiﬁcantly lower among those assigned to ticagrelor

(131 [1.9%] vs 169 [2.4%];

¼ .03). There was no signiﬁcant

difference in major bleeding events as deﬁned by the

TIMI classiﬁcation (1.6% in each group; HR, 1.1;

¼ .4), but

bleeding events more often led to medication discon-

tinuation among subjects randomized to ticagrelor than

to subjects assigned to clopidogrel.

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.

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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Journal of Vascular Surgery

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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 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 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-limiting claudication, 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).

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-adherence.

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.

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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Volume 82, Number 2

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 beneﬁtof

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.

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 p rograms were limited, but outcomes we re

generally similar. The NEXT Step trial investigators

compared SET with structured home-based walking us-

ing an act ivity tracker vs an attenti on-control gro up.

(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.)

Both the SET and HET groups demonstrated improved

outcomes at 12 weeks compared with controls; the au-

thors did not c onclude superiority of one intervention

over the o ther.

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

monitoring.

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

trial

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 trial

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.

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 progra m.

Effective exercise programs should be followed for at

least 12 we eks. These programs should consist of ﬁve

sessionsperweek,upto50minutespersession,where

patients walk at a pace that induces ische mic 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 6 MWT. 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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Journal of Vascular Surgery

August 2025

however, suggested that MCID on the 6MWT may range

from 14 to 30 meters.

More recently, the concept of

patient-speciﬁcself-deﬁned treatment goals has been

proposed as an alternative to standardized patient-

reported outcome metrics.

This underscore s 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 t he importanc e of other patients with claudi-

cation as a resource f or 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 w ere important to patient ad visors when cons id-

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.

54-56

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 trial

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.

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.

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.

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.

Recommendations

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.

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.

The

rate of life-long progression to CLTI is variably low (<5%

to 21%),

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.

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.

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.

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.

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.

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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Journal of Vascular Surgery

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appropriate for preventing graft failure.

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

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.

Journal of Vascular Surgery

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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, MI, or death within 30 days of revascu-

larization, as previously deﬁned in the SVS’s Objective

Performance Goals for revascularization in the setting

of CLTI. This measure is also applicable to revasculariza-

tion for IC.

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.

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.

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.

Notably,

the CIs 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

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 IC include age >80 years (HR, 1.7;

95% CI, 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

femoropopliteal disease carries a lower risk for major

amputation after endovascular intervention compared

with more diffuse disease involving both the femoropopli-

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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Conte et al

Journal of Vascular Surgery

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greater than 10 to 20 cm are also associated with down-

stream risk of major amputation after PVI.

91,95

Reintervention. GiventheprogressivenatureofPAD

and the signiﬁcant inc idence of reste nosis, repeat inter-

vention is relatively common after revascularization. As

amatterofprinciple,openorendovascularrevasculari-

zation for claudi cation should not be consi dered a cure

for the underlying disease. This fact should be discussed

openly with patients, and the expected durability of the

interventions under consideration s hould be explai ned.

Research indi cates 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 I C

suggested a minimum threshold of a >50% likelihood

of sustained efﬁcacy of intervention for at l east 2 years as

a benchmark, with anatomic patency a prerequisite for

sustained efﬁcacy.

Although reintervention is depen-

dent on a myriad of factors, certain patient, lesion, and

device cha racteristics are associated wit h 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

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)

MACE MALE Reintervention Survival Major amputation

Patient factors Age >65

Female

CAD

84-88

CHF

80,81,84-86,90

83,91

84,85,88,90,92

89,90,93,94

Prior intervention

COPD

CAD

81,84,85

COPD

ESRD

Anatomical

factors

Infrapopliteal

disease

a,80

Infrapopliteal disease

a,93

Infrapopliteal

disease

Longer lesion length

(>10 cm)

a,83,91,95

Bilateral disease treated

a,91

Procedural

factors

Open surgery

PBA

a,96,97

No drug elution

a,98-100

CAD

, Coronary artery disease;

CHF

, congestive heart failure;

COPD

, chronic obstructive pulmonary disease;

, diabetes mellitus;

ESRD

, end-stage

renal disease;

PBA

, plain balloon angioplasty.

Risk factors for outcome after endovascular, but not open, revascularization.

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;

, conﬁdence interval;

COPD

, chronic obstructive pulmonary disease;

CVA

, cerebrovascular accident;

, dia-

betes mellitus.

Journal of Vascular Surgery

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Volume 82, Number 2

is more common in patients with multilevel disea se 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).

111,112

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 CPG 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 aorto-iliac dis-

ease remains a durable treatment option for properly

selected patients who are ﬁt for the procedure. Femo-

ropopliteal 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 claudication 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.

Mortality

117

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 femoropopliteal 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 year), moderate- (1-2 years), or long-term (>2years)

follow-up. At moderate-term follow up, both SET and

ER þ 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

Fig 3. Forest plot of factors associated with major adverse limb events (MALE) following revascularization for

intermittent claudication (IC).

, conﬁdence interval;

COPD

, chronic obstructive pulmonary disease;

, dia-

betes mellitus;

, femoropopliteal.

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Conte et al

Journal of Vascular Surgery

August 2025

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

Fig 4. Forest plot of factors associated with reintervention following revascularization for intermittent claudication

(IC).

, Balloon angioplasty;

BMS

, bare metal stent;

, conﬁdence interval;

DCB

, drug-coated balloon;

DES

, drug-

eluting stent;

, diabetes mellitus;

, femoropopliteal.

Fig 5. Forest plot of factors associated with long-term mortality following revascularization for intermittent

claudication (IC).

, Balloon angioplasty;

BMS

, bare metal stent;

CAD

, coronary artery disease;

CHF

, congestive

heart failure;

, conﬁdence interval;

COPD

, chronic obstructive pulmonary disease;

CVA

, cerebrovascular accident;

DCB

, drug-coated balloon;

DES

, drug-eluting stent;

, diabetes mellitus.

Journal of Vascular Surgery

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Volume 82, Number 2

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.

Recommendations 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 claudication) 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 tre atment of infrapopliteal disease d own-

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 tibioper-

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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Journal of Vascular Surgery

August 2025

In summary, comparative effectiveness data for infrain-

guinal interventions in IC is limited, and nowhere is this

more evident than in the treatment of infrapopliteal dis-

ease. We suggest against performing endovascular or

open infrapopliteal 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-

ropopliteal 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 beneﬁtin

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

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;

, conﬁdence

interval;

COPD

, chronic obstructive pulmonary disease;

DES

, drug-eluting stent;

, diabetes mellitus;

femoropopliteal.

Journal of Vascular Surgery

Conte et al

321

Volume 82, Number 2

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 of 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 speciﬁcac-

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

1. Comparative effectiveness studies to compare

outcomes of treatment strategies (pharmacotherapy,

exercise, endovascular, surgical 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, WR, JS

Data collection: MSC, NB, 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

322

Conte et al

Journal of Vascular Surgery

August 2025

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; accepted Apr 24, 2025.

Additional material for this article may be found online

at www.jvascsurg.org.

326

Conte et al

Journal of Vascular Surgery

August 2025

APPENDIX (online only).

Evidence to Decision Framework Worksheets

Intervention: the addition of low dose rivaroxaban 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;

¼ .0047) for composite endpoint of

cardiovascular death, stroke, or MI 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;

¼ .042),

MALE (1% vs 2%;

¼ .0054), vascular amputations (<1% vs

0.1%;

¼ .0069), and major amputations (<1% vs 1%;

.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;

¼ .0089) for

major bleeding.

No signiﬁcant increase (1% vs 1%; HR, 1.13) 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;

MI,

myocardial infarction.

Journal of Vascular Surgery

Conte et al

326.e1

Volume 82, Number 2

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;

¼ .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%;

< .05)

and net clinical beneﬁt (24.9% vs 19.2%;

¼ .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; Virtual.]

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 vs surgical

revascularization.

ALI in the ﬁrst 6 months following revascularization was halved (1.7% vs 3.2%;

¼ .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 claudication vs critical limb

ischemia, whether the revascularization was surgical or endovascular,

whether the conduit for surgical bypass was prosthetic or vein, and

whether clopidogrel 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].

Rivaroxaban had no impact on all-cause mortality [Bonaca 2020].

Moderate

How substantial are the

undesirable

anticipated effects?

No signiﬁcant overall difference (2.65% vs 1.87%; HR, 1.43;

¼ .07) for TIMI

major bleeding. The subgroup with diabetes had higher rates of TIMI

major bleeding (3.9% vs 1.2%; HR, 2.45;

¼ .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;

.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

326.e2

Conte et al

Journal of Vascular Surgery

August 2025

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;

CI,

conﬁdence interval;

CKD,

chronic kidney disease;

HR,

hazard ratio;

ICER,

incremental cost-effectiveness ratio;

ISTH,

In-

ternational Society on Thrombosis and Haemostasis;

MI,

myocardial infarction;

TIMI,

thrombolysis in myocardial infarction.

Journal of Vascular Surgery

Conte et al

326.e3

Volume 82, Number 2

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%) [

Kaplovitch 2021

]

Moderate

How substantial are the undesirable

anticipated effects?

No signiﬁcant difference (2.65% vs 1.87%; HR, 1.43;

¼ .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: VOYAGER 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.

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

CI,

Conﬁdence interval;

HR,

hazard ratio;

ICER,

incremental cost-effectiveness ratio;

TIMI,

thrombolysis in myocardial infarction.

326.e4

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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 þ 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;

¼ .65 [Hiatt et al]).

Compared with clopidogrel, ticagrelor did not signiﬁcantly

reduce rates of hospitalization for ALI(1.7% vs 1.7% for

ticagrelor vs clopidogrel, respectively;

¼ .85), rates of

lower limb revascularization (12.2% vs 12.8%;

¼ .30), or

combined rates of coronary, limb mesenteric, renal,

carotid, and other revascularizations (17.5% vs 18.0%;

¼ .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 [Hiatt 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 [Hiatt et al.] and one

small (40 patient) single-center RCT.

Low

Do the desirable effects outweigh the

undesirable effects?

No e 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? 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 e exchange of one antiplatelet medication for

another.

Yes

ALI,

Acute limb ischemia;

CI,

conﬁdence interval;

HR,

hazard ratio;

ICER,

incremental cost-effectiveness ratio;

MI,

myocardial infarction;

RCT,

ran-

domized controlled trial;

TIMI,

thrombolysis in myocardial infarct ion.

Journal of Vascular Surgery

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326.e5

Volume 82, Number 2

Intervention: vorapaxar 2.5 mg daily in addition to

aspirin for patients with peripheral artery disease.

Alternative strategy: aspirin alone; aspirin þ

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;

¼ .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;

¼ .011).

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;

¼ .53)

[Bonaca

et al.

]

Small

How substantial are the undesirable

anticipated effects?

A signiﬁcant (2.9% absolute) increase in GUSTO moderate

or severe bleeding (7.4% vs 4.5%; HR, 1.62; 95% CI, 1.21-2.18;

¼ .001).

No signiﬁcant difference in rates of intracranial hemorrhage

(0.9% vs 0.4%; HR, 2.03, 95% CI, 0.82-5.02;

¼ .13) or fatal

bleeding (0.5% vs 0.4%; HR, 1.02; 95% CI, 0.35-2.90;

¼ .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 1þ) 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 [Neuwahl

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.

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” [Bonaca

et al.

]

Probably yes

ALI,

Acute limb ischemia;

CI,

conﬁdence interval;

GUSTO,

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.

326.e6

Conte et al

Journal of Vascular Surgery

August 2025

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?

Poorly deﬁned/not reported Unknown

How large is the incremental cost relative to

the net beneﬁt?

Poorly 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

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 6 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.

Journal of Vascular Surgery

Conte et al

326.e7

Volume 82, Number 2

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 þ 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

plus exercise has more signiﬁcant improvement 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 þ

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.

Low

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 (

¼ .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

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.

326.e8

Conte et al

Journal of Vascular Surgery

August 2025

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

How large are the resource requirements

associated with the intervention?

Large costs

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

IC,

Intermittent claudication;

MACE,

major adverse cardiovascular events;

MALE,

major adverse limb events;

PAD,

peripheral artery disease;

QoL,

quality

of life.

Journal of Vascular Surgery

Conte et al

326.e9

Volume 82, Number 2

Intervention: Revascularization for tibial-peroneal

occlusive disease in patients with IC.

Alternative stra tegy: Con ﬁne revascularization to the

aorto-iliac and/or femoral -popliteal segment in

patients with intermittent claudication. Maximize ex-

ercise, smoking cessation, and cardiovascular medica-

tions for patients w ith IC an d tibial-pero neal 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 w60% increase

in occlusion/death, major amputation/death and

reintervention/amputation/death (Levin 2020)

Isolated infrapopliteal PVI is associated with an increased

risk of major amputation (OR, 6.47; 95% CI, 6.45-6.49;

< .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

important

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

infrapopliteal 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

CI,

Conﬁdence interval;

IC,

intermittent claudication;

MALE,

major adverse limb events;

OR,

odds ratio;

PVI,

peripheral vascular intervention.

326.e10

Conte et al

Journal of Vascular Surgery

August 2025

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 >5cm.

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

inequities?

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? Information not available Yes

BMS,

Bare metal stent;

, conﬁdence interval;

DCB,

drug-coated balloon;

DES,

drug-eluting stent;

OR,

odds ratio;

PBA,

plain balloon angioplasty.

Journal of Vascular Surgery

Conte et al

326.e11

Volume 82, Number 2