Original Article

Drug-eluting balloons with provisional bail-out or adjunctive

stenting in de novo coronary artery lesions—a systematic review
and meta-analysis
Smit Patel1, Tatiana Svermova1, Anne Burke-Gaffney1*, Richard G. Bogle2*
1
Vascular Biology, Cardiovascular Science, National Heart & Lung Institute (NHLI), Faculty of Medicine, Imperial College London, London, UK;
2
Cardiology Clinical Academic Group, St George’s University Foundation Hospitals NHS Trust, London, UK
Contributions: (I) Conception and design: S Patel, A Burke-Gaffney, RG Bogle; (II) Administrative support: None; (III) Provision of study material or
patients: None; (IV) Collection and assembly of data: S Patel, T Svermova; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing:
All authors; (VII) Final approval of manuscript: All authors.
*These authors contributed equally to this work.
Correspondence to: Dr. Richard G. Bogle. Cardiology Clinical Academic Group, St George’s University Foundation Hospitals NHS Trust, Blackshaw
Road, London SW17 0RE, UK. Email: richard.bogle1@nhs.net.

Background: Efficacy of drug-eluting balloons (DEB) for treatment of de novo coronary lesions remains
controversial. The present systematic review and meta-analysis of randomised controlled trials assessed DEB
with bare-metal stents (BMS) and also DEB with provisional bail-out stents (‘DEB-only’ strategy), to other
conventional options: plain-old balloon angioplasty (POBA), BMS and drug-eluting stents (DES).
Methods: A systematic literature search from January 2000 until May 2017 was conducted. Primary
outcome measure, late lumen loss (LLL); and secondary outcomes; binary restenosis, major adverse cardiac
events (MACE), target lesion revascularization (TLR), myocardial infarction (MI), cardiovascular death and
stent thrombosis were analysed.
Results: Seventeen RCTs were included with 2,616 patients. Several comparative groups showed significant
differences. DEB with BMS were inferior to DES for LLL [mean difference (MD) =0.12 mm; 95% confidence
interval (CI), 0.03 to 0.22; P=0.01]; and binary restenosis [risk ratio (RR) =1.89; (CI, 1.13 to 3.18); P=0.02].
DEB with BMS was superior to BMS for LLL [MD =−0.27 mm; (−0.45 to −0.10); P=0.002]; and MACE
[RR =0.64; (0.46 to 0.90); P=0.010]. Finally, DEB alone was superior to POBA for LLL [MD =−0.39 mm; (−0.67
to −0.11); P=0.006] and binary restenosis [RR =0.20; (0.05 to 0.85); P=0.03] in bifurcation lesions.
Conclusions: The results of this meta-analysis showed that whilst DEB with BMS is superior to BMS
alone, the combination is inferior to DES for treatment of de novo coronary lesions. Thus, DEB + BMS
should not be applied in de novo lesions unless in patients who have absolute contraindications to DES. DEB
alone, however, should be considered for relative contraindications to DES such as small vessel disease and
bifurcation lesions.

Keywords: Bare-metal stents (BMS); de novo lesions; drug-eluting balloons (DEB); drug-eluting stents (DES);
plain-old balloon angioplasty (POBA)

Submitted Aug 16, 2017. Accepted for publication Sep 28, 2017.
doi: 10.21037/cdt.2017.10.09
View this article at: http://dx.doi.org/10.21037/cdt.2017.10.09

Introduction old balloon angioplasty (POBA) was the first technique (1)

Percutaneous coronary intervention and stenting is the most which facilitated a minimally-invasive expansion of a
commonly used treatment for coronary artery disease. Plain- stenosed coronary artery (2). The technique was limited

© Cardiovascular Diagnosis and Therapy. All rights reserved. cdt.amegroups.com Cardiovasc Diagn Ther 2018;8(2):121-136
122
by acute complications including coronary dissection,
which in some patients progressed to abrupt vessel closure
requiring emergency bypass surgery; and acute elastic recoil,
reducing the luminal gain following balloon dilatation. Post-
procedure, restenosis due to neointimal proliferation of
vascular smooth muscle cells represented another limiting
factor most common in patients with diabetes and complex
coronary artery disease (3-5).
Bare-metal stents (BMS) virtually solved the problem of
dissection; acute vessel closure and the need for emergency
bypass surgery (2), but did not reduce the risk of restenosis.
The implantation of stents also led to a new problem of
acute, late and very late stent thrombosis (6). However,
treatment with dual antiplatelet therapy (DAPT) reduced
this risk (7). The introduction of drug-eluting stents (DES)
and its generational enhancements (i.e., thinner struts)
partially resolved the problem of restenosis through release
of anti-mitotic agents but concerns surrounding prolonged
DAPT still remained (8,9).
To overcome the limitations of POBA, BMS and DES,
the drug-eluting balloons (DEB) was developed. Initially
introduced as a treatment for in-stent restenosis (ISR) in
BMS and DES-lesions (10) they have emerged as a potential
treatment for de novo coronary lesions. This is because the
DEB intervention has several advantages over DES such
as homogenous transfer of drug across vessel wall, lack of
foreign body implantation, reduced bleeding risk (1 month
DAPT versus 6–12 months of therapy for DES) and access
to complex lesions (4,11). However, one disadvantage is
that in a small proportion of DEB-treated patients, bail-
out stenting is required, following recoil or dissections (12).
Despite the promising characteristics of this intervention
type, the indication for DEB use in de novo coronary lesions
is still unclear.
Previous meta-analyses have failed to address the DEB-
only strategy for de novo coronary artery disease (13,14).
Moreover, analyses have not yet explored a DEB-only
approach in bifurcation lesions. As initial studies suggest
that DEB-alone show success for treatment of high-
risk restenotic areas (15,16), we hypothesised that DEB
will also provide superior results compared with other
interventional treatments, for the treatment of small
vessel disease and bifurcation lesions in de novo coronary
disease. This study, which includes data from DEB and
adjunctive BMS as well as DEB-only studies, therefore
aims to provide the most up-to-date and comprehensive
systematic review and meta-analysis for the treatment of
© Cardiovascular Diagnosis and Therapy. All rights reserved.
Patel et al. DEB treatment in de novo coronary lesions
de novo coronary artery disease. The safety and efficacy of
DEB (with or without BMS) will be compared to other
conventional management options (POBA, BMS and
DES) in treating de novo lesions.
Methods
This study was performed in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines.
Literature search
MEDLINE, Embase, PubMed and ClinicalTrials.gov were
searched for RCTs published from 1st January 2000 through
to 1st May 2017 using the key terms: ‘drug eluting balloon’,
‘drug coated balloon’, ‘paclitaxel eluting balloon’, ‘de novo
coronary lesion’, ‘coronary stenosis’, ‘coronary disease’,
‘small vessel disease’, ‘bifurcation’, ‘complex long lesion’,
‘acute myocardial infarction’, ‘acute MI’ and ‘MI’. No
filters were applied. Abstracts and conference proceedings
of the American College of Cardiology and Transcatheter
Cardiovascular Therapeutics Symposia were also screened.
References included in literature reviews were searched
manually to ensure all studies that complied with the
inclusion criteria were identified. Two investigators (S Patel
and T Svermova) independently reviewed the resulting
articles. A qualitative risk of bias in seven domains (random
sequence generation; allocation concealment; blinding of
participants/personnel; outcome; incomplete outcome;
selective reporting and other risk of bias) was conducted.
Study selection
We included all studies that compared angioplasty using
the DEB-only strategy as well as DEB with adjunctive BMS
to: POBA, BMS and DES. For analysis, data pertaining
to the longest available follow up periods were used.
Exclusion criteria were patients treated for ISR and use of
interventions other than DEB, POBA, BMS or DES (e.g.,
endothelial progenitor capturing stents). Non-randomised
controlled trials and non-observational studies were also
excluded. The primary endpoint collected was in-segment
or in-stent late lumen loss (LLL). Secondary angiographic
and clinical endpoints were: binary restenosis (in-stent or
in-segment), target lesion revascularization (TLR), major
adverse cardiac events (MACE), myocardial infarction (MI)
cdt.amegroups.com Cardiovasc Diagn Ther 2018;8(2):121-136
Cardiovascular Diagnosis and Therapy, Vol 8, No 2 April 2018
and cardiac death.
Statistical analysis
Statistical analysis was performed using standard software
packages (Review Manager version 5.3, The Nordic
Cochrane Centre, The Cochrane Collaboration, 2014,
Copenhagen, Norway; Comprehensive Meta-analysis
version 3 software, Biostat Inc., Englewood, NJ, USA) with
two-tailed P values <0.05 considered significant. Analyses
are presented as forest plots—the conventional method
for showing results from individual studies and meta-
analysis. Risk ratios (RRs) with 95% confidence intervals
(CIs) or mean differences (MDs) with standard deviations
are presented as summary statistics. Subgroup analyses
comparing DEB-only studies with DES were also performed.
Heterogeneity between studies was compared by Q and I2
statistics (respectively, P<0.1 indicates heterogeneity; <25%,
25–50% and >50% indicate low, medium and high levels).
Studies were combined using the random effect model.
Publication bias was assessed using funnel plots and Egger’s
test (P<0.05 indicates significant bias).
Results
A PRISMA diagram of the literature search and the
subsequent selection is presented in Figure 1. In total,
606 articles were retrieved. Following screening for
replicates, 405 remained; and after screening abstracts for
relevance, a further 371 studies were removed. Finally, full
text of the remaining 34 studies were screened, of which 17
randomised controlled trials (17-34) fulfilled the inclusion
criteria and were qualitatively and quantitatively analysed.
Characteristics of the patients and study designs
A summary of the included studies is provided in Table 1
and this table also documents: (I) interventions compared;
(II) DEB, DES and BMS type; (III) indication; (IV)
primary endpoint; (V) percent bare metal stenting; and (VI)
angiographic follow-up time.
A total of 2,616 patients, ranging from 30 to 637 per study,
were enrolled in the meta-analysis. There were 1,218 patients
treated with DEB + BMS; whereas, 347 were treated with
BMS; 1,028 with DES; and 32 with POBA. The mean age
of patients recruited was 65 years; and all of the studies had
a majority of male patients. Studies recruited from different
patient populations. In the trial by Ali and colleagues (31), all
© Cardiovascular Diagnosis and Therapy. All rights reserved.
123
patients were diabetic; whereas, in trials conducted by Besic
et al. (23) and Poerner et al. (25) all patients were
hypertensive. Data for each trial are detailed in Table 2.
Risk of bias analysis revealed high-risk bias in open-label
studies (17,22,27) and incomplete outcome data (25,27,30)
where greater than 15% of patients were lost to follow-up
(Table 3).
LLL
In subset analyses, DEB + BMS compared more favourably
to POBA with a statistically significant difference observed
for LLL [MD =−0.39; (−0.67 to −0.11); P=0.006]. DEB +
BMS also had a significantly lower rate of LLL compared
to the BMS group [MD =−0.27; (−0.45 to −0.10); P=0.002].
When compared to the DES group, the DEB + BMS group
had an increased LLL and therefore was significantly less
effective than DES [MD =0.12; (0.03 to 0.22); P=0.01]
(Figure 2).
Binary restenosis
In subset analyses, risk of binary restenosis in the DEB +
BMS group was significantly lower compared to the POBA
group [RR =0.20; (0.05 to 0.85); P=0.03]. This was also
seen in the DEB + BMS and DES groups, where binary
restenosis was significantly lower in the former mode of
intervention [RR =1.89; (1.13 to 3.18); P=0.02]. There was
no statistically significant difference in binary restenosis,
however, between the DEB + BMS and BMS groups [RR
=0.44; (0.18 to 1.06); P=0.07] (Figure 3).
TLR
Compared to the BMS group, the DEB + BMS group had
a significantly lower need for TLR [RR =0.65; (0.44 to
0.97); P=0.04]. The need for TLR, on the other hand, was
higher in the DEB + BMS group compared to the DES
group although this did not reach statistical significance
[RR =1.57; (0.94 to 2.62); P=0.08] (Figure 4).
MACE
Definitions of MACE had slight variations across the
17 studies within this review. However, they were still
interpreted under one global outcome. When compared
to the BMS alone group, DEB + BMS had a significantly
more favourable outcome (lower rate of MACE) [RR =0.64;
cdt.amegroups.com Cardiovasc Diagn Ther 2018;8(2):121-136
124 Patel et al. DEB treatment in de novo coronary lesions

Records identified through

Additional records identified
EMBASE, MEDLINE & PubMed
through other sources
searching
(n=8)
(n=598)

Records after duplicates

removed
(n=405)

Records excluded
Records screened (n=371)
(n=405)
 Observational (n=133) (case-
control, cohort, registry)
 Irrelevant (n=141)
 Review (n=56)
 Systematic review (n=2)
 Meta-analysis (n=10)
 Case Report (n=12)
 Animal model (n=9)
 Study protocol (n=2)
34 trials were included after  Non-randomised (n=5)
review of title and abstract  Commentary (n=1)

Records excluded
(n=17)

 Sequential-order studies (n=2)

 Study design (n=1)
 Irrelevant (n=1)
 Study Protocol (n=1)
 Use of EPC stents (n=4)
 Follow-up studies (n=4)
 Sub-studies (n=4)

17 trials were included after

review of full text

Figure 1 Study selection process. EPC, endothelial progenitor cell-capturing stent.

(0.46 to 0.90); P=0.010]. However, even though the rate the DEB + BMS groups and BMS or DES groups for MI
of MACE was higher in the DEB + BMS group compared [RR =0.66; (0.19 to 2.29); P=0.51]; [RR =1.30; (0.60 to 2.84,
to the DES group, there was no statistically significant 95% CI); P=0.51] (Figure 6).
difference [RR =1.39; (0.96 to 2.01); P=0.08] (Figure 5).

Death
MI
There was also no significant differences reported between
There was no significant differences reported between the DEB + BMS groups and BMS or DES groups for death

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 Table 1 Study characteristics

Publication Device type Primary Bare metal Follow up (months)

Study Comparators Randomisation Indication
year DEB Control(s) endpoint stenting (%) Angiographic Clinical

Chae 2017 (DEB + BMS) 1:1 SeQuent Coroflex blue Acute coronary LLL 100 9 12
et al. (17) vs. DES Please BMS, Resolute syndrome
Integrity DES

PEPCAD-BIF 2016 DEB vs. 1:1 SeQuent POBA Bifurcation LLL 15.6 9 NR
(18) POBA Please

BELLO 2012/2015 DEB vs. 1:1 IN.PACT Taxus DES Small vessel LLL 20.2 6 24
(19, 20) DES Falcon disease

Żurakowski 2015 (BMS + DEB) 1:1 SeQuent Coroflex BMS, Symptomatic LLL 100 9 9
et al. (21) vs. DES Please Coroflex heart disease
Please DES

IN-PACT 2015 BMS vs. (DEB 1:2 IN.PACT Skylor BMS De novo simple Neointimal 100 6 12
CORO (22) + BMS) Falcon lesions hyperplasia

© Cardiovascular Diagnosis and Therapy. All rights reserved.

Besic 2015 (BMS + DEB) 1:1 Elutax + NR NSTEMI LLL and ISR 100 6 6
et al. (23) vs. BMS SeQuent
Cardiovascular Diagnosis and Therapy, Vol 8, No 2 April 2018

Please

Touchard 2015 (DEB + BMS) 1:1 NR NR STEMI LLL 100 9 12

et al. (24) vs. DES

Poerner 2014 (BMS + DEB) 1:1 SeQuent Coroflex blue Native coronary LLL 100 6 6
et al. (25) vs. DES Please BMS, Xience V lesion
DES

cdt.amegroups.com
BABILON 2014 (DEB + BMS) 1:1 SeQuent Coroflex blue Bifurcation LLL 100 9 24
(26) vs. DES Please BMS, Xience V
DES

Liistro 2013 (DEB + BMS) 1:1 Elutax-II Xience DES, De novo Binary 100 9 9
et al. (27) vs. DES Prokinetic coronary artery angiographic
BMS stenosis restenosis

Clever 2013 BMS vs. (DEB 1:1:1 NR Coroflex blue De novo Endothelial 100 9 9
et al. (28) + BMS) vs. BMS, Cypher lesions function,
DES DES coronary
flow reserve
& velocity

Stella 2012 (DEB + BMS) 1:1:1 Dior-I Taxus Liberté Bifurcation LLL 100 6 12
et al. (29) vs. BMS DES, Liberté
DES BMS

Table 1 (continued)

Cardiovasc Diagn Ther 2018;8(2):121-136

125
126 Patel et al. DEB treatment in de novo coronary lesions

[RR =0.20; (0.02 to 1.70); P=0.14]; [RR =1.43; (0.45 to 4.52);

BMS, bare-metal stent; DEB, drug-eluting balloon; DES, drug-eluting stents; ISR, in-stent restenosis; LLL, late lumen loss; NR, not reported; NSTEMI, non ST-elevated
Clinical

P=0.54] (Figure 7).

Follow up (months)

9
Angiographic

Stent thrombosis

Stent thrombosis out of all the outcomes had the lowest

6

9
incident rate. No statistically significant difference
was reported in the DEB + BMS group versus control
stenting (%)

[RR =1.85; (0.84 to 4.08); P=0.13]. This was also the case
Bare metal

for DEB + BMS compared with BMS alone and DES alone
36.0
100

100

100

100
[RR =4.10; (0.46 to 36.40); P=0.21]; [RR =1.64; (0.70 to
3.83); P=0.26] (Figure 8).
Diameter
endpoint

Subgroup analysis
stenosis
Primary

LLL

LLL

LLL

LLL

As part of the subgroup analysis, ‘DEB-only’ interventions

were compared with DES. In terms of LLL, DEB-only had
Stable/unstable
De novo lesions

no statistically significant difference to DES [MD =−0.12;

Small vessel
in diabetics

(−0.25 to 0.01); P=0.06]. This was also seen in binary

Indication

De novo
disease

restenosis, MACE, TLR, MI and death; binary restenosis—

lesions

angina
STEMI

myocardial infarction; POBA, plain-old balloon angioplasty; STEMI, ST-elevated myocardial infarction.

[RR =1.36; (0.31 to 6.04); P=0.69], MACE—[RR =1.15;

(0.27 to 4.98); P=0.85], TLR—[RR =1.26; (0.24 to 6.79);
P=0.78], MI—[RR =0.65; (0.11 to 3.86); P=0.64] and
Genius Magic

Coroflex Blue

Cypher DES
BMS, Taxus

CoCr BMS,
Taxus DES,

Taxus Des,
Taxus DES

death—[RR =0.69; (0.12 to 4.17); P=0.69].

Multi-Link
Control(s)
Device type

BMS

BMS
DES

Publication bias

Egger’s test revealed no evidence of significant publication

Acrostak
SeQuent

Coroflex
DEBlue
Please

GENIE
Dior-II

Dior-I

bias within this meta-analysis (P>0.05). This lack of bias was

DEB

also substantiated by the symmetrical funnel plot for our

primary angiographic endpoint of LLL (Figure 9).
Randomisation

1:1:1

1:1:1
1:1

1:1

1:1

Discussion

This is the first meta-analysis to compare DEB with and

without BMS to all three management options: POBA, BMS
(DEB + BMS)

(DEB + BMS)

(BMS + DEB)

(DEB + BMS)
Comparators

DEB vs. DES

vs. BMS vs.

vs. BMS vs.

alone and DES for treatment of de novo coronary lesions.

vs. DES

vs. DES

Of the 17 RCTs included in the study, 14 studies compared

DES

DES

DEB + BMS with DES and/or BMS, two studies compared

DEB-only to DES and one, DEB alone to POBA.
Publication

2012

2011

2010

2009

2009
year

Findings
Table 1 (continued)

The significant findings of this study can be summarised

PICCOLETO

as follows: (I) DES was superior to DEB + BMS in

Hamm et al.
DEB-AMI

et al. (31)

et al. (33)

angiographic (LLL) and clinical (binary restenosis)

Herdeg
Study

outcomes; (II) DEB + BMS was superior to BMS in LLL

(30)

(32)

(34)
Ali

and clinical outcomes (MACE, TLR); and (III) DEB-

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 Table 2 Main trial-level clinical characteristics
Total number of patients and treatment type (N=2,616) Stable Unstable
Total Males, DM, Smokers, HTN, DLM,
Study DEB + BMS BMS DES POBA Age angina, angina,
randomised n (%) n (%) n (%) n (%) n (%)
(N=1,218) (N=347) (N=1,028) (N=32) n (%) n (%)

Chae 90 − 90 − 180 62 132 54 46 (25.6) 65 (36.1) 33 85 (47.2) 48 (26.7)

et al. (17) (73.3) (30.0) (18.3)
PEPCAD-BIF 32 − − 32 64 67 47 (73.4) 23 16 (25.0) NR NR 41 (64.1) 15 (23.4)
(18) (35.9)
BELLO 90 − 92 − 182 66 143 74 25 (13.7) 147 144 NR 42 (23.1)
(19,20) (78.6) (40.7) (80.8) (79.1)
Żurakowski 102 − 100 − 202 64 138 45 39 (19.3) 169 108 108 94 (46.5)
et al. (21) (68.3) (22.2) (83.7) (53.5) (53.5)
IN-PACT 20 10 − − 30 67 26 (86.7) 0 (0.0) 7 (23.3) 23 (76.7) 24 30 NR
CORO (22) (80.0) (100.0)
Besic 41 44 − − 85 66 68 (80.0) 25 27 (31.8) 85 75 NR 33 (38.8)
et al. (23) (29.4) (100.0) (88.2)

© Cardiovascular Diagnosis and Therapy. All rights reserved.

Touchard 111 112 − − 223 NR NR NR NR NR NR NR NR
et al. (24)
Cardiovascular Diagnosis and Therapy, Vol 8, No 2 April 2018

Poerner 51 − 48 − 90* 69 72 (72.7) 47 NR 99 73 NR NR

et al. (25) (47.5) (100.0) (73.7)
BABILON 52 − 56 − 108 65 70 (64.8) 34 54 (50.0) 67 (62.0) 69 NR NR
(26) (31.5) (63.9)
Liistro 59 − 66 − 125 66 107 17 38 (30.4) 50 (40.0) 16 NR NR
et al. (27) (85.6) (13.6) (12.8)
Clever 27 25 25 − 77 66 57 (74.0) 19 13 (16.9) 70 (90.9) 59 NR 15 (19.5)

cdt.amegroups.com
et al. (28) (24.7) (76.6)
Stella 40 37 40 − 117 64 85 (72.6) 13 69 (59.0) 67 (57.2) 65 NR NR
et al. (29) (11.1) (55.6)
DEB-AMI (30) 50 51 49 − 150 59 124 11 (7.3) 76 (65.0) 50 (33.3) 40 NR NR
(82.7) (26.7)
Ali 45 − 39 − 84 61 64 (76.2) 84 22 (26.3) 71 (84.5) 63 NR 10 (11.9)
et al. (31) (100.0) (75.0)
PICCOLETO 29 − 31 − 60** 68 44 (77.1) 24 NR 41 (71.9) 30 26 (45.6) NR
(32) (42.1) (52.6)
Herdeg 67 68 67 − 202 65 157 72 27 (13.4) 176 146 24 (11.9) NR
et al. (33) (77.7) (35.6) (87.1) (72.2)
Hamm 312 − 325 − 637 66 478 174 381 493 424 471 NR
et al. (34) (75.1) (27.4) (56.6) (77.5) (66.6) (74.0)
*, nine patients with >1 suitable lesion were sequentially included in both device groups; **, three patients lost to follow-up straight after randomisation. BMS, bare-metal
stent; DEB, drug-eluting balloon; DES, drug-eluting stents; DLM, dyslipidaemia; HTN, hypertension; NR, not reported; POBA, plain-old balloon angioplasty.

Cardiovasc Diagn Ther 2018;8(2):121-136

127
128 Patel et al. DEB treatment in de novo coronary lesions

Table 3 Risk of bias

Random sequence Allocation Blinding of participants Blinding of outcome Incomplete Selective Other
Study
generation concealment and personnel assessment outcome data reporting bias

Chae L 0 H L L L L
et al. (17)

PEPCAD- L L L L L L H
BIF (18)

BELLO L L L L L L 0
(19,20)

Żurakowski 0 L L L L 0 L
et al. (21)

IN-PACT 0 0 H L L L L
CORO (22)

Besic 0 0 L 0 L 0 0
et al. (23)

Touchard 0 0 L 0 0 0 0
et al. (24)

Poerner 0 0 L L H L 0
et al. (25)

BABILON L 0 L L L L L
(26)

Liistro L L H L H 0 L
et al. (27)

Clever 0 0 L L L 0 H
et al. (28)

Stella L L L L L 0 H
et al. (29)

DEB-AMI L L L L H L H
(30)

Ali et al. (31) 0 0 L L L L H

PICCOLETO L L L L L 0 0
(32)

Herdeg L L L L L 0 H
et al. (33)

Hamm 0 0 L L L L H
et al. (34)
Table highlights the various risks of biases present in the seven assessed domains. L, low risk of bias; H, high risk of bias; 0, insufficient/
unreported bias.

only approach was superior to POBA for LLL and binary
restenosis in bifurcation lesions.
Data interpretation
The current standard of care for PCI treatment of de novo
coronary lesions is implantation of a second generation
DES (35). However, there is increasing concern about the
longer term risk of DES, such as increased bleeding risk
with prolonged antiplatelet therapy (10,36). Additional risks
include development of ISR and late ST which remain a
factor of concern for DES users despite a lower incidence of

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Cardiovascular Diagnosis and Therapy, Vol 8, No 2 April 2018 129

DEB+ BMS Control Mean difference Mean difference

Stud:t'. or subgroue Mean SD Total Mean SD Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
1.1.1 POBA
PEPCAD-BIF (DEB+ 15.6% BMS) 2016 0.08 0.31 25 0.47 0.61 23 4.7% -0.39 [-0.67, -0.11]
Subtotal (95% Cl) 25 23 4.7% -0.39 [-0.67, -0.11]
Heterogeneity: Not applicable
Test for overall effect: Z = 2.76 (P = 0006)

1.1.2 BMS
Clever et al 2013 027 043 27 0.6 055 25 48% -033 [-060, -0.06]
DEB-AMI 2012 044 055 50 052 0.66 51 51% -008 [-032, 0.16]
Herdeg et al. 2009 0.62 0.45 54 0.95 0.77 56 5.1% -0.33 [-0.56, -0.1OJ
IN-PACT CORO 2015 059 042 8 085 0.28 17 43% -026 [-058, 0.06]
Stella et al. 2012 0.58 0.65 40 0.6 0.65 37 4.5% -0.02 [-0.31, 0.27]
Touchard et al. (2015) 0.32 0.49 111 0.85 0.67 112 5.9% -0.53 [-0.68, -0.38]
Subtotal (95% Cl} 290 298 29.6% -0.27 [-0.45, -0.10] �
Heterogeneity: Tau2 = 0.03; Chi2 = 15.32, df = 5 (P = 0.009), 1 2 = 67%
Test for overall effect: Z = 3.11 (P = 0002)

1.1.3 DES
Ali et al. 2011 037 059 39 035 063 36 47% 002 [-026, 0.30]
BABILON 2014 025 048 43 025 049 43 54% 000 [-021, 0.21]
BELLO (DEB+ 20.2% BMS) 2012/2015 005 037 81 017 045 82 61% -012 [-025, 0.01]
Chae et al. 2017 0.3 0.46 74 0.21 0.44 72 6.0% 0.09 [-0.06, 0.24]
Clever et al 2013 027 043 27 028 0.4 25 52% -001 [-024, 0.22]
DEB-AMI 2012 044 055 50 017 035 49 56% 027 [O09, 0.45]
Hamm et al. 2009 0.2 0.52 312 0.11 0.4 325 6.5% 0.09 [0.02, 0.16]
Herdeg et al. 2009 062 045 54 044 058 54 55% 0.18 [-002, 0.38]
Liistro et al. 2013 1.14 59 0.34 0.7 66 4.4% 0.80 [0.49, 1.11]
Poeme「 et al. 2014 0.24 0.21 42 0.16 0.15 48 6.5% 0.08 [0.00, 0.16]
Stella et al 2012 058 065 40 013 045 40 50% 045 [O21, 0.69]
Zurakowski et al. 2015
I+
0.21 0.5 55 0.3 0.7 37 4.8% -0.09 [-0.35, 0.17]
Subtotal (95% Cl) 876 877 65.7% 0.12 [0.03, 0.22]
Heterogeneity: Tau2 = 002; Ch户= 4780, df = 11 (P < 0.00001); 1 2 = 77%
Test for overall effect: Z = 2.54 (P = 0.01)

。
Total (95% Cl) 1191 1198 100.0% -0.01 [-0.12, 0.10]
Heterogeneity: Tau2 = 0.05; Chi2 = 135.13, df = 18 (P < 0.00001), 1 2 = 87%
-1 -0.5 0.5
Test for overall effect: Z = 0.18 (P = 086) Favours [DEB+ BMS] Favours [control]
Test for subgroup differences. Ch户= 23.68, df = 2 (P < 0.00001), 1 2 = 91.6%

Figure 2 Forest plot of mean differences for late lumen loss. BMS, bare-metal stents; CI, confidence interval; DEB, drug-eluting balloons;
DES, drug-eluting stents; POBA, plain-old balloon angioplasty.

DEB+ BMS Control Risk ratio Risk ratio

Study_ or subgroue Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
1.2.1 POBA
PEPCAD-BIF (DEB+ 15.6% BMS) 2016 2 25 9 23 52% 0.20 [0.05, 0.85]
Subtotal (95% Cl) 25 23 5.2% 0.20 [0.05, 0.85]
Total events 2 9
Heterogeneity: Not applicable
Test for overall effect: Z = 2.19 (P = 0.03)

1.2.2 BMS
Besic et al. 2015 7 41 10 44 6.8% 0.75 [0.32, 1.79]
DEB-AMI 2012 13 50 10 51 72% 1.33 [0.64, 2.74]
Herdeg et al. 2009 8 54 22 56 7.2% 0.38 [0.18, 0.77]
Stella et al. 2012 2 40 5 37 48% 0.37 [0.08, 1.79]
Toucha「d et al. (2015) 2 111 33 112 5.3% 0.06 [0.02, 0.25]
Subtotal (95% Cl) 296 300 31.3% 0.44 [0.18, 1.06]
Total events 32 80
Heterogeneity: Tau2 = 0.74; Chi2 = 16.85, df = 4 (P = 0.002); 1 2 = 76%
Test for overall effect Z = 1 83 (P = 0.07)

1.2.3 DES
Ali et al 2011 5 39 5 36 60% 0.92 [0.29, 2.93]
BABILON 2014 7 43 43 37% 700 (0.90, 54.50]
BELLO (DEB+ 20.2% BMS) 2012/2015 8 81 12 82 6.9% 0.67 [0.29, 1.56]
Chae et al. 2017 9 74 2 72 5.0% 4.38 (0.98, 19.57]
DEB-AMI 2012 13 50 3 49 59% 425 (1.29, 13.99]
Hamm et al. 2009 37 312 13 325 7.5% 2.96 [1.61, 5.47]
Herdeg et al. 2009 8 54 8 54 67% 1.00 [0.40, 2.47]
Liistro et al. 2013 15 59 3 66 5.9% 5.59 (1.70, 18.36]
PICCOLETTO (DEB+ 36.0% BMS) 2010
Poerner et al 2014
Stella et al. 2012
。
9

2
28
42
40
。
3

2
29
48
40
5.8%

4.0%
3.11 (0.94, 10.31]
Not estimable
1.00 [0.15, 6.76]
Zurakowski et al. 2015
I+
6 55 6 37 63% 0 67 [0.23, 1.93]
Subtotal (95% Cl) 877 881 63.5% 1.89 [1.13, 3.18]
Total events 119 58
Heterogeneity: Tau2 = 0.41; Chi2 = 23.73, df = 1O (P = 0.008), 1 2 = 58%
Test fo「overall effect: Z = 2.40 (P = 0.02)

Total (95% Cl) 1198 1204 100.0% 1.08 [0.64, 1.83]

Total events 153 147
Heterogeneity: Tau2 = 0.87; Chi2 = 66.78, df = 16 (P < 0 00001); 1 2 = 76%
0.01 0.1 1 10 100
Test for overall effect: Z = 0.28 (P = 0.78)
Favours [DEB+ BMS] Favours [control]
Test for subqroup differences: Chi2 = 13.72, df = 2 (P = 0.001), 1 2 = 85.4%

Figure 3 Forest plot of risk ratios (RR) for binary restenosis. BMS, bare-metal stents; CI, confidence interval; DEB, drug-eluting balloons;
DES, drug-eluting stents; POBA, plain-old balloon angioplasty.

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130 Patel et al. DEB treatment in de novo coronary lesions

DEB+ BMS Control Risk ratio Risk ratio

Stud�or subgroue Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
2.2.1 BMS
Besic et al. 2015
Cleve「 et al. 2013
DEB-AMI 2012
8

10
。 41
27
50
13
3
9
44
25
51
80%
1.7%
7.7%
0.66 [0.31, 1.43]
0.13 [0.01, 2.45]
1.13 [0.50, 2.55]
Herdeg et al. 2009 9 67 15 67 81% 0.60 [0.28, 1.28]
IN-PACT CORO 2015
Stella et al. 2012
Touchard et al (2015)
4

2
。 20
40
111
3
2
8
10
37
112
5.3%
1.6%
44%
0.67 [0.18, 2.42]
0.19 [0.01, 3.74]
0.25 [0.05, 1.16]
Subtotal (95% Cl) 356 346 36.8% 0.65 [0.44, 0.97] 令
Total events 33 53
Heterogeneity: Tau2 = 0.00; Chi2 = 5.14, df = 6 (P = 0.53); 1 2 = 0%
Test for overall effect: Z = 2.10 (P = 0.04)

2.2.2 DES
Ali et al 2011 3 45 4 39 47% 0 65 [0.15, 2.73]
BABILON 2014 8 43 2 43 4.5% 4.00 (0.90, 17.76]
BELLO (DEB+ 20.2% BMS) 2012/2015 6 90 11 92 7.0% 0.56 [0.22, 1.44]
Chae et al 2017
Clever et al. 2013
DEB-AMI 2012 10
5
。 90
27
50
3
4
90
25
49
49%
1 7%
3.0%
1.67 [0.41, 6.77]
0 10 [0.01, 1.82]
9.80 [1.30, 73.69]
Hamm et al. 2009 28 312 13 325 8.7% 2.24 [1.18, 4.25]
Herdeg et al. 2009 9 67 8 67 73% 1.13 [0.46, 2.74]
Liistro et al. 2013 15 59 3 66 5.8% 5.59 (1.70, 18.36]
PICCOLETTO (DEB+ 36.0% BMS) 2010 9 28 3 29 57% 3 11 (0.94, 10.31]
Poemer et al. 2014
Stella et al. 2012
Zurakowski et al. 2015 7
。 51
40
102
2 48
40
5 100
2.4%
1.5%
61%
0.47 [0.04, 5.02]
0.33 [0.01, 7.95]
1.37 [0.45, 4.18]
Subtotal (95% Cl) 1004 1013 63.2% 1.57 [0.94, 2.62]
Total events 101 60
Heterogeneity: Tau2 = 0.38; Chi2 = 23.42, df = 12 (P = 0.02); 1 2 = 49%
Test for overall effect: Z = 1.73 (P = 0.08)

Total (95% Cl) 1360 1359 100.0% 1.08 [0.72, 1.63]

Total events 134 113
2
Heterogeneity: Tau = 0.40; Chi = 40.52, df = 19 (P = O 003); 1 = 53%
2 2
0.005 01 1 10 200
Test for overall effect: Z = 0.36 (P = 0.72) Favours [DEB+ BMS] Favours [control]
Test for subqroup differences Chi2 = 706, df = 1 (P = 0.008), 1 2 = 858%

Figure 4 Forest plot of risk ratios (RR) for TLR. BMS, bare-metal stents; CI, confidence interval; DEB, drug-eluting balloons; DES, drug-
eluting stents; POBA, plain-old balloon angioplasty; TLR, target lesion revascularization.

DEB+ BMS Control Risk ratio Risk ratio

Stud�or subgroue Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
2.1.1 BMS
Besic et al. 2015
Cleve「et al. 2013
DEB-AMI 2012
。
11

10
41
27
50
13
4
12
44
25
51
68%
1.1%
6.4%
0.91 [0.46, 1.79]
0.10 [0.01, 1.82]
0.85 [0.40, 1.79]
Herdeg et al. 2009 9 67 18 67 65% 0.50 [0.24, 1.03]
IN-PACT CORO 2015 4 20 3 10 3.7% 0.67 [0.18, 2.42]

•
Stella et al. 2012 8 40 11 37 6.1% 0.67 [0.30, 1.49]
Touchard et al (2015) 4 105 13 105 46% 0.31 [0.10, 0.91]
Subtotal (95% Cl) 350 339 35.3% 0.64 [0.46, 0.90]
Total events 46 74
Heterogeneity: Tau2 = 0.00; Chi2 = 5.33, df = 6 (P = 0.50); 1 2 = 0%
Test for overall effect: Z = 2.59 (P = 0.010)

2.1.2 DES
Ali et al 2011 6 45 6 39 48% 0 87 [0.30, 2.47]
BABILON 2014 9 43 4 43 4.5% 2.25 [0.75, 6.75]
BELLO (DEB+ 20.2% BMS) 2012/2015 13 90 23 92 7.2% 0.58 [0.31, 1.07]
Chae et al 2017
Clever et al. 2013
DEB-AMI 2012
。
9

10
90
27
50
7
2
2
90
25
49
53%
1 0%
3.2%
1.29 [0.50, 3.30]
0 19 [0.01, 3.69]
4.90 [1.13, 21.23]
Hamm et al. 2009 65 312 37 325 8.8% 1.83 [1.26, 2.66]
Herdeg et al. 2009 9 67 9 67 57% 1.00 [0.42, 2.36]
Liistro et al. 2013 17 59 4 66 4.8% 4.75 (1.70, 13.33]
PICCOLETTO (DEB+ 36.0% BMS) 2010 10 28 4 29 48% 2 59 [0.92, 7.30]
Poemer et al. 2014 5 51 5 48 4.2% 0.94 [0.29, 3.05]
Stella et al. 2012 8 40 7 40 5.4% 1.14 [0.46, 2.85]
Zurakowski et al. 2015 7 102 7 100 49% 0 98 [0.36, 2.69]
Subtotal (95% Cl) 1004 1013 64.7% 1.39 [0.96, 2.01]
Total events 168 117
Heterogeneity: Tau2 = 0.20; Chi2 = 24.49, df = 12 (P = 0.02); 1 2 = 51%
Test for overall effect: Z = 1.75 (P = 0.08)

Total (95% Cl) 1354 1352 100.0% 1.04 [0.75, 1.42]

Total events 214 191
Heterogeneity: Tau2 = 0.26; Chi2 = 44.44, df = 19 (P = O 0008); 1 2 = 57%
0.005 0.1 1 10 200
Test for overall effect: Z = 0.21 (P = 0.83)
Favours [DEB+ BMS] Favours [control]
Test for subqroup differences Chi2 = 9 21, df = 1 (P = 0.002), 1 2 = 89 1%

Figure 5 Forest plot of risk ratios (RR) for MACE. BMS, bare-metal stents; CI, confidence interval; DEB, drug-eluting balloons; DES,
drug-eluting stents; MACE, major adverse cardiac events; POBA, plain-old balloon angioplasty.

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Cardiovascular Diagnosis and Therapy, Vol 8, No 2 April 2018 131

DEB+BMS Control Risk ratio Risk ratio

Study or subgrou Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
2.4.1 BMS

202000

310300
Besic et al. 2015 41 44 10.6% 0.72 [0.13, 4.07]
Clever et al. 2013 27 25 3.9% 0.31 [0.01, 7.26]
DEB-AMI 2012 50 51 4.2% 5.10 (0.25, 103.60]
Herdeg et al. 2009 67 67 4.4% 0.14 [0.01, 2.71]
IN-PACT CORO 2015 20 10 Not estimable
Stella et al. 2012 40 37 Not estimable
Subtotal (95% Cl) 245 234 23.2% 0.66 [0.19, 2.29]

7
Total events 4
Heterogeneity: Tau2 = 0.02; Chi2 = 3.04, df = 3 (P = 0.39); 1 2 = 1%
Test fo「overall effect: Z = 0.66 (P = 0.51)

2.4.2 DES

1280001110013
Ali et al. 2011 1 45 39 5.0% 0.87 (0.06, 13.40]
BABILON 2014 2 43 43 9.2% 1.00 [0.15, 6.78]
BELLO (DEB+ 20.2% BMS) 2012/2015 3 90 92 16.0% 0.38 [0.11, 1.40]
Chae et al. 2017 2 90 90 4.2% 5.00 (0.24, 102.71]
Clever et al. 2013 0 27 25 Not estimable
DEB-AMI 2012 2 50 49 4.2% 4.90 [0.24, 99.57]
Hamm et al. 2009 14 312 325 8.4% 14.58 (1.93, 110.24]
Herdeg et al. 2009 0 67 67 3.8% 0.33 [0.01, 8.04]
Liistro et al. 2013 0 59 66 3.8% 0.37 [0.02, 8.97]
PICCOLETTO (DEB+ 36.0% BMS) 2010 1 28 29 3.9% 3.10 (0.13, 73.12]
Poerner et al. 2014 0 51 48 Not estimable
Stella et al. 2012 0 40 40 3.9% 0.33 [0.01, 7.95]
Zurakowski et al. 2015 5 102 100 14.4% 1.63 [0.40, 6.66]
Subtotal (95% Cl) 1004 1013 76.8% 1.30 [0.60, 2.84]
Total events 30 18
Heterogeneity: Tau2 = 0.38; Ch户= 12.93, df = 10 (P = 0.23); 1 2 = 23%
Test for overall effect: Z = 0.66 (P = 0.51)

Total (95% Cl) 1249 1247 100.0% 1.10 [0.57, 2.11]

Total events 34 25
Heterogeneity: Tau2 = 0.26; Chi2 = 16.70, df = 14 (P = 0.27); 1 2 = 16%
0.002 0.1 1 10 500
Test for overall effect: Z = 0.28 (P = 0.78)
Favours [DEB+ BMS] Favours [control]
Test for suborouo differences: Chi2 = 0.82. df = 1 (P = 0.36). 1 2 = 0%

Figure 6 Forest plot of risk ratios (RR) for MI. BMS, bare-metal stents; CI, confidence interval; DEB, drug-eluting balloons; DES, drug-
eluting stents; MI, myocardial infarction; POBA, plain-old balloon angioplasty.

DEB+ BMS Control Risk ratio Risk ratio

Study or subgrou Events Total Events Total Weiaht IV, Random, 95% Cl IV, Random, 95% Cl
2.3.1 BMS
0 0 0 0 0 0

0 0 2 2 0 0

Besic et al. 2015 41 44 Not estimable

Clever et al. 2013 27 25 Not estimable
DEB-AMI 2012 50 51 11.3% 0.20 [0.01, 4.14]
Herdeg et al. 2009 67 67 11.3% 0.20 [0.01, 4.09]
IN-PACT CORO 2015 20 10 Not estimable
Stella et al. 2012 40 37 Not estimable
Subtotal (95% Cl) 205 197 22.6% 0.20 [0.02, 1.70]
4

Total events 0
Heterogeneity: Tau•= 0.00; Chi'= 0.00, df = 1 (P = 0.99); 1 2 = 0%
Test for overall effect: Z = 1.47 (P = 0.14)

2.3.2 DES
3943929025492567662948400030
3 0 1 0 0 0 2 0 0 1 2 0 0

0 0 2 2 0 0 0 0 0 1 0 0 0

Ali et al. 2011 45 11.9% 6.09 [0.32, 114.31]

BABILON 2014 43 Not estimable
BELLO (DEB+ 20.2% BMS) 2012/2015 90 17.9% 0.51 [0.05, 5.54]
Chae et al. 2017 90 11.2% 0.20 [0.01, 4.11]
Cleve「 et al. 2013 27 Not estimable
DEB-AMI 2012 50 Not estimable
3

Hamm et al. 2009 312 11.2% 5.21 [0.25, 108.04]

Herdeg et al. 2009 67 Not estimable
Liistro et al. 2013 59 Not estimable
PICCOLETTO (DEB+ 36.0% BMS) 2010 28 13.8% 1.04 (0.07, 15.77]
Poerner et al. 2014 51 11.3% 4.71 (0.23, 95.70]
Stella et al. 2012 40 Not estimable
19

Zurakowski et al. 2015 102 Not estimable

Subtotal (95% Cl) 921 77.4% 1.43 [0.45, 4.52]
5

Total events 9
Heterogeneity: Tau2 = 0.00; Chi2 = 4.63, df = 5 (P = 0.46); 1 2 = 0%
Test for overall effect: Z = 0.61 (P = 0.54)

Total (95% Cl) 1126 1127 100.0% 0.92 (0.33, 2.56]

Total events 9 9
2 2 2
Heterogeneity: Tau = 0.04; Chi = 7.14, df = 7 (P = 0.41); 1 = 2%
0.002 0.1 1 10 500
Test for overall effect: Z = 0.16 (P = 0.87) Favou 「s [DEB+ BMS] Favou 「s [control]
Test for suborouo differences: Chi2 = 2.51. df = 1 (P = 0.11). 1 2 = 60.2%

Figure 7 Forest plot of risk ratios (RR) for death. BMS, bare-metal stents; CI, confidence interval; DEB, drug-eluting balloons; DES, drug-
eluting stents; POBA, plain-old balloon angioplasty.

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132 Patel et al. DEB treatment in de novo coronary lesions

DEB+ BMS Control Risk ratio Risk ratio

Study or subgrou Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl

ooooo
2.5.1 BMS

1 0 2 0 0
Besic et al. 2015 41 44 6.2% 3.21 [0.13, 76.74]
Cleve「et al. 2013 27 25 Not estimable

。
DEB-AMI 2012 50 51 6.9% 5.10 [0.25, 103.60]
IN-PACT CORO 2015 20 10 Not estimable
Stella et al. 2012 40 37 Not estimable
Subtotal (95% Cl) 178 167 13.2% 4.10 [0.46, 36.40]
Total events 3
Heterogeneity: Tau•= 0.00; Chi2 = 0.04, df = 1 (P = 0.84); 1 2 = 0%
Test for overall effect: Z = 1.27 (P = 0.21)

2.5.2 DES

0 1 0 2 0 2 6 0 0 0 0 5

1 1 0 0 0 0 1 1 0 0 1 3
Ali et al. 2011 45 39 6.2% 0.29 (0.01, 6.92]
BABILON 2014 43 43 8.4% 1.00 (0.06, 15.48]
BELLO (DEB+ 20.2% BMS) 2012/2015 90 92 Not estimable
Chae et al. 2017 90 90 6.9% 5.00 [0.24, 102.71]
Cleve「et al. 2013 27 25 Not estimable
DEB-AMI 2012 50 49 6.9% 4.90 (0.24, 99.57]
Hamm et al. 2009 312 325 14.1% 6.25 (0.76, 51.62]
Liistro et al. 2013 59 66 6.2% 0.37 (0.02, 8.97]
PICCOLETTO (DEB+ 36.0% BMS) 2010
Poerner et al. 2014
Stella et al. 2012
。
28

40
。
29

40 6.2%
Not estimable
Not estimable
0.33 [0.01, 7.95]
Zurakowski et al. 2015 102 100 31.9% 1.63 [0.40, 6.66]
Subtotal (95% Cl) 886 898 86.8% 1.64 [0.70, 3.83]
Total events 16 8
Heterogeneity: Tau2 = 0.00; Chi2 = 5.65, df = 7 (P = 0.58); 1 2 = 0%
Test for overall effect: Z = 1.14 (P = 0.26)

Total (95% Cl) 1064 1065 100.0% 1.85 [0.84, 4.08]

Total events 19 8
Heterogeneity: Tau2 = 0.00; Chi2 = 6.28, df = 9 (P = 0.71); 1 2 = 0%
0.005 0.1 1 10 200
Test for overall effect: Z = 1.52 (P = 0.13)
Favours [DEB+ BMS] Favours [control]
Test for subqroup differences: Chi2 = 0.59, df = 1 (P = 0.44), 1 2 = 0%

Figure 8 Forest plot of risk ratios (RR) for stent thrombosis. BMS, bare-metal stents; CI, confidence interval; DEB, drug-eluting balloons;
DES, drug-eluting stents; POBA, plain-old balloon angioplasty.

Funnel Plot of Standard Error by Std diff in means

Funnel plot of standard error by std diff in means
0.0
0.0

0.1
0.1

0.2
Standard error

0.2
Standard Error

0.3
0.3

0.4
0.4

0.5
0.5
-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0
-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0
StdStd
diff indiff in
means means

Figure 9 Funnel plot for publication bias using the primary angiographic endpoint of late lumen loss.

disease compared to BMS (37,38). DEB, advocated for their outcomes. Apparent lack of efficacy of DEB + BMS
ability to reduce DAPT and promote homogeneous drug compared to DES could be explained in part by the high
transfer have been proposed as an alternative to DES (39). use of first-generation paclitaxel based DEB which are
However, drawbacks such as dissection and acute elastic likely to be inferior to DES in terms of drug delivery. Also,
recoil means that DEB treatment is often seen accompanied the relatively short contact time between DEB and vessel
with BMS (39). wall could result in a greater ‘wash-off’ effect than with
In this analysis, it was shown that DEB + BMS were DES. A study investigating DEB techniques found optimal
significantly inferior to DES in clinical and angiographic concentrations of paclitaxel in the vessel wall following

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Cardiovascular Diagnosis and Therapy, Vol 8, No 2 April 2018
short inflation times of 30 to 45 seconds (40). The study
which compared 1st and 2nd generation DIOR balloons in
a porcine model also found higher tissue concentrations of
drug and reduced arterial wall injury with 2nd generation
DEBs (40). Coupling of 2nd generation DEBs with a shorter
inflation time could therefore improve release kinetics and
safety in future studies.
Different generation DES were also used. Eight trials
used 1st generation DES, whilst five used 2nd generation
devices. The TAXUS Liberté paclitaxel-eluting stent was
the most common followed by the Xience V everolimus-
eluting stent. A meta-analysis which compared 1 st and
2nd generation DES found that 1st generation sirolimus-
eluting stents compared well in efficacy to 2nd generation
everolimus/zotarolimus eluting stents in TLR, MACE and
restenosis (41,42); whereas, 2nd generation everolimus-
based stents had better clinical outcomes (MI and ST
rates) (41,42). Thus, it cannot be ruled out that some
heterogeneity within results arose from a lack of uniformity
in the DEB and DES employed.
Implications of DEB-only approach
DEB-only intervention is currently accepted in routine
practice for treatment of ISR, re-restenosis or for side
branch POBA. There may also be other niche indications
including high-risk restenotic lesions such as bifurcations,
long lesions, diffuse disease in diabetic patients and small
vessel disease (43). The PEPCAD-BIF trial was the first
randomised controlled trial to explore DEB-only use in
side branch and/or distal main branch lesions (18). The trial
showed that for bifurcations, DEB alone had a statistically
significant reduction in LLL and binary restenosis (18).
Whilst not having been directly compared to DES, the
DEB-only approach is attractive for bifurcations owing
to preservation of vessel patency and avoidance of carina
shift—a phenomenon largely responsible for side branch
occlusion following DES treatment (16,18). In addition, low
rates of restenosis and TLR seen in the PEPCAD-BIF trial
also suggested some promise for the DEB-only treatment
of bifurcation lesions (18). However, more randomised
controlled trials comparing DES and DEB alone are needed
to determine whether these theoretical benefits translate to
better angiographic and clinical outcomes.
Small vessel disease is another area where the DEB-
only strategy has shown potential because short drug
transfer time and lack of foreign body implantation reduces
higher rates of neointimal proliferation and inflammatory
© Cardiovascular Diagnosis and Therapy. All rights reserved.
133
response found in smaller-calibre vessels treated with BMS
treatment (44). This was substantiated by our findings
which suggested that DEB alone performed comparably
to the current mainstay of treatment, DES, for both
clinical and angiographic outcomes. It should be noted,
however, that our meta-analysis only presented data from
two studies comparing DES and DEB-alone (BELLO
and PICCOLETO) since randomised controlled trials
concerning this topic were scarce.
Despite these two trials portraying DEB-alone in a
favourable light in small vessel disease, data from the
study endpoints were rather heterogeneous. This could be
explained by the use of IN.PACT Falcon, a 2nd generation
DEB in the BELLO trial and DIOR I, a 1st generation DEB
in the PICCOLETO trial. Furthermore, pre-dilatation
rates were very low in the PICCOLETO trial compared
with the BELLO trial (25% versus 96.8% respectively)
(19,32). This is an important difference as pre-dilatation is a
necessary prerequisite for optimal drug absorption through
creation of micro-channels in the plaque and vessel wall (45).
Importantly in this regard, studies did not also report the
use of cutting or scoring balloon which may be important
in improving drug access to the vessel wall. Experience has
indicated that adequate and appropriate lesion preparation
is essential when using DEB. It is important therefore
that in future studies there is a standardised approach to
lesion preparation, use of adjunctive technology such as
cutting or scoring balloon and an adequate description of
the methodology since it is possible that this will have an
important effect on the efficacy of the DEB technique.
Hence, the DEB-only approach with the right variant and
preparation technique could show even more promise for
small vessel lesions.
Limitations
This meta-analysis had several limitations. For example, a
large majority of studies had a small sample size and results
were moderately heterogeneous. However, this was likely
the result of different generations of DEB and DES used
as well as different study design comparators such as DES,
POBA and BMS. For this reason, stratified and subgroup
analyses were taken into account to further isolate sources
of variability. Secondly, 14 trials reported clinical outcomes
from relatively short follow-up periods (≤1 year) which may
have failed to capture episodes of late stent thrombosis and
thus influenced results. As already mentioned, the latest
generations of DES and DEB were not universally studied
cdt.amegroups.com Cardiovasc Diagn Ther 2018;8(2):121-136
134
and therefore results should be interpreted with caution
in the context of latest devices in current clinical use.
Additionally, any future studies of DEB must be against the
latest generation of DES so that a valid comparison can be
made against the technology in current clinical use. Finally,
some studies were susceptible to industry bias owing to
author involvement in relevant device companies such as B.
Braun, Boston Scientific Medtronic and Eurocor GmbH
(18,21,22,28,29,31,33). Similarly, conflicts of interest may
have arisen due to these companies funding studies which
investigated their own products (18,21,26,28,30,31,33,34).
Conclusions
Overall, the results of this meta-analysis found that DEB
in combination with BMS was not superior to DES in both
clinical and angiographic outcomes for de novo coronary
lesions. Compared to BMS alone, however, the combination
of DEB and BMS was superior in LLL and MACE. The
strategy of DEB alone has shown some promise. For
example, DEB-only studies performed comparably to DES
within the setting of small coronary vessels. In addition, the
approach has shown early success in bifurcation lesions with
DEB alone. These findings suggest that for major de novo
coronary lesions, DEB + BMS should not be considered
for treatment unless in patients who have significant
contraindications to DES. Whilst the result from DEB-
alone may be advantageous in cases of high-risk restenotic
lesions such as small vessel disease following successful pre-
dilatation and bifurcation lesions of certain classifications
(Medina type 0, X, X) we conclude that DEB are still not a
widely accepted modality of treatment.
Acknowledgements
Funding: This work was supported by the British Heart
Foundation (grant number FS/14/6/30573) to T Svermova.
Footnote
Conflicts of Interest: The authors have no conflicts of interest
to declare.
Ethical Statement: This study was performed in accordance
with the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines.
© Cardiovascular Diagnosis and Therapy. All rights reserved.
Patel et al. DEB treatment in de novo coronary lesions
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