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P U B L I S H E D B Y E L S E V I E R I N C . h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j c i n . 2 0 1 3 . 0 8 . 0 0 7

Drug-Eluting Stents for Revascularizationof Infrapopliteal Arteries

Updated Meta-Analysis of Randomized Trials

Massimiliano Fusaro, MD,* Salvatore Cassese, MD,* Gjin Ndrepepa, MD,*

Gunnar Tepe, MD,y Lamin King, MD,* Ilka Ott, MD,* Mateja Nerad, MD,zHeribert Schunkert, MD,*x Adnan Kastrati, MD*xMunich and Tübingen, Germany; and Graz, Austria

Objectives This study sought to undertake an updated meta-analysis of randomized trialsinvestigating the outcomes of percutaneous revascularization with primary drug-eluting stenting inpatients with atherosclerotic disease of infrapopliteal arteries.

Background In atherosclerotic disease of infrapopliteal arteries, drug-eluting stents (DESs) improvepatency rates compared with plain balloon angioplasty or bare-metal stents (BMSs). However, theclinical impact of DES placement in this vascular territory still remains uncertain.

Methods We searched MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials),scientific session abstracts, and relevant Websites. The keywords used were “below the knee,”“infrapopliteal artery,” “angioplasty,” “drug-eluting stent(s),” “bare metal stent(s),” “trial,” and“randomized trial.” Inclusion criteria were randomized design, intention-to-treat analysis, anda minimum of 6-month follow-up. Exclusion criteria were vessels treated other than infrapoplitealarteries; devices used other than DESs, plain balloons, or BMSs; and duplicated data. The primaryendpoint was target lesion revascularization; secondary endpoints were restenosis, amputation, death,and improvement in Rutherford class.

Results A total of 611 patients from 5 trials were randomly assigned to DESs (n ¼ 294) versus controltherapy (plain balloon angioplasty/BMS implantation, n ¼ 307). Overall, the median lesion length was26.8 mm (interquartile range [IQR]: 18.2 to 30.0 mm) with a reference vessel diameter of 2.86 mm (IQR:2.68 to 3.00 mm). At a median follow-up of 12 months (IQR: 12 to 36 months), DESs reduced the riskof target lesion revascularization (odds ratio [OR]: 0.31; 95% confidence interval [CI]: 0.18 to 0.54;p < 0.001), restenosis (OR: 0.25; 95% CI: 0.15 to 0.43; p < 0.001), and amputation (OR: 0.50; 95% CI: 0.26to 0.97); p ¼ 0.04) without a significant difference in terms of death (OR: 0.81; 95% CI: 0.45 to 1.49;p ¼ 0.50) and Rutherford class improvement (OR: 1.36; 95% CI: 0.91 to 2.04; p ¼ 0.13) versus controltherapy.

Conclusions In focal disease of infrapopliteal arteries, DES therapy reduces the risk of reinterventionand amputation compared with plain balloon angioplasty or BMS implantation without any impact onmortality and Rutherford class at 1-year follow-up. (J Am Coll Cardiol Intv 2013;6:1284–93) ª 2013 bythe American College of Cardiology Foundation

From *Deutsches Herzzentrum, Technische Universität, Munich, Germany; yRadiologische Klinik, Diagnostische und Inter-

ventionelle Radiologie, Karls-Universität, Tübingen, Germany; zKlinische Abteilung für Kardiologie, Universität Graz, Graz,

Austria; and the xDZHK–German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany.

Dr. Kastrati has received lecture fees or honoraria from Abbott, AstraZeneca, Biosensors, Biotronik, Bristol-Myers Squibb, Merck,

The Medicines Company, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the

contents of this paper to disclose. Dr. Fusaro and Dr. Casseese contributed equally to the manuscript and are joint first authors.

Manuscript received June 7, 2013; revised manuscript received July 30, 2013, accepted August 14, 2013.

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Endovascular therapy represents the preferred option forpatients with occlusive atherosclerotic disease of infrapopli-teal arteries requiring revascularization (1). In this setting,plain balloon angioplasty is still a first-line recommendationdue to the high percentage of acute success and relatively lowcost (2,3). In contrast, stent implantation is recommended asan acute “bail-out” or “salvage” procedure in the event ofa suboptimal result or failure of balloon dilation (2,3).However, the lack of a proven durable antirestenotic effectafter plain balloon angioplasty has led to the investigation ofalternative strategies (4).

See page 1294

Abbreviationsand Acronyms

ARR = absolute risk

reduction

BMS = bare-metal stent(s)

CI = confidence interval

CLI = critical limb ischemia

DAPT = dual antiplatelet

therapy

DES = drug-eluting stent(s)

IQR = interquartile range

NNT = number needed to

treat

OR = odds ratio

RC = Rutherford class

TLR = target lesion

revascularization

The similar vessel diameter of coronary and infrapoplitealarteries had fueled the use of coronary stent platforms in thisperipheral vascular bed. Several small studies investigated theangiographic outcomes of drug-eluting stents (DESs)compared with either plain balloons or bare-metal stents(BMSs) for revascularization of infrapopliteal arteries (5).According to available data, primary drug-eluting stentingdemonstrates superior antirestenotic potency compared witheither plain balloons or BMSs with higher patency rates atmid-term follow-up (6–8). However, the impact of DESs onclinical outcomes such as repeat revascularization, amputa-tion, and mortality still remains a matter of uncertainty. Onthe one hand, the existing randomized, controlled trialsindividually lack the statistical power to discriminate differ-ences in rare clinical outcomes, and results have beeninconsistent (4). On the other hand, recent meta-analysesconsidered only a limited number of the available random-ized, controlled trials (9,10).

Therefore, the purpose of the present study was toundertake an updated meta-analysis of randomized trialsinvestigating outcomes associated with a strategy of percu-taneous revascularization with primary drug-eluting stentingin patients with atherosclerotic disease of infrapoplitealarteries.

Methods

Search strategy and selection criteria. We searched MED-LINE, Embase, CENTRAL (Cochrane Central Register ofControlled Trials), scientific sessions abstracts, and relevantWebsites (www.cardiosource.com, www.clinicaltrialresults.org, www.escardio.org, www.tctmd.com, www.theheart.org)without restricting language or publication status. Thereference lists from all eligible studies and previously pub-lished meta-analyses dealing with a similar topic (5,9–11)were checked to identify further citations. The final searchwas performed on March 23, 2013. Search terms includedthe keywords and the corresponding Medical SubjectHeadings for “below the knee,” “infrapopliteal artery,”

“angioplasty,” “drug-eluting stent(s),” “bare metal stent(s),”“trial,” and “randomized trial.” Inclusion criteria wererandomized design, intention-to-treat analysis, anda minimum of 6 months of follow-up. Exclusion criteriawere vessels treated other than infrapopliteal arteries, devicesused other than DESs, plain balloons, or BMSs, andduplicated data.Data collection and assessment of risk of bias. Two inves-tigators (S.C. and G.N.) independently assessed publica-tions for eligibility at the title and/or abstract level, withdifferences resolved by a third investigator (M.F.). Studiesthat met inclusion criteria were selected for further analysis.Freedom of bias was evaluated for each study by the sameinvestigators, in accordance with the Cochrane Collabora-tion method (12) on the basis of the following methodo-logical items: adequacy of random sequence generation andallocation concealment, blinding (at participant or outcome

assessor level), completeness ofreporting outcome data, selectivepresentation of outcomes, com-pleteness and adequacy of descrip-tion of sample size calculation,and appropriate disclosure offunding sources. We avoided for-mal quality score adjudications asthey have previously been foundpotentially misleading (13).Outcome variables. The degreeof restenosis quantifies the res-ponse of the vessel wall to in-terventions (14) and may not besynonymous of revascularization(15). The primary outcome ofthe present study was targetlesion revascularization (TLR)driven from clinical symptoms aswell as from invasive surveillance. Secondary outcomes were restenosis, amputation, Ruth-erford class (RC) improvement, and death. All endpointswere evaluated at the longest available follow-up accordingto per-protocol definitions: the most updated or mostinclusive data for a given study were analyzed. Where furtherdetails were required, we attempted to obtain them from thestudy investigators directly. However, we did not requestpatient-level data from the investigators of original studies.Statistical analysis. Statistical analysis was performed usingthe RevMan (Review Manager [RevMan] Version 5.1, TheCochrane Collaboration, Copenhagen, Denmark), and Stataversion 11.2 (StataCorp, College Station, Texas) softwarepackages.

The l statistic was used to assess agreement betweenreviewers for study selection. Odds ratio (OR) and 95%confidence interval (CI) were used as summary statistics andwere derived for comparison of DESs and pooled plain

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balloons/BMSs (the control therapy). To test whether thepooling of plain balloons and BMSs as control therapyaffected the analysis of the main outcomes, the risk estimatesassociated with DES therapy were also calculated afterstratification for plain balloons or BMSs as the control arm.The Mantel-Haenszel random-effects model (DerSimonianand Laird) was used to calculate pooled OR for categoricalvariables (16). In the case of statistical significance, absoluterisk reduction (ARR) and the number needed to treat(NNT) with 95% CI were provided. The Breslow-Daychi-square test and the I2 statistic were used to test het-erogeneity across the studies. As a guide, I2 values <25%indicated low, 25% to 50% moderate, and >50% highheterogeneity (12). To estimate the additive (between-study)component of variance, the restricted maximum likelihoodmethod (Tau2) took into account the occurrence of residualheterogeneity. Visual estimation of funnel plots as well asstatistical tests assessed possible publication bias for primaryoutcome (17–19). Similarly, an influence analysis, in whichmeta-analysis estimates are computed omitting 1 study ata time, was performed for primary outcome. A random-effects sensitivity analysis evaluated the extent to whichseveral covariatesdtrial size, length of clinical follow-up,protocol-mandated angiography, lesion length, vesseldiameter, and length of dual antiplatelet therapy(DAPT)dmight have influenced the risk estimates for theprimary outcome. A random-effects meta-regression analysis

Figure 1. PRISMA Flow Chart for the Trial Selection Process

Control arm included patients treated with plain balloon angioplasty or BMS.BMS ¼ bare-metal stent(s); DES ¼ drug-eluting stent(s); PRISMA ¼ Preferred Reportingtrial.

assessed the relationship between the baseline diseaseseverity (expressed as the proportion of patients with criticallimb ischemia [CLI] or with infrapopliteal artery occlusionsand the mean length of the lesions) and the risk estimates forTLR. Two adjusted indirect comparisons according to themethod of Bucher et al. (20) and Song et al. (21) investi-gated whether the various DES platforms included in theexperimental arm (everolimus- vs. sirolimus-eluting stents;polymer-free vs. durable-polymer DESs) provided differ-ences in the main outcomes.

This study was performed in compliance with thePRISMA (Preferred Reporting Items for Systematic reviewsand Meta-Analyses) statement (22).

Results

Eligible studies. The process of trial selection is summarizedin Figure 1. We excluded the trial of Rand et al. (23) becauseit investigated the outcomes of patients randomly assignedto carbon film–coated BMS implantation versus plainballoon angioplasty. Finally, 5 trials (6–8,24,25), all withfull-length reports, were selected. In the DES and BMSarms of original studies, pre-dilation was allowed beforestent implantation, whereas patients in the plain balloon armreceived no therapy other than plain balloon angioplasty.Thus, for the current analysis, the control therapy comprisedpatients treated with BMS implantation (with or without

Items for Systematic reviews and Meta-Analyses; RCT ¼ randomized, controlled

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pre-dilation) and patients receiving plain balloon angioplastyalone. One trial had a 4-arm design and randomly assignedpatients to DES implantation or plain balloon angioplasty orBMS implantation after a pre-treatment with a glycopro-tein IIb/IIIa inhibitor (abciximab) versus plain balloonangioplasty alone (25). For the purpose of this meta-analysis,the outcome data from the plain balloon and BMS arms ofthis trial were grouped to derive pooled estimates. One trial(26) recently reported long-term outcomes, which wereincluded in the present analysis. Thus, a total of 611 patients(294 randomized to DES therapy and 307 to controltherapy) were studied. Interobserver agreement for studyselection was very good, with a l value of 0.95.

The main characteristics of the studies included aredescribed in detail in Table 1. Three (6–8) of 5 trials hada multicenter design. Patients with evidence of >50% to�70% stenosis or occlusion of the infrapopliteal arteries andwith symptoms from disabling intermittent claudication toCLI were randomized to percutaneous revascularization withDESs versus control therapy. Patients presenting with an RCof 3 to 5 (6–8,24) or 6 (25) were enrolled in trials. One trialincluded 10 patients (6.2%) with an RC of 2 at admission (6).Patients with acute limb ischemia, untreated in-/outflowlesions or aneurysms, and previous stenting of the targetlesion were excluded. Among trials comparing DES therapyand plain balloon angioplasty, few cases treated by balloonrequired crossover to provisional stenting due to a suboptimalinitial result after angioplasty (7,25). Protocol-mandatedangiography was performed in 4 (7,8,24,25) of 5 trials.Patients enrolled in the DES arms received limus-elutingstents approved for coronary interventions (sirolimus-elutingstent [6,7,24,25] [Cypher or Cypher Select, Cordis, Johnson& Johnson, Bridgewater, New Jersey; Yukon DES, Trans-lumina, Hechingen, Germany]; everolimus-eluting stent [8][Xience V, Abbott Laboratories, Abbott Park, Illinois]).Patients enrolled in the BMS arms received conventional316L stainless steel stents (Bx-Velocity [25] or Sonic [24],Cordis, Johnson & Johnson) or microstructured 316Lstainless steel, microporous stents (6) (Yukon, Translumina)or 605L cobalt-chromium, thin-strut stents (8) (MultilinkVision, Abbott Laboratories, Abbott Park, Illinois).

The median number of patients included in the trialswas 140 (interquartile range [IQR]: 60 to 161) and theirclinical characteristics matched typical patients with infra-popliteal artery disease (Table 2). Overall, the medianlesion length was 26.8 mm (IQR: 18.2 to 30.0 mm) witha reference vessel diameter of 2.86 mm (IQR: 2.68 to3.00 mm). More specifically, patients undergoing DESimplantation had a median lesion length of 26.9 mm(IQR: 17.4 to 27.0 mm) and a reference vessel diameter of2.90 mm (IQR: 2.69 to 3.00 mm). Patients receivingcontrol therapy had a median lesion length of 26.8 mm(IQR: 18.9 to 30.0 mm) and a reference vessel diameter of2.83 mm (IQR: 2.68 to 2.91 mm).

An overview of endpoint definitions among trialsincluded is reported in Online Table 1. In all cases but 1(25), the primary endpoint was binary restenosis at 6- or 12-month follow-up. The remaining trial primarily evaluatedthe rate of target-vessel reocclusion at 2-month follow-up.All patients received active or control treatment in additionto standard medical therapy. Details of post-proceduralantiplatelet management and prescription were available inall trials. Median duration of DAPT was 12 months (IQR:12 to 36 months).

The risk of bias among studies is reported in OnlineTable 2. Of those randomized, 589 patients (96.3%)were available for assessment of outcomes of interest.The median follow-up was 12 months (IQR: 12 to 36months).Outcomes. TLR occurred in 97 patients (17.5%; dataavailable for 554 [94%] patients, all trials). DES versuscontrol therapy significantly decreased the risk of TLR (OR:0.31; 95% CI: 0.18 to 0.54; p < 0.001; I2 ¼ 15%, p forheterogeneity [phet] ¼ 0.32; ARR: 15.5%; 95% CI: 9.3 to21.6; NNT: 7; 95% CI: 5 to 11) (Fig. 2A).

Restenosis occurred in 183 patients (36.4%; data availablefor 502 patients [85%], all trials). DES versus controltherapy significantly decreased the risk of restenosis (OR:0.25; 95% CI: 0.15 to 0.43; p < 0.001; I2 ¼ 38%, phet ¼0.17; ARR: 29.6%; 95% CI: 21.7 to 37.6; NNT: 4; 95% CI:3 to 5) (Fig. 2B).

Amputation occurred in 52 patients (10.3%; data availablefor 504 patients [85.6%], 4 trials [6–8,25]). DES versuscontrol therapy significantly decreased the risk of amputa-tion (OR: 0.50; 95% CI: 0.26 to 0.97; p ¼ 0.04; I2 ¼ 0%,phet ¼ 0.61; ARR: 7.5%; 95% CI: 2.2 to 12.7; NNT: 13;95% CI: 8 to 45) (Fig. 2C).

Death occurred in 96 patients (16.2%) (data available forall patients). No significant difference in terms of risk ofdeath was found with DES therapy compared with controltherapy (OR: 0.81; 95% CI: 0.45 to 1.49; p 0.50; I2 ¼ 32%;phet ¼ 0.22) (Fig. 2D).

An improvement in RC occurred in 246 patients (55%;data available for 448 patients [76%], 3 trials [6–8]). Nosignificant difference in terms of RC improvement wasfound with DES therapy compared with control therapy(OR: 1.36; 95% CI: 0.91 to 2.04; p ¼ 0.13; I2 ¼ 6%, phet ¼0.34) (Fig. 2E).

DES therapy compared with either plain balloon angio-plasty or BMS implantation significantly decreased the riskof TLR, restenosis, and amputation without affectingmortality or improving RC (Online Table 3).Small study effects, influence, and sensitivity analyses.Funnel plot distribution of primary outcomes was derivedfrom the SE of the natural logarithm OR plotted against theOR of TLR (Online Fig. 1A). Of note, the absence ofbias due to small study effects was confirmed both visuallyand mathematically. Additionally, the influence analysis

Table 1. Main Characteristics of Trials Included in the Study

Trial/FirstAuthor (Ref. #) Years Inclusion Criteria Exclusion Criteria Primary Endpoint Secondary Endpoints DES

RegistrationNo.

ACHILLES(7)

2008–2010 Age �18 and �85 yrs; Rutherfordclasses 3–5; de novo or restenotic(after PTA only) lesions; maximum2 diseased vessels in 1 limb; �4stents required to fully cover thelesions; occlusion or stenosis�70% of vessel diameter; �2.5-and �3.5-mm reference vesseldiameter; �120 mm in length;successful guidewire passage

Outflow free of stenosis >50%;angiographic evidence ofthrombus; thrombolysis �72 hbefore procedure; untreatedsignificant (>75%) inflow lesions;previous stenting of the targetlesion; target lesion requiringbifurcation stenting; MI, stroke, orcoronary intervention <30 daysbefore the index procedure;�1 year life expectancy

12-month in-segment binaryrestenosis

Technical andprocedural success;12-month percentageof diameter stenosis;12-month in-segmentand in-stent LLL; TLR;6-week, 6-, and12-month patency;6-week, 6-, and12-month TLR; TVR;change in mean ABIand Rutherford class,amputations, seriousadverse events,wound status (ifapplicable)

CypherSelect*

NCT00640770

BELOW (25) 2003–2006 Age �18 and �95 yrs; Rutherfordclasses 5 and 6; maximum of 3lesions in 1 vessel; �2 stentsrequired to fully cover the lesions;occlusion or stenosis �70% vesseldiameter; �50 mm in length;successful guidewire passage

Outflow free of stenosis >50% oraneurysms within 30 mm of thetarget lesion; acute limb ischemiaor limb ischemia requiringthrombolysis before intervention;active bleeding; knownabciximab-inducedthrombocytopenia; major surgery,eye surgery or trauma �6 wksbefore index procedure; �1 yr lifeexpectancy

2-month targetvesselreocclusion

Technical success;6-month binaryrestenosis rate; 2- and6-month mortality,amputation, TVR,change in mean ABIand Rutherford class,wound healing, QOL

Cypher* NCT00163254

DESTINY (8) 2008–2010 Age �18 yrs; Rutherford classes 4and 5; de novo or restenotic (afterPTA only) lesions; maximum of 2lesions in �1 vessel; �2 stentsrequired to fully cover the lesions;>50% of vessel diameter; �2.0-and �3.5-mm reference vesseldiameter; �50 mm in length;successful guidewire passage;inflow free of unsuccessfullytreated lesion (>30% residualstenosis)

Buerger disease; reference vesseldiameter not suitable for stentplatforms selected; <1 outflowvessel; untreated significantinflow lesions or aneurysms;previous stenting of the targetlesion; target lesion requiringkissing stenting; active bleedingor malignancy requiringanticancer therapy <30 daysbefore or after index procedure;�1 yr life expectancy

12-month in-stentbinaryrestenosis

Technical success; 12-month clinicalsuccess (�1Rutherford classimprovement),primary patency, limbsalvage rate, seriousadverse events

XIENCEVy

NCT00510393

Falkowskyet al. (24)

2009–2010 Age �30 yrs, Rutherford classes 3–5;de novo lesions; occlusion orstenosis >60% of vessel diameter;�2.0- and �3.5- mm referencevessel diameter; �5 to �30 mmin length; successful guidewirepassage

Buerger disease; <1 outflow vessel;untreated significant inflowlesions or aneurysms; previousintervention of the target limb;active bleeding or malignancy;other intervention performed<30 days before or after indexprocedure; �1 yr life expectancy

6-month in-stentbinaryrestenosis

Technical andprocedural success;6-month percentageof diameter stenosis,in-stent LLL, TLR, andABI

Cypher* N/A

YUKON-BTK(6)

2006–2008 Age �18 yrs; Rutherford classes 3–5;de novo lesions; �2 stentsrequired to fully cover the lesions;>70% of vessel diameter; �2.5-and �3.5-mm reference vesseldiameter; �45 mm in length;successful guidewire passage;inflow free of unsuccessfullytreated lesion (>30% residualstenosis)

Buerger disease; outflow free ofstenosis >50%; angiographicevidence of thrombus;thrombolysis �72 h beforeprocedure; untreated significant(>75%) inflow lesions; previousstenting of the target lesion;target lesion requiring bifurcationstenting; MI, stroke, or coronaryintervention <30 days beforeindex procedure; �1 yr lifeexpectancy

12-month binaryrestenosis

6-month primarypatency rate;12-month secondarypatency rate;12-month death,amputation, TLR, andMI incidence

YukonDESz

NCT00664963

ABI ¼ ankle-brachial index; DES ¼ drug-eluting stent(s); LLL ¼ late lumen loss; MI ¼ myocardial infarction; N/A ¼ not available; PTA ¼ percutaneous transluminal angioplasty; QOL ¼ quality of life;

TLR ¼ target lesion revascularization; TVR ¼ target vessel revascularization. *Cordis, Johnson & Johnson, Bridgewater, New Jersey. yAbbott Laboratories, Abbott Park, Illinois. zTranslumina, Hechingen,

Germany.

Trial acronyms: ACHILLES ¼ Comparing Angioplasty and DES in the Treatment of Subjects With Ischemic Infrapopliteal Arterial Disease; BELOW ¼ Balloon angioplasty or Stents With ReoPro for

Prevention of Subacute Reocclusion in Arteries Below the Knee Angioplasty; DESTINY ¼ Drug Eluting Stents In The Critically Ischemic Lower Leg; YUKON-BTK ¼ YUKON-Drug-Eluting Stent Below The

Knee.

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Table 2. Main Characteristics of Patients Enrolled Among Trials Included in the Study

Trial/FirstAuthor (Ref. #) No. of Patients Age, yrs Males, % Diabetes, % CLI, % Occlusion % Lesion length, mm Vessel Diameter, mm DAPT, mo

LongestFU, months

ACHILLES (7) 200 73.4 71 65 N/A 78.3 26.9 2.60 6 12

BELOW (25) 60 72.4 64 68 100 32.6 27.0 2.90 2 36

DESTINY (8) 140 75.5 64 55 100 16.0 15.9 3.00 12 12

Falkowski et al. (24) 50 69.4 58 66 32 N/A 17.8 2.69 6 6

YUKON-BTK (6) 161 72.9 67 54 47 22.4 30.0 3.00 6 50

Overall mean values are reported.

Trial acronyms as in Table 1.

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demonstrated that no single study significantly altered thesummary OR for TLR (Online Fig. 1B).

There was no modification of risk estimates for TLRaccording to trial size, length of clinical follow-up, proto-col-mandated angiography, lesion length, vessel diameter,and length of DAPT (Fig. 3). Similarly, the degree ofbaseline disease severity did not affect the risk estimates forTLR (Online Figs. 2A to 2C). On adjusted indirectcomparison (Online Table 4), the everolimus- versus siroli-mus-eluting stents, as well as the polymer-free versusdurable-polymer DESs did not affect the risk estimates forthe main outcomes.

Discussion

We undertook this updated meta-analysis to investigate theoutcomes associated with primary drug-eluting stenting forpercutaneous revascularization of patients with atheroscle-rotic disease of infrapopliteal arteries. The main findings arethat at 1-year follow-up, DES therapy demonstratedreduced restenosis and greater clinical efficacy comparedwith plain balloon angioplasty or BMS therapy witha reduced risk of reintervention and amputation, althougha lack of RC improvement and DESs have a safety profilecomparable to that of alternative therapy, with no impact onmortality.

Patients with atherosclerotic disease of infrapoplitealarteries represent an important challenge due to compro-mised functional status, coexisting morbidities, and pooroutcomes (1). In this context, endovascular revascularizationhas become a first-line treatment option in light of superiorfeasibility and similar efficacy compared with surgical repair(2,3,11). Although in the past decades, percutaneousrevascularization has become synonymous with stenting, ininfrapopliteal artery disease, plain balloon angioplastyremains the treatment of choice due to the diffuse nature ofinfrapopliteal atherosclerosis and the lack of data definitivelysupporting a stent-based strategy in this vascular bed (2,3).

In recent studies, BMSs have shown almost similarsurvival, limb salvage, and patency rates compared with plainballoon angioplasty at 1-year follow-up (5,23). In a meta-analysis of observational studies evaluating bail-out stenting

after failed angioplasty (5), stents significantly improvedpatency rates at mid-term follow-up without affecting therisk of TLR and amputation. Although different stentscaffolds (balloon expandable, self-expandable, bio-absorbable) and types of stents (bare metal, carbon coated,drug eluting) contributed to the outcome data, the highestantirestenotic efficacy was attributable to DESs (5).

Initial data from observational registries (27,28) as well assubsequent randomized trials (6–8) consistently showed lessneointimal proliferation at mid-term follow-up after DESimplantation versus plain balloon angioplasty or BMSimplantation in patients with infrapopliteal artery diseasetreated percutaneously. However, the superior antirestenoticproperties of DESs did not always translate into a meaningfulclinical advantage. In a meta-analysis of 3 randomized trials,Katsanos et al. (9) confirmed the antiproliferative efficacy ofDESs for atherosclerotic disease of the infrapopliteal arteries.However, RC improvement, nor amputation, nor mortalitybenefits were found, suggesting a possible discrepancybetween mechanistic and clinical measures of efficacy in thissetting.Antoniou et al. (10) conducted ameta-analysis of bothrandomized and observational studies investigating onlyDESversus BMS therapy for disease of infrapopliteal arteries. Theauthors concluded that DES therapy reduces the risk ofreintervention and improves RC without affecting amputa-tion and survival. As a consequence, given the lack of incon-trovertible evidence, current guideline-writing authorities stillassign the highest grade of recommendation to plain angio-plasty in patients with infrapopliteal atherosclerotic disease,leaving stents with a “bail-out” or “salvage” indication afterfailed angioplasty (2,3).

Against this background, we conducted the present meta-analysis to investigate the impact of primary drug-elutingstenting in the largest population of patients with occlusiveinfrapopliteal atherosclerotic disease undergoing percuta-neous revascularization in the context of randomized trials:at 1-year follow-up, DES therapy compared with plainballoon angioplasty and BMS therapy reduced the risk ofreintervention and amputation with no impact on mortalityand RC. These results merit careful consideration.

First, the present study reports a lower risk of restenosisand reintervention at 1-year follow-up with DES therapy

Figure 2. Risk Estimates of Primary and Secondary Outcomes for DES Therapy Versus Control Therapy

Plot of odds ratio for primary (A) and secondary (B to E) outcomes associated with DES therapy versus control therapy. The diamond indicates the point estimate andthe left and the right ends of the line show the 95% confidence interval (CI). DES ¼ drug-eluting stent(s); M-H ¼ Mantel-Haenszel. Trial acronyms: ACHILLES ¼Comparing Angioplasty and DES in the Treatment of Subjects With Ischemic Infrapopliteal Arterial Disease; BELOW ¼ Balloon angioplasty or Stents With ReoPro forPrevention of Subacute Reocclusion in Arteries Below the Knee Angioplasty; DESTINY ¼ Drug Eluting Stents In The Critically Ischemic Lower Leg; YUKON-BTK ¼YUKON-Drug-Eluting Stent Below The Knee. Continued on the next page.

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versus plain balloon angioplasty or BMS therapy. The mostimportant drawback of plain balloon angioplasty or BMStherapy in the infrapopliteal vascular territory is the poordurability of acute results due to vessel re-narrowing afterintervention (29). In this respect, the finding of reducedrates of TLR with DES therapy at 1-year follow-up, inkeeping with published meta-analyses (9,10), is an impor-tant one. Of interest, 4 of the 5 trials included in the presentmeta-analysis (6,7,24,25) found no difference in terms of

TLR between DESs and comparators. This is most likelyattributable to design of original studies, which containedonly sufficient power for angiographic rather than rarerclinical outcomes, and reinforces the necessity of a meta-analysis.

In this study, the observed benefit of DES therapy versusplain balloon angioplasty or BMS therapy in terms of TLRis independent from trial size, length of clinical follow-up, protocol-mandated angiography, lesion length, vessel

Figure 2. Continued

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diameter, and length of DAPT. These results notwith-standing, some safety considerations exist regarding the riskof DES thrombosis due to suboptimal duration of DAPT(30), and dedicated trials are awaited to ascertain thecontribution of duration of DAPT to the safety and efficacyof DES for infrapopliteal arteries.

Second, in contrast to the meta-analysis of Katsanos et al.(9), we demonstrated that DESs are associated with asignificant reduction in the risk of amputation at 1-yearfollow-up. As many as 50% of patients with infrapoplitealartery occlusive disease may require amputation at variouslevels within the first year after the diagnosis, especially inthose patients presenting with CLI (1,31). As known, lessperfusion is needed to maintain tissue integrity than to avoidamputation: for this reason, restenosis does not always resultin recurrent symptoms unless there has been repeated injuryof the affected limb (32). Assessing prevention of amputationrather than angiographic patency should become the maingoal of trials investigating revascularization of the infrapo-pliteal arteries (32). In line with these arguments, the lowerrisk of amputation and the higher antirestenotic efficacyassociated with DESs in the current analysis are remarkable,especially when a last remaining infrapopliteal vessel must bepreserved to warrant straightforward distal perfusion.

In the current study, the use of DES therapy versus plainballoon angioplasty or BMS therapy has no impact onmortality. On the one hand, this analysis confirms that the

superior clinical efficacy of DES therapy versus plain balloonangioplasty or BMS therapy has no trade-off in safety. Onthe other hand, even reducing reinterventions and amputa-tions, a strategy of primary percutaneous revascularizationwith DESs is still not sufficient to lower the intrinsicmortality risk associated with patients with atheroscleroticdisease of infrapopliteal arteries (2). The possible inadequacyof the sample size and the selective nature per se of patientsenrolled in randomized trials could be responsible for the lackof effect. In addition, pre-existing comorbidities, as well aspoor functional status, 2 common features of patients withinfrapopliteal artery disease (32), may have further contrib-uted to mask significance. Similarly, these features mayaccount for the failure of DES therapy compared with controltherapy to significantly improve RC, although lowering therisk of revascularization and amputation as observed in thepresent study. Taken together, all these considerations rein-force the necessity of more deserved investigations in thissetting to address the portfolio of therapeutic options, otherthan the revascularization strategies, should be reserved forpatients with infrapopliteal artery disease (33).Study limitations. The present study included a total of611 patients by pooling the results of 5 randomizedtrials enrolling patients with infrapopliteal artery disease.Although the number of trials and patients is relativelysmall, it represents the largest population analyzed in suchstudies. However, it presents some limitations. First, this

Figure 3. Sensitivity Analyses of Primary Outcome for DES Therapy Versus Control Therapy

Plot of odds ratio (OR) for target lesion revascularization associated with DES therapy versus control therapy in subgroups of interest. The diamond indicates the pointestimate and the left and the right ends of the line show the 95% CI for the overall population. The squares indicates the point estimate, and the left and the rightends of the line give the 95% CI for the subgroup of interest. The I2 statistic describes heterogeneity across trials included resulting after adjusted indirect comparison.DAPT ¼ dual antiplatelet therapy; pint ¼ p values for interaction between treatment effect and subgroups derived by meta-regression analysis; other abbreviations asin Figure 2.

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meta-analysis is based on study-level data and shares thepossible flaws of the original trials. Moreover, the lack ofpatient-level data precluded in-depth investigation of theplanned/unplanned nature of amputations. Second, differentdevices are grouped in the experimental and control arms,even though efficacy profiles may vary between platforms anddevices. Furthermore, none of the included trials considerednewer-generation balloons coated with antiproliferativedrugs. Third, the median follow-up is limited to 1 year.Longer-term follow-up would certainly be valuable inassessing the late clinical performance of revascularizationstrategies. Fourth, the protocol-mandated angiography mayhave magnified differences in absolute proportion of revas-cularizations across groups, although the relative differencesare likely to remain unaffected. Notwithstanding the possibleinfluence of protocol-mandated angiography on revasculari-zations, available data showed that most of repeat procedureswere driven by clinical symptoms. Finally, the populationincluded in this analysis, reporting disabling claudication aswell as CLI, with an overall median lesion length of 26.8 mmand a reference vessel diameter of 2.86 mm, could beperceived as not representative of that encountered in dailypractice, often presenting with very diffuse disease (>10 cm)and very extensive wounds. For these reasons, the presentfindings should apply only to patients with characteristics

similar to those enrolled in this study and presenting withfocal lesions.

Conclusions

This meta-analysis suggests that in patients with focaldisease of infrapopliteal arteries, DES therapy reduces therisk of reintervention and amputation compared with plainballoon angioplasty or BMS therapy without any impact onmortality and RC at 1-year follow-up. Further randomizedtrials with a focus on clinical endpoints and longer follow-upare still awaited to provide the best scientific evidenceregarding the preferred endovascular treatment for patientswith occlusive disease of infrapopliteal arteries.

Reprint requests and correspondence: Dr. Salvatore Cassese,Deutsches Herzzentrum, Technische Universität, Lazarettstrasse36, Munich 80636, Germany. E-mail: cassese@dhm.mhn.de.

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Key Words: bare-metal stent(s) - drug-eluting stent(s) -

infrapopliteal artery - meta-analysis - plain angioplasty.

APPENDIX

For supplemental material, tables, and figures, please see the online versionof this article.