comparative efficacy of endovascular revascularization...

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PERIPHERAL

Comparative Efficacy of EndovascularRevascularization Versus SupervisedExercise Training in Patients WithIntermittent Claudication
Meta-Analysis of Randomized Controlled Trials
Ambarish Pandey, MD,a Subhash Banerjee, MD,a Christian Ngo, MD,a Purav Mody, MD,a Steven P. Marso, MD,a

Emmanouil S. Brilakis, MD, PHD,a Ehrin J. Armstrong, MD, MS,b Jay Giri, MD, MPH,c Marc P. Bonaca, MD, MPH,d

Aruna Pradhan, MD, MPH,d Anthony A. Bavry, MD, MPH,e Dharam J. Kumbhani, MD, SMa

JACC: CARDIOVASCULAR INTERVENTIONS CME

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CME Objective for This Article: At the end of the activity the reader

should be able to: 1) define the current recommendations for use of

supervised exercise training and endovascular revascularization in the

management of patients with peripheral arterial disease and intermit-

tent claudication; 2) compare the efficacy of combined endovascular

revascularization therapy and supervised exercise training versus su-

pervised exercise training alone as an initial management strategy for

From the aDivision of Cardiology, Department of Internal Medicine, Unive

Texas; bSection of Cardiology, Denver VA Medical Center and UniversitycCardiovascular Medicine Division, Perelman School of Medicine at the UnidDivsion of Cardiovasular Medicine, Brigham and Women’s Hospital, Boston

University of Florida, Gainesville, Florida. Dr. Banerjee has received speak

intermittent claudication; and 3) identify the challenges associated

with implementation of supervised exercise training and alternative

treatment options for the management of patients with peripheral

arterial disease and intermittent claudication.

CME Editor Disclosure: JACC: Cardiovascular Interventions CME Editor

Bill Gogas, MD, PhD, has reported that he has no disclosures.

Author Disclosures: Dr. Banerjee has received speakers honoraria from

Medtronic, CSI, and Gore; and research and educational grants from

Boston Scientific and Merck. Dr. Marso has received grants to his insti-

tution from The Medicines Company, Novo Nordisk; and personal fees

from Novo Nordisk, Abbott Vascular, and AstraZeneca. Dr. Brilakis has

received consulting/speaker honoraria from Abbott Vascular, Asahi,

Cardinal Health, Elsevier, GE Healthcare, and St. Jude Medical; and

research support from InfraRedx and Boston Scientific. Dr. Armstrong has

been a consultant for Abbott Vascular, Boston Scientific, Cardiovascular

Systems, Medtronic, Merck, and Spectranetics. Dr. Giri has received

research funds to his institution from St. Jude Medical. Dr. Bavry has

received honoraria from the American College of Cardiology. Dr. Bonanca

has received research grant support from AstraZeneca andMerck; and is a

consultant for AstraZeneca, Merck, Bayer, and Azalez. Dr. Kumbhani has

received honoraria and research support from the American College of

Cardiology. All other authors have reported that they have no relation-

ships relevant to the contents of this paper to disclose.

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

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Expiration Date: April 9, 2018

rsity of Texas Southwestern Medical Center, Dallas,

of Colorado School of Medicine, Denver, Colorado;

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, Massachusetts; and the eDepartment of Medicine,

ers honoraria from Medtronic, CSI, and Gore; and

http://www.acc.org/jacc-journals-cme

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J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 0 , N O . 7 , 2 0 1 7 Pandey et al.A P R I L 1 0 , 2 0 1 7 : 7 1 2 – 2 4 Exercise Training Only Versus Revascularization for Intermittent Claudication

713

Comparative Efficacy of EndovascularRevascularization Versus SupervisedExercise Training in Patients WithIntermittent Claudication

Meta-Analysis of Randomized Controlled Trials

Ambarish Pandey, MD,a Subhash Banerjee, MD,a Christian Ngo, MD,a Purav Mody, MD,a Steven P. Marso, MD,a

Emmanouil S. Brilakis, MD, PHD,a Ehrin J. Armstrong, MD, MS,b Jay Giri, MD, MPH,c Marc P. Bonaca, MD, MPH,d

Aruna Pradhan, MD, MPH,d Anthony A. Bavry, MD, MPH,e Dharam J. Kumbhani, MD, SMa

ABSTRACT

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OBJECTIVES The authors performed a meta-analysis of randomized controlled trials to compare the efficacy of initial

endovascular treatment with or without supervised exercise training (SET) versus SET alone in patients with intermittent

claudication.

BACKGROUND Current guidelines recommend SET as the initial treatment modality for patients with intermittent

claudication, in addition to optimal medical therapy. The role of endovascular therapy as primary treatment for claudi-

cation has been controversial.

METHODS The primary outcome was treadmill-measured maximal walk distance at the end of follow-up. Secondary

outcomes included resting ankle brachial index (ABI) and treadmill-measured ischemic claudication distance on follow-up.

Risk of revascularization or amputations was also compared. Pooled estimates of the difference in outcomes between

endovascular therapy with or without SET and SET-only groups were calculated using fixed and random effects models.

RESULTS A total of 987 patients from 7 trials were included. In pooled analysis, compared with SET only (reference group),

patients that underwent combined endovascular therapy and SET had significantly higher maximum walk distance (stan-

dardized mean difference 0.79 [95% confidence interval (CI): 0.18 to 1.39]; weighted mean difference 98.9 [95% CI: 31.4 to

166.4 feet], and lower risk of revascularization or amputation (odds ratio 0.19 [95% CI: (0.09 to 0.40]; p< 0.0001, number

needed to treat¼8)over amedian follow-upof 12.4months. By contrast, revascularizationwas not associatedwith significant

improvement in exercise capacity or risk of future revascularization or amputation, compared with SET alone. Follow-up ABI

wassignificantlyhigheramongpatients thatunderwentendovascular therapywithorwithoutSETascomparedwithSETalone.

CONCLUSIONS Compared with initial SET only, endovascular therapy in combination with SET is associated with

significant improvement in total walking distance, ABI, and risk of future revascularization or amputation. By contrast,

endovascular therapy-only was not associated with any improvement in functional capacity or clinical outcomes over

an intermediate duration of follow-up. (J Am Coll Cardiol Intv 2017;10:712–24) © 2017 by the American College of

Cardiology Foundation. Published by Elsevier. All rights reserved.

earch and educational grants from Boston Scientific and Merck. Dr. Marso has received grants to his institution from

e Medicines Company, Novo Nordisk; and personal fees from Novo Nordisk, Abbott Vascular, and AstraZeneca. Dr. Brilakis has

eived consulting/speaker honoraria from Abbott Vascular, Asahi, Cardinal Health, Elsevier, GE Healthcare, and St. Jude

dical; and research support from InfraRedx and Boston Scientific. Dr. Armstrong has been a consultant for Abbott Vascular,

ston Scientific, Cardiovascular Systems, Medtronic, Merck, and Spectranetics. Dr. Giri has received research funds to his

titution from St. Jude Medical. Dr. Bavry has received honoraria from the American College of Cardiology. Dr. Bonanca has

eived research grant support from AstraZeneca and Merck; and is a consultant for AstraZeneca, Merck, Bayer, and Azalez. Dr.

mbhani has received honoraria and research support from the American College of Cardiology. All other authors have reported

t they have no relationships relevant to the contents of this paper to disclose.

nuscript received September 7, 2016; revised manuscript received January 10, 2017, accepted January 27, 2017.

FIGUR

The flo

training

SEE PAGE 725

ABBR EV I A T I ON S

AND ACRONYMS

ABI = ankle brachial index

CI = confidence interval

OR = odds ratio

PAD = peripheral arterial

disease

SET = supervised exercise

training

SMD = standardized mean

difference

WMD = weighted mean

difference

Pandey et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 0 , N O . 7 , 2 0 1 7

Exercise Training Only Versus Revascularization for Intermittent Claudication A P R I L 1 0 , 2 0 1 7 : 7 1 2 – 2 4

714

P eripheral arterial disease (PAD) is amanifestation of systemic athero-sclerosis that affects more than

8.5 million adults >40 years of age andconfers an increased risk for cardiovascularmorbidity and mortality (1–5). Intermittentclaudication is the classical symptomaticclinical presentation of PAD, and is associ-ated with reduced exercise capacity andpoor quality of life among these patients(1,6,7). Current American College of Cardi-ology/American Heart Association guide-lines recommend a program of supervisedexercise training (SET) as an initial treat-

ment modality for patients with intermittentclaudication (Class I) (8). Endovascular therapiesare recommended for patients with intermittentclaudication when they do not respond to initial ex-ercise and medical therapies (Class IIa) and havefavorable anatomy for intervention. However, therole of endovascular therapies as an initial

E 1 Summary of Study Identification and Selection

wchart shows the methodology used in selection of randomized

. Co-authors (A.P. and D.J.K.) retrieved and reviewed the full te

treatment option alone or as an upstream adjunctto SET in patients with intermittent claudication re-mains controversial. Several recent trials havecompared endovascular therapies with or withoutSET versus SET alone as an initial treatment strat-egy for PAD patients with intermittent claudication,and reported inconsistent results (9–12). In thisstudy, we performed a meta-analysis of randomizedcontrolled trials to compare the efficacy ofinitial endovascular treatment with or without SETversus SET alone in patients with intermittentclaudication.

METHODS

SEARCH STRATEGY. A search of MEDLINE andEmbase was performed using these key terms: inter-mittent claudication, claudication, claudicants,peripheral arterial disease, exercise training, exercise

controlled trials for the meta-analysis. SET ¼ supervised exercise

xt articles for this study.

TABLE 1 Baseline Characteristics of Included Studies

First Author (Ref. #)Study Size (Exercise/Revascularization) Women, % Study Population Age, yrs BMI, kg/m2 HTN, % DM, % ETT Parameters

Endovascular vs. SET

Spronk et al. (21) 75/75 44.7 Europe 65.5 (10.3) 25.5 (4.6) 40.0 17.3 3.5 km/h, 0 incline

Mazari et al. (19) 60/60* 38.3 Europe 69.5 NR 67.0 14.0 2.5 km/h, 10� incline

Perkins et al. (20) 26/30 NR Europe NR NR NR NR 3 km/h, 10� incline

Murphy et al. (10) 43/46 40.4 U.S. and Canada 64.5 (9.8) 28.5 (5.7) 82.0 23.9 Gardner protocol

Gelin et al. (17) 88/87 35 Europe 66.5 (NR) NR NR 16.5 Gardner protocol

Endovascular þ SET vs. SET

Mazari et al. (19) 60/58* 40.7 Europe 69.2 NR 62.7 14.4 2.5 km/h, 10� incline

Greenhalgh et al. (18)Femoropopliteal

45/48 36.6 Europe 66.1 (9.2) 27.0 (4.8) 74.2 NR 4 km/h 10� incline

Greenhalgh et al. (18)Aortoiliac

15/19 35.3 Europe 63.3 (9.0) 26.3 (3.7) 55.9 NR 4 km/h 10� incline

Fakhry et al. (12) 106/106 37.7 Europe 65 (10) 26.6 (4.1) 60.3 21 Gardner protocol

Values are n, weighted mean � SD or %. *Mazari et al. (19) included 3 study arms (exercise/revascularization/both) and reported median ages for the study groups.

BMI ¼ body mass index; DM ¼ diabetes; ETT ¼ exercise treadmill test; HTN ¼ hypertension; NR ¼ not reported; SET ¼ supervised exercised therapy.


715

therapy, supervised exercise training, angioplasty,stents, endovascular procedure, surgical revasculari-zation, and percutaneous revascularization. Searchwas limited to human studies published after 1990,with no restriction for language. From these lists,published clinical trials comparing the efficacy of SETversus endovascular therapy (balloon angioplasty orstenting) in patients with PAD and ischemic claudi-cation were identified. The references cited in theincluded papers were also examined for additionalstudies. Trials presented at recent national andinternational cardiovascular conferences werealso assessed. The search strategy, study selectionand analysis were carried out in accordance with

TABLE 2 Angiographic Characteristics of Study Groups

First Author (Ref. #)

Lesion Location

Aortoiliac Femoropopliteal

Endovascular vs. SET

Spronk et al. (21) 70.7 29.3

Mazari et al. (19) 0.0 100.0

Perkins et al. (20) 50.0 50.0

Murphy et al. (10) 100.0 0.0

Gelin et al. (17)* 44.3 55.7

Endovascular þ SET vs. SET

Mazari et al 0.0 100.0

Greenhalgh et al. (18)Femoropopliteal

0 100.0

Greenhalgh et al. (18)Aortoiliac

100 0

Fakhry et al. (12) 53 47

Values are (%). Surgical revascularization refers to use of arterial bypass or end-arterectomy procedures. *Only revascularization group data reported; included36% surgical revascularization.

SET ¼ supervised exercised therapy.

the PRISMA statement for systematic reviews(Figure 1) (13).

STUDY SELECTION. All selected abstracts and titleswere scanned independently by 2 reviewers (A.P.and D.J.K.) to identify papers for potentialinclusion. Studies included in this analysis wererequired to have: 1) a randomized controlled trialdesign with an endovascular therapy arm and a SETarm; 2) data on baseline symptom status of studyparticipants; 3) clearly defined intervention (endo-vascular therapy alone or in combination with SET)and control groups (SET only); and 4) objectivemeasures of exercise capacity at the end of the study.Studies involving unsupervised or home-basedexercise training or exclusively surgical revasculari-zation of PAD lesions were excluded from thestudy; however, hybrid revascularization (endovas-cular therapy þ surgical revascularization) studieswere included.

DATA EXTRACTION AND RISK OF BIAS ASSESSMENT.

Data extraction was performed independently by 3investigators (A.P., P.M., and D.J.K.). Clinical char-acteristics, target lesion location, type of endovas-cular intervention performed, outcomes measuredat baseline and end of study, follow-up period, andinterval clinical events were extracted from individ-ual studies and entered into a data extraction form.For multiple studies published from a single dataset,the largest study with primary findings was includedin the analysis. Discrepancies between reviewerswere resolved through discussion and consensus.Risk of bias was assessed using the Cochrane risk ofbias assessment tool by 2 independent investigators

TABLE 3 Inclusion and Exclusion Criteria of Included Studies

First Author (Ref. #) Inclusion Criteria Exclusion Criteria

Spronk et al. (21) Claudication with a duration of 3months or longer; maximal pain-free walking distance <350 m;ABI <0.9 at rest or decreased by>0.15 after treadmill test; 1 ormore vascular stenosis >50%diameter reduction

Abdominal aortic aneurysm; NYHAfunctional class III or higher;multilevel disease; isolatedtibial artery disease; lesionsdeemed unsuitable forrevascularization; priortreatment of the lesion

Mazari et al. (19) Symptomatic unilateral intermittentclaudication; femoropopliteallesion amenable to angioplasty;symptoms stable after 3 monthson best medical therapy

Critical ischemia; inability totolerate treadmill testing;significant ischemic change onECG during treadmill testing;ipsilateral vascularintervention within previous6 months

Perkins et al. (20) Stable unilateral claudication withfailure of conservativemanagement for 3 months; lesionon angiography suitable forangioplasty; a maximum walkingdistance of <375 m

None

Murphy et al. (10) Moderate-to-severe intermittentclaudication; objective evidenceof a hemodynamically significantaortoiliac arterial stenosis

Critical limb ischemia; comorbidcondition which limitedwalking ability; total aortoiliacocclusion from the level of therenal arteries to the inguinalligaments

Gelin et al. (17) Stable intermittent claudication formore than 6 months; ABI <0.6and maximal post-ischemic calfblood flow <25 ml/min/100 g

Medical contraindication tosurgery; medical disorderseverely limiting walkingevaluation on a treadmill

Greenhalgh et al. (18) Positive outcome on the EdinburghClaudication Questionnaire;ABI <0.9 or >0.9 with a positivestress test; aortoiliac orfemoropopliteal target lesionamendable to angioplasty

Claudication symptoms too mildto consider angioplasty or toosevere that angioplasty wasmandatory; critical limbischemia, concomitant diseasethat was prohibitive toexercise

Fakhry et al. (12) Stable intermittent claudication formore than 3 months, >50%obstruction at aortoiliac orfemoropopliteal level; targetlesion suitable for endovascularrevascularization

Prior treatment with exercisetherapy; any limitation toambulation

ABI ¼ ankle-brachial index; ECG ¼ electrocardiogram; MRA ¼ magnetic resonance angiography; NYHA ¼ NewYork Heart Association; TASC ¼ Trans-Atlantic Inter-Societal Consensus.



716

(A.P. and D.J.K.) and studies were classified as low-,moderate-, or high-quality study (14).

OUTCOME VARIABLES. Primary outcome of interestfor this study was maximal walking distance at follow-up. Secondary outcomes included resting anklebrachial pressure index (ABI) and ischemic claudica-tion distance at follow-up. The follow-up data onoutcomes were consistently reported in most includedstudies for 12 to 18months post-randomization. Pooledincidence of need for revascularization proceduresand amputations during follow-up was also comparedbetween the different study arms.

STATISTICAL ANALYSIS. The included studies wereanalyzed as per the intention-to-treat principle. Twoseparate analyses were conducted: endovascular

therapy with SET versus SET alone, and endovasculartherapy alone versus SET alone, as the initial treatmentoption. For continuous variables, the standardized andweighted mean differences (SMD, WMD) and corre-sponding 95% confidence intervals (CIs) werecomputed, using fixed and random effects modeling.The SMD values are preferentially reported to accountfor differences in treadmill protocols, but wherenecessary, the WMD values are provided for clinicalrelevance. If treadmill measures were reported in timeunits, they were converted to distance units, based onthe treadmill protocol. For the Gardner protocol, dis-tance in meters was calculated as: distance (m) ¼ time(inmin)� (53.33m/min [3.2 km/h]) (15). Summary oddsratios (OR) with 95% CI were computed for eachdichotomous outcome. In situations where no eventswere noted in one arm of a trial, we used an automatic“zero cell” correction so that studies with no events ina given arm would still be included for analysis. Toassess the effect of the location of dominant lesion(aortoiliac vs. femoropopliteal) and the type of endo-vascular therapy (stent vs. no stent), random-effectmeta-regression models were constructed for the pri-mary outcome.

Heterogeneity between studies was assessed usingI2 statistic and publication bias with Egger’smethod (16). For outcomes with significant hetero-geneity, the random effects model is reported inthe text and figures; for all others, the fixedeffects models are reported. All p values were 2-tailed with statistical significance specified at 0.05and CI computed at the 95% level. All statistical an-alyses were conducted using STATA version 12.0statistical software (Stata Corporation, College Sta-tion, Texas).

RESULTS

A total of 987 patients from 7 randomized con-trol trials (constituting 9 total comparison arms)(11,12,17–21) with a weighted median follow-up dura-tion of 12.4 months (range 10 to 18 months) wereenrolled. Of these, 530 were randomized to endo-vascular therapy versus SET and 457 to endovasculartherapy þ SET versus SET. All trials emphasizedoptimal medical therapy in both arms. The baseline,demographic, and clinical characteristics of the studyparticipants are summarized in Table 1, and angio-graphic features in Table 2. An assessment ofanatomic location of stenosis was performed in all theincluded studies. Overall, aortoiliac lesions wereobserved in 45% of the patients.

The SET protocol, endovascular therapy used, andoutcomes assessed in the included studies are

TABLE 4 Study Arms and Primary and Secondary Outcomes of Included Studies

First Author (Ref. #) Exercise Training Intervention Revascularization Intervention Outcomes Measured

Spronk et al. (21) Supervised training, 24 weeks,30 min per session, twice weekly

Balloon angioplasty followed by stentuse if indicated

ABI; exercise capacity, QOL

Mazari et al. (3 groups) (19) Supervised training, 12 weeks,3 times weekly

Balloon angioplasty with completionangiography, no adjunctiveprocedures or stents were used


Perkins et al. (20) Supervised training for 6 months, 30 minper session, twice weekly, dynamicleg exercises with increasing intensityover time, supervised

Balloon angioplasty ABI; exercise capacity

Murphy et al. (10) Supervised training for 26 weeks, 1 h,3 times weekly, graded treadmillexercise

Balloon angioplasty with stents at allsignificant stenosis

Exercise capacity, QOL

Gelin et al. (17) Supervised training for 6 months,30 min, 3 times weekly,walking training

Endovascular intervention or opensurgical procedure determined bystandard angiography, invasive only

ABI; exercise capacity, maximumcalf blood flow, systolic bigtoe pressure

Greenhalgh et al. (18) Supervised training for 6 months,30 min per session,at least once weekly

Supervised exercise with additionalrevascularization using balloonangioplasty with or without stentingat the discretion of the operator


Fakhry et al. (12) Supervised exercise training Supervised exercise training withadditional endovascular therapy


ABI ¼ ankle brachial pressure index; QOL ¼ quality of life (as assessed by different questionnaire-based instruments).


717

detailed in Tables 3 and 4. Treadmill protocolsdiffered among the included studies. Percutaneousendovascular therapy with balloon angioplasty andselective stent placement was used in 5 studies,whereas 2 studies used only balloon angioplasty(stent-use range 0% to 100%, mean 38%). One studyincluded both surgical and endovascular revascular-ization intervention. The MIMIC (Mild to ModerateIntermittent Claudication) trial reported separateoutcome measures among subgroups of participantswith femoropopliteal and aortoiliac disease (18).Thus, data from these subgroups are reported sepa-rately in the pooled analysis.

QUALITY ASSESSMENT. Quality assessment was per-formed through use of the Cochrane risk of biasassessment tool. One study (Perkins et al. [20]) wasidentified as low quality due to lack of reporting onstudy design including randomization technique,lack of blinding in outcome assessment, and missinginformation on dropout among study participants.Other studies (n ¼ 6) were moderate quality withrandom sequence generation, allocation concealment,and blinded assessment of outcome. None ofthe studies were double blind due to the nature ofintervention. Incomplete outcome or selectivereporting was not observed in most (n ¼ 6) includedstudies.

EFFECT OF ENDOVASCULAR THERAPY ONLY

VERSUS SET ONLY (N [ 5 COMPARISON ARMS).

Pooling across the studies using a random effects

model showed no significant difference in themaximum walk distance (SMD: �0.11 [95% CI: �0.59to 0.36]; p ¼ 0.64) (Figure 2) on follow-up between the2 groups. There was evidence of significant hetero-geneity for this endpoint (I2 ¼ 87.5%). There was noevidence of publication bias (p ¼ 0.43). On meta-regression, there were no significant differences inthe pooled maximum walk distance based on stentuse (p ¼ 0.31) or presence of aortoiliac disease(p ¼ 0.54) for this outcome.

Four studies reported ischemic claudication dis-tance on follow-up. On pooled analysis, ischemicclaudication distance was not different between theendovascular and SET arms (WMD: �39.18 [95%CI: �85.9 to 7.54]; p ¼ 0.10). ABI measurement onfollow-up was reported by all 5 studies. On pooledanalysis, ABI was significantly higher among partici-pants that underwent endovascular therapy ascompared with SET only (SMD: 0.64 [95% CI: 0.38 to0.90]; p < 0.0001; WMD: 0.15 [95% CI: 0.10 to 0.19];p < 0.0001) (Figure 3). All 5 studies reported on theneed for subsequent revascularization or amputationon follow-up. On pooled analysis, there was no dif-ference in the risk of revascularization or amputationon follow-up (8.7% vs. 12.3%, OR: 0.68 [95% CI: 0.33 to1.43]; p ¼ 0.31) (Figure 4).

EFFECT OF COMBINED ENDOVASCULAR THERAPY

AND SET VERSUS SET (N [ 4 COMPARISON ARMS).

On pooled analysis using random effects models,endovascular therapy with SET was associated

FIGURE 2 Forest Plot for Maximal Walking Distance on Follow-Up

Forest plot for maximal walking distance on follow-up is based on endovascular therapy versus supervised exercise training (A) and endovascular therapy þ supervised

exercise training versus supervised exercise training alone (B). Results are presented for the pooled analyses of all available studies. CI ¼ confidence interval; SET ¼supervised exercise training; SMD ¼ standardized mean difference. Mazari a: SET only vs. Endovascular therapy only arm comparison; Mazari b: SET only vs. SET þEndovascular therapy comparison; Greenhalgh a: femoropopliteal arm; Greenhalgh b: aortoiliac arm.



718

FIGURE 3 Forest Plot for ABI on Follow-Up

Forest plot for ankle brachial index (ABI) on follow-up is based on endovascular therapy versus supervised exercise training (A) and endovascular therapy þ supervised

exercise training versus supervised exercise training alone (B). Results are presented for the pooled analyses of all available studies. Abbreviations as in Figure 2.


719

FIGURE 4 Forest Plot for Need for Revascularization or Amputation on Follow-Up

Forest plot for need for revascularization or amputation on follow-up is based on endovascular therapy versus supervised exercise training (A) and endovascular

therapy þ supervised exercise training versus supervised exercise training alone (B). Results are presented for the pooled analyses of all available studies. OR ¼ odds

ratio; other abbreviations as in Figure 2.



720


721

with significantly higher maximal walking dis-tance on follow-up compared with SET alone (SMD:0.79 [95% CI: 0.18 to 1.39]; p ¼ 0.01) (Figure 2).Pooled WMD for maximal walking distance betweenthe 2 study groups was 98.9 feet (95% CI: 31.4 to166.4). There was evidence of significant heteroge-neity for this endpoint (I2 ¼ 88.2%). There was noevidence of publication bias (p ¼ 0.46). On meta-regression, there were no significant differences inthe pooled maximal walk distance based on stentuse (p ¼ 0.11) or presence of aortoiliac disease(p ¼ 0.25).

Ischemic claudication distance was reported in 2studies with no difference between the 2 groups inrandom effects pooled analysis (SMD: 0.31 [95%CI: �0.26 to 0.87]; p ¼ 0.29). All 4 studies reported ABIon follow-up. On pooled analysis, the combination ofendovascular therapy and SET was associated withsignificantly higher ABI on follow-up compared withSET only (SMD: 0.62 [95% CI: 0.33 to 0.91]; WMD: 0.14[95% CI: 0.10 to 0.17]; p < 0.0001) (Figure 3). All 4studies reported on the need for subsequent revas-cularization or amputation on follow-up. On pooledanalysis, the combination was associated with asignificantly lower risk of revascularization or ampu-tation on follow-up (3.5% vs. 17.3%, OR: 0.19 [95% CI:0.09 to 0.40]; p < 0.0001) (Figure 4). The corre-sponding number needed to treat was 8 patients (95%CI: 6 to 12).

DISCUSSION

In this meta-analysis of 987 patients with stableintermittent claudication on medical therapy, endo-vascular revascularization only as an initial treatmentstrategy did not improve exercise capacity or lowerrisk of revascularization or amputation onintermediate-term follow-up compared with SETonly. By contrast, the combination of endovasculartherapy with SET significantly improved maximalwalking distance and lowered the risk of downstreamrevascularization or amputation compared with SETonly. Finally, endovascular revascularization with orwithout SET was associated with a significant 20%improvement in ABI.

Our study has important clinical and policy impli-cations. SET has been shown to improve exercise ca-pacity and quality of life in patients with coronaryartery disease, heart failure, and other cardiopulmo-nary conditions. Similar benefits have also beenreported in PAD patients, and SET currently carries aClass I recommendation for initial managementof intermittent claudication (8). These beneficialeffects of SET among PAD patients are attributed

to improvement in endothelial function, improvedvascular obstruction, reduced inflammation, andfavorable changes in skeletal muscle phenotype withimproved mitochondrial function (22). Currentguidelines also state that revascularization should beconsidered only after failure of SET and guidelinedirected medical therapy (Class IIa). These recom-mendations are validated in our study, given the lackof difference in functional and limb outcomesobserved between SET alone and revascularizationalone. However, our study also suggests that thecombination of the 2 therapies may have an additiveeffect over SET alone and deserves consideration inthe next iteration of the guidelines.

Despite being a Class I recommendation, a majorpractical limitation of SET is that it is currently notreimbursed by Centers for Medicare & MedicaidServices (23). In addition, and to some extent as aresult of this, easy availability of supervised exer-cise training programs for PAD patients is poor (24).Further, compliance throughout the prescribedduration of exercise therapy is poor, as also notedin the included studies. Our study suggests thatrenewed attempts are necessary to improve accessand address reimbursement policies for SET. Be-sides SET, recent studies have also evaluated therole of home-based exercise training for manage-ment of PAD patients. In a recent clinical trial,McDermott et al. (25) demonstrated significant im-provements in exercise capacity with use of home-based walking exercise among PAD participants.Other studies comparing home-based exerciseversus revascularization in PAD patients havedemonstrated comparable changes in maximalwalking distance (26). Thus, home-based exercisemay be a useful alternative for PAD patients whenSET is not available as the primary treatment op-tion, and is endorsed as a Class IIa recommendationby the guidelines as well (8). Future trials areneeded to directly compare revascularization tohome-based walking programs. To date, the onlytrial that we encountered on this topic is theIRONIC (Invasive Revascularization or Not in Inter-mittent Claudication) trial (26). One hundred fifty-eight patients with claudication were randomizedto either revascularization with a home-basedwalking program or a home-based program alone.At 1 year, the combination was superior to thehome-based program alone in improving claudica-tion distance. A number of quality-of-life indiceswere also higher in the combination group (26).

From a mechanistic standpoint, we observed aninteresting dichotomy between ABI values andfunctional improvements. Although resting ABI



722

values were higher by approximately 20% duringfollow-up among participants receiving endovas-cular therapy with or without concurrent SET, theclinical benefits of endovascular therapy werelimited to the combined endovascular therapy andSET group. Prior studies have reported that ABI isassociated with exercise capacity and leg function inPAD patients (27,28). However, the association be-tween therapy-related improvement in arterial bloodflow and improvement in functional capacity is lesswell established, suggesting that additional mecha-nisms beyond anatomic disease may play a majorrole in mediating the functional benefits among PADpatients (20,29,30). Taken together, these findingssuggest that whereas ABI may be an effectivescreening tool to identify PAD patients, its useful-ness in guiding therapeutic decisions may belimited.

In a previous meta-analysis, Ahimastos et al. (31)demonstrated improvement in ischemic claudica-tion distance among PAD patients with intermittentclaudication that underwent a combination ofrevascularization and SET as compared with SETalone. However, this meta-analysis was limited bythe small number of included studies, inclusion ofobservational studies, and predominant use ofballoon angioplasty during revascularization.Moreover, several randomized trials have beenpublished in the last 3 years that have demon-strated variable effects of revascularization onfunctional outcomes (11,12,26). To our knowledge,the current meta-analysis with 987 participantswith PAD and intermittent claudication is one ofthe largest and most contemporary analyses on thistopic to date.

STUDY LIMITATIONS. An important limitation of ourstudy is our inability to adequately assess a stan-dardized major adverse limb outcome because infor-mation on acute and critical limb ischemia eventsduring follow-up was not separately reported. Forthis reason, we could not differentiate betweensubsequent revascularization for stable symptoms(which is expected and not necessarily a “failure” ofexercise) from revascularization for limb-threateningevents. We observed a small number of amputationsin the current analysis, and the indications for thesame were not reported. Procedural safety forendovascular revascularization also could not becommented upon because it did not appear to besystematically reported by all studies. Other

limitations include significant heterogeneity in thepooled analysis for exercise capacity. This could berelated to differences in patient characteristics suchas location of the lesions, differences in adherence toexercise training protocols, and differences in inter-vention strategies used. Further, because it is ameta-analysis, the validity of our results is dependenton the validity of the studies included. We didnot have access to patient-level data. Furthermore,data on medical management of study participantsin most trials were not reported completely, limitingour ability to assess the extent to whichoptimal medical therapy was used. Next, onlyintermediate-duration (12 to 18 months) follow-upresults were consistently available in most studies;longer-term data are lacking. Moreover, most datacomparing endovascular therapy with SET are fromEurope, which may limit the generalizability of studyfindings to the U.S. population. Finally, our studyprotocol was not published a priori in a centraldatabase.

CONCLUSIONS

Among patients with stable PAD and intermittentclaudication, compared with SET only, endovascularrevascularization in combination with SET is asso-ciated with an improvement in total walkingdistance, ABI, and lower risk of revascularizationor amputation over an intermediate duration offollow-up. By contrast, revascularization only is notassociated with significant improvement in anyclinical or functional outcomes despite improve-ment in ABI. These findings highlight the need toconsider initial revascularization as an adjunctivetherapy to SET but not as a primary treatment op-tion in the initial management approaches forintermittent claudication. Future studies thathave longer-term follow-up, compare contemporaryrevascularization techniques and exercise trainingprotocols, and are adequately powered to assessrelevant clinical outcomes, are needed to determinethe most effective management strategy for thesepatients.

ADDRESS FOR CORRESPONDENCE: Dr. Dharam J.Kumbhani, UT Southwestern Medical Center, 5323Harry Hines Boulevard, Dallas, Texas 75390-9047.E-mail: [email protected].

mailto:[email protected]

PERSPECTIVES

WHAT IS KNOWN? Supervised exercise training is rec-

ommended as an initial treatment modality for patients

with intermittent claudication.

WHAT IS NEW? Endovascular revascularization only as

an initial management strategy for intermittent claudi-

cation does not improve functional outcomes as

compared with supervised exercise training alone over an

intermediate duration of follow-up. In contrast, when

used as an adjunct to exercise training, endovascular

revascularization is associated with greater improvements

in functional and anatomic outcomes as compared with

exercise training alone.

WHAT IS NEXT? Future studies, with long follow-up and

relevant clinical outcomes, that compare contemporary

revascularization techniques and exercise training proto-

cols are needed to determine the most effective man-

agement strategy for these patients.


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KEY WORDS exercise capacity,intermittent claudication, peripheral arterialdisease, revascularization, supervisedexercise training

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