J. White, John V. White, and R. Eugene Zierler 2011.pdfare available, a survey of current practice...

doi:10.1016/j.jacc.2011.08.023 published online Sep 29, 2011; J. Am. Coll. Cardiol.

J. White, John V. White, and R. Eugene Zierler Michael R. Jaff, Gregory L. Moneta, Jeffrey W. Olin, James C. Stanley, Christopher

Laura K. Findeiss, Jafar Golzarian, Heather L. Gornik, Jonathan L. Halperin, W. Rooke, Alan T. Hirsch, Sanjay Misra, Anton N. Sidawy, Joshua A. Beckman,

Radiology, Society for Vascular Medicine, and Society for Vascular Surgery, Thom Society for Cardiovascular Angiography and Interventions, Society of Interventional

Association Task Force on Practice GuidelinesReport of the American College of Cardiology Foundation/American HeartPatients With Peripheral Artery Disease (Updating the 2005 Guideline): A 2011 ACCF/AHA Focused Update of the Guideline for the Management of

This information is current as of October 6, 2011

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Journal of the American College of Cardiology Vol. 58, No. 19, 2011© 2011 by the American College of Cardiology Foundation and the American Heart Association, Inc. ISSN 0735-1097/$36.00

PRACTICE GUIDELINE

2011 ACCF/AHA Focused Update of the Guideline for theManagement of Patients With Peripheral Artery Disease(Updating the 2005 Guideline)A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice GuidelinesDeveloped in Collaboration With the Society for Cardiovascular Angiography and Interventions,

Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery

2011 WRITING GROUP MEMBERS*Thom W. Rooke, MD, FACC, Chair†; Alan T. Hirsch, MD, FACC, Vice Chair*;

Sanjay Misra, MD, Vice Chair*‡; Anton N. Sidawy, MD, MPH, FACS, Vice Chair§;Joshua A. Beckman, MD, FACC, FAHA*�; Laura K. Findeiss, MD‡; Jafar Golzarian, MD†;

Heather L. Gornik, MD, FACC, FAHA*†; Jonathan L. Halperin, MD, FACC, FAHA*¶;Michael R. Jaff, DO, FACC*†; Gregory L. Moneta, MD, FACS†;

Jeffrey W. Olin, DO, FACC, FAHA*#; James C. Stanley, MD, FACS†;Christopher J. White, MD, FACC, FAHA, FSCAI***; John V. White, MD, FACS†;

R. Eugene Zierler, MD, FACS†2005 WRITING COMMITTEE MEMBERS

Alan T. Hirsch, MD, FACC, Chair; Ziv J. Haskal, MD, FAHA, FSIR, Co-Chair;Norman R. Hertzer, MD, FACS, Co-Chair; Curtis W. Bakal, MD, MPH, FAHA;

Mark A. Creager, MD, FACC, FAHA; Jonathan L. Halperin, MD, FACC, FAHA§;Loren F. Hiratzka, MD, FACC, FAHA, FACS; William R. C. Murphy, MD, FACC, FACS;

Jeffrey W. Olin, DO, FACC; Jules B. Puschett, MD, FAHA; Kenneth A. Rosenfield, MD, FACC;David Sacks, MD, FSIR‡; James C. Stanley, MD, FACS§; Lloyd M. Taylor, Jr, MD, FACS§;

Christopher J. White, MD, FACC, FAHA, FSCAI**; John V. White, MD, FACS§;Rodney A. White, MD, FACS§

ACCF/AHA TASK FORCE MEMBERSAlice K. Jacobs, MD, FACC, FAHA, Chair; Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect;

Nancy Albert, PhD, CCNS, CCRN, FAHA; Mark A. Creager, MD, FACC, FAHA;Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC;

Jonathan L. Halperin, MD, FACC, FAHA; Judith S. Hochman, MD, FACC, FAHA;Frederick G. Kushner, MD, FACC, FAHA; E. Magnus Ohman, MD, FACC;

William Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA

*Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entitiesmay apply; see Appendix 1 for recusal information. †ACCF/AHA Representative. ‡Society of Interventional Radiology Representative. §Society forVascular Surgery Representative. �Society for Vascular Medicine Representative. ¶ACCF/AHA Task Force on Practice Guidelines Liaison. #ACCF/AHATask Force on Performance Measures Liaison. **Society for Cardiovascular Angiography and Interventions Representative.

This document was approved by the American College of Cardiology Foundation Board of Trustees and the American Heart Association ScienceAdvisory and Coordinating Committee in July 2011.

The American College of Cardiology requests that this document be cited as follows: Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA,Findeiss LK, Golzarian J, Gornik HL, Halperin JL, Jaff MR, Moneta GL, Olin JW, Stanley JC, White CJ, White JV, Zierler RE. 2011 ACCF/AHA focusedupdate of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American Collegeof Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:xxx–xxx.

This article is copublished in Circulation, Catheterization and Cardiovascular Interventions, the Journal of Vascular Surgery, and Vascular Medicine.Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.cardiosource.org) and the American

Heart Association (my.americanheart.org). For copies of this document, please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, [email protected].

Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express

Published by Elsevier Inc. doi:10.1016/j.jacc.2011.08.023

permission of the American College of Cardiology Foundation. Please contact Elsevier’s permission department at [email protected].


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TABLE OF CONTENTS

reamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .000

. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .000

1.1. Methodology and Evidence Review . . . . . . . . . .0001.2. Organization of the Writing Group . . . . . . . . . . .0001.3. Document Review and Approval . . . . . . . . . . . . .0001.4. Scope of the Focused Update . . . . . . . . . . . . . . .000

. Lower Extremity PAD. . . . . . . . . . . . . . . . . . . . . . . . . .000

2.5. Diagnostic Methods . . . . . . . . . . . . . . . . . . . . . . . . .0002.5.1. Recommendations for Ankle-Brachial

Index, Toe-Brachial Index, andSegmental Pressure Examination. . . . . . . . . .000

2.6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .0002.6.1.4. RECOMMENDATIONS FOR

SMOKING CESSATION . . . . . . . . . . . . . . . . . . . . .0002.6.1.6. RECOMMENDATIONS FOR

ANTIPLATELET AND ANTITHROMBOTIC DRUGS . . .0002.6.3. Recommendations for Critical Limb

Ischemia: Endovascular andOpen Surgical Treatment forLimb Salvage . . . . . . . . . . . . . . . . . . . . . . . . .000

. Aneurysm of the Abdominal Aorta,Its Branch Vessels, and the Lower Extremities . . .000

5.2.8.1. RECOMMENDATIONS FOR

MANAGEMENT OVERVIEW . . . . . . . . . . . . . . . . .000eferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .000

ppendix 1. Author Relationships With Industrynd Other Entities (Relevant) . . . . . . . . . . . . . . . . . . . . .000

ppendix 2. Reviewer Relationships With Industrynd Other Entities (Relevant). . . . . . . . . . . . . . . . . . . . .000

ppendix 3. 2011 Peripheral Artery Diseasecused Update Summary Table . . . . . . . . . . . . . . . . . .000

reamble

eeping pace with the stream of new data and evolvingidence on which guideline recommendations are based is

ongoing challenge to timely development of clinicalactice guidelines. In an effort to respond promptly to newidence, the American College of Cardiology Foundation/merican Heart Association (ACCF/AHA) Task Force onractice Guidelines (Task Force) has created a “focused update”ocess to revise the existing guideline recommendations thate affected by the evolving data or opinion. New evidence isviewed in an ongoing fashion to more efficiently respond toportant science and treatment trends that could have a majorpact on patient outcomes and quality of care. Evidence is

viewed at least twice a year, and updates are initiated on an-needed basis and completed as quickly as possible whileaintaining the rigorous methodology that the ACCF and AHAve developed during their partnership of �20 years.These updated guideline recommendations reflect a consensus
expert opinion after a thorough review primarily of late- vi
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eaking clinical trials identified through a broad-based vettingocess as being important to the relevant patient population, asell as other new data deemed to have an impact on patient careee Section 1.1, Methodology and Evidence Review, for de-ils). This focused update is not intended to represent an updatesed on a complete literature review from the date of the previousideline publication. Specific criteria/considerations for inclusionnew data include the following:

publication in a peer-reviewed journal;large, randomized, placebo-controlled trial(s);nonrandomized data deemed important on the basis ofresults affecting current safety and efficacy assumptions,including observational studies and meta-analyses;strength/weakness of research methodology and findings;likelihood of additional studies influencing current findings;impact on current and/or likelihood of need to develop newperformance measure(s);request(s) and requirement(s) for review and update from thepractice community, key stakeholders, and other sources freeof relationships with industry or other potential bias;number of previous trials showing consistent results; andneed for consistency with a new guideline or guidelineupdates or revisions.

elected members of the previous writing committee as wellother experts in the subject under consideration are chosenthe ACCF and AHA to examine subject-specific data andwrite guidelines in partnership with representatives from

her medical organizations and specialty groups. Writingoup members review the selected late-breaking clinicalials and other new data that have been vetted through theask Force; weigh the strength of evidence for or againstrticular tests, treatments, or procedures; and include esti-ates of expected outcomes where such data exist. Patient-ecific modifiers, comorbidities, and issues of patient pref-ence that may influence the choice of tests or therapies arensidered. When available, information from studies on costconsidered, but data on efficacy and outcomes constitute theimary basis for the recommendations contained herein.In analyzing the data and developing recommendations andpporting text, the writing group uses evidence-based meth-ologies developed by the Task Force (1). The Class of

ecommendation (COR) is an estimate of the size of theeatment effect considering risks versus benefits in addition

evidence and/or agreement that a given treatment orocedure is or is not useful/effective or in some situationsay cause harm. The Level of Evidence (LOE) is an estimate

the certainty or precision of the treatment effect. Theriting group reviews and ranks evidence supporting eachcommendation with the weight of evidence ranked as LOE, B, or C according to specific definitions that arecluded in Table 1. Studies are identified as observational,trospective, prospective, or randomized where appropri-e. For certain conditions for which inadequate data areailable, recommendations are based on expert consensusd clinical experience and are ranked as LOE C. Whencommendations at LOE C are supported by historicalinical data, appropriate references (including clinical re-
ews) are cited if available. For issues for which sparse data
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3JACC Vol. 58, No. 19, 2011 Rooke et al.November 1, 2011:000–00 PAD Guideline Focused Update

e available, a survey of current practice among the clini-ans on the writing group is the basis for LOE C recommen-tions, and no references are cited. The schema for COR and

OE is summarized in Table 1, which also provides sug-sted phrases for writing recommendations within each

OR. A new addition to this methodology is a separation ofe Class III recommendations to delineate whether thecommendation is determined to be of “no benefit” or issociated with “harm” to the patient. In addition, in view ofe increasing number of comparative effectiveness studies,mparator verbs and suggested phrases for writing recom-

ble 1. Applying Classification of Recommendations and Level

A recommendation with Level of Evidence B or C does not imply that the reconot lend themselves to clinical trials. Although randomized trials are unavaila

eful or effective.*Data available from clinical trials or registries about the usefulness/efficacy

yocardial infarction, history of heart failure, and prior aspirin use.†For comparative effectiveness recommendations (Class I and IIa; Level of Evi

rect comparisons of the treatments or strategies being evaluated.

endations for the comparative effectiveness of one treat- A


ent or strategy versus another have been added for COR Id IIa, LOE A or B only.In view of the advances in medical therapy across theectrum of cardiovascular diseases, the Task Force hassignated the term guideline–directed medical therapyDMT) to represent optimal medical therapy as defined by

CCF/AHA guideline-recommended therapies (primarilylass I). This new term, GDMT, will be used herein androughout all future guidelines.Because the ACCF/AHA practice guidelines address pa-

ent populations (and healthcare providers) residing in North

ence

ation is weak. Many important clinical questions addressed in the guidelinesre may be a very clear clinical consensus that a particular test or therapy is

rent subpopulations, such as sex, age, history of diabetes, history of prior

and B only), studies that support the use of comparator verbs should involve

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merica are discussed in the text without a specific COR. Forudies performed in large numbers of subjects outside Northmerica, each writing group reviews the potential influencedifferent practice patterns and patient populations on the

eatment effect and relevance to the ACCF/AHA targetpulation to determine whether the findings should inform aecific recommendation.The ACCF/AHA practice guidelines are intended to assistalthcare providers in clinical decision making by describ-g a range of generally acceptable approaches to the diag-sis, management, and prevention of specific diseases ornditions. The guidelines attempt to define practices thateet the needs of most patients in most circumstances. Thetimate judgment regarding care of a particular patient mustmade by the healthcare provider and patient in light of all

e circumstances presented by that patient. As a result, situa-ns may arise for which deviations from these guidelines mayappropriate. Clinical decision making should involve consid-

ation of the quality and availability of expertise in the areahere care is provided. When these guidelines are used as thesis for regulatory or payer decisions, the goal should beprovement in quality of care. The Task Force recognizes that

tuations arise in which additional data are needed to informtient care more effectively; these areas will be identified withinch respective guideline when appropriate.Prescribed courses of treatment in accordance with thesecommendations are effective only if followed. Because lackpatient understanding and adherence may adversely affecttcomes, physicians and other healthcare providers shouldake every effort to engage the patient’s active participation inescribed medical regimens and lifestyles. In addition, patientsould be informed of the risks, benefits, and alternatives to articular treatment and be involved in shared decision makinghenever feasible, particularly for COR IIa and IIb, for whiche benefit-to-risk ratio may be lower.The Task Force makes every effort to avoid actual, poten-

al, or perceived conflicts of interest that may arise as a resultindustry relationships or personal interests among the

embers of the writing group. All writing group membersd peer reviewers of the guideline are asked to disclose allch current relationships as well as those existing 12 monthseviously. In December 2009, the ACCF and AHA imple-ented a new policy for relationships with industry and othertities (RWI) that requires the writing group chair plus ainimum of 50% of the writing group to have no relevantWI (Appendix 1 for the ACCF/AHA definition of rele-nce). These statements are reviewed by the Task Force andl members during each conference call and/or meeting ofe writing group and are updated as changes occur. Allideline recommendations require a confidential vote by the

riting group and must be approved by a consensus of theting members. Members are not permitted to write, andust recuse themselves from voting on, any recommendation orction to which their RWI apply. Members who recusedemselves from voting are indicated in the list of writing groupembers, and section recusals are noted in Appendix 1. Au-ors’ and peer reviewers’ RWI pertinent to this guideline aresclosed in Appendixes 1 and 2, respectively. Additionally, to
sure complete transparency, writing group members’ compre- re

nsive disclosure information—including RWI not pertinent tois document—is available as an online supplement. Compre-nsive disclosure information for the Task Force is alsoailable online at www.cardiosource.org/ACC/About-ACC/

eadership/Guidelines-and-Documents-Task-Forces.cardiosource.g. The work of the writing group was supported exclusively bye ACCF and AHA without commercial support. Writing groupembers volunteered their time for this activity.In an effort to maintain relevance at the point of care foracticing physicians, the Task Force continues to oversee angoing process improvement initiative. As a result, insponse to pilot projects, several changes to these guidelinesill be apparent, including limited narrative text and a focus

summary and evidence tables.The recommendations in this focused update will bensidered current until they are superseded by anothercused update or the full-text guideline is revised. Guide-

nes are official policy of both the ACCF and AHA.

Alice K. Jacobs, MD, FACC, FAHAChair, ACCF/AHA Task Force on Practice Guidelines

. Introduction

.1. Methodology and Evidence Reviewhe results of late-breaking clinical trials presented at the annualientific meetings of the ACC, AHA, European Society ofardiology, Society for Vascular Surgery, Society of Interven-nal Radiology, and Society for Vascular Medicine, as well aslected other data/articles published through December 2010,ere reviewed by the 2005 guideline writing committee alongith the Task Force and other experts to identify those trials andher key data that may impact guideline recommendations. One basis of the criteria/considerations noted above, recent trialta and other clinical information were considered importantough to prompt a focused update of the “ACC/AHA 2005uidelines for the Management of Patients With Peripheralrterial Disease (Lower Extremity, Renal, Mesenteric, andbdominal Aortic)” (2). Because clinical research and clinicalre of vascular disease have a global investigative and interna-nal clinical care tradition, efforts were made to harmonize thisdate with the Trans-Atlantic Inter-Society Consensus docu-ent on Management of Peripheral Arterial Disease (TASC)d the Inter-Society Consensus for the Management of

eripheral Arterial Disease (TASC II) Steering Committeeideline writing efforts (3).To provide clinicians with a comprehensive set of data,

henever deemed appropriate or when published, the abso-te risk difference and number needed to treat or harm areovided in the guideline, along with confidence intervals (CIs) andta related to the relative treatment effects, such as odds ratio,lative risk, hazard ratio (HR), or incidence rate ratio.Consult the full-text version (2) or executive summary (4) of

e “ACC/AHA 2005 Guidelines for the Management of Pa-nts With Peripheral Arterial Disease (Lower Extremity, Renal,esenteric, and Abdominal Aortic)” for policy on clinical areast covered by the focused update. Individual recommendationsodified in this focused update will be incorporated into future
visions and/or updates of the full-text guideline.

http://content.onlinejacc.org/cgi/content/full/j.jacc.2011.08.023/DC1

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.2. Organization of the Writing Groupor this focused update, all eligible members of the 2005riting committee were invited to participate; those whoreed (referred to as the 2011 focused update writing group)ere required to disclose all RWI relevant to the data undernsideration. In addition, new members were invited inder to preserve the required RWI balance. The writingoup included representatives from the ACCF, AHA, Soci-y for Cardiovascular Angiography and Interventions, Soci-y of Interventional Radiology, Society for Vascular Medi-ne, and Society for Vascular Surgery.

.3. Document Review and Approvalhis document was reviewed by 2 official reviewers eachminated by the ACCF and the AHA, as well as 2 reviewersch from the Society for Cardiovascular Angiography andterventions, Society of Interventional Radiology, Societyr Vascular Medicine, and Society for Vascular Surgery; andindividual content reviewers (including members from the

llowing groups: ACCF/AHA Task Force on Clinical Datatandards, ACCF Interventional Scientific Council, 2005eripheral Artery Disease Writing Committee, ACCF/AHAask Force on Performance Measures, ACCF Prevention Commit-e, and ACCF Peripheral Vascular Disease Committee). Allformation on reviewers’ RWI was distributed to the writing groupd is published in this document (Appendix 2).This document was approved for publication by the gov-ning bodies of the ACCF and AHA and endorsed by theociety for Cardiovascular Angiography and Interventions,ociety of Interventional Radiology, Society for Vascularedicine, and Society for Vascular Surgery.

.4. Scope of the Focused Updatetudies relevant to the management of patients with periph-al artery disease (PAD) (lower extremity, renal, mesenteric,d abdominal aortic) were identified and reviewed as de-ribed previously in Section 1.1. On the basis of these data,e writing group determined that updates to the 2005commendations were necessary for lower extremity anddominal aortic disease but that the existing recommenda-

ons for renal and mesenteric disease remain valid (4).lthough the specific recommendations for renal and mesen-ric disease did not change, the following observations andarifications were made:

Medical therapy for renal disease: No new pivotal trials orstudies were identified.Revascularization for renal disease: The writing groupacknowledges that some new studies support a morelimited role for renal revascularization. For example, theASTRAL (Angioplasty and Stent for Renal Artery Le-sions) investigators (5) concluded that there were substan-tial risks but no clinical benefit from revascularization inpatients with atherosclerotic renovascular disease. Thewriting group concurred that the criteria for patient selec-tion in this randomized controlled trial (RCT) potentiallyexcluded many patients who might have benefitted fromintervention. It is anticipated that ongoing studies such as
the CORAL (Cardiovascular Outcomes in Renal Athero- m

sclerotic Lesions) trial (6) will provide additional evidencerelevant to these recommendations in the near future.Methods of revascularization for renal disease: The 2005recommendations remain current.

he 2011 focused update acknowledges the declining use ofrgical revascularization and the increasing use of catheter-sed revascularization for renal artery stenoses. The writingoup determined that new data support the equivalency ofrgical and endovascular treatment, with lower morbidityd mortality associated with endovascular treatment butgher patency rates with surgical treatment in those patientsho survived for at least 2 years after randomization (5). Theriting group also notes that new data suggest that: 1) theficacy of revascularization may be reduced in patients withanch artery stenoses (7); and 2) patients undergoing renaltery bypass may do best when surgery is performed ingh-volume centers (8).

. Lower Extremity PAD

.5. Diagnostic Methods

.5.1. Recommendations for Ankle-Brachial Index,oe-Brachial Index, and Segmentalressure Examinationable 2 contains recommendations for ankle-brachial indexBI), toe-brachial index, and segmental pressure examina-

on. See Appendix 3 for supplemental information.The German Epidemiologic Trial on Ankle Brachial Index

tudy Group included 6,880 patients �65 years of age andmonstrated that 21% of the cohort had either asymptomaticsymptomatic PAD (11). On the basis of this large epide-

iologic study, the 2011 writing group modified the age fornsideration of ABI diagnostic testing to �65 years. Theriting group considered the potential impact of lowering theAD detection age to 65 years, acknowledging that the ABI testould be used in an incrementally larger “at-risk” population.his reflects the intent of both the original evidence-basedcument and this focused update to blunt the profound ongoingderdiagnosis and undertreatment of individuals with PADtil limb ischemic symptoms have become severe. This ABIcommendation is intended for office-based and vascularboratory diagnostic use and is not intended to serve as apulation screening tool. The writing group noted withnfidence that no other cardiovascular disease diagnosticst can be applied in an age-defined clinical population withch a high detection rate, low to no risk, and low cost. Wecourage expansion of the evidence base by design andmpletion of ABI screening studies.The definitions of normal and abnormal ABI values haveen modified based on publication of the results of the Ankle

rachial Index Collaboration (24). This includes a normalBI range of 1.00 to 1.40, and abnormal values continue to

defined as those �0.90. ABI values of 0.91 to 0.99 arensidered “borderline” and values �1.40 indicate noncom-essible arteries.The 2005 recommendations stated that segmental pressure

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calization of lower extremity PAD. The 2011 writing groupcognized that vascular diagnostic laboratories could usegmental pressures, Doppler waveform analysis, pulse vol-e recordings, or ABI with duplex ultrasonography (or

me combination of these methods) to document the pres-ce and location of PAD in the lower extremity.

.6. Treatment

6.1.4. RECOMMENDATIONS FOR SMOKING CESSATION

able 3 contains recommendations for smoking cessation.ee Appendix 3 for supplemental informationNo prospective RCTs have examined the effects of smok-

g cessation on cardiovascular events in patients with lowertremity PAD. Observational studies have found that the

sk of death, myocardial infarction, and amputation is sub-antially greater, and lower extremity angioplasty and openrgical revascularization patency rates are lower in individ-ls with PAD who continue to smoke than in those who stopoking (34–36). In some studies, exercise time is greater intients who stop smoking than in current smokers (37,38).

fforts to achieve smoking cessation are recommended fortients with lower extremity PAD. Physician advice coupledith frequent follow-up achieves 1-year smoking cessationtes of approximately 5% compared with only 0.1% individuals who try to quit smoking without a physician’stervention (39). With pharmacological interventions such as

ble 2. Recommendations for Ankle-Brachial Index, Toe-Brachi

05 Recommendations 2011 Focus

ass I

The resting ABI should be used to establish thelower extremity PAD diagnosis in patients withsuspected lower extremity PAD, defined asindividuals with exertional leg symptoms, withnonhealing wounds, who are 70 years and older orwho are 50 years and older with a history ofsmoking or diabetes. (Level of Evidence: C)

1. The resting ABI sextremity PAD dialower extremity Pmore of the follononhealing wounyears and older w(9–11). (Level of

The ABI should be measured in both legs in allnew patients with PAD of any severity to confirmthe diagnosis of lower extremity PAD and establisha baseline (12–14). (Level of Evidence: B)

The toe-brachial index should be used to establishthe lower extremity PAD diagnosis in patients inwhom lower extremity PAD is clinically suspectedbut in whom the ABI test is not reliable due tononcompressible vessels (usually patients withlong-standing diabetes or advanced age) (15–19).(Level of Evidence: B)

Leg segmental pressure measurements are usefulto establish the lower extremity PAD diagnosiswhen anatomic localization of lower extremity PADis required to create a therapeutic plan (20–23).(Level of Evidence: B)

2. ABI results shoulnoncompressiblenormal values 1.and abnormal 0.9

ABI indicates ankle-brachial index; and PAD, peripheral artery disease.

cotine replacement therapy and bupropion, 1-year smoking thcontent.onlinejaccDownloaded from

ssation rates of approximately 16% and 30%, respectively,e achieved in a general population of smokers (33).Varenicline, a nicotinic receptor partial agonist, has demon-

rated superior quit rates when compared with nicotine replace-ent and bupropion in several RCTs (30–32). The superioroking cessation may result from better reductions in cravingd withdrawal symptoms (40). Despite its greater cost, vareni-ine is cost-effective because of its improved quit rates (41). In09, the US Food and Drug Administration released a Public

ealth Advisory noting that both bupropion and vareniclineve been associated with reports of changes in behavior such asstility, agitation, depressed mood, and suicidal thoughts ortions. In patients with PAD specifically, comprehensive smok-g cessation programs that included individualized counselingd pharmacological support significantly increased the rate ofoking cessation at 6 months compared with verbal advice toit smoking (21.3% versus 6.8%, p�0.02) (29). Tobaccossation interventions are particularly critical in individualsith thromboangiitis obliterans, because it is presumed thatmponents of tobacco may be causative in the pathogenesis ofis syndrome, and continued use is associated with a particu-rly adverse outcome (42).

6.1.6. RECOMMENDATIONS FOR ANTIPLATELET AND

TITHROMBOTIC DRUGS

able 4 contains recommendations for antiplatelet and anti-

x, and Segmental Pressure Examination

te Recommendations Comments

e used to establish the lowerin patients with suspectedned as individuals with 1 orertional leg symptoms,65 years and older, or 50istory of smoking or diabetese: B)

Modified recommendation (age modifiedand level of evidence changed fromC to B).

2005 recommendation remains currentin 2011 focused update.



iformly reported withdefined as greater than 1.40,40, borderline 0.91 to 0.99,s (24). (Level of Evidence: B)

New recommendation

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The writing group reviewed 5 RCTs and 1 meta-analysislated to antiplatelet therapy and PAD as part of this focuseddate (45–48,51). Although the 2002 Antithrombotic Trial-

ts’ Collaboration meta-analysis demonstrated a significantduction in cardiovascular events among symptomatic PADtients randomized to antiplatelet therapy versus placebo,ere was significant heterogeneity of enrollment criteria andtiplatelet dosing regimens among the trials (44). The results3 RCTs of aspirin use (100 mg daily) versus placebo for

rdiovascular risk reduction among patients with PAD haveen published since the 2005 guideline (45–47). These trialselded mixed results, with the 2 larger trials with longerration of follow-up demonstrating no benefit of aspirin6,47). However, both of these studies enrolled only asymp-matic patients derived from population screening (notinical populations) based on very mild decrements in ABId thus represented relatively low-risk cohorts. The POPA-AD (Prevention of Progression of Asymptomatic Diabeticrterial Disease) study enrolled individuals with an ABI0.99, whereas the Aspirin for Asymptomatic Atherosclero-s trial used a cutpoint of ABI �0.95 but calculated the ABIing the lower pedal pressure at the ankle. This method is inntrast to standard clinical practice (and this guideline) ofing the higher pedal pressure at the ankle for determiningBI (46,47). These factors limit the generalizability of thesults to patients with clinical PAD who are symptomaticd/or have lower ABI values and face a greater risk of

chemic events. The CLIPS (Critical Leg Ischemia Preven-on Study) trial, which was the smallest of the 3 antiplateleterapy trials reviewed, enrolled patients with more advancedAD, defined by both symptoms and/or ABI values (ABI0.85), and demonstrated a significant reduction in cardio-scular ischemic events among subjects randomized to

ble 3. Recommendations for Smoking Cessation

05 Recommendation 2011 Focused

ass I

1. Patients who are smokerabout status of tobacco u(Level of Evidence: A)

2. Patients should be assistplan for quitting that mayreferral to a smoking ces(Level of Evidence: A)

Individuals with lower extremity PADwho smoke cigarettes or use otherforms of tobacco should be advised byeach of their clinicians to stopsmoking and should be offeredcomprehensive smoking cessationinterventions, including behaviormodification therapy, nicotinereplacement therapy, or bupropion.(Level of Evidence: B)

3. Individuals with lower exuse other forms of tobacclinicians to stop smokinpharmacological treatmen

4. In the absence of contraiindication, 1 or more of ttherapies should be offernicotine replacement ther

PAD indicates peripheral artery disease.

pirin (45). Of note, this trial was stopped early because of ancontent.onlinejaccDownloaded from

or recruitment, with only 366 of a planned 2,000 patientsrolled. The 2009 meta-analysis of aspirin therapy fortients with PAD demonstrated a 34% risk reduction fornfatal stroke among participants taking aspirin but no

atistically significant reduction in overall cardiovascularents (51). This study included the CLIPS and POPADAD

ials but not the Aspirin for Asymptomatic Atherosclerosisial.The recommended dose range of aspirin has been modified75 mg to 325 mg per day to reflect the doses studied in thepirin clinical trials and in use in clinical practice. The 2005commendation of clopidogrel as an alternative to aspirinerapy is unchanged. No new clinical trials have directlympared aspirin monotherapy therapy with clopidogrel

nce the CAPRIE (Clopidogrel versus Aspirin in Patients atisk of Ischemic Events) study demonstrated an incrementalnefit of clopidogrel (43). On the basis of the findings of the

HARISMA (Clopidogrel for High Atherothrombotic Riskd Ischemic Stabilization, Management, and Avoidance)

ial, it may be reasonable to consider combination antiplate-t therapy with aspirin plus clopidogrel for certain high-risktients with PAD who are not considered at increased risk ofeeding (48,49,52). Selection of an antiplatelet regimen fore PAD patient should be individualized on the basis oflerance and other clinical characteristics (i.e., bleeding risk)ong with cost and guidance from regulatory agencies.The WAVE (Warfarin Antiplatelet Vascular Evaluation)

ial provided further evidence against the use of oral antico-ulation therapy in addition to antiplatelet therapy forevention of cardiovascular events among patients with

AD, and the level of evidence is upgraded to B for this ClassI recommendation (50).The writing group emphasizes that selection of the optimal

ecommendations Comments

er smokers should be askedery visit (25–28).

New recommendation

counseling and developing apharmacotherapy and/or

rogram (26,29).

New recommendation

AD who smoke cigarettes orld be advised by each of theirfered behavioral andl of Evidence: C)

Modified recommendation (wordingclarified and level of evidencechanged from B to C).

n or other compelling clinicaling pharmacological

nicline, bupropion, and–33). (Level of Evidence: A)

New recommendation

Update R

s or formse at ev

ed withinclude

sation p

tremity Pco shoug and oft. (Leve

ndicatiohe followed: vareapy (30

tiplatelet therapy and determination of optimum dosage in by on October 6, 2011 .org


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ell-defined populations of patients with PAD are criticalanswered scientific questions. There is a need for addi-

onal data from large-scale RCTs and observational studiesinvestigate the efficacy and risk of antiplatelet medicationsross the spectrum of PAD defined according to symptomass (symptomatic versus asymptomatic) and objective mea-res of atherosclerosis severity (i.e., ABI value).To date, no clinical trials have examined the efficacy of

ble 4. Recommendations for Antiplatelet and Antithrombotic D

05 Recommendations 2011 Focused Upda

ass I

Antiplatelet therapy is indicated toreduce the risk of MI, stroke, orvascular death in individuals withatherosclerotic lower extremity PAD.(Level of Evidence: A)

1. Antiplatelet therapy is indicateand vascular death in individuaatherosclerotic lower extremityintermittent claudication or critextremity revascularization (enamputation for lower extremity(Level of Evidence: A)

Aspirin, in daily doses of 75 to 325mg, is recommended as safe andeffective antiplatelet therapy to reducethe risk of MI, stroke, or vasculardeath in individuals withatherosclerotic lower extremity PAD.(Level of Evidence: A)

2. Aspirin, typically in daily dosesrecommended as safe and effereduce the risk of MI, stroke, owith symptomatic atherosclerothose with intermittent claudicprior lower extremity revasculasurgical), or prior amputation f(44,45). (Level of Evidence: B)

Clopidogrel (75 mg per day) isrecommended as an effectivealternative antiplatelet therapy toaspirin to reduce the risk of MI,stroke, or vascular death in individualswith atherosclerotic lower extremityPAD. (Level of Evidence: B)

3. Clopidogrel (75 mg per day) iseffective alternative antiplatelerisk of MI, ischemic stroke, orsymptomatic atherosclerotic lothose with intermittent claudicprior lower extremity revasculasurgical), or prior amputation f(Level of Evidence: B)

ass IIa

1. Antiplatelet therapy can be usestroke, or vascular death in asABI less than or equal to 0.90

ass IIb

1. The usefulness of antiplateletstroke, or vascular death in asborderline abnormal ABI, definestablished (46,47). (Level of E

2. The combination of aspirin andto reduce the risk of cardiovassymptomatic atherosclerotic lothose with intermittent claudicprior lower extremity revasculasurgical), or prior amputation fwho are not at increased riskperceived cardiovascular risk (

ass III: No benefit

Oral anticoagulation therapy withwarfarin is not indicated to reduce therisk of adverse cardiovascularischemic events in individuals withatherosclerotic lower extremity PAD.(Level of Evidence: C)

1. In the absence of any other praddition to antiplatelet therapycardiovascular ischemic eventsatherosclerotic lower extremitypotentially harmful due to incre(Level of Evidence: B)

ABI indicates ankle-brachial index; MI, myocardial infarction; and PAD, perip

w antithrombotic medications such as prasugrel, ticagrelor, licontent.onlinejaccDownloaded from

vorapaxar to reduce ischemic events in patients with lowertremity PAD.

.6.3. Recommendations for Critical Limb Ischemia:ndovascular and Open Surgical Treatment forimb Salvageable 5 contains recommendations for endovascular and openrgical treatment for limb salvage in patients with critical

mmendations Comments

uce the risk of MI, stroke,symptomaticcluding those withischemia, prior lower

lar or surgical), or prioria (43–45).

Modified recommendation (wording clarified).

o 325 mg, istiplatelet therapy tolar death in individualsr extremity PAD, includingcritical limb ischemia,(endovascular orextremity ischemia

Modified recommendation (wording clarified;and level of evidence changed from A to B).

ended as a safe andy to aspirin to reduce ther death in individuals withemity PAD, includingcritical limb ischemia,(endovascular orextremity ischemia (43).

Modified recommendation (wording clarified).

duce the risk of MI,atic individuals with anevel of Evidence: C)

New recommendation

to reduce the risk of MI,atic individuals with91 to 0.99, is not well: A)

New recommendation

grel may be consideredents in patients withemity PAD, includingcritical limb ischemia,(endovascular orextremity ischemia and

ing and who are at high(Level of Evidence: B)

New recommendation

ication for warfarin, itsce the risk of adverseiduals withof no benefit and is

sk of major bleeding (50).

Modified recommendation (level of evidencechanged from C to B).

tery disease.

rugs

te Reco

d to redls withPAD, in

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ischem

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tic loweation orrizationor lower

recommt therapvasculawer extration orrizationor lower

ful to reymptom(45). (L

therapyymptomed as 0.vidence

clopidocular evwer extration orrizationor lowerof bleed48,49).

oven indto reduin indivPAD isased ri

mb ischemia. See Appendix 3 for supplemental information. by on October 6, 2011 .org


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The writing group has reviewed the results of the multicenterASIL (Bypass Versus Angioplasty in Severe Ischaemia of theeg) trial funded by the United Kingdom National Institute ofealth Research and Health Technology Assessment Pro-amme (54). During a 5-year period, 452 patients with severeb ischemia (characterized by rest/night pain and tissue loss,

ch as skin ulceration and gangrene, and thus including patientsfined by this PAD guideline syndrome term critical limb

chemia) were randomly assigned to an initial treatment strat-y of either open surgery or balloon angioplasty. Major clinicaltcomes evaluated in this trial were amputation-free survivald overall survival. The initial results published in 2005dicated that in patients with severe limb ischemia due tofrainguinal disease, the short-term clinical outcomes betweenpass surgery–first and balloon angioplasty–first were similar4,55). These initial results showed that bypass surgery–firstas one third more expensive and was associated with higherorbidity than balloon angioplasty–first.The trial also initially suggested that after 2 years, patients

eated with balloon angioplasty–first had increased overallrvival rates and fewer amputations. However, this early

nding was based on a post hoc analysis of a relatively smallmber of outcome events. Thus, more prolonged follow-up

as necessary to confirm or refute this finding. The results of a5-year follow-up have been published (54) and confirm thatere was no significant difference in amputation-free survival

ble 5. Recommendations for Critical Limb Ischemia: Endovasc

05 Recommendations 2011 Fo

ass I

For individuals with combined inflow and outflowdisease with critical limb ischemia, inflowlesions should be addressed first. (Level ofEvidence: C)

For individuals with combined inflow and outflowdisease in whom symptoms of critical limbischemia or infection persist after inflowrevascularization, an outflow revascularizationprocedure should be performed (53). (Level ofEvidence: B)

If it is unclear whether hemodynamicallysignificant inflow disease exists, intra-arterialpressure measurements across suprainguinallesions should be measured before and after theadministration of a vasodilator. (Level ofEvidence: C)

ass IIa

1. For patients withand an estimatedpatients in whomavailable, balloonpossible as the in(54). (Level of Evi

2. For patients withestimated life expsurgery, when poconduit is availabtreatment to impr(Level of Evidence

d overall survival between the 2 treatment strategies. How- aocontent.onlinejaccDownloaded from

er, a bypass surgery–first approach was associated with agnificant increase in overall survival of 7.3 months (95% CI:2 to 13.4 months; p�0.02) and a trend toward improvedputation-free survival of 5.9 months (95% CI: 0.2 to 12.0

onths; p�0.06) for those patients who survived for at least 2ars after randomization. In summary, for all patients in the

ial, there was no significant difference between the 2 treatmentrategies in amputation-free survival or overall survival. How-er, these data suggest that it is reasonable for a bypassrgery–first approach to be considered for these carefullylected patients to prolong amputation-free survival and overallrvival. This study has also confirmed that the outcomesllowing prosthetic bypass were extremely poor. Balloon an-oplasty, when possible, may be preferable to prosthetic bypassen in patients with a life expectancy of �2 years (54).

. Aneurysm of the Abdominal Aorta,s Branch Vessels, and theower Extremities

2.8.1. RECOMMENDATIONS FOR MANAGEMENT OVERVIEW

able 6 contains recommendations for management of ab-minal aortic aneurysm (AAA). See Appendix 3 for supple-ental information.Although the methods of treatment for infrarenal abdominal

d Open Surgical Treatment for Limb Salvage

pdate Recommendations Comments

2005 recommendation remainscurrent in 2011 focusedupdate.



eatening lower extremity ischemiaectancy of 2 years or less or ingenous vein conduit is notasty is reasonable to perform whencedure to improve distal blood flow)

New recommendation

eatening ischemia and anof more than 2 years, bypass

nd when an autogenous veinasonable to perform as the initialal blood flow (54).

New recommendation

ular an

cused U

limb-thrlife expan autoangioplitial prodence: B

limb-threctancyssible ale, is reove dist: B)

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st 5 years, a greater understanding of the appropriate applica-n of these technologies and techniques has been gained.

verall, open and endovascular repair techniques have demon-rated clinical equivalence over time, with similar rates oferall and aneurysm-related mortality and morbidity.For patients with an infrarenal AAA who are likely to live2 years and who are good risk surgical candidates, open ordovascular intervention is indicated. There is no long-termvantage to either technique of aneurysm repair. This wasearly demonstrated in 2 large multicenter, randomized,ospective studies. The EVAR (United Kingdom Endovas-lar Aneurysm Repair) trial evaluated the outcomes oftients �60 years of age who were appropriate candidatesr either endovascular or open repair of infrarenal AAAs thatere at least 5.5 cm in diameter based on computed tomo-aphic imaging (56). Over 5 years, 1,252 patients wererolled and randomly assigned to either stent graft or openeurysm repair. The primary outcomes measures werel-cause mortality and aneurysm-related mortality, and dataere analyzed on an intention-to-treat basis. Follow-up was a

ble 6. Recommendations for Management of Abdominal Aortic

2005 Recommendations 2011 F

ass I

Open repair of infrarenal AAA and/or common iliacaneurysms is indicated in patients who are good oraverage surgical candidates. (Level of Evidence: B)

1. Open or eand/or copatients w(56,57). (

Periodic long-term surveillance imaging should beperformed to monitor for an endoleak, to documentshrinkage or stability of the excluded aneurysm sac, and todetermine the need for further intervention in patients whohave undergone endovascular repair of infrarenal aorticand/or iliac aneurysms. (Level of Evidence: B)

2. Periodic lbe perforgraft posiof the excthe needwho haveinfrarenal(56,58). (

ass IIa

Endovascular repair of infrarenal aortic and/or commoniliac aneurysms is reasonable in patients at high risk ofcomplications from open operations because ofcardiopulmonary or other associated diseases. (Level ofEvidence: B)

1. Open aneperform icandidateperiodic lendovasc

ass IIb

Endovascular repair of infrarenal aortic and/or commoniliac aneurysms may be considered in patients at low oraverage surgical risk. (Level of Evidence: B)

1. Endovascaneurysmor anesthpresencepulmonareffectiven

*Indicates merging of deleted 2005 Class IIb recommendation with the modi

AAA indicates abdominal aortic aneurysm.

inimum of 5 years or until death, with a median postpro- ancontent.onlinejaccDownloaded from

dural follow-up of 6 years. The treatment groups, whichere 90.7% male with a mean age of 74 years, were uniformith regard to comorbidities. There was a significant differ-ce in procedural mortality between endovascular and openpair (1.8% endovascular repair versus 4.3% open repair,

0.02, adjusted odds ratio: 0.39; 95% CI: 0.18 to 0.87).ver time, this initial benefit was not sustained. Over theriod of observation, all-cause mortality in the endovascularoup was 7.5 deaths per 100 person-years compared with 7.7aths per 100 person-years in the open-surgery group�0.72; adjusted HR: 1.03; 95% CI: 0.86 to 1.23).neurysm-related mortality was also similar, with 1.0 deathr 100 person-years in the stent graft group compared with2 deaths per 100 person-years in the open-surgery group�0.73; adjusted HR: 0.92; 95% CI: 0.57 to 1.49). Reinter-ntion was required in 5.1% of patients treated with andograft but in only 1.7% of those who underwent openrgery (p�0.001), underscoring the need for careful evalu-ion of the stent graft over time (56).These findings were consistent with those reported in

rysm

Update Recommendations Comments

cular repair of infrarenal AAAsliac aneurysms is indicated ingood surgical candidatesEvidence: A)

Modified recommendation (endovascularrepair incorporated from 2005 Class IIbrecommendation [see below*]; level ofevidence changed from B to A).

surveillance imaging shouldmonitor for endoleak, confirmument shrinkage or stabilityneurysm sac, and determineer intervention in patientsone endovascular repair ofnd/or iliac aneurysmsEvidence: A)

Modified recommendation (level ofevidence changed from B to A).

Deleted recommendation (no longercurrent).

epair is reasonable tots who are good surgicalho cannot comply with the

surveillance required afterair. (Level of Evidence: C)

New recommendation

Deleted recommendation (endovascularrepair incorporated into 2011 Class I,#1 [see above*]).

air of infrarenal aorticients who are at high surgicalas determined by the

isting severe cardiac,r renal disease is of uncertain. (Level of Evidence: B)

New recommendation

1 Class I, #1 recommendation.

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REAM (Dutch Randomized Endovascular Aneurysm Re-ir) trial evaluated the long-term outcomes of patients withfrarenal aortic aneurysms �5 cm who were randomized tother endovascular or open surgical treatment. The primarytcome measure was all-cause mortality. There were nofferences in demographic characteristics or comorbiditiestween the 178 patients assigned to open surgery and the3 patients assigned to endovascular intervention. Similar toe EVAR trial, the majority of patients in the DREAM trialere male (91.7%), with a mean age of 70 years. Theinimum follow-up was 5 years, and the median was 6.4ars. Over this period of time the mortality rate of the 2oups was not different. The overall survival rate was 69.9%the open-surgery group and 68.9% among those undergo-

g stent graft repair (difference: 1.0%; 95% CI: �8.8 to 10.8;0.97). Although cardiovascular disease was the single

ost common cause of death, it accounted for only 33% ofe deaths in the open-surgery group and 27.6% of the deathsthe endovascular treatment group. Deaths from noncardio-scular causes, such as cancer, were more common. Duringe follow-up period, freedom from secondary interventionas more common in the open-repair group compared withe endovascular treatment group (difference 11.5%; 95% CI:0 to 21.0; p�0.03) (58).More recently, a third trial has buttressed the results of the

VAR and DREAM trials. The OVER (Open Surgery Versusndovascular Repair Veterans Affairs Cooperative Study)ial randomized 881 veterans with AAA �5 cm or ansociated iliac artery aneurysm �3 cm or an AAA �4.5 cmith rapid enlargement to surgical or endovascular repair0). The primary outcome was long-term, all-cause mortal-

y. As with both the DREAM and EVAR trials, there were nofferences in baseline demographic characteristics. The trialrticipants were overwhelmingly male (�99%), white7%), and current or former smokers (95%). Over a meanllow-up of 1.8 years, there was no statistical difference inortality, 7% versus 9.8% for endovascular and surgicalpair, respectively (p�0.13). Interestingly, there were nofferences in the rates of secondary therapeutic procedures oreurysm-related hospitalizations between the groups, be-use increases in surgical complications offset the number ofcondary endovascular repairs.As with the EVAR trial, the DREAM and OVER trialsnfirmed that the early benefits of endovascular aneurysmpair, including a lower procedural mortality, are not sus-ined. Therefore, the method of aneurysm repair that isemed to be most appropriate for each individual patientould be chosen (56,58,60). Endovascular treatment shouldt be used in patients who do not meet the establishedatomical criteria or who cannot comply with the requiredllow-up imaging requirements. Patients require either com-ted tomography or magnetic resonance imaging of thegrafted segment of the aortoiliac segment at 1 month, 6onths, and then yearly to confirm that the graft has notoved and there are no endoleaks that have resulted inpressurization and/or growth of the aneurysm sac. Iftients cannot be offered the indicated long-termllow-up evaluation and treatment because of the lack of
cess to required imaging modalities or inability to L

propriately treat problematic endoleaks when identified,en endovascular repair should not be considered thetimal treatment method. Open surgical repair is indi-ted for those patients who do not meet the establishediteria for endovascular treatment.A patient whose general physical condition is deemedsuitable for open aneurysm repair may not benefit fromdovascular repair. This was suggested in a secondaryotocol of the EVAR trial (56). The EVAR 2 trialndomized 404 patients with infrarenal aortic aneurysmsat least 5.5 cm with comorbidities that prevented open

pair to receive either endovascular treatment or notervention (61). One hundred ninety-seven patients werendomized to the endovascular treatment group and 179tually underwent stent graft placement. Of 207 patientsndomly assigned to the no-treatment group, 70 hadeurysm repair. The primary outcome was death from anyuse. The patients were followed up for a minimum of 5ars or until death. The median follow-up period was 3.1ars. Thirty-day operative mortality was 7.3%. Althoughsignificant difference in aneurysm-related mortality be-een the 2 groups was identified (3.6 deaths per 100rson-years for endovascular therapy versus 7.3 deathsr 100 person-years without treatment, adjusted HR: 0.53;% CI: 0.32 to 0.89; p�0.02), this was not associated

ith longer survival. During follow-up there was nognificant difference in overall mortality between the 2oups (21.0 deaths per 100 person-years in the endovas-lar group versus 22.1 deaths per 100 person-years in the-treatment group; HR for endovascular repair: 0.99; CI:78 to 1.27; p�0.97). Although there was no observednefit to the endovascular treatment of infrarenal AAAspatients whose physical health was considered too poorwithstand open aneurysm repair in this trial, optimal

anagement of this challenging patient population has noten definitively established. Additional studies are re-ired to better define the role of endovascular aneurysmpair in patients with significantly impaired physicalalth who are considered to be at high surgical oresthetic risk (61). d to better define the role of endovas-lar aneurysm repair in patients with significantly im-ired physical health who are considered to be at highrgical or anesthetic risk (61).

taff

merican College of Cardiology Foundation

avid R. Holmes, Jr., MD, FACC, President

hn C. Lewin, MD, Chief Executive Officer

net Wright, MD, FACC, Senior Vice President, Scienceand Quality

harlene May, Senior Director, Science and ClinicalPolicy

merican College of Cardiology Foundation/merican Heart Association

isa Bradfield, CAE, Director, Science and Clinical Policy by on October 6, 2011 .org


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ebjani Mukherjee, MPH, Associate Director, Evidence-Based Medicine

aria Koinis, Specialist, Science and Clinical Policy

merican Heart Association

alph L. Sacco, MS, MD, FAAN, FAHA, President

ancy Brown, Chief Executive Officer

ose Marie Robertson, MD, FAHA, Chief Science Officer

ayle R. Whitman, PhD, RN, FAHA, FAAN, Senior VicePresident, Office of Science Operations

ereida A. Parks, MPH, Science and Medicine Advisor,Office of Science Operations

dy Hundley, Production Manager, Scientific Publications,Office of Science Operations

eferences. ACCF/AHA Task Force on Practice Guidelines. Methodologies and

Policies from the ACCF/AHA Task Force on Practice Guideline. Avail-able at http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf and http://circ.ahajournals.org/site/manual/index.xhtml. Accessed July 1, 2011.

. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines forthe management of patients with peripheral arterial disease (lowerextremity, renal, mesenteric, and abdominal aortic): executive summary:a collaborative report from the American Association for VascularSurgery/Society for Vascular Surgery, Society for Cardiovascular An-giography and Interventions, Society for Vascular Medicine and Biology,Society of Interventional Radiology, and the ACC/AHA Task Force onPractice Guidelines (Writing Committee to Develop Guidelines for theManagement of Patients With Peripheral Arterial Disease). J Am CollCardiol. 2006;47:1239–312.

. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus forthe Management of Peripheral Arterial Disease (TASC II). Eur J VascEndovasc Surg. 2007;33 Suppl 1:S1–75.

. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines forthe management of patients with peripheral arterial disease (lowerextremity, renal, mesenteric, and abdominal aortic): a collaborative reportfrom the American Association for Vascular Surgery/Society for Vascu-lar Surgery, Society for Cardiovascular Angiography and Interventions,Society for Vascular Medicine and Biology, Society of InterventionalRadiology, and the ACC/AHA Task Force on Practice Guidelines(Writing Committee to Develop Guidelines for the Management ofPatients With Peripheral Arterial Disease). J Am Coll Cardiol. 2006;47:e1–192.

. Wheatley K, Ives N, Gray R, et al. Revascularization versus medicaltherapy for renal-artery stenosis. N Engl J Med. 2009;361:1953–62.

. Cooper CJ, Murphy TP, Matsumoto A, et al. Stent revascularization forthe prevention of cardiovascular and renal events among patients withrenal artery stenosis and systolic hypertension: rationale and design of theCORAL trial. Am Heart J. 2006;152:59–66.

. Alhadad A, Mattiasson I, Ivancev K, et al. Revascularisation of renalartery stenosis caused by fibromuscular dysplasia: effects on bloodpressure during 7-year follow-up are influenced by duration of hyperten-sion and branch artery stenosis. J Hum Hypertens. 2005;19:761–7.

. Modrall JG, Rosero EB, Smith ST, et al. Operative mortality for renalartery bypass in the United States: results from the National InpatientSample. J Vasc Surg. 2008;48:317–22.

. Criqui MH, Denenberg JO, Bird CE, et al. The correlation betweensymptoms and non-invasive test results in patients referred for peripheralarterial disease testing. Vasc Med. 1996;1:65–71.

. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterialdisease detection, awareness, and treatment in primary care. JAMA.2001;286:1317–24.

. Diehm C, Allenberg JR, Pittrow D, et al. Mortality and vascularmorbidity in older adults with asymptomatic versus symptomatic periph-
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. Fowkes FG. The measurement of atherosclerotic peripheral arterialdisease in epidemiological surveys. Int J Epidemiol. 1988;17:248–54.

. Feigelson HS, Criqui MH, Fronek A, et al. Screening for peripheralarterial disease: the sensitivity, specificity, and predictive value ofnoninvasive tests in a defined population. Am J Epidemiol. 1994;140:526–34.

. Nassoura ZE, Ivatury RR, Simon RJ, et al. A reassessment of Dopplerpressure indices in the detection of arterial lesions in proximity penetrat-ing injuries of extremities: a prospective study. Am J Emerg Med.1996;14:151–6.

. Carter SA. Clinical measurement of systolic pressures in limbs witharterial occlusive disease. JAMA. 1969;207:1869–74.

. Carter SA, Tate RB. Value of toe pulse waves in addition to systolicpressures in the assessment of the severity of peripheral arterial diseaseand critical limb ischemia. J Vasc Surg. 1996;24:258–65.

. Carter SA, Tate RB. The value of toe pulse waves in determination ofrisks for limb amputation and death in patients with peripheral arterialdisease and skin ulcers or gangrene. J Vasc Surg. 2001;33:708–14.

. Brooks B, Dean R, Patel S, et al. TBI or not TBI: that is the question: isit better to measure toe pressure than ankle pressure in diabetic patients?Diabet Med. 2001;18:528–32.

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. Belcaro G, Nicolaides AN, Bull ML, et al. The value of segmentalpressure measurement in the assessment of peripheral vascular disease.Int Angiol. 1986;5:7–12.

. Gundersen J. Segmental measurements of systolic blood pressure in theextremities including the thumb and the great toe. Acta Chir Scand Suppl.1972;426:1–90.

. Johnston KW, Hosang MY, Andrews DF. Reproducibility of noninvasivevascular laboratory measurements of the peripheral circulation. J VascSurg. 1987;6:147–51.

. Kupinski A. Segmental pressure measurement and plethysmography. JVasc Technol. 2002;1:32–8.

. Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combinedwith Framingham Risk Score to predict cardiovascular events andmortality: a meta-analysis. JAMA. 2008;300:197–208.

. Nides MA, Rakos RF, Gonzales D, et al. Predictors of initial smokingcessation and relapse through the first 2 years of the Lung Health Study.J Consult Clin Psychol. 1995;63:60–9.

. Mohiuddin SM, Mooss AN, Hunter CB, et al. Intensive smokingcessation intervention reduces mortality in high-risk smokers with car-diovascular disease. Chest. 2007;131:446–52.

. Lancaster T, Stead LF. Mecamylamine (a nicotine antagonist) forsmoking cessation. Cochrane Database Syst Rev. 2000;CD001009.

. Rothemich SF, Woolf SH, Johnson RE, et al. Effect on cessationcounseling of documenting smoking status as a routine vital sign: anACORN study. Ann Fam Med. 2008;6:60–8.

. Hennrikus D, Joseph A, Lando H, et al. Effectiveness of a smokingcessation program for peripheral artery disease patients: a randomizedcontrolled trial. JACC. 2010;25:2105–12.

. Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2nicotinic acetylcholine receptor partial agonist, vs sustained-releasebupropion and placebo for smoking cessation: a randomized controlledtrial. JAMA. 2006;296:47–55.

. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, analpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo orsustained-release bupropion for smoking cessation: a randomized con-trolled trial. JAMA. 2006;296:56–63.

. Nides M, Oncken C, Gonzales D, et al. Smoking cessation withvarenicline, a selective alpha4beta2 nicotinic receptor partial agonist:results from a 7-week, randomized, placebo- and bupropion-controlledtrial with 1-year follow-up. Arch Intern Med. 2006;166:1561–8.

. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial ofsustained-release bupropion, a nicotine patch, or both for smokingcessation. N Engl J Med. 1999;340:685–91.

. Faulkner KW, House AK, Castleden WM. The effect of cessation ofsmoking on the accumulative survival rates of patients with symptomaticperipheral vascular disease. Med J Aust. 1983;1:217–9.

. Jonason T, Bergstrom R. Cessation of smoking in patients with intermit-tent claudication: effects on the risk of peripheral vascular complications,myocardial infarction and mortality. Acta Med Scand. 1987;221:253–60.

. Lassila R, Lepantalo M. Cigarette smoking and the outcome after lower
limb arterial surgery. Acta Chir Scand. 1988;154:635–40.

http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf

http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf

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. Quick CR, Cotton LT. The measured effect of stopping smoking onintermittent claudication. Br J Surg. 1982;69 Suppl:S24–6.

. Gardner AW. The effect of cigarette smoking on exercise capacity inpatients with intermittent claudication. Vasc Med. 1996;1:181–6.

. Law M, Tang JL. An analysis of the effectiveness of interventionsintended to help people stop smoking. Arch Intern Med. 1995;155:1933–41.

. West R, Baker CL, Cappelleri JC, et al. Effect of varenicline andbupropion SR on craving, nicotine withdrawal symptoms, and rewardingeffects of smoking during a quit attempt. Psychopharmacology (Berl).2008;197:371–7.

. Knight C, Howard P, Baker CL, et al. The cost-effectiveness of anextended course (12�12 weeks) of varenicline compared with otheravailable smoking cessation strategies in the United States: an extensionand update to the BENESCO model. Value Health. 2010;13:209–14.

. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med.2000;343:864–9.

. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrelversus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet.1996;348:1329–39.

. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis ofrandomised trials of antiplatelet therapy for prevention of death, myocar-dial infarction, and stroke in high risk patients [published correctionappears in BMJ. 2002;324:141]. BMJ. 2002;324:71–86.

. Catalano M, Born G, Peto R. Prevention of serious vascular events byaspirin amongst patients with peripheral arterial disease: randomized,double-blind trial. J Intern Med. 2007;261:276–84.

. Belch J, MacCuish A, Campbell I, et al. The prevention of progression ofarterial disease and diabetes (POPADAD) trial: factorial randomised placebocontrolled trial of aspirin and antioxidants in patients with diabetes andasymptomatic peripheral arterial disease. BMJ. 2008;337:a1840.

. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention ofcardiovascular events in a general population screened for a low anklebrachial index: a randomized controlled trial. JAMA. 2010;303:841–8.

. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirinalone for the prevention of atherothrombotic events. N Engl J Med.2006;354:1706–17.

. Cacoub PP, Bhatt DL, Steg PG, et al. Patients with peripheral arterialdisease in the CHARISMA trial. Eur Heart J. 2009;30:192–201.

. Anand S, Yusuf S, Xie C, et al. Oral anticoagulant and antiplatelettherapy and peripheral arterial disease. N Engl J Med. 2007;357:217–27.

. Berger JS, Krantz MJ, Kittelson JM, et al. Aspirin for the prevention ofcardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA. 2009;301:1909–19.

. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardialinfarction, stroke, or symptomatic peripheral arterial disease in theCHARISMA trial. J Am Coll Cardiol. 2007;49:1982–8.

. Bernstein EF, Rhodes GA, Stuart SH, et al. Toe pulse reappearance time
in prediction of aortofemoral bypass success. Ann Surg. 1981;193:201–5. pe

. Bradbury AW, Adam DJ, Bell J, et al. Bypass versus Angioplasty inSevere Ischaemia of the Leg (BASIL) trial: an intention-to-treat analysisof amputation-free and overall survival in patients randomized to a bypasssurgery-first or a balloon angioplasty-first revascularization strategy. JVasc Surg. 2010;51:5S–17S.

. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty insevere ischaemia of the leg (BASIL): multicentre, randomised controlledtrial. Lancet. 2005;366:1925–34.

. Greenhalgh RM, Brown LC, Powell JT, et al. Endovascular versus openrepair of abdominal aortic aneurysm. N Engl J Med. 2010;362:1863–71.

. Blankensteijn JD, de Jong SE, Prinssen M, et al. Two-year outcomes afterconventional or endovascular repair of abdominal aortic aneurysms.N Engl J Med. 2005;352:2398–405.

. De Bruin JL, Baas AF, Buth J, et al. Long-term outcome of open orendovascular repair of abdominal aortic aneurysm. N Engl J Med.2010;362:1881–9.

. Greenhalgh RM, Brown LC, Powell JT, et al. Endovascular repair ofaortic aneurysm in patients physically ineligible for open repair. N EnglJ Med. 2010;362:1872–80.

. Lederle FA, Freischlag JA, Kyriakides TC, et al. Outcomes followingendovascular vs open repair of abdominal aortic aneurysm: a randomizedtrial. JAMA. 2009;302:1535–42.

. Brown LC, Epstein D, Manca A, et al. The UK Endovascular AneurysmRepair (EVAR) trials: design, methodology and progress. Eur J VascEndovasc Surg. 2004;27:372–81.

. Schanzer A, Hevelone N, Owens CD, et al. Statins are independentlyassociated with reduced mortality in patients undergoing infrainguinalbypass graft surgery for critical limb ischemia. J Vasc Surg. 2008;47:774–81.

. Conte MS, Bandyk DF, Clowes AW, et al. Results of PREVENT III: amulticenter, randomized trial of edifoligide for the prevention of veingraft failure in lower extremity bypass surgery. J Vasc Surg. 2006;43:742–51.

. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheralarterial disease and co-morbidity in 6,880 primary care patients: cross-sectional study. Atherosclerosis. 2004;172:95–105.

. Hennrikus D, Joseph AM, Lando HA, et al. Effectiveness of a smokingcessation program for peripheral artery disease patients: a randomizedcontrolled trial. J Am Coll Cardiol. 2010;56:2105–12.

. Bhatt DL, Topol EJ. Clopidogrel added to aspirin versus aspirin alone insecondary prevention and high-risk primary prevention: rationale anddesign of the Clopidogrel for High Atherothrombotic Risk and IschemicStabilization, Management, and Avoidance (CHARISMA) trial. AmHeart J. 2004;148:263–8.

EY WORDS: ACCF/AHA Practice Guidelines � antiplatelet agents �rtic aneurysm � critical limb ischemia � endovascular procedures �b salvage � medical treatment � open surgical treatment �

ripheral artery disease � smoking cessation.



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ppendix 1. Author Relationships With Industry and Other Entities (Relevant)—2011 ACCF/AHA Focused Update of the Guideline fore Management of Patients With Peripheral Artery Disease

iting Groupmber Employment Consultant

Speakers’Bureau

Ownership/Partnership/

Principal Personal Research

Institutional,Organizational, orOther Financial

Benefit Expert WitnessVoting Recusal(by Section)*

om W. Rooke,air

Mayo Clinic—Professor ofMedicine

None None None None None None None

n T. Hirsch,e Chair

University of Minnesota MedicalSchool: Cardiovascular

Division—Vascular MedicineProgram: Director; Professor of

Medicine: Epidemiology andCommunity Health

● eV3 None None ● Abbott Vascular†● BMS/sanofi-

aventis†● Cytokinetics● Sanofi-aventis†● ViroMed (PI)

None None 2.5.12.6.1.62.6.3

njay Misra,e Chair

Mayo Clinic: Division ofVascular and Interventional

Radiology—Associate Professorof Radiology

● Johnson &Johnson

None None None None None 2.6.3

ton N. Sidawy,e Chair

George WashingtonUniversity—Professor andChairman, Department of

Surgery


shua A.ckman

Brigham and Women’s HospitalCardiovascular Division:

Cardiovascular FellowshipProgram—Director

● Bristol-MyersSquibb†

● Sanofi-aventis†

None None None None None 2.6.1.6

ura K. Findeiss University of California, Irvine:Chief, Division of Vascular and

InterventionalRadiology—Associate Professor

of Radiology and Surgery


far Golzarian University of Minnesota MedicalSchool—Professor of Radiology

and Surgery


ather L. Gornik Cleveland Clinic FoundationCardiovascular Medicine:

Noninvasive VascularLaboratory—Medical Director

None None None ● Summit DopplerSystems†

● SummitDopplerSystems†

None 2.5.1

nathan L.lperin

Mount Sinai Medical Center—Professor of Medicine

● BayerHealthCare

● BoehringerIngelheim†

● Daiichi-Sankyo● Johnson &

Johnson● Portola

Pharmaceuticals● Sanofi-aventis†

None None ● NIH-NHLBI (DSMB) None None 2.6.1.6

chael R. Jaff Harvard MedicalSchool—Associate Professor of

Medicine

● AbbottVascular‡

● BostonScientific‡

● MedtronicVascular‡

None None None None None 2.6.3

egory L.neta

Oregon Health & ScienceUniversity—Chief and Professor

of Vascular Surgery


ffrey W. Olin Mount Sinai School ofMedicine—Professor of

Medicine and Director of theVascular Medicine Program

● Genzyme None None ● BMS/sanofi-aventis● Colorado Prevention

Center (DSMB)● Merck

None ● Defendant;pulmonaryembolism; 2009

2.6.1.6

mes C. Stanley University of Michigan, Divisionof Vascular Surgery, UniversityHospital—Handleman Professor

of Surgery


ristopher J.ite

Ochsner Clinic Foundation:Department of Cardiology—

Chairman

None None None ● Boston Scientific‡● Neovasc‡● St. Jude Medical‡

None None 2.6.35.2.6

(Continued)



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ppendix 1. Continued

iting Groupmber Employment Consultant

Speakers’Bureau




Benefit Expert WitnessVoting Recusal(by Section)*

hn V. White Advocate Lutheran GeneralHospital—Chief of Surgery


Eugene Zierler University of Washington—Professor of Surgery


This table represents the relationships of writing group members with industry and other entities that were determined to be relevant to this document. Theselationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing group during the document development process.e table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interestpresents ownership of �5% of the voting stock or share of the business entity, or ownership of �$10,000 of the fair market value of the business entity; or ifnds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefite also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted.According to the ACCF/AHA, a person has a relevant relationship IF: (a) The relationship or interest relates to the same or similar subject matter, intellectual propertyasset, topic, or issue addressed in the document; or (b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressedthe document, or makes a competing drug or device addressed in the document; or (c) the person or a member of the person’s household, has a reasonable potentialr financial, professional or other personal gain or loss as a result of the issues/content addressed in the document.*Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply.†Significant relationship.‡No financial benefit.

DSMB indicates Data and Safety Monitoring Board; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institutes of Health; and PI, principal investigator.



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ppendix 2. Reviewer Relationships With Industry and Other Entities (Relevant)—2011 ACCF/AHA Focused Update of the Guideliner the Management of Patients With Peripheral Artery Disease

er Reviewer Representation Consultant Speakers’ Bureau




BenefitExpert

Witness

c R. Bates Official Reviewer—Board ofTrustees

● Bristol-MyersSquibb

● Daiichi-Sankyo● Merck● Sanofi-aventis

None None None None None

rk A. Creager Official Reviewer—ACCF/AHATask Force on Practice

Guidelines

● Genzyme None None None None None

lliam R. Hiatt Official Reviewer—AHA None None None ● BMS/sanofi-aventis

None None

ni Jneid Official Reviewer—AHA None None None None None Noneishnaswamiayaraghavan

Official Reviewer—Board ofGovernors

● Daiichi-Sankyo ● Sanofi-aventis● Novartis

None None ● Johnson &Johnson*

● Merck

None

ry Ansel Organizational Reviewer—SCAI ● Bard● Boston

Scientific*● Cordis/Johnson

& Johnson*● ev3

● Cordis/Johnson& Johnson*

None ● Abbott/GuidantVascular

● BostonScientific*

● Cook Medical*

None None

ng-wei Chi Organizational Reviewer—SVM None None None None None Nonechael Conte Organizational Reviewer—SVS None None None None None Noneny Das Organizational Reviewer—SCAI ● Abbott

Vascular*● Bard*● Boston

Scientific● Cordis*


omas Huber Organizational Reviewer—SVS None None None None ● AbbottVascular†

● Cook†● Medtronic†

None

hn P. Reilly Organizational Reviewer—SVM None ● Cordis● Johnson &

Johnson● Lilly/Daiichi-

Sankyo*

None None None

el A. Saad Organizational Reviewer—SIR None None None None None NoneGregorylker

Organizational Reviewer—SIR ● MedtronicEndovascular


Dawn Abbott Content Reviewer—ACCF PVDCommittee

● MedtronicEndovascular


ffrey L.derson

Content Reviewer—ACCF/AHATask Force on Practice

Guidelines

None None None None None None

rbert D.onow

Content Reviewer—ACCF PVDCommittee

● MedtronicEndovascular


ffrey Berger Content Reviewer None None None None None Nonee A. Green Content Reviewer—ACCF/AHA

Task Force on PerformanceMeasures


hn Gordon Content Reviewer—Board ofGovernors


rman R.rtzer

Content Reviewer—2005 PADWriting Committee


urtney O.rdan

Content Reviewer—ACCFPrevention Committee


akashishnan

Content Reviewer None None None None None None

chaelnsour

Content Reviewer—Board ofGovernors


am D.ussa

Content Reviewer—ACCFInterventional Scientific Council


hul Patel Content Reviewer—2005 PADWriting Committee


(Continued)



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er Reviewer Representation Consultant Speakers’ Bureau




BenefitExpert

Witness

m N. Peterson Content Reviewer—ACCF/AHATask Force on Clinical Data

Standards


hn Rundback Content Reviewer—2005 PADWriting Committee

● ev3 ● BostonScientific

None None None None

This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review and determined to be relevant.does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interestpresents ownership of �5% of the voting stock or share of the business entity, or ownership of �$10,000 of the fair market value of the business entity; or ifnds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. A relationship is considered to be modest ifis less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency.lationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review.According to the ACCF/AHA, a person has a relevant relationship IF: (a) The relationship or interest relates to the same or similar subject matter, intellectual propertyasset, topic, or issue addressed in the document; or (b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressedthe document, or makes a competing drug or device addressed in the document; or (c) the person or a member of the person’s household, has a reasonable potentialr financial, professional or other personal gain or loss as a result of the issues/content addressed in the document.*Significant relationship.†No financial benefit.

ACCF indicates American College of Cardiology Foundation; AHA, American Heart Association; PAD, peripheral artery disease; PVD, peripheral vascular disease;AI, Society for Cardiovascular Angiography and Interventions; SIR, Society of Interventional Radiology; SVM, Society for Vascular Medicine; and SVS, Society for
scular Surgery.


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ppendix 3. 2011 Peripheral Artery Disease Focused Update Summary Table

dy Title Aim of Study Study Type Study Size

Patient Population/Inclusion and Exclusion Criteria Endpoints

Inclusion Exclusion Primary Secondary

vascularization versusdical therapy for RAS:ASTRAL

estigators (5)

To review the clinicalbenefit ofpercutaneousrevascularization ofthe renal arteries toimprove patency inatheroscleroticrenovascular disease

Randomized,unblinded trial

806 Patients who had substantialanatomical atheroscleroticstenosis in �1 renal arterythat was consideredpotentially suitable forendovascularrevascularization and whosephysician was uncertain thatthe patient would definitelyreceive a worthwhile clinicalbenefit from revascularization,taking into account theavailable evidence

Patients who requiredsurgicalrevascularization orwere considered tohave a high likelihoodof requiringrevascularizationwithin 6 mo, if theyhad nonatheromatousCV disease, or if theyhad undergonepreviousrevascularization forRAS

Renal function,measured bythe reciprocalof the serumcreatinine level

Blood pressure, time torenal and major CVevents, and mortality

I combined with FRS todict CV events andrtality: a meta-analysisI collaboration (24)

To determine if ABIprovides informationon risk of CV eventsand mortalityindependent of FRSand can improve riskprediction

Meta-analysis 24,955 men and 23339 women with480,325 person-years of follow-up.Studies included 16population cohortstudies.

Studies whose participantswere derived from a generalpopulation, measured ABI atbaseline, and individualfollowed up to detect totaland CV mortality

N/A

tcomes followingdovascular vs. openair of AAA: adomized trial (60)

To comparepostoperativeoutcomes up to 2 yafter endovascular oropen repair of AAA(interim report of a9-y trial)

Randomized,multicenter clinicaltrial; electiveendovascular(n�444) or open(n�437) repair ofAAA

881 Veterans (49 y old) from 42VA Medical Centers witheligible AAA who werecandidates for both electiveendovascular repair and openrepair of AAA

N/A Long-term (5 to9 y) all-causemortality

2° outcomes included:1) procedure failure,2) short-term majormorbidity,3) in-hospital and ICUsassociated with initialrepair,4) other procedure-related morbiditiessuch as incisionalhernia or new orworsened claudication,5) HRQOL, and6) erectile dysfunction.2° outcomes covershort-termperioperative period

pirin for prevention ofevents in patients

th PAD: a meta-alysis of randomizedls (51)

To investigate theeffect of ASA on CVevent rates in patientswith PAD

Meta-analysis (18trials involving5,269 personswere identified)

N�5,269; 2,823patients taking ASA(alone or withdipyridamole) and2,446 in controlgroup

Inclusion criteria: 1)prospective, RCTs eitheropen-label or blinded; 2)assignment of PADparticipants to ASA treatmentor placebo or control group;and 3) available data on all-cause mortality, CV death,MI, stroke, and majorbleeding

N/A CV events(nonfatal MI,nonfatal stroke,and CV death)

All-cause mortality,major bleeding, andindividual componentsof the 1° outcomemeasure



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Statistical Analysis (Results) p (95% CI) OR/HR/RRStudy Conclusion (as Reported in

Study Article) Other Information

ring a 5-y period, rate of progressionrenal impairment (as shown by thepe of the reciprocal of the serumatinine level) was �0.07�10�3

icromole/y in the revascularizationup, compared with �0.13�10�3

icromole/y in the medical therapyup, a difference favoringascularization of 0.06�10�3

icromole/y (95% CI: �0.002 to 0.13;0.06). Over the same time, meanum creatinine level was 1.6 mmol/L% CI: �8.4 to 5.2 [0.02 mg/dL; 95%�0.10 to 0.06]) lower in theascularization group than in thedical therapy group. There was nonificance between-groups differencesystolic blood pressure; decrease instolic blood pressure was smaller inrevascularization group than in the

dical-therapy group.

Revascularization group:p�0.88; 95% CI: 1.40; 0.67 to1.40Major CV events: p�0.61; 95%CI: 0.75 to 1.1Death: p�0.46; 95% CI: 0.69 to1.18

The 2 study groups had similarrates of renal events.Revascularization group: HR:0.97; 95% CI: 0.67 to 1.40;p�0.88Major CV events: HR: 0.94; 95%CI: 0.75 to 1.19; p�0.61Death: HR: 0.90; 95% CI: 0.69to 1.18; p�0.46

There are substantial risks but noevidence of a worthwhile clinicalbenefit from revascularization inpatients with atheroscleroticrenovascular disease.

Power�80%, ITT analysis

k of death by ABI had a reverse J-ped distribution with a normal (low-

k) ABI of 1.11 to 1.40. 10-y CVrtality in men with low ABI (0.90)s 18.7% (95% CI: 13.3% to 24.1%)d with normal ABI (1.11 to 1.40) was% (95% CI: 3.2% to 5.7%).rresponding mortalities in womenre 12.6% (95% CI: 6.2% to 19.0%)d 4.1% (95% CI: 2.2% to 6.1%). LowI (0.90) was associated withproximately twice the 10-y totalrtality, CV mortality, and majoronary event rate compared with therall rate in each FRS category.lusion of ABI in CV risk stratificationng the FRS would result inlassification of risk category anddification of treatmentommendations in �19% of men and% of women.

10-y CV mortality:Men: HR: 4.2; 95% CI:3.3 to 5.4Women: HR: 3.5; 95% CI:2.4 to 5.1

Measurement of ABI may improveaccuracy of CV risk predictionbeyond FRS.

Relevant studies were identified.A search of MEDLINE (1950 toFebruary 2008) and EMBASE(1980 to February 2008) wasconducted using common textwords for the term ABI combinedwith text words and medicalsubject headings to captureprospective cohort designs.

rioperative mortality (30-d or inpatient)s lower for endovascular repair (0.5%3.0%; p�0.004); no significant

ference in mortality at 2 y (7.0% vs.%; p�0.13). Patients in endovascularair group had reduced mediancedure time (2.9 vs. 3.7 h), bloods (200 vs. 1,000 mL), transfusionuirement (0 vs. 1.0 units), duration ofchanical ventilation (3.6 vs. 5.0 h),

spital stay (3 vs. 7 d), and ICU stay (14 d), but required substantialosure to fluoroscopy and contrast.differences between the 2 groups injor morbidity, procedure failure, 2°rapeutic procedures, aneurysm-ated hospitalizations, HRQOL, orctile function.

Perioperative mortality:p�0.004;Mortality at 2 y: p�0.13

HR: 0.7; 95% CI: 0.4 to 1.1 Short-term outcomes afterelective AAA repair, perioperativemortality was low for bothprocedures and lower forendovascular than open repair.Early advantage of endovascularrepair was not offset by increasedmorbidity or mortality in the first2 y after repair. Long-termoutcome data are needed.

Analysis by ITT. Trial is ongoing,and report covers October 15,2002 through October 15, 2008.

00 patient meta-analysis with �88%wer to detect a 25% difference (from% to 7.5%) and 70% power to detect0% difference (from 10% to 8%) inof CV death, MI, or stroke in the ASAup vs. placebo or control groups.

tient characteristics, ASA dosages,d length of follow-up differed acrossdies, so RR for each study wasumed to have a random offset frompopulation mean RR (i.e., a random-

ects model). The Cochran Q statisticd I2 statistic were calculated by studythors to assess degree ofterogeneity among the trials.

Effect of any ASA on preventionof composite CV endpoints,p�0.13.Effect of any ASA on preventionof nonfatal MI, nonfatal stroke,and CV death p�0.81;Nonfatal stroke, p�0.02;CV death, p�0.59Effect of any ASA on preventionof any death and majorbleeding: Any death, p�0.85Major bleeding, p�0.98.Effect of ASA monotherapy onprevention of adverse outcomescomposite CV endpoints,p�0.21

Effect of any ASA on preventionof composite CV endpoints: RR:0.88; 95% CI: 0.76 to 1.04Effect of any ASA on preventionof nonfatal MI, nonfatal stroke,and CV death:Nonfatal MI: RR: 1.04; 95% CI:0.78 to 1.39 Nonfatal stroke:RR: 0.66; 95% CI: 0.47 to 0.94CV death: RR: 0.94; 95% CI:0.74 to 1.19ASA effect on prevention of anydeath and major bleeding:Any death RR: 0.98; 95% CI:0.83 to 1.17Major bleeding: RR: 0.99; 95%CI: 0.66 to 1.50Effect of ASA monotherapy onprevention of adverse outcomes:Composite CV endpoints: RR:0.75; 95% CI: 0.48 to 1.18Nonfatal stroke: RR: 0.64; 95%CI: 0.42 to 0.99

In patients with PAD, treatmentwith ASA alone or withdipyridamole resulted in astatistically nonsignificantdecrease in the 1° endpoint of CVevents and a significant reductionin nonfatal stroke. Results for the1° endpoint may reflect limitedstatistical power. Additional RCTsare needed to establish a netbenefit and bleeding risks in PAD.

Outcome measures:1° outcome was RR reduction ofASA therapy on compositeendpoint of nonfatal MI, nonfatalstroke, and CV death in thepopulation of patients whoreceived any ASA therapy (withor without dipyridamole). 2°outcomes were all-causemortality with each component ofthe 1° endpoint. The 1° safetyoutcome evaluated occurrence ofmajor bleeding as defined byeach study. ITT analysis used.

(Continued)



A

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pirin for prevention ofevents in a general

pulation screened for aABI: an RCT (47)

To determineeffectiveness of ASAin preventing eventsin people with a lowABI identified onscreening of thegeneralpopulation

ITT, double-blindRCT

28,980 men andwomen 50 to 75 yold

N/A N/A Composite ofinitial fatal ornonfatalcoronary eventor stroke orrevascularization

All initial vascularevents, defined as acomposite of a 1°endpoint event orangina, intermittentclaudication, or TIA;and all-cause mortality

vention of progressionarterial disease andbetes (POPADAD) trial:torial randomizedcebo-controlled trial of

pirin and antioxidantspatients with diabetesd asymptomaticD (46)

To determine whetherASA and antioxidanttherapy, combined oralone, are moreeffective than placeboin reducingdevelopment of CVevents in patientswith diabetes mellitusand asymptomaticPAD

Multicenter,randomized,double-blind, 2�2factorial, placebo-controlled trial

1,276 Adults of either sex, �40 yold, with type 1 or type 2diabetes who weredetermined to haveasymptomatic PAD asdetected by lower-than-normal ABI (�0.99). The trialused a higher cut-off point(0.99 vs. 0.9) because it isrecognized that calcificationin the vessels of people withdiabetes can produce anormal or high ABI, even inthe presence of arterialdisease.

People with evidenceof symptomatic CVdisease; those whouse ASA or antioxidanttherapy on a regularbasis; those withpeptic ulceration,severe dyspepsia, ableeding disorder, orintolerance to ASA;those with suspectedserious physical illness(such as cancer),which might havebeen expected tocurtail life expectancy;those with psychiatricillness (reported bytheir generalpractitioner); thosewith congenital heartdisease; and thoseunable to giveinformed consent

2 hierarchicalcomposite 1°endpoints ofdeath from CADor stroke,nonfatal MI orstroke, oramputationabove the anklefor CLI; anddeath from CADor stroke

N/A

dovascular vs. openair of AAA: the Unitedgdom EVAR Trialestigators (56)

To investigate thelong-term outcome ofendovascular repair ofAAA compared withopen repair

Randomized trial 1,252 N/A (published in previousreports) (61)

N/A (published inprevious reports) (61)

Death from anycause. Alsoassessed:aneurysm-related death,graft-relatedcomplications,and graft-relatedreinterventions

N/A

dovascular repair ofrtic aneurysm intients physicallyligible for open repair:United Kingdom

AR Trial Investigators)

To investigate whetherendovascular repairreduces the rate ofdeath among patientswho were consideredphysically ineligiblefor open surgicalrepair

Randomized trial 404 N/A (see original study [61]) N/A (see originalstudy [61])

Death from anycause. Alsoassessed:aneurysm-related death,graft-relatedcomplications,and graft-relatedreinterventions

N/A



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endpoint event: 13.5 per 1,000rson-years; 95% CI: 12.2 to 15.0. Notistically significant difference wasnd between groups (13.7 events per00 person-years in the ASA group vs..3 in the placebo group; HR: 1.03;% CI: 0.84 to 1.27).endpoint (vascular event): 22.8 per00 person-years; 95% CI: 21.0 to.8, and no statistically significantference was found between groups.8 events per 1,000 person-years inASA group vs. 22.9 in the placebo

up; HR: 1.00; 95% CI: 0.85 to 1.17).significant difference in all-causertality between groups, 176 vs. 186

aths, respectively; HR: 0.95; 95% CI:7 to 1.16.initial event of major hemorrhageuiring admission to hospital occurred34 participants (2.5 per 1,000 person-rs) in the ASA group and 20 (1.5 per00 person-years) in the placeboup (HR: 1.71; 95% CI: 0.99 to 2.97).

1° endpoint: No statisticallysignificant difference was foundbetween groups. HR: 1.03; 95%CI: 0.84 to 1.272° endpoint (vascular event): Nostatistically significant differencebetween groups, HR: 1.00; 95%CI: 0.85 to 1.17All-cause mortality: HR: 0.95;95% CI: 0.77 to 1.16An initial event of majorhemorrhage requiringadmission: HR: 1.71; 95% CI:0.99 to 2.97

Among participants withoutclinical CV disease, identified witha low ABI based on screening ageneral population, administrationof ASA compared with placebodid not result in a significantreduction in vascular events.

Interventions: Once-daily 100 mgASA (enteric coated) or placebo.Statistics: The trial was poweredto detect a 25% proportional riskreduction in major vascularevents. Predicted risk reductionevidence from 1) event rates inasymptomatic participants with alow ABI were similar to thosewith symptomatic PAD,suggesting that the risk reductioncould be comparable withpatients who have clinicaldisease (�25% to 15%), and 2)in stable angina, unlike ACS withthrombosis complicatingatherosclerotic plaque, riskreduction could reach 33%.Study termination: Subsequently,DSMB stopped the trial 14 moearly due to the improbability offinding a difference in the 1°endpoint by the end date and anincrease in major bleeding(p�0.05) in the ASA group. Eventhough the trial was stoppedearly, the required number ofevents was achieved.

erall, 116 of 638 1° events occurredthe ASA groups compared with 117638 in the no-ASA groups (18.2% vs..3%); 43 deaths from CAD or strokethe ASA groups compared with 35 inno-ASA groups (6.7% vs. 5.5%).ong the antioxidant groups, 117 of

0 (18.3%) 1° events occurredpared with 116 of 636 (18.2%) inno-antioxidant groups. There weredeaths (6.6%) from CAD or stroke inantioxidant groups compared withdeaths (5.7%) in the no-antioxidantups.

Comparison of ASA and no-ASAgroups—Composite endpoint:p�0.86Death from CAD or stroke:p�0.36Comparison of antioxidant andno-antioxidantgroups—Composite endpoint:p�0.85Death from CAD or stroke:p�0.40

ASA groups 1° events: HR:0.98; 95% CI: 0.76 to 1.26ASA groups deaths from CAD orstroke HR: 1.23 (0.79 to 1.93)Antioxidant groups 1° events:HR: 1.03; 95% CI: 0.79 to 1.33Antioxidant groups deaths fromCAD or stroke: HR: 1.21; 95%CI: 0.78 to 1.89

This trial does not provideevidence to support the use ofASA or antioxidants in primaryprevention of CV events andmortality in the population withdiabetes studied.

Power: 1,276 patients wererecruited, and final powercalculations, undertaken in 2003,projected that if follow-upcontinued until June 2006, then256 events would be expected tooccur during the trial. This wouldgive 73% power to detect a 25%relative reduction in event rateand 89% power to detect a 30%reduction in event rate if only 1treatment was effective.Interventions were daily ASA 100mg or placebo tablet, plusantioxidant or placebo capsule.The antioxidant capsulecontained �-tocopherol 200 mg,ascorbic acid 100 mg, pyridoxinehydrochloride 25 mg, zincsulphate 10 mg, nicotinamide 10mg, lecithin 9.4 mg, and sodiumselenite 0.8 mg.

-d operative mortality was 1.8% inendovascular repair group and 4.3%

the open-repair group.

30-d operative mortality (forendovascular repair comparedwith open repair): p�0.02Aneurysm-related mortality:p�0.73Rate of death from any cause:p�0.72

30-d operative mortality (forendovascular repair comparedwith open repair): adjusted OR:0.39; 95% CI: 0.18 to 0.87Aneurysm-related mortality:adjusted HR: 0.92; 95% CI:0.57 to 1.49Rate of death from any cause:adjusted HR: 1.03; 95% CI:0.86 to 1.23

Endovascular repair of AAA wasassociated with a significantlylower operative mortality thanopen surgical repair. However, nodifferences were seen in totalmortality or aneurysm-relatedmortality in the long term.Endovascular repair wasassociated with increased rates ofgraft-related complications andreinterventions and was morecostly.

Rates of graft-relatedcomplications and reinterventionswere higher with endovascularrepair, and new complicationsoccurred up to 8 y afterrandomization, contributing tohigher overall costs. Per-protocolanalysis yielded results verysimilar to those of ITT analysis.

-d operative mortality was 7.3% inendovascular repair group. Therall rate of aneurysm rupture in the

-intervention group was 12.4 (95% CI:to 16.2) per 100 person-years. A

al of 48% of patients who surviveddovascular repair had graft-related

plications, and 27% requiredntervention within the first 6 y.

Aneurysm-related mortality:p�0.02Total mortality: p�0.97

Aneurysm-related mortality waslower in the endovascular repairgroup. Adjusted HR: 0.53; 95%CI: 0.32 to 0.89.Total mortality: adjusted HR:0.99; 95% CI: 0.78 to 1.27

This RCT involved patients whowere physically ineligible for openrepair; endovascular repair of AAAwas associated with asignificantly lower rate ofaneurysm-related mortality thanno repair. However, endovascularrepair was not associated withreduction in the rate of deathfrom any cause. Rates of graft-related complications andreinterventions were higher withendovascular repair, and it wasmore costly.

During 8 y of follow-up,endovascular repair wasconsiderably more expensivethan no repair (cost difference,£9,826 [US $14,867]; 95% CI:£7,638 to £12,013 [$11,556 to$18,176]).

(Continued)



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SIL (54) An ITT analysis of AFSand OS in patientsrandomized to a BSX-first or a BAP-firstrevascularizationstrategy

Randomized trial 452 BASIL trial methods have beenpublished in detailelsewhere (55).

BASIL trial methodshave been publishedin detail elsewhere(55).

1° aim:determinewhether a BSX-first or a BAP-firstrevascularizationstrategy wasassociated withbetter clinicaloutcome forpatients.Defined betteras improvedAFS; used thisas 1° endpointfor powercalculation andprespecifiedstatistical plandesign.

2° outcomes includedpostproceduralmorbidity,reinterventions, HRQOL,and use of hospitalresources.

tins are independentlysociated with reducedrtality in patients

dergoing IBG surgeryCLI (PREVENT III) (62)

To determine efficacyof edifoligide forprevention of graftfailure

Multicenter,randomized,prospective trial

1,404 patients withCLI

Patients �18 y old whounderwent IBG withautogenous vein for CLI,defined as gangrene,nonhealing ischemic ulcer, orischemic rest pain. Seeprimary trial report for furtherinformation (63).

Claudication as anindication for IBGsurgery or use of anonautogenousconduit. See primarytrial report for furtherinformation (63).

Major adverseCV events �30d, vein graftpatency, and1-y survivalassessed byKaplan-Meiermethod

N/A

rtality and vascularrbidity in older adults

th asymptomatic vs.ptomatic PAD

tABI) (11)

To assess risk ofmortality and vascularmorbidity in elderlypersons withasymptomatic vs.symptomatic PAD inthe primary caresetting

Prospective cohortstudy

6880 representativeunselected patients65 y of age: 5,392patients had no PAD,836 hadasymptomatic PAD(ABI: 0.9 withoutsymptoms), and 593had symptomaticPAD (lower extremityperipheralrevascularization,amputation as aresult of PAD, orintermittentclaudicationsymptoms regardlessof ABI)

Age 65 y, legally competent,and able to cooperateappropriately and providewritten informed consent (64)

Life expectancy of 6mo as judged by thegeneral practitioner (64)

1° outcomesandidentification ofCV eventsduring follow-up: severevascular eventswere defined asfollows: CV,including MI orcoronaryrevascularization;cerebrovascular,including strokeor carotidrevascularization;and lowerextremityperipheralvascular,includingperipheralrevascularizationor amputationbecause of PADduring follow-up.

N/A

ectiveness of a smokingsation program for PAD

tients (65)

To test theeffectiveness of asmoking cessationprogram designed forpatients with PAD

RCT 124 Diagnosis of lower extremityPAD, defined as at least 1 ofthe following: ABI �0.90 inat least 1 lower extremity;toe brachial index �0.60;objective evidence of arterialocclusive disease in 1 lowerextremity by duplexultrasound, MRA, or CTA;prior leg arterialrevascularization oramputation due to PAD, andcurrent smoking (defined assmoking at least 1 cigarette/d, at least 6 d/wk).Additional inclusion criteria:desire to quit smoking in thenext 30 d, age �18 y, abilityto speak and write English,no participation in a smokingcessation program in the past30 d, and consumption of�21 alcoholic drinks per wk.

N/A Tobacco use7-d pointprevalence ofsmoking (i.e.,“Have yousmoked acigarette, evena puff, in thepast 7 d?”), atthe 3- and 6-mo follow-ups

N/A



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r those patients who survived for 2 yer randomization: initial randomizationa BSX-first revascularization strategys associated with an increase insequent restricted mean overallvival of 7.3 mo (95% CI: 1.2 to 13.4) and an increase in restricted meanS of 5.9 mo (95% CI: 0.2 to 12.0 mo)ring the subsequent mean follow-up3.1 y (range: 1 to 5.7 y).

For those patients surviving 2 yfrom randomization: BSX-firstrevascularization was associatedwith subsequent AFS ofp�0.108 and subsequent OS ofp�0.009.For those patients who survivedfor 2 y after randomization:initial randomization to a BSX-first revascularization strategywas associated with an increasein subsequent restricted meanoverall survival, p�0.02, and anincrease in restricted mean AFS,p�0.06.

For those patients surviving 2 yfrom randomization: BSX-firstrevascularization was associatedwith reduced HR for subsequentAFS of 0.85 (95% CI: 0.5 to1.07) in an adjusted, time-dependent Cox proportionalhazards model and subsequentOS of 0.61 (95% CI: 0.50 to0.75) in an adjusted, time-dependent Cox proportionalhazards model.

Overall there was no significantdifference in AFS or OS betweenthe 2 strategies. However, forthose patients who survived for�2 y after randomization, a BSX-first revascularization strategywas associated with a significantincrease in subsequent OS and atrend toward improved AFS.

The sample size calculationsproposed that 223 patients pertreatment would be needed for90% power to detect a 15%difference in 3-y AFS at the 5%significance level. Thiscalculation was based on theassumption that the 3-y survivalvalue might be 50% in 1 groupand 65% in the others).

tient treatment breakdown: 636tients (45%) were taking statins, 835%) were taking beta blockers, and21 (80%) were taking antiplateletgs.

rioperative major adverse CV events8%) and early mortality (2.7%) weret measurably affected by use of anyg class. Use of beta blockers and

tiplatelet drugs had no appreciablepact on survival. None of the drugsses were associated with grafttency measures at 1 y. Statin uses associated with a significantvival advantage at 1 y of 86% vs.% by analysis of both unweightedd propensity score–weighted data.

Statin use associated withsignificant survival advantage at1 y: p�0.03Significant predictors of 1-ymortality by Cox regressionmodeling were:Statin use p�0.001Age �75 y, p�0.001CAD, p�0.001CKD stage 4, p�0.001CKD stage 5, p�0.001Tissue loss, p�0.003

Statin use associated with asignificant survival advantage at1 y: HR: 0.71; 95% CI:0.52 to 0.98Significant predictors of 1-ymortality by Cox regressionmodeling were:Statin use HR: 0.67; 95% CI:0.51 to 0.90 Age �75 y HR:2.1; 95% CI: 1.60 to 2.82CAD HR: 1.5; 95% CI:1.15 to 2.01CKD stage 4 HR: 2.0; 95% CI:1.17 to 3.55CKD stage 5 HR: 3.4; 95% CI:2.39 to 4.73Tissue loss HR: 1.9; 95% CI:1.23 to 2.80

Statin use was associated withimproved survival in CLI patients1 y after surgicalrevascularization. Further studiesare indicated to determineoptimal dosing in this populationand to definitively address thequestion of relationship to graftpatency. These data add to thegrowing literature supportingstatin use in patients withadvanced PAD.

Propensity scores used toevaluate the influence of statins,beta blockers, and antiplateletagents on outcomes whileadjusting for demographics,comorbidities, medications, andsurgical variables that mayinfluence drug use.

wer ABI categories were associatedh increased risk. PAD was a strongtor for prediction of the compositedpoint in an adjusted model.

Risk of symptomatic comparedwith asymptomatic PADpatients:Composite of all-cause death orsevere vascular event HR: 1.48;95% CI: 1.21 to 1.80All-cause death alone HR: 0.13,95% CI: 0.89 to 1.43All-cause death/MI/stroke(excluding lower extremityperipheral vascular events andany revascularizations) HR: 1.18;95% CI: 0.92 to 1.52CV events alone HR: 1.20;95% CI: 0.89 to 1.60Cerebrovascular events aloneHR: 1.33; 95% CI: 0.80 to 2.20

Asymptomatic PAD diagnosedthrough routine screening inoffices of PCPs has a high and/orvascular event risk. Notably, riskof mortality was similar insymptomatic and asymptomaticpatients with PAD and wassignificantly higher than in thosewithout PAD. In the primary caresetting, the diagnosis of PAD hasimportant prognostic value.

Incidence rates and 95% CIswere calculated as events per1,000 person-years. Thecomposite endpoint of all-causemortality or severe vascularevents occurred in 27.2 (noPAD), 60.4 (asymptomatic PAD),and 104.7 (symptomatic PAD)cases per 1,000 patient-years.In analysis by ABI category,patients with an ABI of 1.1 to 1.5had the lowest event rate per1,000 patient-years (24.3events), whereas event ratesincreased substantially withdecreasing ABI. In patients withan ABI of 0.5, lower extremityperipheral revascularization, oramputation resulting from PAD,event rates were increased 6-fold (146.3), and thecorresponding adjusted risk wasincreased 4.65-fold (95% CI:3.57 to 6.05).

rticipants randomized to the intensiveervention group were significantlyre likely to be confirmed abstinent ato follow-up: 21.3% vs. 6.8% in the

nimal intervention group: chi-ared�5.21.

Members of the intensiveintervention group weresignificantly more likely to beconfirmed abstinent at 6-mofollow-up: p�0.023.

N/A Many long-term smokers withPAD are willing to initiate aserious quit attempt and toengage in an intensive smokingcessation program. Intensiveintervention for tobaccodependence is a more effectivesmoking cessation interventionthan minimal care. Studies shouldbe conducted to examine thelong-term effectiveness ofintensive smoking cessationprograms in this population inorder to examine the effect of thisintervention on clinical outcomesrelated to PAD.

(Continued)



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vention of seriousscular events bypirin among patientsth PAD: randomized,uble-blind trial: CLIPSup (45)

To assess theprophylactic efficacyof ASA and a high-dose antioxidantvitamin combination inpatients with PAD interms of reduction ofrisk of a first vascularevent (MI, stroke,vascular death) andCLI

RCT, double-blindclinical trial with2�2 factorialdesign

366 outpatients withstage I to II PADdocumented byangiography orultrasound, with ABI�0.85 or toeindex �0.6

Study involved outpatientswith symptomatic (claudicant)or asymptomatic PADdocumented by angiographyor ultrasound, who had 1 ABI�0.85 or 1 toe index �0.6.Patients were referred eitherby the GP or ER physician fora diagnostic workup. Diabeticpersons could be included,provided metabolic controlwas stable (HbA1c). Onlypatients who acceptedrandomization (i.e.,continuation after run-inperiod) were included in thestudy.

Exclusion criteria:Fontaine stage III or IVPVD; life expectancy�24 mo; vascularsurgery or angioplastyin the last 3 mo;pregnancy or lactation;contraindication toASA; major CV eventsrequiring antiplatelettherapy; participationin another clinical trial;uncooperative patients;treatment with drugsthat interfere withhemostasis, such asanticoagulants,antiplatelet agents,and prostanoids,peripheral vasodilators,ASA and/orsupplementaryvitamins that could notbe discontinued or hadto be introduced

Major vascularevents: CVdeath, MI, orstroke and CLI

N/A

tients with PAD in theARISMA trial (49)

To determine whetherclopidogrel plus ASAprovides greaterprotection againstmajor CV events thanASA alone in patientswith PAD

Prospective,multicenter,randomized,double-blind,placebo-controlledstudy

3,096 patients withsymptomatic (2,838)or asymptomatic(258) PAD

To fulfill the symptomaticPAD inclusion criterion,patients had to have eithercurrent intermittentclaudication together with anABI of 0.85 or a history ofintermittent claudicationtogether with a previousrelated intervention(amputation, surgical orcatheter-based peripheralrevascularization).Asymptomatic patients withan ABI of 0.90 wereidentified among those withmultiple risk factors.

The details of the trialdesign have beenpublished previously(66)

1° efficacyendpoint: firstoccurrence ofMI, stroke (ofany cause), ordeath from CVcauses(includinghemorrhage).1° safetyendpoint:severe bleedingaccording tothe GUSTOdefinition

Principal 2° efficacyendpoints: firstoccurrence of MI,stroke, death from CVcauses, hospitalizationfor UA, TIA, or arevascularizationprocedure (coronary,cerebral, or peripheral)

ARISMA (48) To view dualantiplatelet therapywith clopidogrel pluslow-dose ASA in abroad population ofpatients at high riskfor atherothromboticevents

Prospective,multicenter,randomized,double-blind,placebo-controlledstudy

15,603 See study for the inclusioncriteria for those withmultiple risk factors andthose with establishedvascular disease.

Patients wereexcluded from the trialif they were takingoral antithromboticmedications or NSAIDson a long-term basis(although COX-2inhibitors werepermitted). Patientswere also excluded if,in the judgment of theinvestigator, they hadestablished indicationsfor clopidogrel therapy(such as recent ACS).Patients who werescheduled to undergorevascularization werenot allowed to enrolluntil the procedurehad been completed;such patients wereexcluded if they wereconsidered to requireclopidogrel afterrevascularization.

1° efficacyendpoint:composite ofMI, stroke, ordeath from CVcauses.1° safetyendpoint:severebleeding,according tothe GUSTOdefinition

Principal 2° efficacyendpoint: firstoccurrence of MI,stroke, death from CVcauses, orhospitalization for UA,TIA, or arevascularizationprocedure (coronary,cerebral, or peripheral)



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f 185 patients who were allocated toA and 20 of 181 patients who werecated to placebo suffered a majorcular event (risk reduction 64%). 5

d 8 patients, respectively, suffered CLItal 12 vs. 28).ere was no evidence that antioxidantmins were beneficial (16/185 vs.

/181 vascular events).ither treatment was associated withy significant increase in adversents.

Major vascular event: p�0.022;CLI: p�0.014

N/A For the first time direct evidenceshows that low-dose ASA shouldroutinely be considered forpatients with PAD, including thosewith concomitant type 2 diabetes.

The safety endpoint wasincidence of bleeding. Inclusionof this trial in a meta-analysis ofother RCTs of antiplatelet therapyin PAD makes the overall resultshighly significant (p�0.001) andsuggests that low-dose ASAreduces the incidence of vascularevents by 26%.

st hoc analysis of the 3,096 patientsh symptomatic (2,838) ormptomatic (258) PAD from theARISMA trial. CV death, MI, or strokees (1° endpoint) were higher in PADtients than in those without PAD:% vs. 6.8%. Severe, fatal, orderate bleeding rates did not differ

tween groups, whereas minoreding was increased with clopidogrel:.4% vs. 20.8%.ong patients with PAD:

e 1° endpoint occurred in 7.6% in thepidogrel plus ASA group and 8.9% inplacebo plus ASA group.

e rate of MI was lower in the dualtiplatelet arm than the ASA-alone arm:% vs. 3.7%.

e rate of hospitalization for ischemicnts: 16.5% vs. 20.1%.

Rates of minor bleeding: OR:1.99; 95% CI: 1.69 to 2.34.Among the patients with PAD:1° endpoint: HR: 0.85; 95% CI:0.66 to 1.08Rate of MI: HR: 0.63; 95% CI:0.42 to 0.96Rate of hospitalization: HR:0.81; 95% CI: 0.68 to 0.95Rate of hospitalization forischemic events: HR: 0.81;95% CI: 0.68 to 0.95

Dual therapy provided somebenefit over ASA alone in PADpatients for the rate of MI and therate of hospitalization for ischemicevents, at cost of an increase inminor bleeding.

N/A

efficacy rate endpoint: 6.8% withpidogrel plus ASA and 7.3% withcebo plus ASA. Principal 2° efficacye endpoint, including hospitalizationsischemic events, was 16.7% and

.9%. Principal 2° efficacy endpoint,luding the rate of severe bleeding,% and 1.3%. 1° endpoint rateong patients with multiple risk factorss 6.6% with clopidogrel and 5.5%h placebo. The rate of death from CVses also was higher with clopidogrel

9% vs. 2.2%). In the subgroup withically evident atherothrombosis, the

e was 6.9% with clopidogrel and% with placebo.

1° endpoint rate among patientswith multiple risk factors:p�0.201° endpoint rate in the subgroupwith clinically evidentatherothrombosis: p�0.046Rate of death from CV causes:p�0.011° efficacy endpoint rate:p�0.22Principal 2° efficacy rateendpoint, including rate ofsevere bleeding: p�0.09Principal 2° efficacy rateendpoint, includinghospitalizations for ischemicevents: p�0.04

1° efficacy endpoint rate: RR0.93; 95% CI: 0.83 to 1.051° endpoint rate in subgroupwith clinically evidentatherothrombosis: RR: 0.88;95% CI: 0.77 to 0.9981° endpoint rate among patientswith multiple risk factors: RR:1.2; 95% CI: 0.91 to 1.59Principal 2° efficacy endpoint,including the rate of severebleeding: RR: 1.25, 95% CI:0.97 to 1.61.Principal 2° efficacy rateendpoint, includinghospitalizations for ischemicevents: RR: 0.92; 95% CI: 0.86to 0.995

There was a suggestion of benefitwith clopidogrel treatment inpatients with symptomaticatherothrombosis and asuggestion of harm in patientswith multiple risk factors. Overall,clopidogrel plus ASA was notsignificantly more effective thanASA alone in reducing rate of MI,stroke, or death from CV causes.

Other efficacy endpoints includeddeath from any cause and deathfrom CV causes, as well as MI,ischemic stroke, any stroke, andhospitalization for UA, TIA, orrevascularization consideredseparately.

(Continued)



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al anticoagulant andtiplatelet therapy andD: the WAVE trialestigators (50)

To view the role oforal anticoagulants inprevention of CVcomplications inpatients with PAD

Randomized,open-label, clinicaltrial

2,161 patients Men and women who were35 to 85 y old and had PAD

Patients who had anindication for oralanticoagulanttreatment, wereactively bleeding or athigh risk for bleeding,had had a strokewithin 6 mo beforeenrollment, or requireddialysis

First coprimaryoutcome: MI,stroke, or deathfrom CVcauses. Secondcoprimaryoutcome: MI,stroke, severeischemia of theperipheral orcoronaryarteries leadingto urgentintervention, ordeath from CVcauses

N/A

AAA indicates Abdominal Aortic and Iliac Aneurysms; ABI, ankle brachial index; ACS, acute coronary syndrome; AFS, amputation-free survival; ASA, aspirin; ASTRAL,gioplasty and Stent for Renal Artery Lesions trial; BAP, balloon angioplasty; BASIL, Bypass versus Angioplasty in Severe Ischaemia of the Leg trial; BSX-first, bypassrgery; CAD, coronary artery disease; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CI, confidenceterval; CKD, chronic kidney disease; CLI, critical limb ischemia; CLIPS, Critical Leg Ischemia Prevention Study; COX-2, cyclooxygenase; CTA, computed tomographicgiography; CV, cardiovascular; DSMB, data safety monitoring board; Embase, Excerpta Medica Database; ER, emergency room; EVAR, endovascular aneurysmpair; FRS, Framingham Risk Score; GP, general practitioner; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronaryteries; HbA1c, hemoglobin A1c; HR; hazard ratio; HRQOL, health-related quality of life; IBG, infrainguinal bypass graft; ICU, intensive care unit; ITT, intention-to-treat;EDLINE, Medical Literature Analysis and Retrieval System Online; MI, myocardial infarction; N/A, not available; NSAIDs, nonsteroidal anti-inflammatory drugs; OR,ds radio; OS, overall survival; MRA, magnetic resonance angiography; PAD, peripheral artery disease; PCP, primary care physician; POPADAD, prevention ofogression of arterial disease and diabetes; PREVENT III, The Project of Ex-Vivo Vein Graft Engineering via Transfection III; PVD, peripheral vascular disease; RAS,nal artery stenosis; RCT, randomized controlled trial; RR, relative risk; SLI, severe leg ischemia; TIA, transient ischemic attack; UA, unstable angina; VA, Department
Veterans Affairs; WAVE, Warfarin Antiplatelet Vascular Evaluation trial; 1°, primary; and 2°, secondary.


A

MIoccrecananstrCVreccomanthrpa(4.rec(1.





, stroke, or death from CV causesurred in 132 of 1,080 patientseiving combination therapy (12.2%)d in 144 of 1,081 patients receivingtiplatelet therapy alone (13.3%). MI,oke, severe ischemia, or death fromcauses occurred in 172 patientseiving combination therapy (15.9%)pared with 188 patients receiving

tiplatelet therapy alone (17.4%). Life-eatening bleeding occurred in 43tients receiving combination therapy0%) compared with 13 patientseiving antiplatelet therapy alone2%).

MI, stroke, or death from CVcauses: p�0.48MI, stroke, severe ischemia, ordeath from CV causes: p�0.37Life-threatening bleeding:p�0.001

MI, stroke, or death from CVcauses: RR: 0.92; 95% CI:0.73 to 1.16MI, stroke, severe ischemia, ordeath from CV causes: RR:0.91; 95% CI: 0.74 to 1.12Life-threatening bleeding: RR:3.41; 95% CI: 1.84 to 6.35

The combination of an oralanticoagulant and antiplatelettherapy was no more effectivethan antiplatelet therapy alone inpreventing major CVcomplications and was associatedwith an increase in life-threatening bleeding.

Safety outcomes were life-threatening, moderate, or minorbleeding episodes.



doi:10.1016/j.jacc.2011.08.023 published online Sep 29, 2011; J. Am. Coll. Cardiol.

J. White, John V. White, and R. Eugene Zierler Michael R. Jaff, Gregory L. Moneta, Jeffrey W. Olin, James C. Stanley, Christopher

Laura K. Findeiss, Jafar Golzarian, Heather L. Gornik, Jonathan L. Halperin, W. Rooke, Alan T. Hirsch, Sanjay Misra, Anton N. Sidawy, Joshua A. Beckman,

Radiology, Society for Vascular Medicine, and Society for Vascular Surgery, Thom Society for Cardiovascular Angiography and Interventions, Society of Interventional

Association Task Force on Practice GuidelinesReport of the American College of Cardiology Foundation/American HeartPatients With Peripheral Artery Disease (Updating the 2005 Guideline): A 2011 ACCF/AHA Focused Update of the Guideline for the Management of

This information is current as of October 6, 2011

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