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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 . 9 , N O . 1 6 , 2 0 1 6
ª 2 0 1 6 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O
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Drug-Coated Balloon Versus PlainBalloon Angioplasty for the
Treatmentof Femoropopliteal Artery DiseaseAn Updated Systematic
Review and Meta-Analysis ofRandomized Clinical Trials
Daniele Giacoppo, MD,a Salvatore Cassese, MD, PHD,a Yukinori
Harada, MD,a Roisin Colleran, MBCHB,a
Jonathan Michel, MBBS,a Massimiliano Fusaro, MD,a Adnan
Kastrati, MD,a,b Robert A. Byrne, MBCHB, PHDa
ABSTRACT
Fro
for
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pli
an
the
Ma
OBJECTIVES This study sought to assess the risk of target lesion
revascularization (TLR) and all-cause death at
12 months and at the maximum available follow-up. Secondary
objectives included the identification of factors which
could have influenced general findings.
BACKGROUND Recently several randomized trials comparing
drug-coated balloon (DCB) with conventional plain
balloon (PB) for the treatment of femoropopliteal artery disease
have been reported, but no updated meta-analyses are
available and questions remain surrounding the long-term
antirestenotic effectiveness of the 2 therapies.
METHODS We searched main electronic databases for randomized
trials comparing DCB and PB for femoropopliteal
artery disease. Random effects models were used to estimate the
risk of TLR and all-cause death at 12 months, whereas
long-term TLR and death risk were assessed by mixed effects
Poisson regression models and incident rates of each
outcome per patient-year. Main analyses were supplemented by
sensitivity analyses, Bayesian estimates, and trial
sequential analysis.
RESULTS A total of 8 eligible trials were identified. DCB was
associated with a marked 12-month TLR risk reduction as
compared with PB (risk ratio: 0.33; 95% confidence interval
[CI]: 0.19 to 0.57). The risk of death was similar between
groups (risk ratio: 0.96; 95% CI: 0.47 to 1.95). Long-term
outcomes assessment showed a reduced incidence of TLR with
DCB (0.35; 95% CI: 0.24 to 0.51) and a similar incidence of
all-cause death (incidence rate ratio: 1.13; 95% CI: 0.60 to
2.15). Similar findings were observed in Bayesian analyses.
Significant heterogeneity was present with evidence of dif-
ferential efficacy across devices. Trial sequential analysis
indicated that available evidence is sufficient to prove
superior
antirestenotic efficacy of DCB over PB.
CONCLUSIONS DCB significantly reduces the risk of TLR as
compared with PB without any effect on all-cause
death. Evidence exists for differential efficacy according to
the type of device used. Future trials investigating DCB
angioplasty should include potentially more effective comparator
therapies. (J Am Coll Cardiol Intv 2016;9:1731–42)
© 2016 by the American College of Cardiology Foundation.
S ubstantial improvements in endovascular tech-niques and
outcomes mean that percutaneoustransluminal angioplasty is now the
first-line revascularization strategy for patients with
m the aDeutsches HerzzentrumMünchen, Technische Universität
Münche
Cardiovascular Research), partner site Munich Heart Alliance,
Munich, Ge
m the EAPCI (European Association Percutaneous Coronary
Intervention
cations in relation to drug-eluting stent technology. Dr. Byrne
has received
d Boston Scientific; and institutional research grants from
Boston Scientific
y have no relationships relevant to the contents of this paper
to disclose
nuscript received April 19, 2016; revised manuscript received
May 26, 20
symptomatic peripheral arterial disease (1). Plainballoon (PB)
angioplasty for femoropopliteal arterydisease has a high rate of
procedural success and anacceptable safety profile, however, rates
of restenosis
n, Munich, Germany and the bDZHK (German Centre
rmany. Dr. Giacoppo has been awarded with a grant
). Dr. Kastrati has reported submission of patent ap-
lecture fees from B. Braun Melsungen AG, Biotronik
and Heartflow. All other authors have reported that
.
16, accepted June 2, 2016.
http://crossmark.crossref.org/dialog/?doi=10.1016/j.jcin.2016.06.008&domain=pdfhttp://dx.doi.org/10.1016/j.jcin.2016.06.008
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ABBR EV I A T I ON S
AND ACRONYMS
CI = confidence interval
DCB = drug-coated balloon
IRR = incidence rate ratio
PB = plain balloon
PRISMA = Preferred Reporting
Items for Systematic Reviews
and Meta-Analyses
RR = risk ratio
TLR = target lesion
revascularization
Giacoppo 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 . 9 , N O . 1 6 , 2 0 1 6
DCB vs. PB for Femoropopliteal Artery Disease A U G U S T 2 2 ,
2 0 1 6 : 1 7 3 1 – 4 21732
are considerable (2). For this reason, a num-ber of alternative
percutaneous treatmentstrategies have been investigated (3–8).
Drug-coated balloons (DCBs) are standardballoon angioplasty
catheters surface coatedwith a thin layer of antiproliferative
drugcombined with an excipient or spacer sub-stance, which
facilitates drug transfer to thevessel wall (9). The advantages of
DCB ther-apy include drug delivery and inhibition ofneointimal
proliferation without require-ment for a permanent metallic
implant, moreuniform drug–tissue transfer, potential
amelioration of vessel healing due to the absence
ofproinflammatory durable polymer surface coating,and preservation
of arterial regulatory functions (9).
SEE PAGE 1743
Recently, several randomized clinical trialscomparing DCB with
conventional PB angioplasty forthe treatment of femoropopliteal
artery disease havebeen reported but no updated meta-analyses
areavailable and data relating to the long-term assess-ment of the
2 therapies is scant (10–12). In addition,there continues to be
ongoing discussion of the use-fulness of systematic use of DCB
instead of PB for denovo lesions and results obtained with
differentDCBs may be not uniform (13). Against this back-ground, we
conducted a comprehensive meta-analysis of randomized clinical
trials comparingDCB versus PB for the treatment of
femoropoplitealartery disease with the primary objective to
assessthe treatment effect for need for repeat targetlesion
revascularization (TLR) and death at 12months and at the longest
available follow-up.Secondary aims were the assessment of
trial-levelfactors that could have influenced the anti-restenotic
effectiveness of the 2 devices and in-troduced heterogeneity, the
exploration of thepotential differential efficacy among available
typesof DCB, and the definition of functional benefits ofa
DCB-based revascularization.
METHODS
This meta-analysis was conducted in accordancewith the Preferred
Reporting Items for SystematicReviews and Meta-Analyses (PRISMA)
statement andCochrane’s Collaboration recommendations (14,15).The
PRISMA checklist is reported in the OnlineAppendix. Data used were
from intention-to-treatanalyses. Statistical analyses were
performed usingR (version 3.2.3), WinBUGS (version 1.4.3), and
TSA(version 0.9).
LITERATURE SEARCH AND STUDY SELECTION.
We searched PubMed, ScienceDirect, Scopus, Web ofKnowledge, and
Cochrane Library electronic data-bases for randomized trials
comparing DCB versus PBfor the treatment of femoropopliteal artery
diseasefrom the date of inception to December 1, 2015. Nolanguage
restrictions or specific clinical subsets wereimposed. The search
algorithm applied for trialsidentification and the corresponding
results are re-ported in the Online Table 1. Tangential
explorationof relevant scientific websites (Online Table 1) as
wellas bibliography screening of relevant reviews on thetopic was
conducted to minimize the risk of missingreports.
Pre-specified inclusion criteria were: 1) random-ized trials of
patients receiving DCB versus PB; 2)single-treatment strategy,
either DCB or PB, withbailout stenting in case of unsuccessful
angioplastywith balloon; 3) treatment of femoropopliteal
lesionswith critical stenosis ($70%); and 4) original
resultspublished in a peer-reviewed medical journal.Exclusion
criteria included: 1) observational studies;2) treatments other
than DCB or PB; 3) use of othertreatments in combination with DCB
or PB; 4) appli-cation of DCB or PB only after stenting
(post-dilation);and 5) lesion location in nonfemoropopliteal
arterialsegment (below-the-knee arteries disease, iliacartery, and
so on). Trials including both de novo andrestenotic lesions were
allowed. Additional informa-tion about search and selection methods
is reportedin the Online Appendix. The risk of bias in each
trialwas qualitatively assessed as recommended by theCochrane
Collaboration (15).
PRIMARY AND SECONDARY OUTCOMES. The pri-mary objective of this
meta-analysis was the evalua-tion of the risk of TLR at 12 months
and at long-termfollow-up. Secondary outcomes of interest
were12-month and long-term all-cause death.
STATISTICAL ANALYSES. The analyses of 12-monthTLR and 12-month
all-cause death were performedby using DerSimonian–Laird random
effects models(16,17). Effect size was estimated as risk ratio (RR)
and95% confidence intervals (CIs).
The analyses of long-term TLR and long-term all-cause death were
performed by using mixed–effectsPoisson regression models with
random study effects(18). The analyses used the incident rate of
theoutcome per patient-years to obtain the pooled inci-dence rate
ratio (IRR) with 95% CI of DCB versus PB(18). IRR was considered
the most appropriateoutcome for this analysis because it allowed
incor-porating the different follow-up durations of theincluded
trials. A Bayesian analysis was also
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TABLE 1 Design of the Included Trials
Study (Ref.#)Randomization
(DCB:PB) Center (n) Region Identification Number* Enrolment
TimePrimaryEndpoint
MaximumAvailable Follow-Up
(months)
Biolux P-I (25) 1:1 5 Austria, Germany NCT01221610 Oct 2010/Aug
2011 6-month LLL 12
FAIR (8) 1:1 5 Germany NCT01305070 Jan 2010/Nov 2012 6-month BR*
12
FemPac (26) 1:1 2 Germany NCT00472472 July 2004/Jan 2006 6-month
LLL 24
IN.PACT SFA(27,30)
2:1 57 Austria, Belgium,Germany, Italy,Switzerland, USA
NCT01175850 Sep 2010/Apr 2011(Phase I)
Apr 2012/Jan 2013(Phase II)
12-month PP† 12
LEVANT I (28) 1:1 9 Belgium, Germany, USA NCT00930813 Jun
2009/Dec 2009 6-month LLL 24
LEVANT 2 (6) 2:1 54 Austria, Germany, USA NCT01412541 Jul
2011/Jul 2012 12-month PP† 12
PACIFIER (29) 1:1 3 Germany NCT01083030 Mar 2010/Aug 2011
6-month LLL 24
THUNDER (7,31) 1:1:1‡ 3 Germany NCT00156624 Jun 2004/Jun 2005
6-month LLL 60
*Assessed by Duplex ultrasonography: peak systolic velocity
ratio $2.4 w $50% luminal reduction. †The third group of the
THUNDER trial (paclitaxel diluted in the contrastmedia) was not
included in the study. ‡PP was the composite of freedom from
clinically driven target lesion revascularization and restenosis as
determined by a Duplexultrasonography–derived peak systolic
velocity ratio of #2.4.
Biolux P-I ¼ A Prospective, Multi-centre, Randomized Controlled,
First in Man Study to Assess the Safety and Performance of the
Passeo-18 Lux Paclitaxel Releasing PTABalloon Catheter vs. the
Uncoated Passeo 18 Balloon Catheter in Patients With Stenosis and
Occlusion of the Femoropopliteal Arteries; DCB ¼ drug-coated
balloon; FemPac ¼Paclitaxel Coated Balloon Catheter for Inhibition
of Restenosis in Femoropopliteal Arteries; FAIR¼ Randomized Femoral
Artery In–Stent Restenosis; IN.PACT SFA¼ The IN.PACTSFA Clinical
Study for the Treatment of Atherosclerotic Lesions in the
Superficial Femoral Artery and/or Proximal Popliteal Artery Using
the IN.PACT Admiral� Drug-ElutingBalloon in a Chinese Patient
Population; LEVANT I ¼ A Prospective, Multicenter, Single Blind,
Randomized, Controlled Trial Comparing the Lutonix Catheter vs.
StandardBalloon Angioplasty for Treatment of Femoropopliteal
Arteries With and Without Stenting; LEVANT 2 ¼ A Prospective,
Multicenter, Single Blind, Randomized, Controlled TrialComparing
the Moxy Drug Coated Balloon vs. Standard Balloon Angioplasty for
Treatment of Femoropopliteal Arteries; LLL ¼ late lumen loss;
PACIFIER ¼ Paclitaxel-coatedBalloons in Femoral Indication to
Defeat Restenosis; PB ¼ plain balloon; PP ¼ primary patency;
THUNDER ¼ Local Taxan With Short Time Contact for Reduction of
Restenosis inDistal Arteries.
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 . 9 , N O . 1 6 , 2 0 1 6 Giacoppo et al.A U G U S T 2 2 , 2
0 1 6 : 1 7 3 1 – 4 2 DCB vs. PB for Femoropopliteal Artery
Disease
1733
performed. Hierarchical models (binomial or Poissonlikelihood
and logit or log-link function, respec-tively) with random effects
were computed by Mar-kov Chain Monte Carlo method with Gibbs
samplingand posterior inference was based on 100,000 sim-ulations
following discard of a “burn-in” of 50,000simulations (19,20).
Noninformative priors wereused (21) and convergence was graphically
appraisedaccording to Gelman–Brooks (22). Posterior inferencewas
expressed as RR or IRR, as appropriate, and theaccompanying 95%
credible intervals came fromthe 2.5th and 97.5th centiles of the
posteriordistribution.
HETEROGENEITY AND PUBLICATION BIAS/SMALL
STUDY EFFECT. Heterogeneity and publication bias/small study
effect assessment are described in theOnline Appendix.
SENSITIVITY AND SUBGROUP ANALYSES. Rationaland specifications of
sensitivity and subgroup anal-yses are described in the Online
Appendix.
TRIAL SEQUENTIAL ANALYSIS. We performed a trialsequential
analysis to assess whether cumulativeevidence deriving from
randomized trials was suffi-ciently large to declare the
superiority of one treat-ment over the other (23,24). Considering
the realdistribution of the events in the 2 groups of patients,we
anticipated a 25% relative risk reduction (a ¼ 0.05;1–b ¼ 0.80) in
the risk of 12-month TLR by the
O’Brien–Fleming a-spending function which allowsgenerating
monitoring boundaries accounting forrepeated statistical testing.
Accordingly, we calcu-lated the required diversity-adjusted
information sizeas number of patients (24).
RESULTS
A total of 8 randomized clinical trials were
identified(6–8,25–31) (Online Appendix). Online Figure 1
illus-trates the selection process in detail (PRISMA flowdiagram).
Trial design and methodology are shown inTable 1. Trial inclusion
and exclusion criteria aresummarized in the Online Table 2. More
than one-halfof the included trials were not powered to
detectdifferences in TLR and had an angiographic endpoint(late
lumen loss) as primary endpoint. The IN.PACTSFA (IN.PACT SFA
Clinical Study for the Treatment ofAtherosclerotic Lesions in the
Superficial FemoralArtery and/or Proximal Popliteal Artery Using
theIN.PACT Admiral� Drug-Eluting Balloon in a ChinesePatient
Population) and LEVANT 2 (A Prospective,Multicenter, Single Blind,
Randomized, ControlledTrial Comparing the Moxy Drug Coated Balloon
vs.Standard Balloon Angioplasty for Treatment ofFemoropopliteal
Arteries), the 2 largest trials, werepowered for a composite
endpoint of major adverseevents, including Duplex ultrasonography
measure-ments (Table 1). Within-trial clinical characteristicswere
comparable and described patients with high
http://dx.doi.org/10.1016/j.jcin.2016.06.008http://dx.doi.org/10.1016/j.jcin.2016.06.008http://dx.doi.org/10.1016/j.jcin.2016.06.008http://dx.doi.org/10.1016/j.jcin.2016.06.008http://dx.doi.org/10.1016/j.jcin.2016.06.008https://clinicaltrials.gov/ct2/show/NCT01221610?term=NCT01221610%26rank=1https://clinicaltrials.gov/ct2/show/NCT01305070?term=NCT01305070%26rank=1https://clinicaltrials.gov/ct2/show/NCT00472472?term=NCT00472472%26rank=1https://clinicaltrials.gov/ct2/show/NCT01175850?term=NCT01175850%26rank=1https://clinicaltrials.gov/ct2/show/NCT00930813?term=NCT00930813%26rank=1https://clinicaltrials.gov/ct2/show/NCT01412541?term=NCT01412541%26rank=1https://clinicaltrials.gov/ct2/show/NCT01083030?term=NCT01083030%26rank=1https://clinicaltrials.gov/ct2/show/NCT00156624?term=NCT00156624%26rank=1
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TABLE 2 Main Trial-Level Clinical Characteristics
Study (Ref. #)DCB:PB
n:n (Total) Age (yrs)* Male DM Smokers HTN DLM CKD CADCarotid
Artery
Disease
Biolux P-I (25) 30:30 (60) 71 56.7 (34) 33.3 (20) 68.3 (41) 73.3
(44) 61.6 (37) NR NR NR
FAIR (8) 62:57 (119) 68 68.9 (82) 37.8 (45) 31.9 (38) 88.2 (105)
78.1 (93) 15.1 (18) 40.3 (48) 20.2 (24)
FemPac (26) 45:42 (87) 69 59.8 (52) 47.1 (41) 41.4 (36) 79.3
(69) 58.1 (50) NR NR NR
IN.PACT SFA (27,30) 220:111 (311) 68 70.1 (218) 46.0 (143) 37.8
(125) 90.3 (299) 83.7 (277) NR 56.3 (182) 33.9 (105)
LEVANT I (28) 49:52 (101) 69 63.4 (64) 47.5 (48) 34.7 (35) 91.1
(92) 64.4 (65) NR 41.6 (42) NR
LEVANT 2 (6) 316:160 (476) 68 63.0 (300) 42.9 (204) 34.7 (165)
88.7 (422) 88.4 (421) 3.8 (18) 49.2 (234) NR
PACIFIER (29) 41:44 (85) 71 61.5 (56) 35.2 (32) 53.8 (49) 65.9
(60) 48.4 (44) NR 31.9 (29) NR
THUNDER (7,31) 48:54 (102) 68 65.7 (67) 49.0 (50) 22.5 (23) 81.4
(83) 65.7 (67) NR NR NR
Values are % (n) unless otherwise indicated. Original reports
did not show within-trial differences for all these variables.
*Pooled mean of arm-level rounded mean values.
CAD ¼ coronary artery disease; CKD ¼ chronic kidney disease; DLM
¼ dyslipidemia; DM ¼ diabetes mellitus; HTN ¼ hypertension; NR ¼
not reported; other abbreviations as in Table 1.
TABLE 3
Study
Biolux P-I
FAIR (8)
FemPac (2
IN.PACT S
LEVANT I
LEVANT 2
PACIFIER
THUNDER
Values are %THUNDER,difference i
BR ¼ bina
Giacoppo 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 . 9 , N O . 1 6 , 2 0 1 6
DCB vs. PB for Femoropopliteal Artery Disease A U G U S T 2 2 ,
2 0 1 6 : 1 7 3 1 – 4 21734
cardiovascular risk (Table 2). Superficial femoralartery disease
was predominant and variable rates ofde novo target lesions,
ranging from 0% to 94.9%,were observed (Table 3, Online Table 3).
In 3 trials(6,7,25), bailout stenting was significantly
morefrequent in the PB group and in the 5 remaining trials(8,26–29)
was numerically higher (Table 2). Meanlesion length across trials
was
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TABLE 4 Main Characteristics of DCBs
Study (Ref. #) DCB Type Drug
Drug DoseDensity
(mg/mm2) Excipient Manufacturer
Biolux P-I (25) Passeo–18 Lux Paclitaxel 3.0
Butyryl-tri-n-hexylcitrate (BTHC)
Biotronik
FAIR (8) IN.PACTAdmiral
Paclitaxel 3.5 Urea Medtronic
FemPac (26) Paccocath* Paclitaxel 3.0 Iopromide Bavaria
MedizinTechnologie*
IN.PACT SFA(27,30)
IN.PACTAdmiral
Paclitaxel 3.5 Urea Medtronic
LEVANT I (28) Lutonix†‡ Paclitaxel 2.0 Polysorbate
andSorbitol
Lutonix†
LEVANT 2 (6) Lutonix†‡ Paclitaxel 2.0 Polysorbate
andSorbitol
Lutonix†
PACIFIER (29) IN.PACT Pacific Paclitaxel 3.0 Urea Medtronic
THUNDER (7,31) Paccocath* Paclitaxel 3.0 Iopromide Bavaria
MedizinTechnologie*
*Current DCB version (manufacturer) is SeQuent Please (Braun).
†Current DCB version (manufacturer) is Lutonix(Bard). ‡Although in
the original manuscripts of the LEVANT I and LEVANT 2 trials the
DCB name was “Lutonix”,in some reports and in the protocol of the
LEVANT 2 trial the device was designated as “Moxy.”
Abbreviations as in Table 1.
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 . 9 , N O . 1 6 , 2 0 1 6 Giacoppo et al.A U G U S T 2 2 , 2
0 1 6 : 1 7 3 1 – 4 2 DCB vs. PB for Femoropopliteal Artery
Disease
1735
the RR ranged from 0.28 (without LEVANT I orLEVANT 2, the trials
in which DCB showed the lowestbenefit as compared with PB) to 0.38
(without theIN.PACT SFA, the trial in which DCB showedthe greatest
benefit as compared with PB) and thesummary effect in all cases
remained highly signifi-cant. Visual inspection of the
contour-enhancedfunnel plot for 12-month TLR revealed an
asym-metric distribution, quantified by “trim and fill” with4
missing trials to the right of the pooled effects andresulted
significant (p ¼ 0.01) at Egger’s linearregression (Online Figure
5).
To analyze the individual impact on heterogeneity,a single trial
was removed one at a time, and the in-dividual influence on I2 was
estimated (Figure 2).Using this method, we identified 3 trials that
ampli-fied the I2: the LEVANT I, IN.PACT SFA, and LEVANT 2trials
(6,27,28). This was also graphically appraisableby Baujat plot
(Figure 2, left panel). Subsequently,because the global I2 remained
high, we investigatedthe possible combinations of trials, which
resulted inan I2 value below the threshold of low
heterogeneity(71.3%)(Figure 4). Results in the 2 groups remained
consis-tent with the main analysis. Finally, although theFAIR
(Randomized Femoral Artery In–Stent Reste-nosis) trial
significantly differs from the others,enrolling only patients with
in-stent restenoticlesions, its removal did not change the
superiority ofDCB over PB (RR: 0.35; 95% CI: 0.20 to 0.63) and
thepoint estimate after exclusion was similar to mainanalysis
pooled value.
The impact of prevalence of target lesion total oc-clusion at
baseline was explored by grouping trialsaccording to rate #27.6% or
>27.6% (Online Figure 7).The cutoff rate was extracted by the
median rate oftarget lesion total occlusion across the included
trials.The subgroup analysis confirmed the results of
mainanalysis.
The additional primary endpoint of long-term TLR(Figure 5, left
panel) was assessed by using themaximum trial-level available
follow-up (meanfollow-up time: 1.9 years; range: 1-5) for a total
of1,843 patient-years. The meta-analysis of long-termTLR confirmed
that the superior effectiveness ofDCB over PB was stable over time
(IRR 0.35; 95%CI: 0.24 to 0.51). Heterogeneity was moderate(I2 ¼
44.2%) and also in this case mainly due to theLEVANT I and LEVANT 2
trials (6,28), which showed anonsignificant effect moderately
favoring DCB. Afterexcluding these 2 trials, heterogeneity was no
longerdetected and the summary estimate favoring DCBseemed to be
magnified compared with main analysis(Online Figure 8). The
analyses were repeated using aBayesian framework with concordant
results.
Results of the meta-analysis for the secondaryendpoints of
12-month all-cause death are illustratedin the Online Figure 9: the
pooled risk of all-causedeath at 12 months was similar between the
2 treat-ments (RR: 0.96; 95% CI: 0.47 to 1.95). No
significantasymmetry was visualized in the contour-enhancedfunnel
plot for 12-month all-cause death and Egger’stest was
nonsignificant (Online Figure 10). After per-forming a
meta-analysis for the long-term all-causedeath outcome (Figure 5,
right panel), summary IRR
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FIGURE 1 Risk of Target Lesion Revascularization. Risk at 12
Months Comparing DCB With PB
The forest plot illustrates the results of the main analysis:
DCB compared with PB produced a 67% RR reduction in 12-month target
lesion revascularization. Bayesian
estimate (lower summary effect, RR: 0.30; 95% credible
intervals: 0.14 to 0.58) was consistent. CI ¼ confidence interval;
DCB ¼ drug-coated balloon; PB ¼ plainballoon; RR ¼ risk ratio.
*Credible intervals for the Bayesian estimate.
Giacoppo 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 . 9 , N O . 1 6 , 2 0 1 6
DCB vs. PB for Femoropopliteal Artery Disease A U G U S T 2 2 ,
2 0 1 6 : 1 7 3 1 – 4 21736
did not favor one treatment over the other (IRR: 1.13;95% CI:
0.60 to 2.15). An excess of mortality with DCBwas observed in 1
study, the IN.PACT SFA trial.Bayesian analysis was consistent with
frequentistestimate. Other major adverse events were
overallextremely rare and comparable in the 2 groups,although
functional benefits at follow-up were lessevident than TLR
reduction (Online Table 6).
Trial sequential analysis showed that the numberof available
trials is likely sufficient to demonstrateoverall superior 12-month
antirestenotic efficacy ofDCB over PB (Figure 6). Indeed, after
sequentialaddition of trials according to a chronological
order(Z-score), very early the cumulative evidence reachednot only
the conventional boundary (standard esti-mate of required
evidence), but also the a-spendingfunction monitoring boundary
(adjusted estimate ofrequired evidence). The analysis predicted
that a totalof 421 patients was required to gain sufficient
statis-tical power and adjusting the CI of the main analysisfor
repeated statistical testing the summary effectremained highly
significant (adjusted 95% CI: 0.15to 0.69).
DISCUSSION
In this meta-analysis, we observed 5 key findings: 1)DCB is
significantly superior to PB in reducing the riskof TLR at 12
months in patients with femoropopliteal
artery disease and this benefit appears to persist overtime with
reduced rates of TLR at long-term follow-up; 2) the antirestenotic
benefits of DCB are consis-tent across subsets of either de novo or
restenoticlesions; 3) there was some evidence of
differentialefficacy of available paclitaxel DCBs; 4) there was
nodifference in terms of mortality between treatmentwith DCB or PB;
and 5) additional randomized clinicaltrials comparing currently
available DCB with PB in ageneral clinical and angiographic subset
do not seemto be required.
Our meta-analysis differs from prior meta-analyses(10–12) in
several aspects: 1) it is updated to includerecently published
randomized trials; 2) we focus onclinical outcome measures, such as
TLR and all-causedeath, both at 12 months and in the long term; 3)
itsystematically assesses and explores reasons forobserved
heterogeneity in trial-level results; and 4) itprovides novel
insights regarding the availableevidence on DCB versus PB using
trial sequentialanalysis.
This meta-analysis provides evidence of clear su-periority of
DCB over PB for the treatment of femo-ropopliteal artery disease,
in terms both of 12-monthand long-term TLR. Indeed, the durability
of DCBtherapy superiority is particularly noteworthy. Con-cerns had
been raised that the lower late lumen lossand binary restenosis
observed at 6 months in patientswith lower limb disease treated
with DCB enrolled in
http://dx.doi.org/10.1016/j.jcin.2016.06.008
-
FIGURE 2 Inspection of Individual Contribution to Main Analysis
Heterogeneity
(Left) Baujat plot inspecting overall heterogeneity. (Right)
Removing each trial at a time from the others, the individual
impact on I2 was estimated. Trials contributing to
heterogeneity increase are disposed to the right of main
analysis I2 value of 69.4% (red line), whereas trials reducing
heterogeneity are disposed to the left. The
circle size is proportional to inverse of variance and I2
estimates reported into each circle correspond to the I2 value
without the influence of that trial. The removal of
the LEVANT I, the IN.PACT SFA, and the LEVANT 2 trials reduced
I2 below the main analysis value and therefore they increased
heterogeneity. The extent of the I2
percentage variation is described on the horizontal axis.
However, individual removal of trials did not lead I2 below 25%
threshold (“low” heterogeneity) and p values
of significance testing remained significant. Removing 2 trials
each time to the right of main analysis I2 value, heterogeneity was
no longer detectable without the
LEVANT I and LEVANT 2 trials. After removal of other
combinations of trials, heterogeneity remained high. In conclusion,
the LEVANT I and LEVANT 2 trials majorly
contributed to the high heterogeneity observed in the main
analysis.
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 . 9 , N O . 1 6 , 2 0 1 6 Giacoppo et al.A U G U S T 2 2 , 2
0 1 6 : 1 7 3 1 – 4 2 DCB vs. PB for Femoropopliteal Artery
Disease
1737
trials with planned angiographic surveillance may notpersist
over the longer term. Our analysis, however,shows that DCB therapy
continues to be associatedwith a reduced risk of TLR at a mean
follow-up of 1.9years. This finding is also in agreement with
therecently available long-term follow-up of trialscomparing DCB
with PB in the treatment of coronaryin-stent restenosis (32,33).
The cumulative incidenceof TLR in the PB group was slightly higher
thanrecently reported (4,34). This may have exaggeratedthe
magnitude of the results favoring DCB but themargin of significance
of summary effect was clear.
The observed heterogeneity between trials seemedto be explained
by the inclusion of the 2 trials usingthe Lutonix DCB (6,28).
Indeed, heterogeneity wasnot detected by excluding the trials using
the LutonixDCB and using an influence analysis we showed thatthe
LEVANT I and LEVANT 2 trials majorly contrib-uted to I2 increase.
The different effectiveness of theDCB treatment in the 2 trials
using the Lutonix DCBhas 2 possible explanations: on the one hand,
thisresult may suggest a lower efficacy of this type of DCBcompared
with the others; in contrast, the findings
may reflect trial design characteristics specific toLEVANT I and
LEVANT 2 trials. This interpretationof the heterogeneity is
graphically expressed bythe strong asymmetry of the funnel plot,
with theLEVANT I and LEVANT 2 trials falling in the
non-significance area. However, the different results ofthese 2
trials may have introduced only heterogeneitywithout implying a
publication bias (“true” hetero-geneity) and the 4 missing trials
to the right of meaneffect required to make symmetric the funnel
plotwere corresponding to the high-significance area (p <0.01),
which is not associated generally with thepresence of a small study
effect (35).
Another important finding of this meta-analysis isthe possible
differential effectiveness observedamong DCBs. This finding is in
agreement with theheterogeneity analyses, providing a reasonable
clin-ical explanation. Indeed, the attenuated anti-restenotic
effects associated with the trials using theLutonix DCB could be
explained by the lower pacli-taxel dose density compared with the
other DCBs(2 vs. $3 mg/mm2). In the animal model, DCB
effec-tiveness appeared at the dose of 1 mg/mm2 with an
-
FIGURE 3 Subgroup Analysis According to DCB Catheter Type
The forest plots illustrate the results of the subgroup analysis
according to DCB type. The 2 trials using the Lutonix DCB showed a
mild
nonsignificant RR reduction, whereas antirestenotic efficacy of
the other DCBs remained consistent with main analysis. Formal
testing for
differences among groups was highly significant. Abbreviations
as in Figure 1.
Giacoppo 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 . 9 , N O . 1 6 , 2 0 1 6
DCB vs. PB for Femoropopliteal Artery Disease A U G U S T 2 2 ,
2 0 1 6 : 1 7 3 1 – 4 21738
incremental antirestenotic effect up to 3 mg/mm2, butbeyond this
value neointimal area remained compa-rable (36). However,
paclitaxel dose density is onlyone of the factors influencing DCB
efficacy. Indeed,excipients are key components of the balloon
coatingand regulate paclitaxel elution (37). The Lutonix DCBcoating
drug carrier consists of polysorbate and sor-bitol, which have not
been extensively explored inanimal models and may have different
effectivenesscompared with excipients of the other
DCBs(6,10,28,38).
Despite the clear reduction in TLR associated withDCB, there was
no difference in terms of mortalitybetween DCB treatment and PB.
This findingremained unchanged after comparing incidence rateof
all-cause death in the 2 groups at longest availablefollow-up.
We did not meta-analyze other secondary clinicaloutcomes because
the qualitative review of datashowed incomplete reporting (i.e.,
primary patency)and extremely rare occurrence (i.e., major
amputation,thrombosis, and myocardial infarction).
Nevertheless,
data review indicated some interesting findings.Indeed, with the
exception of the FAIR trial, thenumber of target lesion thrombosis
in patients treatedwith DCB was in all trials equal to or lower
thanPB group, suggesting that concerns about a potentialDCB
thrombogenic tendency compared with PB couldnot be supported.
Moreover, periprocedural dissec-tions were comparable between both
treatmentgroups though large differences among trials
wereobserved.
Finally, we also performed a trial sequential anal-ysis with the
aim to assess the requirement for furtherstudies investigating the
comparative efficacy of DCBversus PB in the treatment of
femoropopliteal arterydisease. Our findings indicate that evidence
ofsuperiority of currently available DCBs is clear andsuggests that
future investigations should be orientedto comparisons between DCB
and underexploredpromising devices for femoropopliteal artery
diseasetreatment, such as drug-eluting stents, or specificcommon
high-risk clinical and angiographic subsets,such as diabetes, long
lesion, in-stent restenosis, and
-
FIGURE 4 Subgroup Analysis According to Trial-Level Prevalence
of De Novo Target Lesion
Considering the median prevalence of de novo lesions, included
trials were divided in 2 groups according to their individual rate,
either #71.3%
or >71.3%. Regardless more or less de novo target lesions,
main analysis conclusions remained unchanged. Abbreviations as in
Figure 1.
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 . 9 , N O . 1 6 , 2 0 1 6 Giacoppo et al.A U G U S T 2 2 , 2
0 1 6 : 1 7 3 1 – 4 2 DCB vs. PB for Femoropopliteal Artery
Disease
1739
total occlusion. However, although general pro-prieties of the
IN.PACT, Paccocath and Lutonix DCBsseem to be well-evaluated,
further evidence withPasseo–18 Lux is required.
STUDY LIMITATIONS. As with any meta-analysis, ourreport shares
the limitations of the original trials andpotential sources of
heterogeneity in clinical and
FIGURE 5 Long-Term Target Lesion Revascularization and
All-Cause
The meta-analysis of IRR (mean follow-up time of 1.9 years for
1,843 pa
revascularization (left) and the secondary endpoint of all-cause
death (r
toward the left side of the forest plots favor DCB, while
effects toward
Bayesian estimate. IRR ¼ incidence rate ratio; other
abbreviations as in
procedural characteristics cannot be fully exploredwithout
individual patient data. Metaregression canonly partially overcome
the absence of individualpatient data and given the strong
dependence on thenumbers of trials was not performed (39).
More specifically, the results of our meta-analysisshould be
interpreted taking the following limita-tions into account. First,
2 of the included trials
Death in DCB Versus PB
tient-years) for the other primary endpoint of long-term target
lesion
ight) confirmed main analysis findings (12-month follow-up).
Effects
the right side of the forest plots favor PB. *Credible intervals
for the
Figure 1.
-
FIGURE 6 Trial Sequential Analysis for 12-Month Target Lesion
Revascularization
Trial sequential analysis showed that available evidence seems
sufficiently large to prove a superior antirestenotic effect
associated with DCB as compared with PB.
Indeed, the anticipated adjusted number of patients required to
have enough statistical power for a RRR of 25% was 421 and the
Z-score (blue line) crossed
very early not only the conventional boundary (green line; 1.96
cumulative Z-score), but also the monitoring boundary (upper red
line) generated by the
O’Brien–Fleming a-spending function accounting for repeated
testing. The green zone illustrates the extent of the cumulative
Z-score between conventional
boundary and monitoring boundary (conventional significance
area), while the light blue zone describes the extent of the
statistical significance reached by pooled
evidence (Z-score line, blue line) over the monitoring boundary.
The lower red line (futility boundary) was not crossed, which means
that available evidence
did not fall in the zone indicating uselessness of adding new
trials (orange area). RRR ¼ relative risk reduction; other
abbreviations as in Figure 1.
Giacoppo 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 . 9 , N O . 1 6 , 2 0 1 6
DCB vs. PB for Femoropopliteal Artery Disease A U G U S T 2 2 ,
2 0 1 6 : 1 7 3 1 – 4 21740
(Biolux P–I and FemPac [Paclitaxel Coated BalloonCatheter for
Inhibition of Restenosis in Femo-ropopliteal Arteries]) included
minimal rates (n ¼ 12)of target lesion involving below-the-knee
arteries(25,26). Additionally, the analyses of 12-month TLRand
all-cause death include 6-month data for theFemPac trial, because
events at 12 months were notprovided (26). Moreover, the third arm
of the THUN-DER (Local Taxan With Short Time Contact forReduction
of Restenosis in Distal Arteries) trial(paclitaxel in contrast
media) was not pooled,implying a remote possibility that benefits
ofrandomization could have been lost (7). Second, inthe LEVANT I
trial a 1:1 randomization was donefollowing stratification
according to flow limiting
dissection or $70% resistant stenosis after initialtreatment
and, although DCB or PB assignment wasrandom, 25% of patients
(namely “stent group”)received provisional stenting (28). Third, we
detectedsignificant differences between trials using theLutonix DCB
and those using the other catheters.However, no randomized clinical
trials directlycompared the different devices and the
differenceobserved could be due to confounding factors.Fourth, only
50% of trials reported a clinical follow-up between 24 and 60
months and the mean follow-up in this meta-analysis was of 1.9
months.Although the methodology used attempted to ac-count for
these issues, it cannot replace time-to-eventanalyses with
individual patient data and uniform
-
PERSPECTIVES
WHAT IS KNOWN? In randomized clinical trials, DCBs are
generally
associated with superior antirestenotic efficacy compared with
plain
balloon. However, these trials are powered only for surrogate
endpoints or
composite endpoints, including clinical and surrogate
parameters. The
clinical impact of femoropopliteal artery revascularization with
DCB is var-
iable across reports and not explored in an adequately large
number of
patients. Moreover, the influence of target lesion type and the
long-term
durability of DCB effects are poorly defined. Finally, no
randomized trials
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 . 9 , N O . 1 6 , 2 0 1 6 Giacoppo et al.A U G U S T 2 2 , 2
0 1 6 : 1 7 3 1 – 4 2 DCB vs. PB for Femoropopliteal Artery
Disease
1741
long-term follow-up. Fifth, the significant funnel plotasymmetry
in relation to TLR was considered likely tobe representative of
“true” heterogeneity derivingfrom the different catheter types
within DCB grouprather than a small study effect. However, due to
thelimited number of trials, this question cannot becompletely
answered. Finally, the paucity of majoradverse events and the
significant variations inreporting functional variations of lower
limb revas-cularization with DCB and PB across the trials did
notallow the meta-analysis of these outcomes. Func-tional benefits
at follow-up of femoropoplitealrevascularization with DCB over PB
were less evidentthan antirestenotic effects. Future trials with
DCBshould specifically address very late clinical andfunctional
improvements.
directly comparing the different available DCB devices have
been
conducted.
WHAT IS NEW? In patients undergoing femoropopliteal artery
inter-
vention, DCB therapy should be preferred over conventional plain
balloon
angioplasty due to superior antirestenotic effectiveness in
terms of TLR.
At long-term follow-up, the lower incidence of TLR associated
with DCB
seems to be durable. Although DCB performance seems not
influenced by
target lesion type, differential effectiveness across currently
available
devices was detected. Survival is not influenced by the
revascularization
strategy.
WHAT IS NEXT? Differences between the 2 treatments in terms
of
symptoms and functional improvement are not delineated
sufficiently in
randomized clinical trials and the specific subgroups of
patients which might
receive greatest benefit from revascularization with DCB is not
defined.
Future trials on DCB should potentially include more effective
comparators
such as drug-eluting stents.
CONCLUSIONS
The treatment of femoropopliteal artery disease withDCB
significantly reduces the risk of 12-month TLRcompared with PB
without any effect on all-causemortality. The observed treatment
effect persists atlong-term follow-up. Results were consistent
acrosssubsets of included lesions, but trials using theLutonix DCB
introduced significant heterogeneity,suggesting an attenuated
antirestenotic effect.Additional trials to confirm the superior
anti-restenotic efficacy of currently available DCBs versusPB
angioplasty in a general clinical and angiographicsubset of
patients with femoropopliteal artery dis-ease are not required.
Future trials should focuson the comparison between DCB and
potentiallymore effective comparators such as
drug-elutingstents.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.Robert Byrne, Deutsches
Herzzentrum München, Laza-rettstrasse 36, 80636,Munich, Germany.
E-mail: [email protected].
RE F E RENCE S
1. Tendera M, Aboyans V, Bartekink ML, et al.ESC Guidelines on
the diagnosis and treatmentof peripheral artery diseases: document
coveringatherosclerotic disease of extracranial carotid
andvertebral, mesenteric, renal, upper and lower ex-tremity
arteries. Eur Heart J 2011;32:2851–906.
2. Norgren L, Hiatt WR, Dormandy JA, et al. Inter–Society
Consensus for the Management ofPeripheral Arterial Disease (TASC
II). Eur J VascEndovasc Surgery 2007;33 Suppl 1:S1–75.
3. Schillinger M, Sabeti S, Loewe C, et al. Balloonangioplasty
versus implantation of nitinol stents inthe superficial femoral
artery. N Engl J Med 2006;354:1879–88.
4. Krankenberg H, Schluter M, Steinkamp HJ, et al.Nitinol stent
implantation versus percutaneoustransluminal angioplasty in
superficial femoralartery lesions up to 10 cm in length: the
femoral
artery stenting trial (FAST). Circulation 2007;116:285–92.
5. Dake MD, Ansel GM, Jaff MR, et al. Sustainedsafety and
effectiveness of paclitaxel–elutingstents for femoropopliteal
lesions: 2–year follow–up from the Zilver PTX randomized and
single–armclinical studies. J Am Coll Cardiol 2013;61:2417–27.
6. Rosenfield K, Jaff MR, White CJ, et al. Trial of
apaclitaxel–coated balloon for femoropoplitealartery disease. N
Engl J Med 2015;373:145–53.
7. Tepe G, Zeller T, Albrecht T, et al. Local deliveryof
paclitaxel to inhibit restenosis during angio-plasty of the leg. N
Engl J Med 2008;358:689–99.
8. Krankenberg H, Tubler T, Ingwersen M, et al.Drug–coated
balloon versus standard balloon forsuperficial femoral artery
in–stent restenosis: theRandomized Femoral Artery In–Stent
Restenosis(FAIR) Trial. Circulation 2015;132:2230–6.
9. Byrne RA, Joner M, Alfonso F, et al. Drug–coated balloon
therapy in coronary and peripheralartery disease. Nat Rev Cardiol
2014;11:13–23.
10. Cassese S, Byrne RA, Ott I, et al. Paclitaxel–coated versus
uncoated balloon angioplasty re-duces target lesion
revascularization in patientswith femoropopliteal arterial disease:
a meta–analysis of randomized trials. Circ CardiovascInterv
2012;5:582–9.
11. Fusaro M, Cassese S, Ndrepepa G, et al. Pacli-taxel–coated
balloon or primary bare nitinol stentfor revascularization of
femoropopliteal artery: ameta–analysis of randomized trials versus
un-coated balloon and an adjusted indirect compari-son. Int J
Cardiol 2013;168:4002–9.
12. Katsanos K, Spiliopoulos S, Karunanithy N,Krokidis M,
Sabharwal T, Taylor P. Bayesiannetwork meta–analysis of nitinol
stents, covered
mailto:[email protected]:[email protected]://refhub.elsevier.com/S1936-8798(16)30830-5/sref1http://refhub.elsevier.com/S1936-8798(16)30830-5/sref1http://refhub.elsevier.com/S1936-8798(16)30830-5/sref1http://refhub.elsevier.com/S1936-8798(16)30830-5/sref1http://refhub.elsevier.com/S1936-8798(16)30830-5/sref1http://refhub.elsevier.com/S1936-8798(16)30830-5/sref1http://refhub.elsevier.com/S1936-8798(16)30830-5/sref2http://refhub.elsevier.com/S1936-8798(16)30830-5/sref2http://refhub.elsevier.com/S1936-8798(16)30830-5/sref2http://refhub.elsevier.com/S1936-8798(16)30830-5/sref2http://refhub.elsevier.com/S1936-8798(16)30830-5/sref3http://refhub.elsevier.com/S1936-8798(16)30830-5/sref3http://refhub.elsevier.com/S1936-8798(16)30830-5/sref3http://refhub.elsevier.com/S1936-8798(16)30830-5/sref3http://refhub.elsevier.com/S1936-8798(16)30830-5/sref4http://refhub.elsevier.com/S1936-8798(16)30830-5/sref4http://refhub.elsevier.com/S1936-8798(16)30830-5/sref4http://refhub.elsevier.com/S1936-8798(16)30830-5/sref4http://refhub.elsevier.com/S1936-8798(16)30830-5/sref4http://refhub.elsevier.com/S1936-8798(16)30830-5/sref4http://refhub.elsevier.com/S1936-8798(16)30830-5/sref5http://refhub.elsevier.com/S1936-8798(16)30830-5/sref5http://refhub.elsevier.com/S1936-8798(16)30830-5/sref5http://refhub.elsevier.com/S1936-8798(16)30830-5/sref5http://refhub.elsevier.com/S1936-8798(16)30830-5/sref5http://refhub.elsevier.com/S1936-8798(16)30830-5/sref6http://refhub.elsevier.com/S1936-8798(16)30830-5/sref6http://refhub.elsevier.com/S1936-8798(16)30830-5/sref6http://refhub.elsevier.com/S1936-8798(16)30830-5/sref7http://refhub.elsevier.com/S1936-8798(16)30830-5/sref7http://refhub.elsevier.com/S1936-8798(16)30830-5/sref7http://refhub.elsevier.com/S1936-8798(16)30830-5/sref8http://refhub.elsevier.com/S1936-8798(16)30830-5/sref8http://refhub.elsevier.com/S1936-8798(16)30830-5/sref8http://refhub.elsevier.com/S1936-8798(16)30830-5/sref8http://refhub.elsevier.com/S1936-8798(16)30830-5/sref8http://refhub.elsevier.com/S1936-8798(16)30830-5/sref9http://refhub.elsevier.com/S1936-8798(16)30830-5/sref9http://refhub.elsevier.com/S1936-8798(16)30830-5/sref9http://refhub.elsevier.com/S1936-8798(16)30830-5/sref10http://refhub.elsevier.com/S1936-8798(16)30830-5/sref10http://refhub.elsevier.com/S1936-8798(16)30830-5/sref10http://refhub.elsevier.com/S1936-8798(16)30830-5/sref10http://refhub.elsevier.com/S1936-8798(16)30830-5/sref10http://refhub.elsevier.com/S1936-8798(16)30830-5/sref10http://refhub.elsevier.com/S1936-8798(16)30830-5/sref11http://refhub.elsevier.com/S1936-8798(16)30830-5/sref11http://refhub.elsevier.com/S1936-8798(16)30830-5/sref11http://refhub.elsevier.com/S1936-8798(16)30830-5/sref11http://refhub.elsevier.com/S1936-8798(16)30830-5/sref11http://refhub.elsevier.com/S1936-8798(16)30830-5/sref11http://refhub.elsevier.com/S1936-8798(16)30830-5/sref12http://refhub.elsevier.com/S1936-8798(16)30830-5/sref12http://refhub.elsevier.com/S1936-8798(16)30830-5/sref12
-
Giacoppo 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 . 9 , N O . 1 6 , 2 0 1 6
DCB vs. PB for Femoropopliteal Artery Disease A U G U S T 2 2 ,
2 0 1 6 : 1 7 3 1 – 4 21742
stents, drug–eluting stents, and drug–coated bal-loons in the
femoropopliteal artery. J Vasc Surg2014;59:1123–33.e8.
13. Cortese B, Granada JF, Scheller B, et al. Drug-coated
balloon treatment for lower extremityvascular disease intervention:
an internationalpositioning document. Eur Heart J
2016;37:1096–103.
14. Liberati A, Altman DG, Tetzlaff J, et al. ThePRISMA
statement for reporting systematicreviews and meta–analyses of
studies that eval-uate healthcare interventions: explanation
andelaboration. BMJ 2009;339:b2700.
15. Higgins JPT, Green S. Cochrane handbook forsystematic
reviews of interventions 5.1.0 [Upda-ted March 2011]. Available at:
www.cochrane–handbook.org. 2011. Accessed December 10,2015.
16. DerSimonian R, Laird N. Meta–analysis in clin-ical trials.
Control Clin Trials 1986;7:177–88.
17. Borenstein M, Hedges LV, Higgins JPT,Rothstein HR.
Introduction to meta–analysis. WestSussex (UK): John Wiley &
Sons, 2009.
18. Bagos PG, Nikopoulos GK. Mixed–effectsPoisson regression
models for meta–analysis offollow–up studies with constant or
varying dura-tions. Int J Biostat 2009;5:1–33.
19. Spiegelhalter D, Abrams K, Myles J. Bayesianapproaches to
clinical trials and health–care eval-uation. Statistics in
practice. New York: John Wileyand Sons, 2004.
20. Dias S, Sutton AJ, Welton NJ, et al. Evidencesynthesis for
decision making 6: embedding evi-dence synthesis in probabilistic
cost–effectivenessanalysis. Med Decis Making 2013;33:671–8.
21. Lambert PC, Sutton AJ, Burton PR, et al. Howvague is vague?
A simulation study of the impactof the use of vague prior
distributions in MCMCusing WinBUGS. Stat Med 2005;24:2401–28.
22. Brooks SP, Gelman A. General methods formonitoring
convergence of iterative simulations.J Comput Graph Stat
1998;7:434–55.
23. Wetterslev J, Thorlund K, Brok J, Gluud C. Trialsequential
analysis may establish when firm
evidence is reached in cumulative meta–analysis.J Clin Epidemiol
2008;61:64–75.
24. Wetterslev J, Thorlund K, Brok J, et al. Esti-mating
required information size by quantifyingdiversity in random–effects
model meta–analyses.BMC Med Res Methodol 2009;9:86.
25. Scheinert D, Schulte KL, Zeller T, et al.
Pacli-taxel–releasing balloon in femoropopliteal lesionsusing a
BTHC excipient: twelve–month resultsfrom the BIOLUX P–I randomized
trial. J EndovascTher 2015;22:14–21.
26. Werk M, Langner S, Reinkensmeier B, et al.Inhibition of
restenosis in femoropopliteal arteries:paclitaxel–coated versus
uncoated balloon:femoral paclitaxel randomized pilot trial.
Circula-tion 2008;118:1358–65.
27. Tepe G, Laird J, Schneider P, et al. Drug–coated balloon
versus standard percutaneoustransluminal angioplasty for the
treatment of su-perficial femoral and popliteal peripheral
arterydisease: 12–month results from the IN.PACT SFArandomized
trial. Circulation 2015;131:495–502.
28. Scheinert D, Duda S, Zeller T, et al. TheLEVANT I (Lutonix
paclitaxel–coated balloon forthe prevention of femoropopliteal
restenosis) trialfor femoropopliteal revascularization:
first–in–human randomized trial of low–dose drug–coatedballoon
versus uncoated balloon angioplasty.J Am Coll Cardiol Intv
2014;7:10–9.
29. Werk M, Albrecht T, Meyer DR, et al. Pacli-taxel–coated
balloons reduce restenosis afterfemoro–popliteal angioplasty:
evidence from therandomized PACIFIER trial. Circ Cardiovasc
Interv2012;5:831–40.
30. Laird JR, Schneider PA, Tepe G, et al. Durabilityof
treatment effect using a drug–coated balloon forfemoropopliteal
lesions: 24–month results of IN.PACT SFA. J Am Coll Cardiol
2015;66:2329–38.
31. Tepe G, Schnorr B, Albrecht T, et al.Angioplasty of
femoral–popliteal arteries withdrug–coated balloons: 5–year
follow–up of theTHUNDER trial. J Am Coll Cardiol Intv
2015;8:102–8.
32. Xu B, Qian J, Ge J, et al. Two-year results andsubgroup
analyses of the PEPCAD China in-stent
restenosis trial: a prospective, multicenter, ran-domized trial
for the treatment of drug-elutingstent in-stent restenosis.
Catheter CardiovascInterv 2016;87:624–9.
33. Kufner S, Cassese S, Valeskini M, et al. Long–Term efficacy
and safety of paclitaxel–elutingballoon for the treatment of
drug–eluting stentrestenosis: 3–year results of a randomized
controlledtrial. J Am Coll Cardiol Intv 2015;8:877–84.
34. Dake MD, Ansel GM, Jaff MR, et al. Paclitaxel–eluting stents
show superiority to balloon angio-plasty and bare metal stents in
femoropoplitealdisease: twelve–monthZilver PTX randomized
studyresults. Circ Cardiovasc Interv 2011;4:495–504.
35. Sterne JA, Sutton AJ, Ioannidis JP, et al. Rec-ommendations
for examining and interpretingfunnel plot asymmetry in
meta–analyses of rand-omised controlled trials. BMJ
2011;343:d4002.
36. Kelsch B, Scheller B, Biedermann M, et al.Dose response to
Paclitaxel-coated balloon cath-eters in the porcine coronary
overstretch and stentimplantation model. Invest Radiol
2011;46:255–63.
37. Radke PW, Joner M, Joost A, et al. Vasculareffects of
paclitaxel following drug-elutingballoon angioplasty in a porcine
coronary model:the importance of excipients.
EuroIntervention2011;7:730–7.
38. Yazdani SK, Pacheco E, Nakano M, et al.Vascular, downstream,
and pharmacokinetic re-sponses to treatment with a low dose
drug-coatedballoon in a swine femoral artery model.
CatheterCardiovasc Interv 2014;83:132–40.
39. Thompson SG, Higgins JP. How shouldmeta–regression analyses
be undertaken andinterpreted? Stat Med 2002;21:1559–73.
KEY WORDS balloon angioplasty,drug-coated balloon,
meta-analysis,peripheral arterial disease
APPENDIX For supplemental methods aswell as tables and figures,
please see the onlineversion of this article.
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Drug-Coated Balloon Versus Plain Balloon Angioplasty for the
Treatment of Femoropopliteal Artery DiseaseMethodsLiterature search
and study selectionPrimary and secondary outcomesStatistical
analysesHeterogeneity and publication bias/small study
effectSensitivity and subgroup analysesTrial sequential
analysis
ResultsDiscussionStudy Limitations
ConclusionsReferences