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Comparison of new-generation drug-eluting stents versus drug-coated balloon for in-stent restenosis: A meta-analysis
of randomized controlled trials
Journal: BMJ Open
Manuscript ID bmjopen-2017-017231
Article Type: Research
Date Submitted by the Author: 12-Apr-2017
Complete List of Authors: Cai, Jin-Zan; cardiology Zhu, Yong-Xiang Bourantas, Christos
Iqbal, Javaid Zhu, Hao Cummins, Paul Dong, Sheng-Jie Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Cardiovascular medicine
Keywords: Drug-coated balloon, Drug-eluting stents, In-stent restenosis, Meta-analysis
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Title page
Comparison of new-generation drug-eluting stents versus drug-coated balloon for
in-stent restenosis: A meta-analysis of randomized controlled trials
Authors: Jin-Zan Cai1, MSc; Yong-Xiang Zhu
1, MSc; Christos V. Bourantas
3, 4, PhD; Javaid Iqbal
2, PhD; Hao Zhu
1,
MSc; Paul Cummins5, BSc; Sheng-jie Dong
6, PhD; Anthony Mathur
4, PhD; Yao-Jun Zhang
1* PhD
Cai JZ and Zhu YX are equally contributed to this manuscript.
Author Affiliations:
1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China;
2Sheffield Teaching Hospitals and the University of Sheffield, Sheffield, United Kingdom;
3Department of Cardiovascular Sciences, University College London, London, UK;
4Department of Cardiology, Barts Heart Centre, London, UK;
5Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands;
6Department of the Joint and Bone Surgery, Yantaishan hospital, Yantai, China;
Running title: DES versus DCB for ISR
*Correspondence to:
Yao-Jun Zhang MD, PhD, FESC
No. 68, Changle Road, Nanjing, 210006, China
Email: [email protected]; Tel & Fax: +86-025-52271340
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Abstract
Objective: The study sought to compare angiographic and clinical results of new-generation drug-eluting
stents (DES) versus drug-coated balloon (DCB) in patients with coronary in-stent restenosis (ISR).
Design: Meta-analyses using data from randomised trial found by searches on PubMed, the Cochrane Library,
Clinicaltrials.gov, and major cardiovascular congresses.
Setting: Only randomised trials comparing DES with DCB was included.
Participants: Patients with ISR in the including trails.
Interventions: DES or DCB.
Primary and secondary outcomes: The primary outcome were cardiac death, all-cause death, myocardial
infarction, target lesion revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac
events (MACE), and stent thrombosis. Secondary outcomes were angiographic endpoints.
Results: Five trials were eligible and included. Meta-analyses showed that DES had significantly reduced the
risk of target lesion revascularization (TLR, RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01), however no statistical
differences were seen in terms of major adverse cardiac events (MACE, RR: 1.21, 95% CI: 0.67 to 2.17,
p=0.53), myocardial infarction (RR: 1.16, 95% CI: 0.55 to 2.48, p=0.69), and cardiac death (RR: 1.80, 95% CI:
0.60 to 5.39, p=0.29) when compared with DCB. Pooled analyses in angiographic results identified that
new-generation DES were associated with higher acute luminal gain (-0.31 mm, 95% CI: -0.42 to -0.20,
p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04).
Conclusions: Interventions with new-generation DES are associated with significant reductions in % diameter
stenosis and TLR, but similar MACE, myocardial infarction, and cardiac death for coronary ISR patients
compared to DCB. Appropriately powered studies with longer term follow-up are warranted to confirm the
findings from the present meta-analysis.
Keywords: Drug-coated balloon; Drug-eluting stents; In-stent restenosis; Meta-analysis.
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Strengths and limitations of this study
1、 Only randomized trials comparing DES with DCB for patients with ISR were allowed to include in this
meta-analysis.
2、、、、 This study demonstrates the largest patient population presenting with ISR.
3、、、、 The results were based on the trial level and shares the limitations of the original trials.
Introduction
Percutaneous coronary intervention with bare-metal stents (BMS) or drug-eluting stents (DES) has become
one of the most frequently performed therapeutic procedures for coronary artery disease1)
. The rate of
in-stent restenosis (ISR) in clinical practice is nearly 5% of patients treated with DES and 10% with BMS after
5 years2)
. Given the number of patients undergoing a stent implantation, which accounts for approximately
954,000 in USA each year, ISR will continue to be an undesirable adverse entity3)
.
The management of patients with ISR remains challenging to the extent that the therapeutic choices remain
debatable. Currently, the treatment strategies for ISR mainly include cutting balloon angioplasty, plain old
balloon angioplasty, drug-coated balloon (DCB) and DES4)
. Several recent studies have reported that both
new-generation DES and DCB with favorable prognosis are superior to other interventional strategies for
ISR5-12)
. Moreover, recent guidelines on myocardial revascularization from the European Society of Cardiology
recommends DCB and new-generation DES (class I, level A) for patients presenting with ISR1)
. However,
published literature comparing new-generation DES versus DCB in randomized settings conclude with
diverging results8,13-17)
. Additionally, these studies were constrained by the small number of ISR patients
which were inconclusive in terms of clinical outcomes. As a consequence, we performed a meta-analysis of
randomized controlled trials to compare the clinical outcomes and coronary angiographic results of
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new-generation DES with DCB in patients with coronary ISR.
Methods
Search strategy and selection criteria
Randomized trials comparing new-generation DES versus DCB for coronary ISR were searched in PubMed,
the Cochrane Library, and Clinicaltrials.gov as well as major cardiovascular congresses. The subject keywords
included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting stent(s), and
randomized trial were applied to identify studies. The last search was performed on September 12th, 2016
by two independent investigators (Cai JZ and Zhu YX). All studies comparing new-generation DES versus DCB
irrespective of patients presenting with any types of ISR were included.
Data extraction and quality assessment
Two investigators (Cai JZ and Zhu YX) independently screened the title and abstract of retrieved reports,
reviewed the full articles of relevant citations in detail, and extracted study characteristics, angiographic, and
longest available clinical outcomes. Any discrepancies or disagreements were settled by a third investigator
(Zhang YJ). The following variables were extracted from all eligible studies: enrollment periods, patient
characteristics, types of ISR, definition of ISR, follow-up duration, dual antiplatelet therapy, and clinical and
angiographic outcomes. The risk of bias for individual trials was assessed in accordance with the Cochrane
Collaboration’s tool18)
.
Angiographic and clinical outcomes
The clinical outcomes of interest were cardiac death, all-cause death, myocardial infarction, target lesion
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revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac events (MACE), and stent
thrombosis. TLR was defined as any repeated revascularization involving the target lesion. MACE was defined
as individual trial. The angiographic endpoints were minimum lumen diameter (MLD), late lumen loss (LLL)
and % diameter stenosis at 6 to 12 months. In-segment (the treated segment plus 5 mm proximal/distal
margins) measurements were adopted for the analyses, but in-stent parameters was incorporated if
in-segment data were not available.
Statistical analysis
Risk ratio (RR) and mean differences with 95% confidence interval (CI) were utilized as summary statistics.
The Mantel-Haenszel fixed-effects model and Inverse Variance fixed-effects model were used for categorical
variables and continuous variables, respectively. We performed the I2 test and chi-square test to evaluate
heterogeneity among studies. An I2 > 50% or p values < 0.10 was considered as significant heterogeneity. A
random-effects model was performed to calculate the risk estimation if a significant heterogeneity was
detected. Sensitivity analyses were carried out by omitting one study at a time. The Egger’s linear regression
tests were employed to test for funnel plot asymmetry at the p<0.10 level of significance. We also repeated
analyses in the subsets of studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents,
and patients only with BMS-ISR. All the statistical analyses were performed using STATA Version 13.0 (Stata
Corp., College Station, TX, USA) and Review Manager Version 5.3 (The Nordic Cochrane Centre, Copenhagen,
Denmark).
Results
Five trials with a total of 913 patients treated either with new-generation DES (n=414) or DCB (n=499) were
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eligible and included8,13-17)
. The screening process is described in Figure 1. The summary of risk judgment in
individual trials is showed in Supplement Figure 1. The trial, patient and angiographic characteristics are
summarized (Table 1, Supplement Table 1 and 2). Apart from 229 patients (25.1%) with mixed types of ISR in
1 trial17)
, 309 patients (33.9%) with DES-ISR were recruited in 1 trial8)
, while 375 patients (41.0%) with
BMS-ISR were in 3 trials14-16)
. The patients follow up ranged from 6 to 12 months angiographically, and 12 to
36 months clinically.
TLR, TVR, and MACE
TLR was reported in 4 trials including 777 patients8,13,16,17)
. The incidence of TLR in the DCB group (10.9%) was
significantly higher than that in new-generation DES (5.2%) (RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01; I2=32%,
P=0.22; Figure 2A). TVR was not available in the BIOLUX RCT trial17)
. There was no significant difference in the
risk of TVR between DCB and DES (RR: 1.06, 95% CI: 0.48 to 2.34, p=0.89; I2=60%, P=0.06; Figure 2B).
All but the SEDUCE trial reported the rates of MACE16)
. The rates of MACE between DCB (14.7%) and DES
(9.0%) were comparable (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53; I2=58%, P=0.07; Figure 2C).
Cardiac death, all-cause death, myocardial infarction, and stent thrombosis
Myocardial infarction, stent thrombosis and cardiac death were all available in 5 trials but all-cause death
was not reported in the BIOLUX RCT trial17)
. The pooled RR showed no significant differences in cardiac death
(RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29; I2=0%, P=0.92; Figure 3A) and myocardial infarction (RR: 1.16, 95% CI:
0.55 to 2.48, p=0.69; I2=0%, P=0.76; Figure 3B) between the two arms, as well as all-cause death (RR: 1.50,
95% CI: 0.62 to 3.62, p=0.37; I2=0%, P=0.55) and stent thrombosis (RR: 1.26, 95% CI: 0.39 to 4.04, p=0.70;
I2=0%, P=0.75; Figure 3C).
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Angiographic endpoints
All 5 trials contributed to the angiographic follow-up results. Patients treated with new-generation DES had a
significant increase of acute luminal gain (-0.31 mm, 95% CI: -0.42 to -0.20, p<0.001; I2=52%, p=0.08; Figure
4A) and reduction of % diameter stenosis (RR: 0.28, RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006;
Figure 4B) compared to DCB.
A strong trend towards an increase in MLD (-0.23 mm, 95% CI: -0.47 to 0.01, p=0.06; I2=65%, P=0.02, Figure
5A) was noted in the new-generation DES arm but this difference was not statistically significant compared to
DCB.
All but the BIOLUS RCT trial reported the incidences of binary restenosis. Patients treated with
new-generation DES were associated with a similar risk of binary restenosis (RR: 1.25, 95% CI: 0.57 to 2.75,
p=0.58; I2=56%, P=0.08; Figure 5B) and LLL (-0.06mm, 95% CI: -0.37, 0.25, p=0.71; I
2=80%, P=0.0006; Figure
5C) compared to DCB.
Repeated analyses in the subsets of patient population
In the setting of patients with BMS-ISR13,15,16)
, no significant differences were found in DCB versus
new-generation DES in all angiographic and clinical outcomes except for acute luminal gain (-0.39 mm, 95%
CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).
Patients treated exclusively with everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95%
CI: 1.35 to 5.18, p=0.005; I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17,
p<0.001; I2=64%, P=0.04), and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I
2=60%, P=0.06;). But
no statistical differences in other clinical and angiographic outcomes were observed between the 2
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groups8,13,15,16)
.
Publication bias and sensitivity analyses
No publication biases were found in all clinical and angiographic outcomes (Supplement Figure 2). Sensitivity
analyses suggested that the favorable results of new-generation DES were concealed in TLR when the RIBS IV
trial was omitted (RR: 1.49, 95% CI: 0.77 to 2.90, p=0.24; I2=27%, P=0.26). Conversely, DCB was associated
with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03; I2=19%, P=0.29) as well as an increase in in
MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I2=64%, P=0.04) and binary restenosis (RR: 1.85, 95% CI: 1.11
to 3.10, p=0.02; I2=0%, P=0.99) when the TIS trial was omitted. New-generation DES had a greater MLD when
the BIOLUX RCT trial was excluded (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06).
Discussion
This meta-analysis included 5 randomized trials examining the angiographic and clinical outcomes of
new-generation DES versus DCB in the treatment of any types of coronary ISR. The study, for the first time,
showed that new-generation DES was associated with an improved angiographic and clinical effectiveness
when compared with DCB irrespective of the types of ISR. The main findings are as follows: (1) new
generation DES had significantly reduced the risk of TLR compared to DCB at the longest available follow-up;
(2) there were no statistical differences in cardiac death, myocardial infarction, and MACE between the two
treatment strategies; (3) New-generation DES was related to favorable angiographic results for coronary ISR
with significant increase of acute luminal gain and reduction in % diameter stenosis at 6 to 12 months
follow-up.
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Previous meta-analyses
The choice of therapeutic methods for coronary ISR remains debatable. Several meta-analyses demonstrated
that DCB and DES had comparable clinical and angiographic results for patients with coronary ISR5,19,20)
.
However obvious pitfalls existed in these studies. Firstly, Mamuti W et al. 20)
combined new-generation DES
and first-generation DES in the same group, whereas cumulative evidence has illustrated the difference in
clinical performance of different generation DES21)
. In the Liou’ study, which compared DES with DCB,
demonstrated no superiority of the new-generation DES with respect to similar clinical parameters in the
overall analysis. Regrettably, they included four observational studies in which an inequality of baseline
characteristics was observed19)
. A further limitation of this meta-analysis was minimal number of patients
(n=548) in the 3 randomised trials19)
. Additionally, in a Bayesian network meta-analysis comparing the
performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal
strategy with pronounced improvements in terms of clinical outcomes6. Nevertheless, the effect was
transitive and mainly derived from indirect comparison5)
. In the present meta-analysis, we, for the first time,
included only randomized trials of new generation DES in comparison with DCB, so the possibility of
confounders influencing estimates for various endpoints is less likely. Furthermore, this meta-analysis
included the largest number of ISR patients to date and demonstrated that contemporary DES with improved
design was associated with favorable outcomes and a lower risk of re-intervention at mid-term follow-up
compared to DCB.
Angiographic and clinical outcomes
Compared with DCB, new-generation DES were related to favorable prognosis for coronary ISR with superior
angiographic outcomes and reduced TLR. The advantages of new-generation DES comprised of persistent
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radial strength which prevents acute or subacute prolapse of the disrupted plaque and elastic recoil of the
vessel wall, sufficient antiproliferative drugs, and subsequent excellent neointimal hyperplasia inhibition
compared with DCB8,22)
. In the present study, we found that the key angiographic parameters analysed were
in favor of new generation DES in treatment with ISR patients.
Although one may argue that DES add one more stent layer in the finite lesion segment, 80-100 μm of lumen
loss due to the implants seems negligible when considering that new generation DES assumes less
re-intervention. Alternatively, one may express concern regard the long-term safety of stent implantation as
studies have shown that the vascular inflammatory response with the thin-strut platform profile and also its
biocompatibility or biodegradable polymer were extremely low4,21,23)
. The present study, however, remains
limited by its small sample size and short periods of follow-up. By virtue of previously published literature, it
is reasonable to assume that the benefit of new generation DES will remain consistent.
In the RIBS V trial13,14)
, the authors have observed 1 TLR events in the EES group and 2 in the DCB group from
1 to 3 years. In the RESTENT-ISR (Prospective Randomized Comparison of Clinical and Angiographic
Outcomes Between Everolimus-eluting vs. Zotarolimus-eluting Stents for Treatment of Coronary Restenosis
in Drug-Eluting Stents: Intravascular Ultrasound Volumetric Analysis) trial, Hong et al. reported an
approximate rate of 6.0% in late (>1 year) TLR in patients with ISR treated with everolimus-eluting stents and
zotarolimus-eluting stents24)
, similar to several subgroups from all-comers study25,26)
. Similarly, rates of TLR
after 1 year of DCB angioplasty were varied between 0% to 10%6,7,11,12)
. Thus, whether the potential
long-term benefit of DCB compared to addition stent implantation remains to be seen27)
.
The limitations of the current study are henceforth highlighted. Firstly, The RIBS IV trial contributed
significantly in the endpoint of TLR in favor of DES on the basis of our sensitivity analysis11)
. Moreover, our
study presented high heterogeneities in the majority of angiographic and clinical outcomes, which were
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mainly driven by the TIS trial15)
. The investigators elucidated that more severe ISR lesions (regarding both
minimal lumen diameter and percent diameter stenosis) and frequently unfavorable pattern (regarding type
of occlusion and proliferative) allocated in the new-generation DES group could be confounding factors28)
29)
.
In addition, the proportion of usage of scoring balloon pre-dilation, which may have a potential role in
improving the anti-proliferation potency of DCB30)
, were significant higher in the DCB group15,28)
. Therefore,
further researches with a careful follow-up protocol and large sample size should be performed to provide
more confirmative information.
Future perspectives
Currently, new-generation DES represents a superior treatment strategy with similar safety and improved
angiographic and clinical efficacy. We recommends that it should be considered as one of primary treatment
options for coronary ISR. Although new-generation DES reduce the possibility of recurrent ISR, the risk
remains high as multilayers of metal stents in the vessel wall will entail difficulty in further treatments and an
inherent poorer clinical prognosis31)
. Bioresorbable scaffold (BRS) with proven safety and efficacy profiles for
ISR while avoiding in the mid-long term an additional metal layer may be an alternative treatment choice in
the future32,33)
. The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs. Drug Coated Balloon for Treatment of
In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable vascular scaffold with DCB to treat ISR will
shed light in terms of clinical utility of BRS for coronary ISR. However for patients with intolerable long-term
dual antiplatelet therapy or high risk of bleeding, DCB may be more suitable. Furthermore, researchers
should pursue further optimization of DCB and its auxiliary strategy34,35)
, such as use of scoring balloon before
DCB30)
.
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Limitations
The following potential limitations of the present study are acknowledged. Firstly, the results were based on
the trial level and shares the limitations of the original trials. Secondly, the imbalance of baseline
characteristics may have had led to bias. Thirdly, the studied DCB group included Sequent PleaseTM
and
Pantera LuxTM
paclitaxel-eluting balloons, which have different coatings design, as well as the implemental
methods of DCB in individual trials10)
.Fourthly, the definitions of clinical and angiographic parameters were
not identical in some studies. Finally, in light of the fairly highly selected criteria in our study, only a total of
912 patients were enrolled. However, our study demonstrates the largest patient population presenting with
ISR and is likely to remain the most powerful evidence base for evaluation of DCB versus new-generation
DES.
Conclusions
New-generation DES seems an acceptable treatment strategy with comparable safety and favorable
angiographic and clinical efficacy compared to DCB for coronary ISR. But either new generation DES or DCB
should be recommended as the first choice in the setting of patients with ISR still relies on further larger
scale, longer-term follow-up and randomized trials.
Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, ZH, BC, DXJ and IJ conceived the study design. CJZ, ZYX, ZH
and MA performed the report screening, study inclusion, data extraction. CP, MA, DXJ and ZH analysis the data. ZYJ,
CJZ, ZYX, BC, IJ, CP and MA drafted the manuscript. CP, MA, DXJ and ZH reviewed the manuscript for important
intellectual content. All authors have significantly contributed to the design of study, analysis of data and
drifting or revising manuscript. All authors have read and approved this article.
Funding: This work was supported by Medical Science and technology development Foundation, Nanjing
Department of Health [YKK15100], and Key Project of Nanjing Science and Technology Development
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Foundation [201503024]. For the others authors none were declared.
Competing interests: The authors declare that there is no conflict of interest.
Data sharing statement: no additional data are available.
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Balloons in Patients With Bare-Metal In-Stent Restenosis: 3-Year Follow-Up of the RIBS V Clinical Trial. JACC Cardiovasc
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stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents:
paclitaxel-eluting balloon vs. everolimus-eluting stent). J Am Coll Cardiol 2014; 63: 1378-86.
15. Pleva L, Kukla P, Kusnierova P, Zapletalova J, Hlinomaz O. Comparison of the Efficacy of Paclitaxel-Eluting Balloon
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16. Adriaenssens T, Dens J, Ughi G, et al. Optical coherence tomography study of healing characteristics of paclitaxel-eluting
balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in
Coronary artery rEstenosis) randomised clinical trial. EuroIntervention 2014; 10: 439-48.
17. Naber CK. Clinical performance of the Pantera Lux paclitaxel coated balloon vs. the drug-eluting Orsiro hybrid stent system in
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patients with in-stent restenosis: a randomised controlled trial. Available at:
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18. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
BMJ 2011; 343: d5928.
19. Liou K, Jepson N, Cao C, Luo R, Pala S, Ooi SY. Drug-eluting Balloon versus Second Generation Drug Eluting Stents in the
Treatment of In-stent Restenosis: A Systematic Review and Meta-analysis. Heart Lung Circ 2016 .
20. Mamuti W, Ablimit A, Kelimu W, et al. Comparison of drug-eluting balloon versus drug-eluting stent in patients with in-stent
restenosis: insight from randomized controlled trials. Int J Cardiol 2015; 179: 424-9.
21. Palmerini T, Benedetto U, Biondi-Zoccai G, et al. Long-Term Safety of Drug-Eluting and Bare-Metal Stents: Evidence From a
Comprehensive Network Meta-Analysis. J Am Coll Cardiol 2015; 65: 2496-507.
22. Waksman R, Pakala R. Drug-eluting balloon: the comeback kid. Circ Cardiovasc Interv 2009; 2: 352-8.
23. Xu B, Zhang YJ, Sun ZW, et al. Comparison of long-term in-stent vascular response between abluminal groove-filled
biodegradable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent: 3-year OCT follow-up from the
TARGET I trial. Int J Cardiovasc Imaging 2015; 31: 1489-96.
24. Hong SJ, Ahn CM, Kim BK, et al. Prospective randomized comparison of clinical and angiographic outcomes between
everolimus-eluting vs. zotarolimus-eluting stents for treatment of coronary restenosis in drug-eluting stents: intravascular
ultrasound volumetric analysis (RESTENT-ISR trial). Eur Heart J 2016 .
25. Richardt G, Leschke M, Abdel-Wahab M, et al. Clinical outcomes of the Resolute zotarolimus-eluting stent in patients with
in-stent restenosis: 2-year results from a pooled analysis. JACC Cardiovasc Interv 2013; 6: 905-13.
26. Campo G, Punzetti S, Malagù M, Ferrari R, Valgimigli M. Two-year outcomes after first- or second-generation drug-eluting
stent implantation in patients with in-stent restenosis. A PRODIGY trial substudy. Int J Cardiol 2014; 173: 343-5.
27. De Labriolle A, Pakala R, Bonello L, Lemesle G, Scheinowitz M, Waksman R. Paclitaxel-eluting balloon: from bench to bed.
Catheter Cardiovasc Interv 2009; 73: 643-52.
28. Alfonso F, Cuesta J, Romaguera R. Letter by Alfonso et al Regarding Article, "Comparison of the Efficacy of
Paclitaxel-Eluting Balloon Catheters and Everolimus-Eluting Stents in the Treatment of Coronary In-Stent Restenosis: The
Treatment of In-Stent Restenosis Study". Circ Cardiovasc Interv 2016; 9 .
29. Habara S, Kadota K, Shimada T, et al. Late Restenosis After Paclitaxel-Coated Balloon Angioplasty Occurs in Patients With
Drug-Eluting Stent Restenosis. J Am Coll Cardiol 2015; 66: 14-22.
30. Robert A. B, Kufner S, Joner M, et al. Neointimal Modification with Scoring-Balloon and Efficacy of Drug-Coated Balloon
Therapy in Patients with Restenosis in Drug Eluting Coronary Stents. Available at:
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Accessed Nov 17, 2016.
31. Kubo S, Kadota K, Otsuru S, et al. Optimal treatment of recurrent restenosis lesions after drug-eluting stent implantation for
in-stent restenosis lesions. EuroIntervention 2013; 9: 788-96.
32. Moscarella E, Ielasi A, Granata F, et al. Long-Term Clinical Outcomes After Bioresorbable Vascular Scaffold Implantation for
the Treatment of Coronary In-Stent Restenosis: A Multicenter Italian Experience. Circ Cardiovasc Interv 2016; 9: e003148.
33. Jamshidi P, Nyffenegger T, Sabti Z, et al. A novel approach to treat in-stent restenosis: 6- and 12-month results using the
everolimus-eluting bioresorbable vascular scaffold. EuroIntervention 2016; 11: 1479-86.
34. Scheller B, Fontaine T, Mangner N, et al. A novel drug-coated scoring balloon for the treatment of coronary in-stent restenosis:
Results from the multi-center randomized controlled PATENT-C first in human trial. Catheter Cardiovasc Interv 2016; 88:
51-9.
35. Verheye S, Vrolix M, Kumsars I, et al. Sirolimus Eluting Angioplasty Balloon for In-Stent Restenosis SABRE Trial: 6 Month
Clinical and Angiographic Results. Available at:
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https://www.tctmd.com/slide/sirolimus-eluting-angioplasty-balloon-stent-restenosis-sabre-trial-six-month-clinical-and.
Accessed Nov 17, 2016.
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Table
Table 1 Main characteristics of the included trials
Study Type Treatment arms Sampl
e size
Definition
of ISR
Follow-up, months DAPT,
months Definition of MACE
Angiograph
ic Clinical DCB DES
TIS BMS SP
PCB PE EES 68/68 ≥50% DS 12 12 3 6-12 Death, any MI, and TVR
RIBS IV DES SP
PCB XP EES
154/15
5 ≥50% DS 9 12 3 12 Death, MI, and TLR
SEDUCE BMS SP
PCB XP EES 25/25 >70% DS 9 12 n/a n/a n/a
RIBS V BMS SP
PCB XP EES 95/94 ≥50% DS 9 36 3 12 Death, MI, and TLR
BILUX
RCT Both PL PCB
Orsiro
SES 157/72 n/a 6 12 n/a n/a
Cardiac death, MI, and
TLR
Abbreviations: BMS = bare-metal stents; CAG = coronary angiography; DAPT = dual antiplatelet therapy; DCB =
drug-eluting balloon; DES = drug-eluting stents; DS=diameter stenosis; ISR=in-stent restenosis; MACE = major adverse
cardiac events; MI = myocardial infarction; n/a = not available; PE EES = Promus Element everolimus-eluting stents; PL PCB
= Pantera Lux paclitaxel-coated balloon; SES = sirolimus-eluting balloon; SP PCB = SeQuent Please paclitaxel-coated
balloon; TLR = target lesion revascularization; TVR = target vessel revascularization; XP EES = Xience Prime
everolimus-eluting stent.
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Figure legends
Figure 1
Title: Flow diagram of meta-analysis
Figure 2
Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR,
(B) TVR, and (C) MACE.
Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse
cardiac events; TLR = target lesion revascularization; TVR= target vessel revascularization.
Figure 3
Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent
thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
Figure 4
Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute
lumen gain, and (B) % DS.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
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Figure 5
Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD,
(B) binary restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen
diameter; LLL = late lumen loss.
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Figure 1 Title: Flow diagram of meta-analysis
179x155mm (300 x 300 DPI)
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Figure 2 Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR, (B) TVR,
and (C) MACE. Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse cardiac
events; TLR = target lesion revascularization; TVR= target vessel revascularization.
254x190mm (300 x 300 DPI)
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Figure 3 Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
254x190mm (300 x 300 DPI)
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Figure 4 Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute lumen gain, and (B) % DS.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
254x124mm (300 x 300 DPI)
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Figure 5 Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD, (B) binary restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen diameter; LLL = late lumen loss.
254x185mm (300 x 300 DPI)
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Supplement
Figure 1
Title: Risk of bias
Caption: Proportions of studies classified as having low (green), unclear (yellow), and high (red) risk of bias across domains of study quality.
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Figure 2
Title: Publication biases.
Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target vessel revascularization, (C) major adverse cardiac
events, (D) myocardial infarction, (E) cardiac death, and (F) stent thrombosis.
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Table 1 Patient characteristics
Study Age Male Hypertension
Diabetes
mellitus Dyslipidemia Previous MI Multi-vessel
DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)
RIBS IV 66 (10) 66 (10) 127
(82)
130
(84)
110
(71)
121
(78) 75 (49) 66 (43)
110
(71)
121
(78) 73 (47) 77 (50) n/a n/a
SEDUCE 68 (8) 64 (11) 18 (72) 25
(100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a
RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a
BILUX
RCT 67 (10) 69 (9)
122
(78) 49 (68)
144
(92) 70 (97) 48 (31) 24 (33)
134
(85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)
Values are mean (SD) or n (%).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; EES = everolimus-eluting stents; n/a = not available; MI
= myocardial infarction.
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Table 2 Angiographic characteristics
Study length of pre-stent Mehran III-IV Pre-%DS Pre-MLD Pre-RVD
DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92
(0.5)
0.79
(0.5)
2.64
(0.5)
2.66
(0.5)
RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79
(0.4)
0.75
(0.4)
2.59
(0.5)
2.67
(0.5)
SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98
(0.6)
0.57
(0.4) 3.0 (0.5)
2.85
(0.4)
RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02
(0.4)
0.93
(0.4)
2.64
(0.6)
2.64
(0.6)
BIOLUX
RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)
Values are mean (SD).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; DS = diameter stenosis; MLD = minimum lumen
diameter; RVD = reference vessel diameter; n/a = not available.
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Section/topic # Checklist item Reported on page #
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 3
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
3
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale. 4
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
4
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
4
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis). 4
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
4
Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
4-5
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 4-5
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I
2) for each meta-analysis.
4-5
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Page 1 of 2
Section/topic # Checklist item Reported on page #
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
4-5
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
4-5
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
5-6
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
5-6
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5-6
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
6-7
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6-7
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 8
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 8
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
8-11
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
11
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 12
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
12
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
For more information, visit: www.prisma-statement.org.
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Comparison of new-generation drug-eluting stents versus
drug-coated balloon for in-stent restenosis: A meta-analysis of randomized controlled trials
Journal: BMJ Open
Manuscript ID bmjopen-2017-017231.R1
Article Type: Research
Date Submitted by the Author: 18-Aug-2017
Complete List of Authors: Cai, Jin-Zan; Nanjing First Hospital, Nanjing Medical University Zhu, Yong-Xiang ; Nanjing First Hospital, Nanjing Medical University, Department of Cardiology Wang, Xin-Yu; Xuzhou Cancer Hospital, Jiangsu University, Department of Cardiology Bourantas, Christos ; University College London, Cardiovascular Sciences Iqbal, Javaid; Barts Heart Centre, Department of Cardiology Zhu, Hao; Nanjing First Hospital, Nanjing Medical University,, Department of Cardiology
Cummins, Paul ; Erasmus MC, Rotterdam, Department of Cardiology Dong, Sheng-Jie; Yantaishan hospital, Department of the Joint and Bone Surgery Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun; Xuzhou Cancer Hospital, Jiangsu University, Department of Cardiology,
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Cardiovascular medicine
Keywords: Drug-coated balloon, Drug-eluting stents, In-stent restenosis, Meta-analysis
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Title page
Comparison of new-generation drug-eluting stents versus drug-coated balloon for
in-stent restenosis: A meta-analysis of randomized controlled trials
Authors: Jin-Zan Cai1, MSc; Yong-Xiang Zhu
1, MSc; Xin-Yu Wang
2, BSc; Christos V. Bourantas
3, 4, PhD; Javaid
Iqbal5, PhD; Hao Zhu
1, MSc; Paul Cummins
6, BSc; Sheng-jie Dong
7, PhD; Anthony Mathur
4, PhD; Yao-Jun
Zhang2* PhD
Cai JZ, Zhu YX, and Wang XY are equally contributed to this manuscript.
Author Affiliations:
1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China;
2Department of Cardiology, Xuzhou Cancer Hospital, Jiangsu University, Xuzhou, China;
3Sheffield Teaching Hospitals and the University of Sheffield, Sheffield, United Kingdom;
4Department of Cardiovascular Sciences, University College London, London, UK;
5Department of Cardiology, Barts Heart Centre, London, UK;
6Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands;
7Department of the Joint and Bone Surgery, Yantaishan hospital, Yantai, China;
Running title: DES versus DCB for ISR
*Correspondence to:
Yao-Jun Zhang MD, PhD, FESC
No. 131, Huancheng Road, Xuzhou, 221005, China
Email: [email protected]; Tel & Fax: +86-0516-85538617
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Abstract
Objective: The study sought to compare angiographic and clinical results of new-generation drug-eluting
stents (DES) versus drug-coated balloon (DCB) in patients with coronary in-stent restenosis (ISR).
Design: Meta-analyses using data from randomised trial found by searches on PubMed, the Cochrane Library,
Clinicaltrials.gov, and major cardiovascular congresses.
Setting: Only randomised trials comparing DES with DCB was included.
Participants: Patients with ISR in the including trails.
Interventions: new-generation DES or DCB.
Primary and secondary outcomes: The angiographic and clinical outcomes including cardiac death, all-cause
death, myocardial infarction, target lesion revascularization (TLR), target vessel revascularization (TVR), major
adverse cardiac events (MACE), and stent thrombosis were investigated.
Results: Five trials including 913 patients were eligible and included. Meta-analyses showed that DES had
significantly reduced the risk of target lesion revascularization (TLR, RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01),
however no statistical differences were seen in terms of major adverse cardiac events (MACE, RR: 1.21, 95%
CI: 0.67 to 2.17, p=0.53), myocardial infarction (RR: 1.16, 95% CI: 0.55 to 2.48, p=0.69), and cardiac death (RR:
1.80, 95% CI: 0.60 to 5.39, p=0.29) when compared with DCB. Pooled analyses in angiographic results
identified that new-generation DES were associated with higher acute luminal gain (-0.31 mm, 95% CI: -0.42
to -0.20, p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04).
Conclusions: Interventions with new-generation DES appeared to be associated with significant reductions
in % diameter stenosis and TLR at short-term follow-up, but similar MACE, myocardial infarction, and cardiac
death for coronary ISR patients compared to DCB. Appropriately powered studies with longer term follow-up
are warranted to confirm the findings from the present meta-analysis.
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Keywords: Drug-coated balloon; Drug-eluting stents; In-stent restenosis; Meta-analysis.
Strengths and limitations of this study
1、 Only randomized trials comparing DES with DCB for patients with ISR were allowed to include in this
meta-analysis.
2、、、、 This study demonstrates the largest patient population presenting with ISR.
3、、、、 The results were based on the trial level and shares the limitations of the original trials.
Introduction
Percutaneous coronary intervention with bare-metal stents (BMS) or drug-eluting stents (DES) has become
one of the most frequently performed therapeutic procedures for coronary artery disease(1). The rate of
in-stent restenosis (ISR) in clinical practice is nearly 5% of patients treated with DES and 10% with BMS after
5 years(2). Given the number of patients undergoing a stent implantation, which accounts for approximately
954,000 in USA each year, ISR will continue to be an undesirable adverse entity(3).
The management of patients with ISR remains challenging to the extent that the therapeutic choices remain
debatable. Currently, the treatment strategies for ISR mainly include cutting balloon angioplasty, plain old
balloon angioplasty, drug-coated balloon (DCB) and DES(4). Several recent studies have reported that both
new-generation DES and DCB with favorable prognosis are superior to other interventional strategies for
ISR(5-12). Moreover, recent guidelines on myocardial revascularization from the European Society of
Cardiology recommends DCB and new-generation DES (class I, level A) for patients presenting with ISR(1).
However, published literature comparing new-generation DES versus DCB in randomized settings conclude
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with diverging results(8, 13-17). Additionally, these studies were constrained by the small number of ISR
patients which were inconclusive in terms of clinical outcomes. As a consequence, we performed a
meta-analysis of randomized controlled trials to compare the clinical outcomes and coronary angiographic
results of new-generation DES with DCB in patients with coronary ISR.
Methods
Search strategy and selection criteria
Randomized trials comparing new-generation DES versus DCB for coronary ISR were searched in PubMed,
the Cochrane Library, and Clinicaltrials.gov as well as major cardiovascular congresses. The subject keywords
included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting stent(s), and
randomized trial were applied to identify studies. The last search was performed on September 12th, 2016
by two independent investigators (Cai JZ and Zhu YX). All studies comparing new-generation DES versus DCB
irrespective of patients presenting with any types of ISR were included.
Data extraction and quality assessment
Two investigators (Cai JZ and Zhu YX) independently screened the title and abstract of retrieved reports,
reviewed the full articles of relevant citations in detail, and extracted study characteristics, angiographic, and
longest available clinical outcomes. Any discrepancies or disagreements were settled by a third investigator
(Zhang YJ). The following variables were extracted from all eligible studies: enrollment periods, patient
characteristics, types of ISR, definition of ISR, follow-up duration, dual antiplatelet therapy, and clinical and
angiographic outcomes. The risk of bias for individual trials was assessed in accordance with the Cochrane
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Collaboration’s tool(18).
Angiographic and clinical outcomes
The clinical outcomes of interest were cardiac death, all-cause death, myocardial infarction, target lesion
revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac events (MACE), and stent
thrombosis. TLR was defined as any repeated revascularization involving the target lesion. MACE was defined
as individual trial. The angiographic endpoints were minimum lumen diameter (MLD), late lumen loss (LLL)
and % diameter stenosis at 6 to 12 months. In-segment (the treated segment plus 5 mm proximal/distal
margins) measurements were adopted for the analyses, but in-stent parameters was incorporated if
in-segment data were not available.
Statistical analysis
Risk ratio (RR) and mean differences with 95% confidence interval (CI) were utilized as summary statistics.
The Mantel-Haenszel fixed-effects model and Inverse Variance fixed-effects model were used for categorical
variables and continuous variables, respectively. We calculated the I2 index and performed chi-square test to
measure statistical heterogeneity among studies. An I2 > 50% or p values < 0.10 was considered as significant
heterogeneity. A random-effects model was performed to calculate the risk estimation if a significant
heterogeneity was detected. Sensitivity analyses were carried out by omitting one study at a time, excluding
the studies with a high level of risk of bias, and including only studies with a low proportion of missing data.
The Egger’s linear regression tests were employed to test for funnel plot asymmetry at the p<0.10 level of
significance. However, the analysis for publication bias can only be tentative, as there is not enough power to
support the test results due to the limited number of studies included. We also repeated analyses in the
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subsets of studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents, and patients
only with BMS-ISR. All the statistical analyses were performed using STATA Version 13.0 (Stata Corp., College
Station, TX, USA) and Review Manager Version 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).
Results
Five trials with a total of 913 patients treated either with new-generation DES (n=414) or DCB (n=499) were
eligible and included(8, 13-17). The screening process is described in Figure 1. The median and interquartile
range of sample size were 189 and 176 respectively. Only the TIS trail was single center, and the others were
multicentre. Patients enrolled were from Czech in TIS trial, Spain in RIBS IV and RIBS V trials, Belgium in
SEDUCE trial, and Germany and Latvia in BIOLUX RCT. All trial had a high risk of bias with respect to
performance bias and the details of methodology in BIOLUX RCT trial was not available. The summary of risk
judgment in individual trials is showed in Supplement Figure 1. The trial, patient and angiographic
characteristics are summarized (Table 1, Supplement Table 1 and 2). Apart from 229 patients (25.1%) with
mixed types of ISR in 1 trial(17), 309 patients (33.9%) with DES-ISR were recruited in 1 trial(8), while 375
patients (41.0%) with BMS-ISR were in 3 trials(14-16). The patients follow up ranged from 6 to 12 months
angiographically, and 12 to 36 months clinically.
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Table
Table 1 Main characteristics of the included trials
Study Type Treatment arms Sampl
e size
Definition
of ISR
Follow-up, months DAPT,
months Definition of MACE
Angiograph
ic Clinical DCB DES
TIS BMS SP
PCB PE EES 68/68 ≥50% DS 12 12 3 6-12 Death, any MI, and TVR
RIBS IV DES SP
PCB XP EES
154/15
5 ≥50% DS 9 12 3 12 Death, MI, and TLR
SEDUCE BMS SP
PCB XP EES 25/25 >70% DS 9 12 n/a n/a n/a
RIBS V BMS SP
PCB XP EES 95/94 ≥50% DS 9 36 3 12 Death, MI, and TLR
BILUX
RCT Both PL PCB
Orsiro
SES 157/72 n/a 6 12 n/a n/a
Cardiac death, MI, and
TLR
Abbreviations: BMS = bare-metal stents; CAG = coronary angiography; DAPT = dual antiplatelet therapy; DCB =
drug-eluting balloon; DES = drug-eluting stents; DS=diameter stenosis; ISR=in-stent restenosis; MACE = major adverse
cardiac events; MI = myocardial infarction; n/a = not available; PE EES = Promus Element everolimus-eluting stents; PL PCB
= Pantera Lux paclitaxel-coated balloon; SES = sirolimus-eluting balloon; SP PCB = SeQuent Please paclitaxel-coated
balloon; TLR = target lesion revascularization; TVR = target vessel revascularization; XP EES = Xience Prime
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everolimus-eluting stent.
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Target lesion revascularization, target vessel revascularization, major adverse cardiac events
TLR was reported in 4 trials including 777 patients(8, 13, 16, 17). The incidence of TLR in the DCB group
(10.9%) was significantly higher than that in new-generation DES (5.2%) (RR: 1.96, 95% CI: 1.17 to 3.28,
p=0.01; I2=32%, P=0.22; Figure 2A). TVR was not available in the BIOLUX RCT trial(17). There was no
significant difference in the risk of TVR between DCB and DES (RR: 1.06, 95% CI: 0.48 to 2.34, p=0.89; I2=60%,
P=0.06; Figure 2B).
All but the SEDUCE trial reported the rates of MACE(16). The rates of MACE between DCB (14.7%) and DES
(9.0%) were comparable (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53; I2=58%, P=0.07; Figure 2C).
Cardiac death, all-cause death, myocardial infarction, and stent thrombosis
Myocardial infarction, stent thrombosis and cardiac death were all available in 5 trials but all-cause death
was not reported in the BIOLUX RCT trial(17). The pooled RR showed no significant differences in cardiac
death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29; I2=0%, P=0.92; Figure 3A) and myocardial infarction (RR: 1.16,
95% CI: 0.55 to 2.48, p=0.69; I2=0%, P=0.76; Figure 3B) between the two arms, as well as all-cause death (RR:
1.50, 95% CI: 0.62 to 3.62, p=0.37; I2=0%, P=0.55) and stent thrombosis (RR: 1.26, 95% CI: 0.39 to 4.04,
p=0.70; I2=0%, P=0.75; Figure 3C).
Angiographic endpoints
All 5 trials contributed to the angiographic follow-up results. Patients treated with new-generation DES had a
significant increase of acute luminal gain (-0.31 mm, 95% CI: -0.42 to -0.20, p<0.001; I2=52%, p=0.08; Figure
4A) and reduction of % diameter stenosis (RR: 0.28, RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006;
Figure 4B) compared to DCB.
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A strong trend towards an increase in MLD (-0.23 mm, 95% CI: -0.47 to 0.01, p=0.06; I2=65%, P=0.02, Figure
5A) was noted in the new-generation DES arm but this difference was not statistically significant compared to
DCB.
All but the BIOLUS RCT trial reported the incidences of binary restenosis. Patients treated with
new-generation DES were associated with a similar risk of binary restenosis (RR: 1.25, 95% CI: 0.57 to 2.75,
p=0.58; I2=56%, P=0.08; Figure 5B) and LLL (-0.06mm, 95% CI: -0.37, 0.25, p=0.71; I
2=80%, P=0.0006; Figure
5C) compared to DCB.
Publication bias and sensitivity analyses
No publication biases were found in all clinical and angiographic outcomes (Supplement Figure 2). Sensitivity
analyses suggested that the favorable results of new-generation DES were concealed in TLR when the RIBS IV
trial was omitted (RR: 1.49, 95% CI: 0.77 to 2.90, p=0.24; I2=27%, P=0.26). Conversely, DCB was associated
with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03; I2=19%, P=0.29) as well as an increase in in
MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I2=64%, P=0.04) and binary restenosis (RR: 1.85, 95% CI: 1.11
to 3.10, p=0.02; I2=0%, P=0.99) when the TIS trial was omitted. New-generation DES remains a greater MLD
when the BIOLUX RCT trial was omitted (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06).
Repeated analyses in the subsets of patient population
In the setting of patients with BMS-ISR(13, 15, 16), no significant differences were found in DCB versus
new-generation DES in all angiographic and clinical outcomes except for acute luminal gain (-0.39 mm, 95%
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CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).
Patients treated exclusively with everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95%
CI: 1.35 to 5.18, p=0.005; I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17,
p<0.001; I2=64%, P=0.04), and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I
2=60%, P=0.06;). But
no statistical differences in other clinical and angiographic outcomes were observed between the 2 groups(8,
13, 15, 16).
Discussion
This meta-analysis included 5 randomized trials examining the angiographic and clinical outcomes of
new-generation DES versus DCB in the treatment of any types of coronary ISR. The study, for the first time,
showed that new-generation DES appealed to associated with an improved angiographic and clinical
effectiveness when compared with DCB irrespective of the types of ISR at short term follow-up. The main
findings are as follows: (1) new generation DES had significantly reduced the risk of TLR compared to DCB at
the longest available follow-up; (2) there were no statistical differences in cardiac death, myocardial
infarction, and MACE between the two treatment strategies; (3) New-generation DES was related to
favorable angiographic results for coronary ISR with significant increase of acute luminal gain and reduction
in % diameter stenosis at 6 to 12 months follow-up.
Previous meta-analyses
The choice of therapeutic methods for coronary ISR remains debatable. Several meta-analyses demonstrated
that DCB and DES had comparable clinical and angiographic results for patients with coronary ISR(5, 19, 20).
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However obvious pitfalls existed in these studies. Firstly, Mamuti W et al.(20) combined new-generation DES
and first-generation DES in the same group, whereas cumulative evidence has illustrated the difference in
clinical performance of different generation DES(21). In the Liou’ study, which compared DES with DCB,
demonstrated no superiority of the new-generation DES with respect to similar clinical parameters in the
overall analysis. Regrettably, they included four observational studies in which an inequality of baseline
characteristics was observed(19). A further limitation of this meta-analysis was minimal number of patients
(n=548) in the 3 randomised trials(19). Additionally, in a Bayesian network meta-analysis comparing the
performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal
strategy with pronounced improvements in terms of clinical outcomes6. Nevertheless, the effect was
transitive and mainly derived from indirect comparison(5). In the present meta-analysis, we, for the first time,
included only randomized trials of new generation DES in comparison with DCB, so the possibility of
confounders influencing estimates for various endpoints is less likely. Furthermore, this meta-analysis
included the largest number of ISR patients to date and demonstrated that contemporary DES with improved
design was associated with favorable outcomes and a lower risk of re-intervention at mid-term follow-up
compared to DCB.
Angiographic and clinical outcomes
Compared with DCB, new-generation DES were related to favorable prognosis for coronary ISR with superior
angiographic outcomes and reduced TLR. The advantages of new-generation DES comprised of persistent
radial strength which prevents acute or subacute prolapse of the disrupted plaque and elastic recoil of the
vessel wall, sufficient antiproliferative drugs, and subsequent excellent neointimal hyperplasia inhibition
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compared with DCB(8, 22). Interestingly, the rate of recurrent binary restenosis was similar in two groups.
The difference of TLR was possibly related to the factor that presence of an existing additional stent layer in
the DES group discouraged the operator from repeat intervention.
Although one may argue that DES add one more stent layer in the finite lesion segment, 80-100 μm of lumen
loss due to the implants seems negligible when considering that new generation DES assumes less
re-intervention. Alternatively, one may express concern regard the long-term safety of stent implantation as
studies have shown that the vascular inflammatory response with the thin-strut platform profile and also its
biocompatibility or biodegradable polymer were extremely low(4, 21, 23). The present study, however,
remains limited by its small sample size and short periods of follow-up. By virtue of previously published
literature, it is reasonable to assume that the short term (less than 1 year) benefit of new generation DES will
remain consistent.
In the RIBS V trial(13, 14), the authors have observed 1 TLR events in the EES group and 2 in the DCB group
from 1 to 3 years. In the RESTENT-ISR (Prospective Randomized Comparison of Clinical and Angiographic
Outcomes Between Everolimus-eluting vs. Zotarolimus-eluting Stents for Treatment of Coronary Restenosis
in Drug-Eluting Stents: Intravascular Ultrasound Volumetric Analysis) trial, Hong et al. reported an
approximate rate of 6.0% in late (>1 year) TLR in patients with ISR treated with everolimus-eluting stents and
zotarolimus-eluting stents(24), similar to several subgroups from all-comers study(25, 26). Similarly, rates of
TLR after 1 year of DCB angioplasty were varied between 0% to 10%(6, 7, 11, 12). The ISAR-DESIRE 3 and
PEPCAD China trials have shown a late mortality benefit of DCB treatment vs. first generation DES treatment
on longer follow up times. On the other hand, there were similar death in the EES group and DCB group from
1 to 3 years in the RIBS V trial. Thus, whether the potential long-term benefit of DCB compared to addition
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stent implantation remains to be seen(27) .
The limitations of the current study are henceforth highlighted. Firstly, The RIBS IV trial contributed
significantly in the endpoint of TLR in favor of DES on the basis of our sensitivity analysis(11) . The RIBS IV and
RIBS V trial, which account for nearly 64% of studied patient populations in this meta-analysis, allowed acute
pre-dilatation residual stenosis of up to 50 % before DCB application. This is in strong opposition to what is
accepted by most high volume DCB centers and published as the German Consensus Recommendations(10).
Therefore, it is clear that lower acute gains of DCB treatment arm in these 2 trials were documented
compared to other trials. Moreover, our study presented high heterogeneities in the majority of angiographic
and clinical outcomes, which were mainly driven by the TIS trial(15). The extensive inclusion criteria and
small including patients number induce more severe ISR lesions (regarding both minimal lumen diameter and
percent diameter stenosis) and frequently unfavorable pattern (regarding type of occlusion and proliferative)
allocated in the new-generation DES group (28-29). Compared with other including trails, the use of scoring
balloon catheters and implantation of another bail-out stent were more aggressive in TIS trial. The
proportion of usage of scoring balloon pre-dilation, which may have a potential role in improving the
anti-proliferation potency of DCB(30), were significant higher in the DCB group(15, 28). Therefore, further
researches with a careful follow-up protocol and large sample size should be performed to provide more
confirmative information.
Future perspectives
Currently, new-generation DES represents a superior treatment strategy with similar safety and improved
angiographic and clinical efficacy at short-term follow-up, which suggested a potential benefit of the use of
new-generation DES for coronary ISR. But both new-generation DES and DCB for the treatment of ISR are on
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the same class I (A) recommendation in the latest European Society of Cardiology guideline on myocardial
revascularization(1). Although new-generation DES reduce the possibility of recurrent ISR, the risk remains
high as multilayers of metal stents in the vessel wall will entail difficulty in further treatments and an
inherent poorer clinical prognosis(31). Bioresorbable scaffold (BRS) with proven safety and efficacy profiles
for ISR while avoiding in the mid-long term an additional metal layer may be an alternative treatment choice
in the future (32, 33). The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs. Drug Coated Balloon for
Treatment of In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable vascular scaffold with DCB to
treat ISR will shed light in terms of clinical utility of BRS for coronary ISR. However for patients with
intolerable long-term dual antiplatelet therapy or high risk of bleeding, DCB may be more suitable.
Furthermore, researchers should pursue further optimization of DCB and its auxiliary strategy(34, 35), such
as use of scoring balloon before DCB (30).
Limitations
The following potential limitations of the present study are acknowledged. Firstly, the results were based on
the trial level and shares the limitations of the original trials. Secondly, the studied DCB group included
Sequent PleaseTM
and Pantera LuxTM
paclitaxel-eluting balloons, which have different coatings design, as well
as the implemental methods of DCB in individual trials(10). Thirdly, the definitions of clinical and
angiographic parameters were not identical in some studies. Finally, in light of the fairly highly selected
criteria in our study, only a total of 913 patients were enrolled. However, our study demonstrates the largest
patient population presenting with ISR and is likely to remain the most powerful evidence base for evaluation
of DCB versus new-generation DES.
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Conclusions
New-generation DES seems an acceptable treatment strategy with comparable safety and favorable
angiographic and clinical efficacy compared to DCB for coronary ISR at short term follow-up. But either new
generation DES or DCB should be recommended as the first choice in the setting of patients with ISR still
relies on further larger scale, longer-term follow-up and randomized trials.
Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, WXY, ZH, BC, DXJ and IJ conceived the study design. CJZ,
ZYX, WXY, ZH and MA performed the report screening, study inclusion, data extraction. CP, MA, DXJ and ZH
analysis the data. ZYJ, CJZ, ZYX, WXY, BC, IJ, CP and MA drafted the manuscript. CP, MA, DXJ and ZH reviewed
the manuscript for important intellectual content. All authors have significantly contributed to the design of study,
analysis of data and drifting or revising manuscript. All authors have read and approved this article.
Funding: This work was supported by Medical Science and technology development Foundation, Nanjing
Department of Health [YKK15100], and Key Project of Nanjing Science and Technology Development
Foundation [201503024]. For the others authors none were declared.
Competing interests: The authors declare that there is no conflict of interest.
Data sharing statement: no additional data are available.
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Figure legends
Figure 1
Title: Flow diagram of meta-analysis
Figure 2
Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR,
(B) TVR, and (C) MACE.
Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse
cardiac events; TLR = target lesion revascularization; TVR= target vessel revascularization.
Figure 3
Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent
thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
Figure 4
Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute
lumen gain, and (B) % DS.
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Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
Figure 5
Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD,
(B) binary restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen
diameter; LLL = late lumen loss.
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Figure 1 Flow diagram of meta- analysis
191x165mm (300 x 300 DPI)
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Figure 2 Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR, (B) TVR,
and (C) MACE. Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse cardiac
events; TLR = target lesion revascularization; TVR= target vessel revascularization.
254x190mm (300 x 300 DPI)
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Figure 3 Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
254x190mm (300 x 300 DPI)
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Figure 4 Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute lumen gain, and (B) % DS.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
254x124mm (300 x 300 DPI)
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Figure 5 Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD, (B) binary restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen diameter; LLL = late lumen loss.
254x185mm (300 x 300 DPI)
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Supplement
Figure 1
Title: Risk of bias
Caption: Proportions of studies classified as having low (green), unclear (yellow), and high (red) risk of bias across domains of study quality.
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Figure 2
Title: Publication biases.
Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target vessel revascularization, (C) major adverse cardiac events, (D)
myocardial infarction, (E) cardiac death, and (F) stent thrombosis.
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Table 1 Patient characteristics
Study Age Male Hypertension Diabetes mellitus Dyslipidemia Previous MI Multi-vessel
DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)
RIBS IV 66 (10) 66 (10) 127 (82) 130 (84) 110 (71) 121 (78) 75 (49) 66 (43) 110 (71) 121 (78) 73 (47) 77 (50) n/a n/a
SEDUCE 68 (8) 64 (11) 18 (72) 25 (100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a
RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a
BILUX RCT 67 (10) 69 (9) 122 (78) 49 (68) 144 (92) 70 (97) 48 (31) 24 (33) 134 (85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)
Values are mean (SD) or n (%).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; EES = everolimus-eluting stents; n/a = not available; MI = myocardial
infarction.
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Table 2 Angiographic characteristics
Study length of pre-stent Mehran III-IV Pre-%DS Pre-MLD Pre-RVD
DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92 (0.5) 0.79 (0.5) 2.64 (0.5) 2.66 (0.5)
RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79 (0.4) 0.75 (0.4) 2.59 (0.5) 2.67 (0.5)
SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98 (0.6) 0.57 (0.4) 3.0 (0.5) 2.85 (0.4)
RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02 (0.4) 0.93 (0.4) 2.64 (0.6) 2.64 (0.6)
BIOLUX RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)
Values are mean (SD).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; DS = diameter stenosis; MLD = minimum lumen diameter; RVD = reference
vessel diameter; n/a = not available.
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Table 3 Search strategy for the Pubmed electronic database
#1 restenosis
#2 coronary
#3 #1 and #2
#4 eluting stent[Title/Abstract]
#5 eluting balloon[Title/Abstract]
#6 drug eluting balloon[Title/Abstract]
#7 #5 or #6
#8 #6 and #4
#9 #3 and #8
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Section/topic # Checklist item Reported on page #
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 3
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
3
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale. 4
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
4
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
4
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis). 4
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
4
Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
4-5
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 4-5
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I
2) for each meta-analysis.
4-5
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Page 1 of 2
Section/topic # Checklist item Reported on page #
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
4-5
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
4-5
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
5-6
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
5-6
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5-6
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
6-7
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6-7
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 8
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 8
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
8-11
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
11
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 12
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
12
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
For more information, visit: www.prisma-statement.org.
Page 2 of 2
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Comparison of new-generation drug-eluting stents versus drug-coated balloon for in-stent restenosis: A meta-analysis
of randomized controlled trials
Journal: BMJ Open
Manuscript ID bmjopen-2017-017231.R2
Article Type: Research
Date Submitted by the Author: 09-Oct-2017
Complete List of Authors: Cai, Jin-Zan; Nanjing Medical University Zhu, Yong-Xiang ; Nanjing Medical University Wang, Xin-Yu; Xuzhou Cancer Hospital, Jiangsu University, Department of
Cardiology Bourantas, Christos ; University College London, Cardiovascular Sciences Iqbal, Javaid; Barts Heart Centre, Department of Cardiology Zhu, Hao; Nanjing Medical University Cummins, Paul ; Erasmus MC, Rotterdam, Department of Cardiology Dong, Sheng-Jie; Yantaishan hospital, Department of the Joint and Bone Surgery Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun; Xuzhou Cancer Hospital, Nanjing Medical University, Department of Cardiology
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Cardiovascular medicine
Keywords: Drug-coated balloon, Drug-eluting stents, In-stent restenosis, Meta-analysis
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Title page
Comparison of new-generation drug-eluting stents versus drug-coated balloon for
in-stent restenosis: A meta-analysis of randomized controlled trials
Authors: Jin-Zan Cai1, MSc; Yong-Xiang Zhu
1, MSc; Xin-Yu Wang
2, BSc; Christos V. Bourantas
3, 4, PhD; Javaid
Iqbal5, PhD; Hao Zhu
1, MSc; Paul Cummins
6, BSc; Sheng-jie Dong
7, PhD; Anthony Mathur
4, PhD; Yao-Jun
Zhang2* PhD
Cai JZ, Zhu YX, and Wang XY are equally contributed to this manuscript.
Author Affiliations:
1Nanjing Medical University, Nanjing, China;
2Xuzhou Cancer Hospital, Nanjing Medical University, Nanjing, China;
3Sheffield Teaching Hospitals and the University of Sheffield, Sheffield, United Kingdom;
4Department of Cardiovascular Sciences, University College London, London, UK;
5Department of Cardiology, Barts Heart Centre, London, UK;
6Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands;
7Department of the Joint and Bone Surgery, Yantaishan hospital, Yantai, China;
Running title: DES versus DCB for ISR
*Correspondence to:
Yao-Jun Zhang MD, PhD, FESC
No. 131, Huancheng Road, Xuzhou, 221005, China
Email: [email protected]; Tel & Fax: +86-0516-85538617
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Abstract
Objective: The study sought to compare angiographic and clinical outcomes of new-generation drug-eluting
stents (DES) versus drug-coated balloon (DCB) in patients with coronary in-stent restenosis (ISR).
Design: Meta-analysis using data from randomised trial found by searches on PubMed, the Cochrane Library,
Clinicaltrials.gov, and websites of major cardiovascular congresses.
Setting: Only randomised trials comparing DES with DCB was included.
Participants: Patients with ISR in the including trials.
Interventions: new-generation DES versus DCB.
Outcomes: The angiographic and clinical outcomes including cardiac death, all-cause death, myocardial
infarction, target lesion revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac
events (MACE), and stent thrombosis were investigated.
Results: Five trials including 913 patients were eligible and included. Pooled analysis in angiographic results
identified that new-generation DES were associated with higher acute luminal gain (-0.31 mm, 95% CI: -0.42
to -0.20, p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04). DES significantly
reduced the risk of TLR (RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01) compared with DCB; however there was no
statistical differences for MACE (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53), myocardial infarction (RR: 1.16, 95%
CI: 0.55 to 2.48, p=0.69), and cardiac death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29).
Conclusions: Interventions with new-generation DES appears to be associated with significant reduction in %
diameter stenosis and TLR at short-term follow-up, but had similar MACE, myocardial infarction, and cardiac
death for coronary ISR patients compared to DCB. Appropriately powered studies with longer term follow-up
are warranted to confirm these findings.
Keywords: Drug-coated balloon; Drug-eluting stents; In-stent restenosis; Meta-analysis.
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Strengths and limitations of this study
1、 Only randomized trials comparing DES with DCB for patients with ISR were allowed to include in this
meta-analysis.
2、、、、 This study includes the largest patient population presenting with ISR.
3、、、、 The results were based on the trial level and share the limitations of the original trials.
Introduction
Percutaneous coronary intervention with bare-metal stents (BMS) or drug-eluting stents (DES) has become
one of the most frequently performed therapeutic procedures for coronary artery disease(1). The rate of
in-stent restenosis (ISR) in clinical practice is nearly 5% of patients treated with DES and 10% with BMS after
5 years(2). Given the number of patients undergoing a stent implantation, which amounts to approximately
one million per annum in USA, ISR will continue to remain an undesirable adverse outcome(3).
The management of patients with ISR remains challenging. Currently, the treatment strategies for ISR mainly
include cutting balloon angioplasty, plain old balloon angioplasty, drug-coated balloon (DCB) and DES(4).
Several recent studies have reported that both new-generation DES and DCB are superior to other
interventional strategies for ISR(5-12). Moreover, recent guidelines on myocardial revascularization from the
European Society of Cardiology recommends DCB and new-generation DES (class I, level A) for patients
presenting with ISR(1). However, published literature comparing new-generation DES versus DCB in
randomized settings conclude with diverging results(8, 13-17). Additionally, these studies were constrained
by the small sample size. To overcome these limitation, we performed a meta-analysis of randomized
controlled trials to compare the clinical and angiographic outcomes results of new-generation DES versus
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DCB in patients with coronary ISR.
Methods
Search strategy and selection criteria
Randomized trials comparing new-generation DES versus DCB for coronary ISR were searched in PubMed,
the Cochrane Library, and Clinicaltrials.gov as well as the websites of major cardiovascular congresses. The
subject keywords included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting
stent(s), and randomized trial were applied to identify studies. The last search was performed on September
12th, 2016 by two independent investigators (Cai JZ and Zhu YX). All studies comparing new-generation DES
versus DCB irrespective of patients presenting with any types of ISR were included.
Data extraction and quality assessment
Two investigators (Cai JZ and Zhu YX) independently screened the title and abstract of retrieved reports,
reviewed the full articles of relevant citations in detail, and extracted study characteristics, angiographic, and
longest available clinical outcomes. Any discrepancies or disagreements were settled by a third investigator
(Zhang YJ). The following variables were extracted from all eligible studies: enrollment periods, patient
characteristics, types of ISR, definition of ISR, follow-up duration, dual antiplatelet therapy, and clinical and
angiographic outcomes. The risk of bias for individual trials was assessed in accordance with the Cochrane
Collaboration’s tool(18).
Angiographic and clinical outcomes
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The clinical outcomes of interest were cardiac death, all-cause death, myocardial infarction, target lesion
revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac events (MACE), and stent
thrombosis. TLR was defined as any repeated revascularization involving the target lesion. MACE was defined
as individual trial. The angiographic endpoints were minimum lumen diameter (MLD), late lumen loss (LLL)
and % diameter stenosis at 6 to 12 months. In-segment (the treated segment plus 5 mm proximal/distal
margins) measurements were adopted for the analyses, but in-stent parameters was incorporated if
in-segment data were not available.
Statistical analysis
Risk ratio (RR) and mean differences with 95% confidence interval (CI) were utilized as summary statistics.
The Mantel-Haenszel fixed-effects model and Inverse Variance fixed-effects model were used for categorical
variables and continuous variables, respectively. We calculated the I2 index and performed chi-square test to
measure statistical heterogeneity among studies. An I2 > 50% was considered as significant heterogeneity. A
random-effects model was performed to calculate the risk estimation if a significant heterogeneity was
detected. Sensitivity analyses were carried out by excluding the studies with a high level of risk of bias, and
including only studies with a low proportion of missing data. We also repeated analyses in the subsets of
studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents, and patients only with
BMS-ISR. The Egger’s linear regression tests were employed to test for funnel plot asymmetry at the p<0.10
level of significance. However, the analysis for publication bias can only be tentative, as there is not enough
power to support the test results due to the limited number of studies included. All the statistical analyses
were performed using STATA Version 13.0 (Stata Corp., College Station, TX, USA) and Review Manager Version
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5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).
Results
Five trials with a total of 913 patients treated either with new-generation DES (n=414) or DCB (n=499) were
eligible and included(8, 13-17). The screening process is described in Figure 1. The median sample size were
189 (interquartile range 83-269). Only the TIS trial was single center, and the others were multicentre.
Patients enrolled were from Czech in TIS trial, Spain in RIBS IV and RIBS V trials, Belgium in SEDUCE trial, and
Germany and Latvia in BIOLUX RCT. All trial had a high risk of bias with respect to performance bias and the
details of methodology in BIOLUX RCT trial was not available. The summary of risk judgment in individual
trials is showed in Supplement Figure 1. The trial, patient and angiographic characteristics are summarized
(Table 1, Supplement Table 1 and 2). Apart from 229 patients (25.1%) with mixed types of ISR in 1 trial(17),
309 patients (33.9%) with DES-ISR were recruited in 1 trial(8), while 375 patients (41.0%) with BMS-ISR were
in 3 trials(14-16). The patients follow up ranged from 6 to 12 months angiographically, and 12 to 36 months
clinically.
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Table
Table 1 Main characteristics of the included trials
Study Type Treatment arms Sampl
e size
Definition
of ISR
Follow-up, months DAPT,
months Definition of MACE
Angiograph
ic Clinical DCB DES
TIS BMS SP
PCB PE EES 68/68 ≥50% DS 12 12 3 6-12 Death, any MI, and TVR
RIBS IV DES SP
PCB XP EES
154/15
5 ≥50% DS 9 12 3 12 Death, MI, and TLR
SEDUCE BMS SP
PCB XP EES 25/25 >70% DS 9 12 n/a n/a n/a
RIBS V BMS SP
PCB XP EES 95/94 ≥50% DS 9 36 3 12 Death, MI, and TLR
BILUX
RCT Both PL PCB
Orsiro
SES 157/72 n/a 6 12 n/a n/a
Cardiac death, MI, and
TLR
Abbreviations: BMS = bare-metal stents; CAG = coronary angiography; DAPT = dual antiplatelet therapy; DCB =
drug-eluting balloon; DES = drug-eluting stents; DS=diameter stenosis; ISR=in-stent restenosis; MACE = major adverse
cardiac events; MI = myocardial infarction; n/a = not available; PE EES = Promus Element everolimus-eluting stents; PL PCB
= Pantera Lux paclitaxel-coated balloon; SES = sirolimus-eluting balloon; SP PCB = SeQuent Please paclitaxel-coated
balloon; TLR = target lesion revascularization; TVR = target vessel revascularization; XP EES = Xience Prime
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everolimus-eluting stent.
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Target lesion revascularization, target vessel revascularization, major adverse cardiac events
TLR was reported in 4 trials including 777 patients(8, 13, 16, 17). The incidence of TLR in the DCB group
(10.9%) was significantly higher than that in new-generation DES (5.2%) (RR: 1.96, 95% CI: 1.17 to 3.28,
p=0.01; I2=32%, P=0.22; Figure 2A). TVR was not available in the BIOLUX RCT trial(17). There was no
significant difference in the risk of TVR between DCB and DES (RR: 1.06, 95% CI: 0.48 to 2.34, p=0.89; I2=60%,
P=0.06; Figure 2B).
All but the SEDUCE trial reported the rates of MACE(16). The rates of MACE between DCB (14.7%) and DES
(9.0%) were comparable (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53; I2=58%, P=0.07; Figure 2C).
Cardiac death, all-cause death, myocardial infarction, and stent thrombosis
Myocardial infarction, stent thrombosis and cardiac death were all available in 5 trials but all-cause death
was not reported in the BIOLUX RCT trial(17). The pooled RR showed no significant differences in cardiac
death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29; I2=0%, P=0.92; Figure 3A) and myocardial infarction (RR: 1.16,
95% CI: 0.55 to 2.48, p=0.69; I2=0%, P=0.76; Figure 3B) between the two arms, as well as all-cause death (RR:
1.50, 95% CI: 0.62 to 3.62, p=0.37; I2=0%, P=0.55) and stent thrombosis (RR: 1.26, 95% CI: 0.39 to 4.04,
p=0.70; I2=0%, P=0.75; Figure 3C).
Angiographic endpoints
All 5 trials contributed to the angiographic follow-up results. Patients treated with new-generation DES had a
significant increase of acute luminal gain (-0.31 mm, 95% CI: -0.42 to -0.20, p<0.001; I2=52%, p=0.08; Figure
4A) and reduction of % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006; Figure 4B)
compared to DCB.
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A strong trend towards an increase in MLD (-0.23 mm, 95% CI: -0.47 to 0.01, p=0.06; I2=65%, P=0.02, Figure
5A) was noted in the new-generation DES arm but this difference was not statistically significant compared to
DCB.
All but the BIOLUS RCT trial reported the incidences of binary restenosis. Patients treated with
new-generation DES were associated with a similar risk of binary restenosis (RR: 1.25, 95% CI: 0.57 to 2.75,
p=0.58; I2=56%, P=0.08; Figure 5B) and LLL (-0.06mm, 95% CI: -0.37, 0.25, p=0.71; I
2=80%, P=0.0006; Figure
5C) compared to DCB.
Publication bias and sensitivity analyses
No publication biases were found in all clinical and angiographic outcomes (Supplement Figure 2). Sensitivity
analyses suggested that DCB was associated with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03;
I2=19%, P=0.29) as well as an increase in in MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I
2=64%, P=0.04)
and binary restenosis (RR: 1.85, 95% CI: 1.11 to 3.10, p=0.02; I2=0%, P=0.99) while excluding the TIS trial
which come from single center. Detailed methodology in BIOLUX RCT trial was not available, however MLD
remained greater in DES group when the BIOLUX RCT trial was omitted (-0.29 mm, 95% CI: -0.55 to -0.04,
p=0.03; I2=60%, P=0.06).In the setting of patients with BMS-ISR(13, 15, 16), no significant differences were
found in DCB versus new-generation DES in all angiographic and clinical outcomes except for acute luminal
gain (-0.39 mm, 95% CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).Patients treated exclusively with
everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95% CI: 1.35 to 5.18, p=0.005;
I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17, p<0.001; I
2=64%, P=0.04),
and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06;). But no statistical differences in
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other clinical and angiographic outcomes were observed between the 2 groups.
Discussion
This meta-analysis included 5 randomized trials examining the angiographic and clinical outcomes of
new-generation DES versus DCB in the treatment of any types of coronary ISR. The study, for the first time,
showed that new-generation DES appears to be associated with an improved angiographic and clinical
outcomes when compared with DCB irrespective of the types of ISR at short term follow-up. The main
findings are as follows: (1) new generation DES were associated with a significant reduction in TLR compared
to DCB at the longest available follow-up; (2) there were no statistical differences in cardiac death,
myocardial infarction, and MACE between the two treatment strategies; (3) New-generation DES were
associated with favorable angiographic results with significant increase in acute luminal gain and reduction
in % diameter stenosis at 6 to 12 months follow-up.
Previous meta-analyses
The choice of therapeutic methods for coronary ISR remains debatable. Several meta-analyses demonstrated
that DCB and DES had comparable clinical and angiographic results for patients with coronary ISR(5, 19, 20).
However obvious pitfalls existed in these studies. Firstly, Mamuti W et al.(20) combined new-generation DES
and first-generation DES in the same group, whereas cumulative evidence has illustrated the difference in
clinical performance of different generation DES(21). ILiou et al. demonstrated no superiority of the
new-generation DES over DCB but their analysis included four observational studies in which an inequality of
baseline characteristics was observed(19). A further limitation of this meta-analysis was small number of
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randomized patients (n=548 from 3 RCTs)(19). Additionally, in a Bayesian network meta-analysis comparing
the performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal
strategy with pronounced improvements in clinical outcomes6. However, the effect was mainly derived from
indirect comparison(5). In the present meta-analysis, we, for the first time, included only randomized trials of
new generation DES in comparison with DCB, so the possibility of confounders influencing estimates for
various endpoints is less likely. Furthermore, this meta-analysis included the largest number of ISR patients to
date and demonstrated that contemporary DES with improved design were associated with favorable
outcomes and a lower risk of re-intervention at mid-term follow-up, compared to DCB.
Angiographic and clinical outcomes
Compared with DCB, new-generation DES were related to favorable prognosis for coronary ISR with superior
angiographic outcomes and reduced TLR. The advantages of new-generation DES comprised of persistent
radial strength which prevents acute or subacute prolapse of the disrupted plaque and elastic recoil of the
vessel wall, sufficient antiproliferative drugs, and subsequent excellent neointimal hyperplasia inhibition
compared with DCB(8, 22). Interestingly, the rate of recurrent binary restenosis was similar in two groups.
The difference of TLR was possibly related to the factor that presence of an existing additional stent layer in
the DES group discouraged the operator from repeat intervention.
Although one may argue that DES add one more stent layer in the finite lesion segment, 80-100 μm of lumen
loss due to the implants seems negligible when considering that new generation DES assumes less
re-intervention. Although one may express concern regarding the long-term safety of stent implantation,
studies have shown that the vascular inflammatory response with the thin-strut platform profile and also its
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biocompatibility or biodegradable polymer is extremely low(4, 21, 23). The present study, however, remains
limited by its small sample size and short periods of follow-up. By virtue of previously published literature, it
is reasonable to assume that the short term (less than 1 year) benefit of new generation DES will remain
consistent.
In the RIBS V trial(13, 14), the authors have observed 1 TLR events in the EES group and 2 in the DCB group
from 1 to 3 years. In the RESTENT-ISR (Prospective Randomized Comparison of Clinical and Angiographic
Outcomes Between Everolimus-eluting vs. Zotarolimus-eluting Stents for Treatment of Coronary Restenosis
in Drug-Eluting Stents: Intravascular Ultrasound Volumetric Analysis) trial, Hong et al. reported an
approximate rate of 6.0% in late (>1 year) TLR in patients with ISR treated with everolimus-eluting stents and
zotarolimus-eluting stents(24), similar to several subgroups from all-comers study(25, 26). Similarly, rates of
TLR after 1 year of DCB angioplasty were varied between 0% to 10%(6, 7, 11, 12). The ISAR-DESIRE 3 and
PEPCAD China trials have shown a late mortality benefit of DCB treatment vs. first generation DES treatment
on longer follow up. On the other hand, there were similar death in the EES group and DCB group from 1 to 3
years in the RIBS V trial. Thus, any potential long-term benefit of DCB compared with additional new
generation DES implantation remains unproven(27).
The studies included in this meta-analysis have several differences. Firstly, The RIBS IV trial contributed
significantly in the endpoint of TLR in favor of DES on the basis of our sensitivity analysis(11) . The RIBS IV and
RIBS V trial, which account for nearly 64% of studied patient populations in this meta-analysis, allowed acute
pre-dilatation residual stenosis of up to 50 % before DCB application. This is in strong opposition to what is
accepted by most high volume DCB centers and published as the German Consensus Recommendations(10).
Moreover, our study presented high heterogeneities in the majority of angiographic and clinical outcomes,
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which were mainly driven by the TIS trial(15). TIS trial had small sample size and extensive
inclusion/exclusion criteria(28-29). Furthermore, the use of scoring balloons and implantation of another
bail-out stent were more common in TIS trial, which may have a potential role in improving the
anti-proliferation potency of DCB(30). Further researches with a careful follow-up protocol and large sample
size should be performed to provide more confirmative information.
Future perspectives
Both new-generation DES and DCB for the treatment of ISR are on the same class I (A) recommendation in
the latest European Society of Cardiology guideline on myocardial revascularization(1). However, our
meta-analysis suggests that new-generation DES represent a superior treatment strategy with similar safety
and improved angiographic and clinical efficacy at short-term follow-up. Nevertheless, concerns remain
about multilayers of metal stents in the vessel wall which may entail difficulty in further treatments and an
inherent poorer clinical prognosis(31). Similarly, for patients with intolerable long-term dual antiplatelet
therapy or high risk of bleeding, DCB may be more suitable. Bioresorbable scaffold (BRS) may be an
alternative treatment choice in the future (32, 33). The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs.
Drug Coated Balloon for Treatment of In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable
vascular scaffold with DCB to treat ISR will shed light in terms of clinical utility of BRS for coronary ISR. Finally,
further refinements in DCB technology and auxiliary strategies (34, 35), such as use of scoring balloon before
DCB (30), are warranted.
Limitations
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The following potential limitations of the present study are acknowledged. Firstly, the results were based on
the trial level and shares the limitations of the original trials. Secondly, the studied DCB group included
Sequent PleaseTM
and Pantera LuxTM
paclitaxel-eluting balloons, which have different coatings design, as well
as the implemental methods of DCB in individual trials(10). Thirdly, the definitions of clinical and
angiographic parameters were not identical in some studies. Finally, in light of the fairly highly selected
criteria in our study, only a total of 913 patients were enrolled. However, our study demonstrates the largest
patient population presenting with ISR and is likely to remain the most powerful evidence base for evaluation
of DCB versus new-generation DES.
Conclusions
New-generation DES seems an acceptable treatment strategy with comparable safety and favorable
angiographic and clinical efficacy compared to DCB for coronary ISR at short term follow-up. Further larger
scale randomized trials with longer term follow-up are warranted.
Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, WXY, ZH, BC, DSJ and IJ conceived the study design. CJZ,
ZYX, WXY, ZH and MA performed the report screening, study inclusion, data extraction. CP, MA, DSJ and ZH
analysis the data. ZYJ, CJZ, ZYX, WXY, BC, IJ, CP and MA drafted the manuscript. CP, MA, DSJ and ZH reviewed
the manuscript for important intellectual content. All authors have significantly contributed to the design of study,
analysis of data and drifting or revising manuscript. All authors have read and approved this article.
Funding: This work was supported by Medical Science and technology development Foundation, Nanjing
Department of Health [YKK15100], Key Project of Nanjing Science and Technology Development Foundation
[201503024], and six talent peaks project [WSN-212]. For the others authors none were declared.
Competing interests: The authors declare that there is no conflict of interest.
Data sharing statement: no additional data are available.
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Figure legends
Figure 1
Title: Flow diagram of meta-analysis
Figure 2
Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR,
(B) TVR, and (C) MACE.
Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse
cardiac events; TLR = target lesion revascularization; TVR= target vessel revascularization.
Figure 3
Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent
thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
Figure 4
Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute
lumen gain, and (B) % DS.
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Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
Figure 5
Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD,
(B) binary restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen
diameter; LLL = late lumen loss.
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Figure 1 Flow diagram of meta- analysis
191x165mm (300 x 300 DPI)
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Figure 2 Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR, (B) TVR,
and (C) MACE. Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse cardiac
events; TLR = target lesion revascularization; TVR= target vessel revascularization.
254x190mm (300 x 300 DPI)
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Figure 3 Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
254x190mm (300 x 300 DPI)
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Figure 4 Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute lumen gain, and (B) % DS.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
254x124mm (300 x 300 DPI)
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Figure 5 Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD, (B) binary restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen diameter; LLL = late lumen loss.
254x185mm (300 x 300 DPI)
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Supplement
Figure 1
Title: Risk of bias
Caption: Proportions of studies classified as having low (green), unclear (yellow), and high (red) risk of bias across domains of study quality.
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Figure 2
Title: Publication biases.
Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target vessel revascularization, (C) major adverse cardiac events, (D)
myocardial infarction, (E) cardiac death, and (F) stent thrombosis.
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Table 1 Patient characteristics
Study Age Male Hypertension Diabetes mellitus Dyslipidemia Previous MI Multi-vessel
DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)
RIBS IV 66 (10) 66 (10) 127 (82) 130 (84) 110 (71) 121 (78) 75 (49) 66 (43) 110 (71) 121 (78) 73 (47) 77 (50) n/a n/a
SEDUCE 68 (8) 64 (11) 18 (72) 25 (100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a
RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a
BILUX RCT 67 (10) 69 (9) 122 (78) 49 (68) 144 (92) 70 (97) 48 (31) 24 (33) 134 (85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)
Values are mean (SD) or n (%).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; EES = everolimus-eluting stents; n/a = not available; MI = myocardial
infarction.
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Table 2 Angiographic characteristics
Study length of pre-stent Mehran III-IV Pre-%DS Pre-MLD Pre-RVD
DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92 (0.5) 0.79 (0.5) 2.64 (0.5) 2.66 (0.5)
RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79 (0.4) 0.75 (0.4) 2.59 (0.5) 2.67 (0.5)
SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98 (0.6) 0.57 (0.4) 3.0 (0.5) 2.85 (0.4)
RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02 (0.4) 0.93 (0.4) 2.64 (0.6) 2.64 (0.6)
BIOLUX RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)
Values are mean (SD).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; DS = diameter stenosis; MLD = minimum lumen diameter; RVD = reference
vessel diameter; n/a = not available.
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Table 3 Search strategy for the Pubmed electronic database
#1 restenosis
#2 coronary
#3 #1 and #2
#4 eluting stent[Title/Abstract]
#5 eluting balloon[Title/Abstract]
#6 drug eluting balloon[Title/Abstract]
#7 #5 or #6
#8 #6 and #4
#9 #3 and #8
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Section/topic # Checklist item Reported on page #
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 3
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
3
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale. 4
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
4
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
4
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis). 4
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
4
Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
4-5
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 4-5
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I
2) for each meta-analysis.
4-5
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Page 1 of 2
Section/topic # Checklist item Reported on page #
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
4-5
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
4-5
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
5-6
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
5-6
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5-6
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
6-7
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6-7
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 8
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 8
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
8-11
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
11
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 12
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
12
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
For more information, visit: www.prisma-statement.org.
Page 2 of 2
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Comparison of new-generation drug-eluting stents versus drug-coated balloon for in-stent restenosis: A meta-analysis
of randomized controlled trials
Journal: BMJ Open
Manuscript ID bmjopen-2017-017231.R3
Article Type: Research
Date Submitted by the Author: 22-Jan-2018
Complete List of Authors: Cai, Jin-Zan; Nanjing Medical University Zhu, Yong-Xiang ; Nanjing Medical University Wang, Xin-Yu; Xuzhou Cancer Hospital, Jiangsu University, Department of
Cardiology Bourantas, Christos ; University College London, Cardiovascular Sciences Iqbal, Javaid; Barts Heart Centre, Department of Cardiology Zhu, Hao; Nanjing Medical University Cummins, Paul ; Erasmus MC, Rotterdam, Department of Cardiology Dong, Sheng-Jie; Yantaishan hospital, Department of the Joint and Bone Surgery Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun; Xuzhou Cancer Hospital, Nanjing Medical University, Department of Cardiology
<b>Primary Subject Heading</b>:
Cardiovascular medicine
Secondary Subject Heading: Cardiovascular medicine
Keywords: Drug-coated balloon, Drug-eluting stents, In-stent restenosis, Meta-analysis
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Title page
Comparison of new-generation drug-eluting stents versus drug-coated balloon for
in-stent restenosis: A meta-analysis of randomized controlled trials
Authors: Jin-Zan Cai1, MSc; Yong-Xiang Zhu
1, MSc; Xin-Yu Wang
2, BSc; Christos V. Bourantas
3, 4, PhD; Javaid
Iqbal5, PhD; Hao Zhu
1, MSc; Paul Cummins
6, BSc; Sheng-jie Dong
7, PhD; Anthony Mathur
4, PhD; Yao-Jun
Zhang2* PhD
Cai JZ, Zhu YX, and Wang XY are equally contributed to this manuscript.
Author Affiliations:
1Nanjing Medical University, Nanjing, China;
2Xuzhou Cancer Hospital, Nanjing Medical University, Nanjing, China;
3Sheffield Teaching Hospitals and the University of Sheffield, Sheffield, United Kingdom;
4Department of Cardiovascular Sciences, University College London, London, UK;
5Department of Cardiology, Barts Heart Centre, London, UK;
6Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands;
7Department of the Joint and Bone Surgery, Yantaishan hospital, Yantai, China;
Running title: DES versus DCB for ISR
*Correspondence to:
Yao-Jun Zhang MD, PhD, FESC
No. 131, Huancheng Road, Xuzhou, 221005, China
Email: [email protected]; Tel & Fax: +86-0516-85538617
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Abstract
Objective: The study sought to compare angiographic and clinical outcomes of new-generation drug-eluting
stents (DES) versus drug-coated balloon (DCB) in patients with coronary in-stent restenosis (ISR).
Design: Meta-analysis using data from randomised trial found by searches on PubMed, the Cochrane Library,
Clinicaltrials.gov, and websites of major cardiovascular congresses.
Setting: Only randomised trials comparing DES with DCB was included.
Participants: Patients with ISR in the including trials.
Interventions: new-generation DES versus DCB.
Outcomes: The angiographic and clinical outcomes including cardiac death, all-cause death, myocardial
infarction, target lesion revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac
events (MACE), and stent thrombosis were investigated.
Results: Five trials including 913 patients were eligible and included. Pooled analysis in angiographic results
identified that new-generation DES were associated with higher acute luminal gain (-0.31 mm, 95% CI: -0.42
to -0.20, p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04). DES significantly
reduced the risk of TLR (RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01) compared with DCB; however there was no
statistical differences for MACE (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53), myocardial infarction (RR: 1.16, 95%
CI: 0.55 to 2.48, p=0.69), and cardiac death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29).
Conclusions: Interventions with new-generation DES appears to be associated with significant reduction in %
diameter stenosis and TLR at short-term follow-up, but had similar MACE, myocardial infarction, and cardiac
death for coronary ISR patients compared to DCB. Appropriately powered studies with longer term follow-up
are warranted to confirm these findings.
Keywords: Drug-coated balloon; Drug-eluting stents; In-stent restenosis; Meta-analysis.
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Strengths and limitations of this study
- Only randomized trials comparing DES with DCB for patients with ISR were allowed to include in this
meta-analysis.
- This study includes the largest patient population presenting with ISR.
- The results were based on the trial level and share the limitations of the original trials.
Introduction
Percutaneous coronary intervention with bare-metal stents (BMS) or drug-eluting stents (DES) has become
one of the most frequently performed therapeutic procedures for coronary artery disease(1). The rate of
in-stent restenosis (ISR) in clinical practice is nearly 5% of patients treated with DES and 10% with BMS after
5 years(2). Given the number of patients undergoing a stent implantation, which amounts to approximately
one million per annum in USA, ISR will continue to remain an undesirable adverse outcome(3).
The management of patients with ISR remains challenging. Currently, the treatment strategies for ISR mainly
include cutting balloon angioplasty, plain old balloon angioplasty, drug-coated balloon (DCB) and DES(4).
Several recent studies have reported that both new-generation DES and DCB are superior to other
interventional strategies for ISR(5-12). Moreover, recent guidelines on myocardial revascularization from the
European Society of Cardiology recommends DCB and new-generation DES (class I, level A) for patients
presenting with ISR(1). However, published literature comparing new-generation DES versus DCB in
randomized settings conclude with diverging results(8, 13-17). Additionally, these studies were constrained
by the small sample size. To overcome these limitation, we performed a meta-analysis of randomized
controlled trials to compare the clinical and angiographic outcomes results of new-generation DES versus
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DCB in patients with coronary ISR.
Methods
Search strategy and selection criteria
Randomized trials comparing new-generation DES versus DCB for coronary ISR were searched in PubMed,
the Cochrane Library, and Clinicaltrials.gov as well as the websites of major cardiovascular congresses. The
subject keywords included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting
stent(s), and randomized trial were applied to identify studies (Supplement Table 1). The last search was
performed on September 12th, 2016 by two independent investigators (Cai JZ and Zhu YX). All studies
comparing new-generation DES versus DCB irrespective of patients presenting with any types of ISR were
included.
Data extraction and quality assessment
Two investigators (Cai JZ and Zhu YX) independently screened the title and abstract of retrieved reports,
reviewed the full articles of relevant citations in detail, and extracted study characteristics, angiographic, and
longest available clinical outcomes. Any discrepancies or disagreements were settled by a third investigator
(Zhang YJ). The following variables were extracted from all eligible studies: enrollment periods, patient
characteristics, types of ISR, definition of ISR, follow-up duration, dual antiplatelet therapy, and clinical and
angiographic outcomes. The risk of bias for individual trials was assessed in accordance with the Cochrane
Collaboration’s tool(18).
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Angiographic and clinical outcomes
The clinical outcomes of interest were cardiac death, all-cause death, myocardial infarction, target lesion
revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac events (MACE), and stent
thrombosis. TLR was defined as any repeated revascularization involving the target lesion. MACE was defined
as individual trial. The angiographic endpoints were minimum lumen diameter (MLD), late lumen loss (LLL)
and % diameter stenosis at 6 to 12 months. In-segment (the treated segment plus 5 mm proximal/distal
margins) measurements were adopted for the analyses, but in-stent parameters was incorporated if
in-segment data were not available.
Statistical analysis
Risk ratio (RR) and mean differences with 95% confidence interval (CI) were utilized as summary statistics.
The Mantel-Haenszel fixed-effects model and Inverse Variance fixed-effects model were used for categorical
variables and continuous variables, respectively. We calculated the I2 index and performed chi-square test to
measure statistical heterogeneity among studies. An I2 > 50% was considered as significant heterogeneity. A
random-effects model was performed to calculate the risk estimation if a significant heterogeneity was
detected. Sensitivity analyses were carried out by excluding the studies with a high level of risk of bias, and
including only studies with a low proportion of missing data. We also repeated analyses in the subsets of
studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents, and patients only with
BMS-ISR. The Egger’s linear regression tests were employed to test for funnel plot asymmetry at the p<0.10
level of significance. However, the analysis for publication bias can only be tentative, as there is not enough
power to support the test results due to the limited number of studies included. All the statistical analyses
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were performed using STATA Version 13.0 (Stata Corp., College Station, TX, USA) and Review Manager Version
5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).
Results
Five trials with a total of 913 patients treated either with new-generation DES (n=414) or DCB (n=499) were
eligible and included(8, 13-17). The screening process is described in Figure 1. The median sample size were
189 (interquartile range 83-269). Only the TIS trial was single center, and the others were multicentre.
Patients enrolled were from Czech in TIS trial, Spain in RIBS IV and RIBS V trials, Belgium in SEDUCE trial, and
Germany and Latvia in BIOLUX RCT. All trial had a high risk of bias with respect to performance bias and the
details of methodology in BIOLUX RCT trial was not available. The summary of risk judgment in individual
trials is showed in Supplement Figure 1. The trial, patient and angiographic characteristics are summarized
(Table 1, Supplement Table 2 and 3). Apart from 229 patients (25.1%) with mixed types of ISR in 1 trial(17),
309 patients (33.9%) with DES-ISR were recruited in 1 trial(8), while 375 patients (41.0%) with BMS-ISR were
in 3 trials(14-16). The patients follow up ranged from 6 to 12 months angiographically, and 12 to 36 months
clinically.
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Table
Table 1 Main characteristics of the included trials
Study Type Treatment arms Sample
size
Definition
of ISR
Follow-up, months DAPT, months
Definition of MACE Angiographi
c Clinical DCB DES
TIS BMS SP PCB PE EES 68/68 ≥50% DS 12 12 3 6-12 Death, any MI, and TVR
RIBS IV DES SP PCB XP EES 154/155 ≥50% DS 9 12 3 12 Death, MI, and TLR
SEDUCE BMS SP PCB XP EES 25/25 >70% DS 9 12 n/a n/a n/a
RIBS V BMS SP PCB XP EES 95/94 ≥50% DS 9 36 3 12 Death, MI, and TLR
BILUX RCT Both PL PCB Orsiro SES 157/72 n/a 6 12 n/a n/a Cardiac death, MI, and TLR
Abbreviations: BMS = bare-metal stents; CAG = coronary angiography; DAPT = dual antiplatelet therapy; DCB = drug-eluting balloon;
DES = drug-eluting stents; DS=diameter stenosis; ISR=in-stent restenosis; MACE = major adverse cardiac events; MI = myocardial
infarction; n/a = not available; PE EES = Promus Element everolimus-eluting stents; PL PCB = Pantera Lux paclitaxel-coated balloon; SES =
sirolimus-eluting balloon; SP PCB = SeQuent Please paclitaxel-coated balloon; TLR = target lesion revascularization; TVR = target vessel
revascularization; XP EES = Xience Prime everolimus-eluting stent.
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Target lesion revascularization, target vessel revascularization, major adverse cardiac events
TLR was reported in 4 trials including 777 patients(8, 13, 16, 17). The incidence of TLR in the DCB group
(10.9%) was significantly higher than that in new-generation DES (5.2%) (RR: 1.96, 95% CI: 1.17 to 3.28,
p=0.01; I2=32%, P=0.22; Figure 2A). TVR was not available in the BIOLUX RCT trial(17). There was no
significant difference in the risk of TVR between DCB and DES (RR: 1.06, 95% CI: 0.48 to 2.34, p=0.89; I2=60%,
P=0.06; Figure 2B).
All but the SEDUCE trial reported the rates of MACE(16). The rates of MACE between DCB (14.7%) and DES
(9.0%) were comparable (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53; I2=58%, P=0.07; Figure 2C).
Cardiac death, all-cause death, myocardial infarction, and stent thrombosis
Myocardial infarction, stent thrombosis and cardiac death were all available in 5 trials but all-cause death
was not reported in the BIOLUX RCT trial(17). The pooled RR showed no significant differences in cardiac
death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29; I2=0%, P=0.92; Figure 3A) and myocardial infarction (RR: 1.16,
95% CI: 0.55 to 2.48, p=0.69; I2=0%, P=0.76; Figure 3B) between the two arms, as well as all-cause death (RR:
1.50, 95% CI: 0.62 to 3.62, p=0.37; I2=0%, P=0.55) and stent thrombosis (RR: 1.26, 95% CI: 0.39 to 4.04,
p=0.70; I2=0%, P=0.75; Figure 3C).
Angiographic endpoints
All 5 trials contributed to the angiographic follow-up results. Patients treated with new-generation DES had a
significant increase of acute luminal gain (-0.31 mm, 95% CI: -0.42 to -0.20, p<0.001; I2=52%, p=0.08; Figure
4A) and reduction of % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006; Figure 4B)
compared to DCB.
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A strong trend towards an increase in MLD (-0.23 mm, 95% CI: -0.47 to 0.01, p=0.06; I2=65%, P=0.02, Figure
5A) was noted in the new-generation DES arm but this difference was not statistically significant compared to
DCB.
All but the BIOLUS RCT trial reported the incidences of binary restenosis. Patients treated with
new-generation DES were associated with a similar risk of binary restenosis (RR: 1.25, 95% CI: 0.57 to 2.75,
p=0.58; I2=56%, P=0.08; Figure 5B) and LLL (-0.06mm, 95% CI: -0.37, 0.25, p=0.71; I
2=80%, P=0.0006; Figure
5C) compared to DCB.
Publication bias and sensitivity analyses
No publication biases were found in all clinical and angiographic outcomes (Supplement Figure 2). Sensitivity
analyses suggested that DCB was associated with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03;
I2=19%, P=0.29) as well as an increase in in MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I
2=64%, P=0.04)
and binary restenosis (RR: 1.85, 95% CI: 1.11 to 3.10, p=0.02; I2=0%, P=0.99) while excluding the TIS trial
which come from single center. Detailed methodology in BIOLUX RCT trial was not available, however MLD
remained greater in DES group when the BIOLUX RCT trial was omitted (-0.29 mm, 95% CI: -0.55 to -0.04,
p=0.03; I2=60%, P=0.06).In the setting of patients with BMS-ISR(13, 15, 16), no significant differences were
found in DCB versus new-generation DES in all angiographic and clinical outcomes except for acute luminal
gain (-0.39 mm, 95% CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).Patients treated exclusively with
everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95% CI: 1.35 to 5.18, p=0.005;
I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17, p<0.001; I
2=64%, P=0.04),
and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06;). But no statistical differences in
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other clinical and angiographic outcomes were observed between the 2 groups.
Discussion
This meta-analysis included 5 randomized trials examining the angiographic and clinical outcomes of
new-generation DES versus DCB in the treatment of any types of coronary ISR. The study, for the first time,
showed that new-generation DES appears to be associated with an improved angiographic and clinical
outcomes when compared with DCB irrespective of the types of ISR at short term follow-up. The main
findings are as follows: (1) new generation DES were associated with a significant reduction in TLR compared
to DCB at the longest available follow-up; (2) there were no statistical differences in cardiac death,
myocardial infarction, and MACE between the two treatment strategies; (3) New-generation DES were
associated with favorable angiographic results with significant increase in acute luminal gain and reduction
in % diameter stenosis at 6 to 12 months follow-up.
Previous meta-analyses
The choice of therapeutic methods for coronary ISR remains debatable. Several meta-analyses demonstrated
that DCB and DES had comparable clinical and angiographic results for patients with coronary ISR(5, 19, 20).
However obvious pitfalls existed in these studies. Firstly, Mamuti W et al.(20) combined new-generation DES
and first-generation DES in the same group, whereas cumulative evidence has illustrated the difference in
clinical performance of different generation DES(21). ILiou et al. demonstrated no superiority of the
new-generation DES over DCB but their analysis included four observational studies in which an inequality of
baseline characteristics was observed(19). A further limitation of this meta-analysis was small number of
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randomized patients (n=548 from 3 RCTs)(19). Additionally, in a Bayesian network meta-analysis comparing
the performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal
strategy with pronounced improvements in clinical outcomes6. However, the effect was mainly derived from
indirect comparison(5). In the present meta-analysis, we, for the first time, included only randomized trials of
new generation DES in comparison with DCB, so the possibility of confounders influencing estimates for
various endpoints is less likely. Furthermore, this meta-analysis included the largest number of ISR patients to
date and demonstrated that contemporary DES with improved design were associated with favorable
outcomes and a lower risk of re-intervention at mid-term follow-up, compared to DCB.
Angiographic and clinical outcomes
Compared with DCB, new-generation DES were related to favorable prognosis for coronary ISR with superior
angiographic outcomes and reduced TLR. The advantages of new-generation DES comprised of persistent
radial strength which prevents acute or subacute prolapse of the disrupted plaque and elastic recoil of the
vessel wall, sufficient antiproliferative drugs, and subsequent excellent neointimal hyperplasia inhibition
compared with DCB(8, 22). Interestingly, the rate of recurrent binary restenosis was similar in two groups.
The difference of TLR was possibly related to the factor that presence of an existing additional stent layer in
the DES group discouraged the operator from repeat intervention.
Although one may argue that DES add one more stent layer in the finite lesion segment, 80-100 μm of lumen
loss due to the implants seems negligible when considering that new generation DES assumes less
re-intervention. Although one may express concern regarding the long-term safety of stent implantation,
studies have shown that the vascular inflammatory response with the thin-strut platform profile and also its
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biocompatibility or biodegradable polymer is extremely low(4, 21, 23). The present study, however, remains
limited by its small sample size and short periods of follow-up. By virtue of previously published literature, it
is reasonable to assume that the short term (less than 1 year) benefit of new generation DES will remain
consistent.
In the RIBS V trial(13, 14), the authors have observed 1 TLR events in the EES group and 2 in the DCB group
from 1 to 3 years. In the RESTENT-ISR (Prospective Randomized Comparison of Clinical and Angiographic
Outcomes Between Everolimus-eluting vs. Zotarolimus-eluting Stents for Treatment of Coronary Restenosis
in Drug-Eluting Stents: Intravascular Ultrasound Volumetric Analysis) trial, Hong et al. reported an
approximate rate of 6.0% in late (>1 year) TLR in patients with ISR treated with everolimus-eluting stents and
zotarolimus-eluting stents(24), similar to several subgroups from all-comers study(25, 26). Similarly, rates of
TLR after 1 year of DCB angioplasty were varied between 0% to 10%(6, 7, 11, 12). The ISAR-DESIRE 3 and
PEPCAD China trials have shown a late mortality benefit of DCB treatment vs. first generation DES treatment
on longer follow up. On the other hand, there were similar death in the EES group and DCB group from 1 to 3
years in the RIBS V trial. Thus, any potential long-term benefit of DCB compared with additional new
generation DES implantation remains unproven(27).
The studies included in this meta-analysis have several differences. Firstly, The RIBS IV trial contributed
significantly in the endpoint of TLR in favor of DES on the basis of our sensitivity analysis(11) . The RIBS IV and
RIBS V trial, which account for nearly 64% of studied patient populations in this meta-analysis, allowed acute
pre-dilatation residual stenosis of up to 50 % before DCB application. This is in strong opposition to what is
accepted by most high volume DCB centers and published as the German Consensus Recommendations(10).
Moreover, our study presented high heterogeneities in the majority of angiographic and clinical outcomes,
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which were mainly driven by the TIS trial(15). TIS trial had small sample size and extensive
inclusion/exclusion criteria(28-29). Furthermore, the use of scoring balloons and implantation of another
bail-out stent were more common in TIS trial, which may have a potential role in improving the
anti-proliferation potency of DCB(30). Further researches with a careful follow-up protocol and large sample
size should be performed to provide more confirmative information.
Future perspectives
Both new-generation DES and DCB for the treatment of ISR are on the same class I (A) recommendation in
the latest European Society of Cardiology guideline on myocardial revascularization(1). However, our
meta-analysis suggests that new-generation DES represent a superior treatment strategy with similar safety
and improved angiographic and clinical efficacy at short-term follow-up. Nevertheless, concerns remain
about multilayers of metal stents in the vessel wall which may entail difficulty in further treatments and an
inherent poorer clinical prognosis(31). Similarly, for patients with intolerable long-term dual antiplatelet
therapy or high risk of bleeding, DCB may be more suitable. Bioresorbable scaffold (BRS) may be an
alternative treatment choice in the future (32, 33). The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs.
Drug Coated Balloon for Treatment of In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable
vascular scaffold with DCB to treat ISR will shed light in terms of clinical utility of BRS for coronary ISR. Finally,
further refinements in DCB technology and auxiliary strategies (34, 35), such as use of scoring balloon before
DCB (30), are warranted.
Limitations
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The following potential limitations of the present study are acknowledged. Firstly, the results were based on
the trial level and shares the limitations of the original trials. Specially, the clinical outcomes of TLR, TVR and
MACE were only reported in four trials respectively, which may, in some degree, affect the outcomes of this
meta-analysis. Secondly, the studied DCB group included Sequent PleaseTM
and Pantera LuxTM
paclitaxel-eluting balloons, which have different coatings design, as well as the implemental methods of DCB
in individual trials(10). Thirdly, the definitions of clinical and angiographic parameters were not identical in
some studies. Finally, in light of the fairly highly selected criteria in our study, only a total of 913 patients
were enrolled. However, our study demonstrates the largest patient population presenting with ISR and is
likely to remain the most powerful evidence base for evaluation of DCB versus new-generation DES.
Conclusions
New-generation DES seems an acceptable treatment strategy with comparable safety and favorable
angiographic and clinical efficacy compared to DCB for coronary ISR at short term follow-up. Further larger
scale randomized trials with longer term follow-up are warranted.
Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, WXY, ZH, BC, DSJ and IJ conceived the study design. CJZ,
ZYX, WXY, ZH and MA performed the report screening, study inclusion, data extraction. CP, MA, DSJ and ZH
analysis the data. ZYJ, CJZ, ZYX, WXY, BC, IJ, CP and MA drafted the manuscript. CP, MA, DSJ and ZH reviewed
the manuscript for important intellectual content. All authors have significantly contributed to the design of study,
analysis of data and drifting or revising manuscript. All authors have read and approved this article.
Funding: This work was supported by Medical Science and technology development Foundation, Nanjing
Department of Health [YKK15100], Key Project of Nanjing Science and Technology Development Foundation
[201503024], and six talent peaks project [WSN-212]. For the others authors none were declared.
Competing interests: The authors declare that there is no conflict of interest.
Data sharing statement: no additional data are available.
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biodegradable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent: 3-year OCT follow-up from the
TARGET I trial. Int J Cardiovasc Imaging 2015;31:1489-96.
24. Hong SJ, Ahn CM, Kim BK, et al. Prospective randomized comparison of clinical and angiographic outcomes between
everolimus-eluting vs. zotarolimus-eluting stents for treatment of coronary restenosis in drug-eluting stents: intravascular
ultrasound volumetric analysis (RESTENT-ISR trial). Eur Heart J 2016.
25. Richardt G, Leschke M, Abdel-Wahab M, et al. Clinical outcomes of the Resolute zotarolimus-eluting stent in patients with
in-stent restenosis: 2-year results from a pooled analysis. JACC Cardiovasc Interv 2013;6:905-13.
26. Campo G, Punzetti S, Malagù M, Ferrari R,Valgimigli M. Two-year outcomes after first- or second-generation drug-eluting
stent implantation in patients with in-stent restenosis. A PRODIGY trial substudy. Int J Cardiol 2014;173:343-5.
27. De Labriolle A, Pakala R, Bonello L, Lemesle G, Scheinowitz M,Waksman R. Paclitaxel-eluting balloon: from bench to bed.
Catheter Cardiovasc Interv 2009;73:643-52.
28. Alfonso F, Cuesta J,Romaguera R. Letter by Alfonso et al Regarding Article, "Comparison of the Efficacy of Paclitaxel-Eluting
Balloon Catheters and Everolimus-Eluting Stents in the Treatment of Coronary In-Stent Restenosis: The Treatment of In-Stent
Restenosis Study". Circ Cardiovasc Interv 2016;9.
29. Habara S, Kadota K, Shimada T, et al. Late Restenosis After Paclitaxel-Coated Balloon Angioplasty Occurs in Patients With
Drug-Eluting Stent Restenosis. J Am Coll Cardiol 2015;66:14-22.
30. Robert A. B, Kufner S, Joner M, et al. Neointimal Modification with Scoring-Balloon and Efficacy of Drug-Coated Balloon
Therapy in Patients with Restenosis in Drug Eluting Coronary Stents. Available at:
https://www.tctmd.com/search?keyword=Robert%20A&type=slide&topic=&conference=&searched=true&subtype=&page=4.
Accessed Nov 17, 2016..
31. Kubo S, Kadota K, Otsuru S, et al. Optimal treatment of recurrent restenosis lesions after drug-eluting stent implantation for
in-stent restenosis lesions. EuroIntervention 2013;9:788-96.
32. Moscarella E, Ielasi A, Granata F, et al. Long-Term Clinical Outcomes After Bioresorbable Vascular Scaffold Implantation for
the Treatment of Coronary In-Stent Restenosis: A Multicenter Italian Experience. Circ Cardiovasc Interv 2016;9:e003148.
33. Jamshidi P, Nyffenegger T, Sabti Z, et al. A novel approach to treat in-stent restenosis: 6- and 12-month results using the
everolimus-eluting bioresorbable vascular scaffold. EuroIntervention 2016;11:1479-86.
34. Scheller B, Fontaine T, Mangner N, et al. A novel drug-coated scoring balloon for the treatment of coronary in-stent restenosis:
Results from the multi-center randomized controlled PATENT-C first in human trial. Catheter Cardiovasc Interv 2016;88:51-9.
35. Verheye S, Vrolix M, Kumsars I, et al. Sirolimus Eluting Angioplasty Balloon for In-Stent Restenosis SABRE Trial: 6 Month
Clinical and Angiographic Results. Available at:
https://www.tctmd.com/slide/sirolimus-eluting-angioplasty-balloon-stent-restenosis-sabre-trial-six-month-clinical-and.
Accessed Nov 17, 2016.
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Figure legends
Figure 1
Title: Flow diagram of meta-analysis
Figure 2
Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR, (B) TVR,
and (C) MACE.
Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse cardiac events;
TLR = target lesion revascularization; TVR= target vessel revascularization.
Figure 3
Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
Figure 4
Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute lumen
gain, and (B) % DS.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
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Figure 5
Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD, (B) binary
restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen diameter; LLL =
late lumen loss.
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Figure 1 Flow diagram of meta- analysis
191x165mm (300 x 300 DPI)
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Figure 2 Title: Forest plots of risk ratios for TLR, TVR and MACE
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR, (B) TVR,
and (C) MACE. Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse cardiac
events; TLR = target lesion revascularization; TVR= target vessel revascularization.
254x190mm (300 x 300 DPI)
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Figure 3 Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis
Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent thrombosis.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.
254x190mm (300 x 300 DPI)
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Figure 4 Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute lumen gain, and (B) % DS.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.
254x124mm (300 x 300 DPI)
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Figure 5 Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.
Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD, (B) binary restenosis, and (C) LLL.
Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen diameter; LLL = late lumen loss.
254x185mm (300 x 300 DPI)
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1
Supplement
Figure 1
Title: Risk of bias
Caption: Proportions of studies classified as having low (green), unclear (yellow), and high (red)
risk of bias across domains of study quality.
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Figure 2
Title: Publication biases.
Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target
vessel revascularization, (C) major adverse cardiac events, (D) myocardial infarction, (E)
cardiac death, and (F) stent thrombosis.
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Table 1 Search strategy for the Pubmed electronic database
#1 restenosis
#2 coronary
#3 #1 and #2
#4 eluting stent[Title/Abstract]
#5 eluting balloon[Title/Abstract]
#6 drug eluting balloon[Title/Abstract]
#7 #5 or #6
#8 #6 and #4
#9 #3 and #8
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Table 2 Patient characteristics
Study Age Male Hypertension Diabetes mellitus Dyslipidemia Previous MI Multi-vessel
DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)
RIBS IV 66 (10) 66 (10) 127 (82) 130 (84) 110 (71) 121 (78) 75 (49) 66 (43) 110 (71) 121 (78) 73 (47) 77 (50) n/a n/a
SEDUCE 68 (8) 64 (11) 18 (72) 25 (100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a
RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a
BILUX RCT 67 (10) 69 (9) 122 (78) 49 (68) 144 (92) 70 (97) 48 (31) 24 (33) 134 (85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)
Values are mean (SD) or n (%).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; EES = everolimus-eluting stents; n/a = not available; MI = myocardial
infarction.
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Table 3 Angiographic characteristics
Study length of pre-stent Mehran III-IV Pre-%DS Pre-MLD Pre-RVD
DCB DES DCB DES DCB DES DCB DES DCB DES
TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92 (0.5) 0.79 (0.5) 2.64 (0.5) 2.66 (0.5)
RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79 (0.4) 0.75 (0.4) 2.59 (0.5) 2.67 (0.5)
SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98 (0.6) 0.57 (0.4) 3.0 (0.5) 2.85 (0.4)
RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02 (0.4) 0.93 (0.4) 2.64 (0.6) 2.64 (0.6)
BIOLUX RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)
Values are mean (SD).
Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; DS = diameter stenosis; MLD = minimum lumen diameter; RVD = reference
vessel diameter; n/a = not available.
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Section/topic # Checklist item Reported on page #
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 3
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
3
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale. 4
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
4
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
4
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis). 4
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
4
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
4
Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
4-5
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 4-5
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I
2) for each meta-analysis.
4-5
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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Page 1 of 2
Section/topic # Checklist item Reported on page #
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
4-5
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
4-5
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
5-6
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
5-6
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5-6
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
6-7
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6-7
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 8
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 8
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
8-11
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
11
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 12
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
12
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
For more information, visit: www.prisma-statement.org.
Page 2 of 2
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