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J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 2 , N O . 2 2 , 2 0 1 8

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JACC GUIDELINE COMPARISON

ACC/AHA Versus ESC Guidelines forDiagnosis and Management ofPeripheral Artery Disease

JACC Guideline Comparison

Aaron P. Kithcart, MD, PHD,a Joshua A. Beckman, MD, MSCb

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ISSN 0735-1097/$36.00

From the aDepartment of Medicine, Division of Cardiovascular Medicine, Brig

and the bDepartment of Medicine, Division of Cardiovascular Medicine, Vand

has served as a consultant for AstraZeneca, Janssen, Antidote Pharmaceutica

served on the data and safety monitoring board for Bayer and Novartis. Dr

relevant to the contents of this paper to disclose.

Manuscript received April 17, 2018; revised manuscript received September

Method of Participation and Receipt of CME/MOC/ECME Certificate

To obtain credit for JACC CME/MOC/ECME, you must:

1. Be an ACC member or JACC subscriber.

2. Carefully read the CME/MOC/ECME-designated article available on-

line and in this issue of the Journal.

3. Answer the post-test questions. A passing score of at least 70%must be

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ically by following the instructions given at the conclusion of the activity.

CME/MOC/ECME Objective for This Article: Upon completion of

this activity, the learner should be able to: 1) discuss the factors that

increase the risk of developing PAD; 2) identify the standard evaluation

pathway for PAD; and 3) select the proper therapies to improve ambu-

lation in patients with symptomatic PAD.

CME/MOC/ECME Editor Disclosure: JACC CME/MOC/ECME Editor Raga-

vendra R. Baliga, MD, FACC, has reported that he has no financial re-

lationships or interests to disclose.

Author Disclosures: Dr. Beckman has served as a consultant for AstraZe-

neca, Janssen, Antidote Pharmaceuticals, Sanofi, Bristol-Myers Squibb, and

Merck; and has served on the data and safety monitoring board for Bayer

and Novartis. Dr. Kithcart has reported that he has no relationships relevant

to the contents of this paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME/MOC/ECME Term of Approval

Issue Date: December 4, 2018

Expiration Date: December 3, 2019

https://doi.org/10.1016/j.jacc.2018.09.041

ham and Women’s Hospital, Boston, Massachusetts;

erbilt University, Nashville, Tennessee. Dr. Beckman

ls, Sanofi, Bristol-Myers Squibb, and Merck; and has

. Kithcart has reported that he has no relationships

5, 2018, accepted September 11, 2018.

Kithcart and Beckman J A C C V O L . 7 2 , N O . 2 2 , 2 0 1 8

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ACC/AHA Versus ESC Guidelines for Diagnosis andManagement of Peripheral Artery Disease

JACC Guideline Comparison

Aaron P. Kithcart, MD, PHD,a Joshua A. Beckman, MD, MSCb

ABSTRACT

Peripheral artery disease is a common yet underdiagnosed cause of morbidity worldwide. Significant recent advances in

management have resulted in new guideline creation for the diagnosis and management of peripheral artery disease in

the United States and Europe. Here, we analyze each set of guidelines with special attention to those areas where the 2

groups disagree. Both groups emphasize the importance of risk factor reduction, including smoking cessation, lipid

lowering, blood pressure management, and glucose control. The U.S. guidelines place additional attention on lifestyle

factors, including regular physical activity and supervised exercise. The European guidelines offer a number of recom-

mendations for revascularization in patients with limb-threatening ischemia. Both agree that more evidence is needed to

understand which patients are at highest risk for tissue loss. A consistent charge to each committee fostering a similar

approach to available data and more randomized studies would align recommendations across both organizations.

(J Am Coll Cardiol 2018;72:2789–801) © 2018 by the American College of Cardiology Foundation.

T he last decade has seen a surge of clinical tri-als studying the management of patientswith peripheral artery disease (PAD). Appro-

priately, we have seen a corresponding revision ofPAD clinical guidelines addressing diagnostic, medi-cal, and revascularization strategies. In 2016, theAmerican Heart Association (AHA) and American Col-lege of Cardiology (ACC), together with allied stake-holder organizations, issued an update to the 2005guidelines and 2011 focused update on the manage-ment and diagnosis of lower extremity PAD (1). In2017, the European Society of Cardiology (ESC)together with the European Society for Vascular Sur-gery (ESVS) did the same with an update to theirown comprehensive 2011 guidelines (2). Unlike theirU.S. counterparts, the Europeans included not onlylower-extremity PAD, but also a broader definitionof peripheral vascular disease (PVD). This commen-tary will examine the similarities and differences be-tween the approaches taken by these 2organizations to PAD in the ACC/AHA guidelines orlower-extremity artery disease in the ESC/ESVSguidelines.

METHODOLOGY

The creation of guidelines by both the ESC/ESVS andACC/AHA share more similarities than differences.For example, both the ESC/ESVS and ACC/AHA selectwriting committee members and allow partnering

organizations the same opportunity, provide thedescription of relationships with industry, use struc-tured evidence acquisition and review, and undergopeer review by each participating organization priorto endorsement of the guideline. These overridingprinciples, however, provide significant latitude inthe orientation of the document and selection ofdiagnostic and therapeutic modalities to address andrecommend.

Perhaps the most important difference betweenthe documents is their stated purpose. The ACC/AHAsought to “provide a contemporary guideline fordiagnosis and management of patients with lowerextremity PAD” (1), whereas the ESC/ESVS believesthat “it is of the utmost importance that everycardiologist should be sensitive in regard to thediagnosis and management of patients with PADs, asmany of them are seen and managed for concomitantcardiac conditions” (2). The variation in intendedaudience and focus drives the most significant dif-ference between documents: the American documentlimits its focus to PAD but is applicable to practi-tioners of every background, whereas the Europeanguideline extends the discussion to all PADs toinclude carotid and vertebral, upper extremities,mesenteric, and renal arteries in addition to lower-extremity artery disease; but is designed to be asource for cardiologists.

The ACC/AHA guideline methodology requires theidentification of systematic review questions of great

AB BR E V I A T I O N S

AND ACRONYM S

ABI = ankle-brachial index

ACC = American College of

Cardiology

AHA = American Heart

Association

ALI = acute limb ischemia

CLI = critical limb ischemia

ESC = European Society of

Cardiology

ESVS = European Society for

Vascular Surgery

LEAD = lower-extremity artery

disease

PAD = peripheral artery

disease

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importance to the guideline topic. In this case, therewere 3:

1. “Is antiplatelet therapy beneficial for preventionof cardiovascular events in the patient withsymptomatic or asymptomatic lower extremityPAD?”

2. “What is the effect of revascularization, comparedwith optimal medical therapy and exercisetraining, on functional outcome and quality of life(QoL) among patients with claudication?”

3. “Is one revascularization strategy (endovascular orsurgical) associated with improved cardiovascularand limb-related outcomes in patients with criticallimb ischemia (CLI)?” (1).

The ACC/AHA has narrowed its focus from multiplevascular diseases in 2011 to provide an in-depth re-view of a single disease location, whereas the ESC/ESVS began with a broader concern. As a result, thereare PAD topics covered by the ACC/AHA notmentioned in the ESC/ESVS guideline, includingmethods to minimize tissue loss in patients in PADand recommendations for longitudinal follow-up. Incontrast, with the focus on cardiologists, there aretopics covered in the ESC/ESVS guidelines absentfrom the ACC/AHA document, including a section onpolyvascular disease, antithrombotic therapy for thepatient who requires oral anticoagulation, and othercardiac conditions in the PAD patient. These sectionsare beset by limited evidence but are common clinicalconundrums for the practicing cardiologist. The valueproposition for each document and what it discussesnot only derives from its intended audience, but alsosignificantly affects the format in which the guide-lines are presented.

FORMAT

Inherent to the decision-making of both organiza-tions is the perceived method of use for the docu-ments. The current guidelines from the ACC/AHAprovide recommendations for all of the areas withsupporting data in great depth. The ACC/AHA guide-lines are 67 journal pages before references and 294pages if one includes the authors’ relationships withindustry, Methodology and Evidence Review, and52 evidence tables. In contrast, the lower-extremityportion of the European guidelines requires about 18pages to cover the same material. To our view, theACC/AHA document serves as a reference documentfor treatment of PAD. The document from the ESC/ESVS provides some detail with significant portions

relegated to online-only availability to permitmore rapid answers to clinician questions.This easy-to-access data is enhanced in the“To Do/Not To Do” section at the end of theESC/ESVS guideline. This section summarizesall of the Class I and III recommendations in 1place. In contrast, the ACC/AHA provides allevidence tables in 1 document, allowing theclinician to understand the basis for arecommendation. In our opinion, the last 300or more pages filled with evidence tables andrelationships with industry encumber thedocument. For a clinician on-the-go, thefocused version may be easier to navigate.For those interested, the details underpin-ning the recommendations may be betterplaced in easily accessible online

repositories.

Another byproduct of the differing formats is theapproach to medical treatment. The decision to focuson PAD by the ACC/AHA requires evidence for eachtreatment specifically for PAD, while the treatmentsection in the ESC/ESVS document is oriented forgeneral atherosclerosis more than PAD alone.Recommendations for smoking cessation, healthydiet and physical activity, statins and low-densitylipoprotein goals, diabetes, hypertension, andangiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) are made for allPADs, not just lower-extremity disease. The ESC/ESVS guidelines, when examining medical therapy,have a more holistic flavor, whereas the ACC/AHAguidelines are specific to the lower-extremity com-plications of atherosclerosis.

DIFFERENCES IN RECOMMENDATIONS

Discussing the differences between guideline recom-mendations is of particular interest, as the evidencebase for both is the same. In our view, variation be-tween the documents derives from 3 sources: writinggroup topic interest, evidence weighting, and docu-ment focus. Perhaps the most interesting of the 3 isthe valuation of evidence. Although each organiza-tion organizes levels of evidence into randomizedcontrolled trials and nonrandomized studies, theACC/AHA is more inclusive of smaller, well-donenonrandomized studies, whereas the ESC/ESVS rele-gates small studies to Level of Evidence: C. Webelieve this difference drives the variation of thera-peutic recommendations more than any other factor.Divergent approaches to revascularization, for

TABLE 1 Guidelines for the Diagnosis of PAD

Class AHA/ACC ESC/ESVS

I In patients with history or physical examination findings suggestive ofPAD, the resting ABI, with or without segmental pressures andwaveforms, is recommended to establish the diagnosis(Level of Evidence: B-NR)

Measurement of the ABI is indicated as first-linenoninvasive test for screening and diagnosis of LEAD(Level of Evidence: C)

Resting ABI results should be reported as abnormal (ABI #0.90),borderline (ABI 0.91–0.99), normal (1.00–1.40), ornoncompressible (ABI >1.40) (Level of Evidence: C-LD)

Toe-brachial index (TBI) should be measured to diagnosepatients with suspected PAD when the ABI is >1.40(Level of Evidence: B-NR)

In the case of incompressible ankle arteries or ABI >1.40,alternative methods such as the toe-brachial index, Dopplerwaveform analysis, or pulse volume recording are indicated(Level of Evidence: C)

Patients with exertional non–joint-related leg symptoms andnormal or borderline resting ABI (>0.90 and #1.40) shouldundergo exercise treadmill ABI testing to evaluate for PAD(Level of Evidence: B-NR)

Duplex ultrasound is indicated as a first-line imagingmethod to confirm LEAD lesions (Level of Evidence: C)

Duplex ultrasound, CTA, or MRA of the lower extremities isuseful to diagnose anatomic location and severity ofstenosis for patients with symptomatic PAD in whomrevascularization is considered (Level of Evidence: B-NR)

Duplex ultrasound and/or CTA and/or MRA are indicated foranatomical characterization of LEAD lesions and guidance foroptimal revascularization strategy (Level of Evidence: C)

IIa In patients at increased risk of PAD but without history or physicalexamination findings suggestive of PAD, measurement of the restingABI is reasonable (Level of Evidence: B-NR)

III In patients not at increased risk of PAD and without history or physicalexamination findings suggestive of PAD, the ABI is notrecommended (Level of Evidence: B-NR)

Invasive and noninvasive angiography (i.e., CTA, MRA) should not beperformed for the anatomic assessment of patients withasymptomatic PAD (Level of Evidence: B-R)

ABI¼ ankle brachial index; ACC ¼ American College of Cardiology; AHA¼ American Heart Association; B-R, Randomized trial; B-NR, Nonrandomized trial; C-EO, Expert Opinion;C-LD, Limited Data; CTA ¼ computed tomography angiography; ESC ¼ European Society of Cardiology; ESVS ¼ European Society for Vascular Surgery; LEAD ¼ lower-extremityartery disease; MRA ¼ magnetic resonance angiography; PAD ¼ peripheral artery disease.

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example, are driven by a greater reliance on non-randomized studies in the ACC/AHA document. Theinclusion or downplaying of smaller studies hasimportant implications beyond just these sets ofguidelines that would warrant further discussionelsewhere. Once the selection of evidence has beenmade, however, both guidelines use similar (Class I,IIa, IIb, and III) recommendation definitions. In thefollowing sections, we will review important simi-larities and differences in management.

DIAGNOSIS OF PAD

The U.S. and European guidelines recommend restingankle-brachial index (ABI) as the first-line study andtoe-brachial index as back-up in the setting of sig-nificant calcification artifact for the diagnosis of PAD(Class I) (Table 1). The value of ABI screening iscontentious in the medical community at large. Onlythe AHA/ACC recommends screening, stating: “inpatients at increased risk of PAD but without historyor physical examination findings suggestive of PAD,measurement of the resting ABI is reasonable.” The

patient population suitable for PAD screening in-cludes 1 of the following criteria: age $65 years, age50 to 64 years with risk factors for atherosclerosis or afamily history of PAD, age <50 years with diabetesand an additional risk factor for atherosclerosis, andindividuals with known atherosclerotic disease inanother vascular bed. The ESC/ESVS is silent on thisissue. It should be noted that most of these criteriaare based on prospective screening studies includingmore than 5,000 patients (PARTNERS, getABI, VIVA),so this appears to be a variation in topic of interestrather than data available (3–5).

Although both groups recommend against duplexultrasound, computed tomography angiography,magnetic resonance angiography, or catheter-basedangiography in initial diagnosis, the use of treadmilltesting highlights a case where the U.S. documentfinds the data sufficient for a Level I recommendationfor patients with suspicious symptoms but a normalABI, whereas this form of testing is only mentioned inthe text without stated recommendation in the Eu-ropean guideline. The absence of a treadmill ABIrecommendation suggests a perception of inadequate

TABLE 3 Guidelines for Antiplatelet and Anticoagulation Therapy in PAD

Class AHA/ACC ESC/ESVS

I Antiplatelet therapy with aspirin alone (range 75–325 mg/day) or clopidogrelalone (75 mg/day) is recommended to reduce MI, stroke, and vasculardeath in patients with symptomatic PAD (Level of Evidence: A)

Long-term single antiplatelet therapy is recommended insymptomatic patients (Level of Evidence: A)

In patients with PADs and AF, oral anticoagulation isrecommended when the CHA2DS2-VASc score is $2(Level of Evidence: A)

IIa In asymptomatic patients with PAD (ABI #0.90), antiplatelet therapy isreasonable to reduce the risk of MI, stroke, or vascular death (Level ofEvidence: C-EO)

Because of lack of proven benefit, antiplatelet therapy is notroutinely indicated in patients with isolated asymptomaticLEAD (Class III) (Level of Evidence: A)

In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness ofantiplatelet therapy to reduce the risk of MI, stroke, or vascular death isuncertain (Class IIb) (Level of Evidence: B-R)

IIb Dual antiplatelet therapy (aspirin and clopidogrel) may be reasonable toreduce the risk of limb-related events in patients with symptomatic PADafter lower extremity revascularization (Level of Evidence: C-LD)

Dual antiplatelet therapy with aspirin and clopidogrel for atleast one month should be considered after infra-inguinalstent implantation (Class IIa) (Level of Evidence: C)

In patients requiring antiplatelet therapy, clopidogrel may bepreferred over aspirin (Class B)

The effectiveness of dual antiplatelet therapy (aspirin and clopidogrel) toreduce the risk of cardiovascular ischemic events in patients withsymptomatic PAD is not well established (Level of Evidence: B-R)

The overall clinical benefit of vorapaxar adding to existing antiplatelet therapyin patients with symptomatic PAD is uncertain (Level of Evidence: B-R)

III Anticoagulation should not be used to reduce the risk of cardiovascularischemic events in patients with PAD (Level of Evidence: A)

Abbreviations as in Table 1.

TABLE 2 Guidelines for the Medical Management of Patients With PAD

Class AHA/ACC ESC/ESVS

I Patients with PAD who smoke cigarettes or use other formsof tobacco should be advised at every visit to quit(Level of Evidence: A)

Smoking cessation is recommended in all patientswith PADs (Level of Evidence: B)

Treatment with a statin medication is indicated for all patientswith PAD (Level of Evidence: A)

Statins are recommended in all patients with PADs(Level of Evidence: A)

In patients with PADs, it is recommended to reduceLDL-C to <70 mg/dl or decrease it by $50% if baselinevalues are 70–135 mg/dl (Level of Evidence: C)

Management of diabetes mellitus in the patient with PAD should becoordinated between members of the health care team.(Level of Evidence: C-EO)

In diabetic patients with PADs, strict glycemic control isrecommended (Level of Evidence: C)

Antihypertensive therapy should be administered to patients withhypertension and PAD to reduce the risk of MI, stroke, heartfailure, and cardiovascular death (Level of Evidence: A)

In patients with PADs and hypertension, it isrecommended to control blood pressure at<140/90 mm Hg (Level of Evidence: A)

Cilostazol is an effective therapy to improve symptoms an increase walkingdistance in patients with claudication (Level of Evidence: A)

Patients with PAD should have an annual influenza vaccination(Level of Evidence: C-EO)

IIa The use of angiotensin-converting enzyme inhibitors or angiotensinreceptor blockers can be effective to reduce the risk of cardiovascularischemic events in patients with PAD (Level of Evidence: A)

ACEIs or ARBs should be considered as first-line therapy inpatients with PADs and hypertension (Level of Evidence: B)

III Pentoxifylline is not effective for treatment of claudication(Level of Evidence: A)

Chelation therapy (e.g., ethylenediaminetetraacetic acid) is not beneficial fortreatment of claudication (Level of Evidence: B-R)

B-complex vitamin supplementation to lower homocysteine levels forprevention of cardiovascular events in patients with PAD is notrecommended (Level of Evidence: C-EO)

LDL ¼ low-density lipoprotein; other abbreviations as in Table 1.

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evidence and a different practice pattern from phy-sicians in the United States. Interestingly, there is afear that patients are going untreated due to “maskedPAD” in the ESC/ESVS guidelines, even in the absenceof a recommendation for treadmill ABI testing.

MEDICAL MANAGEMENT OF PATIENTS

WITH PAD

Recognizing that the majority of PAD is caused byatherosclerosis, recommendations from the ACC/AHAand ESC/ESVS address the same risk factors as coro-nary disease. Both guidelines issue Class I recom-mendations for smoking cessation, statin therapy,glucose control, and blood pressure management(Table 2). The European guidelines are prescriptiveand recommend specific therapeutic goals, includinglow-density lipoprotein cholesterol reductionto <70 mg/dl (or >50% reduction if baseline is 70 to135 mg/dl) and a blood pressure <140/90 mm Hg(Class I). Both guidelines agree that ACE inhibitors orARBs should be considered to reduce ischemic events(Class IIa) (6,7). The value of reiterating treatmentgoals discussed in full in other guidelines is in the eyeof the beholder.

ANTIPLATELET AND ANTICOAGULATION THERAPY

IN PAD. Both guidelines call out antithrombotictherapy for particular attention. The U.S. and Euro-pean guidelines both recommend antiplatelet mono-therapy, either aspirin or clopidogrel, in symptomaticPAD patients (Table 3). These Class I recommenda-tions are based on a number of large clinical trials,now totaling many thousands of patients, which haveshown a consistent benefit for antiplatelet therapy(8,9). The European guidelines suggest clopidogrelmay be superior to aspirin, largely based on the re-sults of the CAPRIE (Clopidogrel Versus Aspirin inPatients at Risk of Ischemic Events) trial (Class IIb)(10). The U.S. guidelines, while referencing the CAP-RIE trial in the text, did not make a preferencestatement between agents.

The benefit of antiplatelet therapy in asymptom-atic patients remains less well defined and is onemajor point of contention between the 2 organiza-tions. The U.S. guidelines state that aspirin or clopi-dogrel therapy may be useful to reducecardiovascular events, although the strength of thisrecommendation is based on ABIs that are abnormal(Class IIa) versus borderline (Class IIb). The Europeanguidelines, on the other hand, recommend againstantiplatelet therapy in patients with asymptomaticPAD unless they have another indication, such ascoronary artery disease. This Class III recommenda-tion is based on 2 clinical trials that did not show

benefit in patients without symptoms (11,12). Itshould be noted that neither trial used the standardABI criteria for study inclusion, resulting in a car-diovascular risk profile similar to patients withoutPAD at study entry (13). For instance, the trial byFowkes et al. (11) used an ABI #0.95 derived from thelower ankle pressure rather than the standard higherpressure, whereas POPADAD (Prevention of Progres-sion of Arterial Disease and Diabetes) used anABI #0.99, both would be considered borderline inthe current guidelines. Moreover, the Europeanguideline notes a significant frequency of “masked”symptoms that would require treadmill testing todiagnose. Following this logic, many patients who arediagnosed as asymptomatic may actually be symp-tomatic with testing and merit therapy. Therefore, itis surprising that the European guidelines do notrecommend exercise testing, because this is the onlyway to identify patients with “masked symptoms.”

Dual antiplatelet therapy (DAPT), the combinationof aspirin and clopidogrel, is a second point ofdisagreement. The European guidelines suggest thatDAPT can be considered for the first month afterpercutaneous and surgical revascularization (Class I),although this is based on limited data. Long-termDAPT receives a Class IIb recommendation in theU.S. guidelines for reduction of cardiovascularevents, citing the CHARISMA (Clopidogrel for HighAtherothrombotic Risk and Ischemic Stabilization,Management, and Avoidance) study. There is norecommendation in the European guideline, but thediscussion concerning the risk of polyvascular diseaseis more detailed and highlights the increased risk ofmultiple vascular bed involvement, citing thePEGASUS trial and registries. CHARISMA was afrankly negative study and had a negative primaryendpoint for the PAD subgroup (14). Thus, the use ofClass IIb and not III remains unclear in the U.S.guideline.

Vorapaxar, a thrombin receptor antagonist, incombination with antiplatelet therapy, receives aClass IIb recommendation in the U.S. guidelines.Although referenced in the text, the Europeanguidelines do not make specific recommendationsregarding vorapaxar, recognizing some benefit but atthe cost of greater bleeding (15). These recommen-dations are interesting in the face of regulatoryagency approval for cardiovascular event reduction inboth the United States and Europe.

The discussion concerning anticoagulationhighlights the difference in intended audiences ofboth documents. The U.S. guidelines cite theWAVE (Warfarin Antiplatelet Vascular Evaluation)trial to give anticoagulation a Level III: harm

TABLE 4 Guidelines for the Management of Patients With Intermittent Claudication

Class AHA/ACC ESC/ESVS

I In patients with claudication, a supervised exercise program is recommendedto improve functional status and quality of life and to reduce legsymptoms (Level of Evidence: A)

In patients with intermittent claudication, supervised exercisetraining is recommended (Level of Evidence: A)

In patients with PAD, a structured community- or home-based exerciseprogram with behavioral change techniques can be beneficial to improvewalking ability and functional status (Class IIa) (Level of Evidence: A)

In patients with intermittent claudication, nonsupervisedexercise training is recommended when supervised exerciseis not feasible or available (Level of Evidence: C)

Endovascular procedures are effective as a revascularization option forpatients with lifestyle-limiting claudication and hemodynamicallysignificant aortoiliac occlusive disease (Level of Evidence: A)

An endovascular-first strategy is recommended for short(<5 cm) aortoiliac occlusive lesions (Level of Evidence: C)

Endovascular procedures are reasonable as a revascularization option forpatients with lifestyle-limiting claudication and hemodynamicallysignificant femoropopliteal occlusions (Class IIa) (Level of Evidence: B-R)

An endovascular-first strategy is recommended for short(<25 cm) femoropopliteal lesions (Level of Evidence: C)

In patients unfit for surgery, endovascular therapy may beconsidered in patients with long (>25 cm) femoropopliteallesions (Class IIb) (Level of Evidence: C)

IIa Revascularization is a reasonable treatment option for the patient withlifestyle-limiting claudication with an inadequate response to guideline-directed management and therapy (Level of Evidence: A)

When daily activities are compromised despite exercisetherapy, revascularization should be considered (Level ofEvidence: C)

Surgical procedures are reasonable as a revascularization option forpatients with lifestyle-limiting claudication with inadequate response toguideline-directed management and therapy, acceptable perioperativerisk, and technical factors suggesting advantages over endovascularprocedures (Level of Evidence: B-NR)

In patients fit for surgery, aorto-(bi)femoral bypass should beconsidered in aortoiliac occlusions (Level of Evidence: B)

Open surgery should be considered in fit patients with an aorticocclusion extending up to the renal arteries (Level ofEvidence: C)

In patients who are not at high risk for surgery, bypass surgeryis indicated for long (>25 cm) superficial femoral arterylesions when an autologous vein is available and lifeexpectancy is >2 yrs (Class I) (Level of Evidence: B)

An endovascular-first strategy should be considered in longand/or bilateral aortoiliac lesions in patients with severecomorbidities (Level of Evidence: B)

IIb The usefulness of endovascular procedures as a revascularization option forpatients with claudication due to isolated infrapopliteal disease isunknown (Level of Evidence: C-LD)

III Endovascular procedures should not be performed in patients with PAD solelyto prevent progression to CLI (Level of Evidence: B-NR)

Surgical procedures should not be performed in patients with PAD solely toprevent progression to CLI (Level of Evidence: B-NR)

Femoral-tibial artery bypass with prosthetic graft material should not be usedfor the treatment of claudication (Level of Evidence: B-R)

CLI ¼ critical limb ischemia.

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recommendation (16–18). The European guidelineprovides an antiplatelet management algorithm forpatients who require anticoagulation for otherreasons.

MEDICATION RECOMMENDATION

CLASS DETERMINATION

The Food and Drug Administration approves medi-cations found to be safe and effective on the basis ofrandomized clinical trials. Similarly, the EuropeanMedicines Agency (EMA) mandates certain re-quirements for the demonstration of quality, safety,and efficacy testing of medications. It is unclear howthese extensive processes are incorporated into theguidelines process for both organizations. In bothguidelines, aspirin receives a Class I indication forsymptomatic PAD and is placed at a similar level toclopidogrel. Aspirin has never been tested in a

randomized controlled trial, has been unable to getU.S. Food and Drug Administration approval for PAD,and was found to be inferior to clopidogrel, whichholds an indication for PAD, in a study of more than19,000 patients (10).

In both guidelines, the recommendations for sta-tins and ACE inhibitors derive from a single ran-domized clinical trial each: the HPS (Heart ProtectionStudy) for statins and the HOPE (Heart OutcomesPrevention Evaluation) trial for ACE inhibitors (6,19).In patients with PAD, ramipril reduced the absoluterisk of cardiovascular mortality, MI, and stroke bymore than 5% over 4.5 years of follow-up, no matterhow you “carved up” the PAD group (by ABI or bysymptom status). Indeed, ramipril reduced all-causemortality in the subclinical PAD population alone ortogether with the symptomatic population. In HPS,simvastatin reduced MI, stroke, or revascularizationby w6% over 5 years of follow-up, but it is unclear if it

TABLE 5 Guidelines for the Management of Patients With Critical Limb Ischemia

Class AHA/ACC ESC/ESVS

I In patients with CLI, revascularization should be performed whenpossible to minimize tissue loss (Level of Evidence: B-NR)

In the case of CLTI, infrapopliteal revascularization is indicatedfor limb salvage (Level of Evidence: C)

When surgery is performed for CLI, bypass to the popliteal or infrapoplitealarteries (i.e., tibial, pedal) should be constructed with autologous vein(Level of Evidence: A)

For revascularization of infra-popliteal arteries, bypass usingthe great saphenous vein is indicated (Level of Evidence: A)

An evaluation for revascularization options should be performed by aninterdisciplinary care team before amputation in the patient with CLI(Level of Evidence: C-EO)

In patients with CLTI, assessment of the risk of amputation isindicated (Level of Evidence: C)

Early recognition of tissue loss and/or infection and referral tothe vascular team is mandatory to improve limb salvage(Level of Evidence: C)

An interdisciplinary care team should evaluate and provide comprehensivecare for patients with CLI and tissue loss to achieve complete woundhealing and a functional foot (Level of Evidence: B-NR)

Patients with PAD and diabetes mellitus should be counseled about self-footexamination and healthy foot behaviors (Level of Evidence: C-LD)

In patients with CLTI and diabetes, optimal glycemic control isrecommended (Level of Evidence: C)

IIa A staged approach to endovascular and surgical procedures is reasonable inpatients with CLI (Level of Evidence: C-LD)

IIb Use of an angiosome-directed endovascular therapy may be reasonable inpatients with CLI and nonhealing wounds or gangrene (Level of Evidence:B-NR)

III Prostanoids are not indicated in patients with CLI (Level of Evidence: B-R) In patients with CLTI, stem cell/gene therapy is notindicated (Class B)

CLTI ¼ chronic limb-threatening ischemia; other abbreviations as in Tables 1 and 4.

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reduced death in the 6,748 patients who comprisedthe PAD population (19). Why do statins get a Class Iindication and ACE inhibitors a Class IIa indication inboth guidelines? We believe that both classes shouldreceive a Class I indication.

In the American guidelines, dual antiplatelet ther-apy with clopidogrel and aspirin, which failed in arandomized clinical trial to provide benefit (14), re-ceives the same Class IIb recommendation asvorapaxar, a U.S. Food and Drug Administration–approved medication whose benefit on majoradverse cardiovascular event reduction does not differfrom the coronary artery disease subjects recruited inthe same trial (20). Vorapaxar gets no recommenda-tion at all in the European guideline despite EMAapproval. Neither guideline agrees with its own regu-latory agency about the interpretation of the data.

We would submit that the guidelines’ writingcommittees should provide clearer reasoning in theirdecision to deviate from regulatory agency approvedmedications. Moreover, medications with similarevidentiary support for benefit should receive similarrecommendation levels unless specific evidence canbe brought to bear to explain the variation. The valueof guidelines to the community derives from itsexpert synthesis of available data across the spectrumof topic areas within the larger subject of the guide-line. Variation in recommendations for medicationsbetween the documents suggests that additionalexpertise in parsing out the value of medications maybe beneficial.

MANAGEMENT OF SYMPTOMS IN

INTERMITTENT CLAUDICATION

Both groups place supervised exercise therapy as theinitial treatment of choice and give a Class I recom-mendation (Table 4). Both groups place home-basedexercise as a treatment to use when supervisedexercise is not available. The U.S. guideline giveshome-based therapy a Class IIa recommendation,whereas the European document gives it Class I. It isunclear why there is a difference in strength ofrecommendation, but functionally, the course of careis similar.

In contrast to the recommendations for atheroscle-rotic risk reduction and exercise therapy, medicationsrecommended for symptomatic improvement varysignificantly. The U.S. guidelines recommend the useof cilostazol based on a Cochrane review supporting itsefficacy (Class I) (21). In contrast, the ESC/ESVS writinggroup reports that objective documentation of a sig-nificant effect is limited and does not recommend thetherapy. This is in line with the stance by the EMA tolimit cilostazol’s use because of its modest efficacy andadverse events (22). It is interesting to note that theESC/ESVS guideline speaks favorably about prosta-noid infusion for limb function but does not provide arecommendation for it. Both guidelines discount thevalue of pentoxifylline.INVASIVE THERAPY. Both sets of guidelines recom-mend, with a Class IIa level, that revascularizationmay be considered in patients with intermittent

TABLE 6 Guidelines for Management of Acute Limb Ischemia

Class AHA/ACC ESC/ESVS

I Patients with suspected ALI should be emergently evaluated by a clinician withsufficient experience to access limb viability (Level of Evidence: C-EO)

In the case of neurological deficit, urgentrevascularization is indicated (Level of Evidence: C)

In the absence of neurological deficit, revascularization isindicated within hours after imaging in acase-by-case decision (Level of Evidence: C)

In patients with ALI, systemic anticoagulation with heparin should beadministered unless contraindicated (Level of Evidence: C-EO)

Heparin and analgesics are indicated as soon aspossible (Level of Evidence: C)

Catheter-based thrombolysis is effective for patients with ALI and a salvageablelimb (Level of Evidence: C-LD)

Amputation should be performed as the first procedure in patients with anonsalvageable limb (Level of Evidence: C-LD)

Patients with ALI should be monitored and treated (e.g., fasciotomy) forcompartment syndrome after revascularization (Level of Evidence: C-LD)

IIa In patients with ALI with a salvageable limb, percutaneous mechanicalthrombectomy can be useful as adjunctive therapy to thrombolysis(Level of Evidence: B-NR)

In patients with ALI due to embolism and with a salvageable limb, surgicalthromboembolectomy can be effective (Level of Evidence: C-LD)

IIb The usefulness of ultrasound-accelerated catheter-based thrombolysis forpatients with ALI and a salvageable limb is unknown (Level of Evidence: C-LD)

ALI ¼ acute limb ischemia; other abbreviations as in Table 1.

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claudication after failure of guideline-directedmanagement and exercise therapy. The role ofrevascularization in this patient population is toimprove functional status and quality of life. The U.S.guidelines recommend against revascularization forthe purposes of avoiding critical limb ischemia (ClassIII). The Europeans do not provide a recommendationfor or against revascularization to avoid CLI, and theydo not provide an avenue for intervention in theasymptomatic or minimally symptomatic patients intheir algorithm figure.

When revascularization is recommended, the rec-ommendations are largely based on large amounts ofdata about each technique, limited amounts ofcomparative data, and expert opinion, leading to adivergence in the guidelines. Both groups recom-mend endovascular approaches for patients withlifestyle-limiting claudication and hemodynamicallysignificant aortoiliac disease. In femoropopliteal dis-ease, however, the guidelines diverge. The U.S.guidelines state that an endovascular strategy can beconsidered in these patients (Class IIa); however, theEuropean guidelines support endovascular revascu-larization first for femoropopliteal occlusions <25 cm(Class I). The European guidelines, in general, offerfar more granular recommendations regardingrevascularization, often relying on single clinicaltrials. The guidelines regarding femoropopliteal dis-ease, for example, are taken from the VIASTAR (Via-bahn Endoprosthesis With PROPATEN BioactiveSurface [VIA] Versus Bare Nitinol Stent in the Treat-ment of Long Lesions in Superficial Femoral Artery

Occlusive Disease) study, which showed sustainedbenefit after 2 years using this contemporaryapproach (23). The ACC/AHA guidelines, on the otherhand, are far more reluctant to recommend specificrevascularization strategies.

Both guidelines agree that patients fit for surgerymay be considered for surgical bypass (Class IIa). TheEuropean guidelines again are far more specific andmake a special exemption for patients with a long(>25 cm) superficial femoral artery lesion and availableautologous vein. This specific Class I recommendationwas based on the results of the BASIL (Bypass versusAngioplasty in Severe Ischemia of the Leg) trial, whichenrolled patients with critical limb ischemia, notclaudication (24). According to the European guide-lines, patients unfit for surgery may be considered forendovascular revascularization (Class IIb).

Notably, the U.S. guidelines place additionalemphasis on post-procedure surveillance, includingwound care, whereas the European guidelines do notmention these aspects of care.

MANAGEMENT OF PATIENTS WITH

CRITICAL LIMB ISCHEMIA

Revascularization is the mainstay of therapy in pa-tients with CLI, in the U.S. guidelines, or chroniclimb-threatening ischemia, in the European guide-lines (Table 5). The ESC/ESVS guidelines endorse theWIFI classification system to evaluate for the risk ofamputation, which gives scores based on Wound,Ischemia, and Foot Infection (25). The American

CENTRAL ILLUSTRATION Management of Lower Extremity Peripheral Artery Disease (PAD) Requires aCoordinated Comparison of Both American and European Guidelines

American College of Cardiology Foundation/American Heart Association

(ACCF/AHA) Guidelines (2016)

European Society of Cardiology/European Society for Vascular Surgery

(ESC/ESVS) Guidelines (2017)

Recommend against axial/anatomic imaging modalities for initial diagnosis

Similarities

Smoking cessation, statin therapy, blood pressure management, glucose control, supervised exercise rehabilitation, antiplatelet therapy

Diagnostictools

(ACCF/AHA) Guidelines (2016) (ESC/ESVS) Guidelines (2017)

In-depth review ofa single disease location

Extends to all non-coronaryatherosclerotic vascular disease Focus

Practitioners of every background Cardiologists, primarily Audience

Requires evidence for each treatment, Oriented for systemic atherosclerosis generally more than PAD alone

Treatment approach

Inclusive of smaller,well-done nonrandomized studies

Relegates small studiesto Level of Evidence: C

Selectionof evidence

Clopidogrel = aspirin to reducecardiovascular events

Clopidogrel > to aspirin to reducecardiovascular events

Medicalmanagement

Recommend cilostazol (Class I) Does not recommend cilostazol

Emphasis on post-proceduresurveillance and wound care

Greater attention on revascularization strategies and contemporary therapies

Managementof symptoms

Risk factor reduction& Medical

Management

Surgical, endovascular, or hybrid Revascularization

Revascularization

Kithcart, A.P. et al. J Am Coll Cardiol. 2018;72(22):2789–801.

This includes risk factor reduction through smoking cessation, statin therapy, and blood pressure and glucose control, as well as medical therapy, and when

appropriate, revascularization.

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document suggests that there are no definitive clin-ical classification systems for PAD and believes this isan evidence gap that needs more investigation.

The U.S. and European guidelines concur thatoutcomes are similar among endovascular and surgi-cal approaches, relying on data from the BASIL trial.Both address factors that may favor an endovascularstrategy, including the presence of comorbidities andabsence of suitable autologous veins for bypass

grafts. The guidelines cite 2 ongoing studies, BASIL-2(Bypass versus Angioplasty in Severe Ischemia of theLeg 2) and BEST-CLI (Best Endovascular vs. BestSurgical Therapy in Patients with Critical LimbIschemia), that may answer the question of whichpatient population benefits the most from whichrevascularization strategy (26,27).

The guidelines emphasize the role that glucosecontrol plays in limb loss. The Europeans use chronic

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limb-threatening ischemia to emphasize the role thatother factors, including glucose, play in limb events.Both guidelines make glycemic control a Class Irecommendation for patients with diabetes and PAD.They quote the increased risk for limb loss in patientswith foot wounds and infection, the majority of whomalso have diabetes. Both guidelines also call attentionto the importance of multidisciplinary wound carebefore and after revascularization (Class I).

Finally, both guidelines acknowledge the limitedalternatives available to patients without reasonableoptions for revascularization, only offering recom-mendations against certain therapies. The ACC/AHAguidelines recommend against the use of prostanoids,citing lack of benefit (Class III). Similarly, the ESC/ESVA guidelines recommend against stem cell andgene therapies in patients with CLI (Class III).

MANAGEMENT OF ACUTE LIMB ISCHEMIA

Both sets of guidelines agree that suspected acutelimb ischemia (ALI) requires emergent clinical eval-uation and treatment (Table 6), including algorithmsthat are worth noting here. The U.S. guidelines sup-port a “pulse first” approach, where patients aredivided based on the presence or absence of arterialand venous pulses (Class I). The European guidelinespropose early assessment of symptom severity afterthe initiation of anticoagulation. The Americanapproach is more granular and provides most of thesteps needed for rapid evaluation. However, thedetection of these pulses in ALI is difficult and mayrequire more expertise. The recommendations, in ourview, are directed at the end-user of the document:vascular providers for the ACC/AHA and cardiologistsfor the ESC/ESVS.

The guidelines agree that once the diagnosis of ALIis made, anticoagulation with heparin should bestarted immediately in the absence of a significantcontraindication (Class I). The strategy for revascu-larization should be made on a case-by-case basis.Approaches include catheter-based thrombolysis,surgical thrombectomy, percutaneous mechanicalthrombectomy, and ultrasound-accelerated catheter-based thrombolysis. On this point, the guidelinesagain diverge, with the U.S. favoring catheter-based thrombolysis (Class I) over percutaneousmechanical thrombectomy (Class IIa), surgicalthromboembolectomy (Class IIa), and ultrasound-accelerated catheter-based thrombolysis (IIb) basedon small studies. The European guidelines, on theother hand, present these various modalities as partof an expanded toolkit, citing a Cochrane reviewshowing no superiority of thrombolysis over

open surgery in terms of 30-day mortality or limbsalvage (28).

ON THE HORIZON

Results of the COMPASS (Cardiovascular Outcomesfor People Using Anticoagulation Strategies) trial, inwhich patients were randomized to low-dose rivar-oxaban 2.5 mg twice a day and aspirin 100 mg oncedaily, rivaroxaban 5 mg twice daily alone, or aspirin100 mg daily in 27,395 patients with stable cardio-vascular disease, including PAD, were not available atthe time of publication of the ACC/AHA and ESC/ESVSguidelines (29). This study demonstrated a benefit interms of cardiovascular events, including adverselimb events, compared with patients taking aspirinalone. However, this did come at an increased risk ofbleeding, but there was no difference in intracranialor fatal bleeding between the groups. The VOYAGER-PAD (Vascular Outcomes Study of ASA Along WithRivaroxaban In Endovascular Or Surgical LimbRevascularization For Peripheral Artery Disease) trial,enrolling now, will specifically look at rivaroxaban inpatients undergoing revascularization for PAD (30).This will contribute necessary evidence beforeanticoagulation can be broadly recommended in pa-tients with lower-extremity disease undergoingrevascularization.

CONCLUSIONS

Our review of the 2 sets of guidelines shows that thereis consensus across the majority of recommendations.The U.S. guidelines place more emphasis on lifestylechanges, multidisciplinary vascular teams, andwound care. The European guidelines, on the otherhand, place greater attention on revascularizationstrategies, incorporating some of the most contem-porary endovascular therapies. These differenceslargely reflect greater emphasis placed on singleclinical trials rather than larger meta-analyses. Bothwriting groups take different views of medicationrecommendations than their respective governingbodies. Despite similar evidence-based classificationsystems, we see variance between the ACC/AHA andESC/ESVS regarding what qualifies as sufficientevidence.

There are still a number of critical questions thatremain unanswered. For instance, in patients failingguidelines-directed management and therapy, whenis the right time to proceed to revascularization?What is the role of local expertise in determining thepreferred approach? Where do comorbidities fit intothe algorithm for care for a patient with CLI and an

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expected 6-month or more wound care requirementafter revascularization? Several trials on the horizonwill begin to answer these questions, includingBASIL-2, BEST-CLI, and VOYAGER-PAD.

The management of PAD has progressed a greatdeal over the last decade with the emergence of ran-domized controlled trials for supervised exercise,antiplatelet and anticoagulation therapy, and revas-cularization strategies. Several clinical trials over thecoming years should help clarify how revasculariza-tion should be approached, and which patients aremost likely to benefit. Until then, maintaining good

cardiovascular health, including regular physical ac-tivity, smoking cessation, lipid-lowering therapy,blood pressure management, and glucose controlhave the most benefit in patients with PAD (CentralIllustration).

ADDRESS FOR CORRESPONDENCE: Dr. Joshua A.Beckman, Vanderbilt University, 1215 21st Avenue South,Nashville, Tennessee 37215. E-mail: joshua.a.beckman@vanderbilt.edu. Twitter: @JoshuaBeckmanMD,@APKithcartMDPhD.

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KEY WORDS anticoagulation, antiplatelet,guidelines, peripheral artery disease,revascularization

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