REVIEW Drug-Eluting Balloons in the Treatment of Coronary De Novo Lesions: A Comprehensive Review Rasmus Kapalu Broge Richelsen . Thure Filskov Overvad . Svend Eggert Jensen Received: May 13, 2016 / Published online: July 6, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com ABSTRACT Drug-eluting balloons (DEBs) have emerged as a new application in percutaneous coronary intervention. DEBs have proven successful in the treatment of in-stent restenosis, but their role in de novo lesions is less clear. This paper provides a review of the current studies where DEBs have been used in coronary de novo lesions, either as part of a DEB-only strategy or in combination with another device, mainly a bare metal stent (BMS). By searching Pubmed and Embase we were able to identify 52 relevant studies, differing in design, intervention, and clinical setting, including patients with small vessel disease, bifurcation lesions, complex long lesions, acute myocardial infarction, diabetes mellitus, and elderly. In 23 studies, a DEB was combined with a BMS, 25 studies used a DEB-only strategy with only provisional BMS implantation, and four studies combined a DEB with a drug-eluting stent (DES). In the vast majority of studies, DEB in combination with BMS does not seem to improve clinical or angiographic outcome compared with DES, whereas a DEB-only strategy seems promising, especially when predilatation and geographical mismatch are taken into account. A lower risk of recurrent thrombosis with DEB compared with DES is not evident from the current studies. In conclusion, the main indication for DEB seems to be small vessel disease, especially in clinical scenarios in which a contraindication to dual antiplatelet therapy exists. The main approach should be a DEB-only strategy with only provisional bailout stenting, which has shown interesting results in different clinical scenarios. In general, larger randomized controlled studies with prolonged follow-up comparing DEB with Enhanced content: To view enhanced content for this article go to http://www.medengine.com/Redeem/6ED4 F060344985C9. Electronic supplementary material The online version of this article (doi:10.1007/s40119-016-0064-4) contains supplementary material, which is available to authorized users. R. K. B. Richelsen (&) Á T. F. Overvad Á S. E. Jensen Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark e-mail: [email protected]T. F. Overvad Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark S. E. Jensen Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Cardiol Ther (2016) 5:133–160 DOI 10.1007/s40119-016-0064-4
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REVIEW
Drug-Eluting Balloons in the Treatment of CoronaryDe Novo Lesions: A Comprehensive Review
Received: May 13, 2016 / Published online: July 6, 2016� The Author(s) 2016. This article is published with open access at Springerlink.com
ABSTRACT
Drug-eluting balloons (DEBs) have emerged as a
new application in percutaneous coronary
intervention. DEBs have proven successful in
the treatment of in-stent restenosis, but their role
in de novo lesions is less clear. This paper
provides a review of the current studies where
DEBshavebeenused incoronarydenovo lesions,
either as part of a DEB-only strategy or in
combination with another device, mainly a
bare metal stent (BMS). By searching Pubmed
and Embase we were able to identify 52 relevant
studies, differing in design, intervention, and
clinical setting, including patients with small
vessel disease, bifurcation lesions, complex long
lesions, acute myocardial infarction, diabetes
mellitus, and elderly. In 23 studies, a DEB was
combined with a BMS, 25 studies used a
DEB-only strategy with only provisional BMS
implantation, and four studies combined a DEB
with a drug-eluting stent (DES). In the vast
majority of studies, DEB in combination with
BMS does not seem to improve clinical or
angiographic outcome compared with DES,
whereas a DEB-only strategy seems promising,
especially when predilatation and geographical
mismatch are taken into account. A lower risk of
recurrent thrombosis with DEB compared with
DES is not evident from the current studies. In
conclusion, themain indication forDEB seems to
be small vessel disease, especially in clinical
scenarios in which a contraindication to dual
antiplatelet therapy exists. The main approach
should be a DEB-only strategy with only
provisional bailout stenting, which has shown
interesting results in different clinical scenarios.
In general, larger randomized controlled studies
with prolonged follow-up comparing DEB with
Enhanced content: To view enhanced content for thisarticle go to http://www.medengine.com/Redeem/6ED4F060344985C9.
Electronic supplementary material The onlineversion of this article (doi:10.1007/s40119-016-0064-4)contains supplementary material, which is available toauthorized users.
R. K. B. Richelsen (&) � T. F. Overvad � S. E. JensenDepartment of Cardiology, Aalborg UniversityHospital, Aalborg, Denmarke-mail: [email protected]
T. F. OvervadAalborg Thrombosis Research Unit, Department ofClinical Medicine, Aalborg University, Aalborg,Denmark
S. E. JensenDepartment of Clinical Medicine, AalborgUniversity, Aalborg, Denmark
Product nameProduct name ManufacturerManufacturer Coa�ngCoa�ng Studies Studies Coroflex DEBlue*Coroflex DEBlue* B. Braun Melsungen AG (Berlin, B. Braun Melsungen AG (Berlin,
Germany)Germany)IopromideIopromide IVUS Study IVUS Study [30][30], Clever , Clever et al. et al. [22][22]
PAPPA PAPPA [71][71], Costopoulos , Costopoulos et al. et al. [69][69]***, DELUX Registry ***, DELUX Registry [46][46], Sgueglia , Sgueglia et al.et al. [61][61]***, BIOLUX***, BIOLUX--I I [65][65]
SeQuent PleaseSeQuent Please B. Braun Melsungen AG (Berlin, B. Braun Melsungen AG (Berlin, Germany)Germany)
IopromideIopromide PERfECT PERfECT [24][24], PEPCAD CTO , PEPCAD CTO [67][67], INDICOR , INDICOR [33][33], OCTOPUS , OCTOPUS [28][28], Zurakowski , Zurakowski et al.et al.[27][27], Shin , Shin et al. et al. [54][54], PEPCAD I , PEPCAD I [37][37], , SeQuent Please World Wide Registry SeQuent Please World Wide Registry [39][39], Sgueglia , Sgueglia et al.et al.[61][61]***, Calé ***, Calé et al. et al. [40][40], SeQuent Please Small Vessel , SeQuent Please Small Vessel ‘PCB only’ Registry ‘PCB only’ Registry [35][35], Kleber , Kleber et al. et al. [52][52]***, ***, The Leipzig The Leipzig Registry Registry [42][42], PEPCAD V , PEPCAD V [60][60], Schultz , Schultz et al. et al. [63][63]***, ***, BABILON BABILON [64][64], PEPCAD, PEPCAD--BIF BIF [58][58], PEPCAD IV DM , PEPCAD IV DM [76][76], , Mahmood Mahmood Zuhdi Zuhdi et al.et al.[44][44],, Sinaga Sinaga et al. et al. [43][43], Ong , Ong et al.et al.[45][45], Her , Her et al.et al. [53][53], Benezet , Benezet et al. et al. [41][41], Hee Hwa , Hee Hwa et al. et al. [73][73]
* * Hybrid system consisting of a Coroflex BMS mounted onto a SeQuent Please DEBHybrid system consisting of a Coroflex BMS mounted onto a SeQuent Please DEB** ** Catheter basedCatheter based system with a distal an proximal occlusive segment, allowing for delivery of liquid drug at the central segment system with a distal an proximal occlusive segment, allowing for delivery of liquid drug at the central segment *** Studies using more than one type of DEB *** Studies using more than one type of DEB
Fig. 1 Paclitaxel-coated balloons used in the treatment of coronary de novo lesions
in the case of acute elastic recoil or dissection,
136 Cardiol Ther (2016) 5:133–160
Table 1 Drug-eluting balloon in combination with bare metal stent
Study, year DesignIntervention
Numberofpatients
Reference meanvessel diameter(mm)
Outcome (months offollow-up)ClinicalAngiographic
LOCAL-TAX [21],
2009
Randomized
BMS ? Genie DEB vs.
BMS vs. Taxus DES
202 2.48 MACE, %: 13.4 vs. 26.8 vs. 14.9
(6)
TLR, %: 13.4 vs. 22.1 vs. 13.4 (6)
In-stent LLL, mm: 0.61 vs. 0.98 vs.
0.44 (6)
PERfECT [24, 25],
2011/2016
Randomized
SeQuent Please
DEB ? EPC stent vs.
EPC stent
120 2.65 vs. 2.74 MACE, %: 4.8 vs. 17.2 (6)
TLR, %: 4.8 vs. 15.5 (6)
MACE, %: 23.5 vs. 30.4 (60)
TLR, %: 15 vs. 23.2 (60)
In stent LLL, mm: 0.34 vs. 0.88
(6)
De novo pilot study
[32], 2011
Randomized
Moxy DEB ? BMS vs
BMS ?Moxy DEB
26 2.81 vs. 2.41 MACE, %: 15.4 vs. 30.8 (6)
TLR, %: 15.4 vs. 15.4 (6)
In-stent LLL, mm: 0.34 vs. 0.88
(6)
In-stent neointimal volume
obstruction, %: 25.5 vs. 24.9 (6)
IVUS study [30], 2012
(PEPCAD III
substudy)
Randomized
Coroflex DEBlue ? BMS
vs. Cypher DES
55 Not reported Clinical outcomes not reported
Stent malapposition, %: 6.9 vs.
15.4 (9)
In-stent restenosis, %: 19.7 vs. 11.0
(9)
In-stent neointimal hyperplasia,
mm2: 1.08 vs. 0.69 (9)
PEPCAD CTO [67],
2012
Observational
BMS ? SeQuent Please
DEB vs. Taxus DES
96 2.98 vs. 2.95
(post-procedure)
MACE, %: 14.6 vs. 18.8 (12)
TLR, %: 14.6 vs. 14.6 (12)
In-stent LLL, mm: 0.64 vs. 0.43
(6)
Cardiol Ther (2016) 5:133–160 137
Table 1 continued
Study, year DesignIntervention
Numberofpatients
Reference meanvessel diameter(mm)
Outcome (months offollow-up)ClinicalAngiographic
Liistro et al. [31],
2013
Randomized
Elutax DEB ? BMS vs. Xience
DES
125 2.85 vs. 2.77 MACE, %: 29 vs. 6 (9)
TLR, %: 25 vs. 4 (9)
In-stent LLL, mm: 1.14 vs. 0.34
(9)
Binary in-stent restenosis, %: 17
vs. 3 (9)
INDICOR [33],
2013
Randomized
SeQuent Please DEB ? BMS
vs. BMS ? SeQuent Please
DEB
97 2.8 vs. 2.8 MACE, %: 16.3 vs. 8.4 (12)
Target lesion related MACE, %:
10.2 vs. 4.2 (12)
In-stent LLL, mm: 0.52 vs. 0.46
(6)
PEGASUS [26],
2013
Observational
IN.PACT Falcon DEB ? EPC
Stent
40 2.78 MACE, %: 18; TLR, %: 10 (9)
In-stent LLL, mm: 0.38 (6)
Diameter stenosis, %: 25.3 (6)
Clever et al. [22],
2014 (PEPCAD
III substudy)
Randomized
BMS vs. Coroflex DEBlue vs.
Cypher DES
77 3.3 vs. 2.8 vs. 2.9 MACE, %: 16 vs. 0 vs. 8 (9)
TLR, %: 12 vs. 0 vs. 8 (9)
In-stent LLL, mm: 0.85 vs. 0.36 vs.
0.25
OCTOPUS [28],
2014
Randomized
BMS ? SeQuent Please DEB
vs. Xience V DES
90 2.59 vs. 2.61 MACE, %: 9.8 vs. 10.4(6)
TLR, %: 2 vs. 4.2 (6)
In-stent LLL, mm; 0.24 vs. 0.16
(6)
Uncovered stent struts, %: 5.64 vs.
4.93 (6)
IN-PACT CORO
[23], 2015
Randomized
BMS vs. IN.PACT Falcon
DEB ? BMS vs.
BMS ? IN.PACT Falcon
DEB
30 2.78 vs. 3.03 vs.
2.86
Both DEB groups combined:
MACE, %: 30 vs. 20 (12)
TLR, %: 30 vs. 20 (12)
In-stent LLL, mm: 0.85 vs. 0.50 vs.
0.64 (6)
Mean neointimal area, mm2: 3.03
vs. 1.96 vs. 2.06 (6)
Area obstruction, %: 37.5 vs. 19.5
vs. 29.1 (6)
138 Cardiol Ther (2016) 5:133–160
so-called bailout stenting, see Table 2. The
studies presented have mainly focused on
small vessel de novo lesions. No clear
definition of small vessel in terms of the
reference vessel diameter exists, but a vessel
diameter less than 2.8 mm is often regarded a
small vessel [35]. The absolute LLL is similar and
independent of vessel diameter; and since small
vessels have less room to accommodate
neointimal tissue growth, restenosis of small
vessels has remained a challenge even in the
DES era [36]. Hence, it would be promising to
totally avoid a stent implantation in such
lesions. Studies using a DEB-only strategy in
specific clinical scenarios other than small
vessel disease are presented later.
The first study using a DEB-only strategy in
de novo lesions was the PEPCAD I
(Paclitaxel-Eluting PTCA-Balloon Catheter to
Treat Small Vessel Coronary Artery Disease)
study [37]. A SeQuent Please DEB was used for
dilatation, and the proportion of patients
requiring additional BMS deployment was
27%. An intention-to-treat analysis showed
MACE at 15.3% after 12 months. However, a
per-protocol analysis indicated significantly
different outcomes both clinically and
angiographically in favor of the DEB-only
strategy, with TLR of 5% in the DEB-only
group and 28% in the DEB ? BMS group. This
difference was likely explained by geographical
mismatch, i.e., the BMS was partly deployed
Table 1 continued
Study, year DesignIntervention
Numberof patients
Reference meanvessel diameter(mm)
Outcome (months offollow-up)ClinicalAngiographic
_Zurakowski
et al. [27],
2015
Randomized
BMS ? SeQuent Please DEB
vs. Coroflex Please DES
202 2.52 vs. 2.62 MACE, %: 7.0 vs. 6.9 (9)
TLR, %: 6.9 vs. 5.0 (9)
In-stent, LLL, mm: 0.21 vs. 0.30
(9)
Otto et al. [29],
2016
(substudy [28])
Observational
BMS ? SeQuent Please DEB
21 Not reported Incomplete stent strut apposition,
%: 11.4 at 2 months and 1.8 at
6 months
Uncovered stent struts, %: 14.5 at
2 months and 2.0 at 6 months
Positive vessel remodelling
4.9 at 2 months and 2.0 at
6 months
LLL late lumen loss—reflects the loss of lumen in the treated segment usually measured by subtracting the lumen diameterat follow-up from the lumen diameter just after the PCI procedure; MACE major adverse cardiac event—not consistentlydefined among the different studies, but most frequently including the combination of either death, myocardial infarct,target lesion revascularization, or target vessel revascularization; TLR target lesion revascularization—revascularizationwithin the treated/stented area, usually including 5 mm of the proximal and distal segment adjacent to the treated/stentedarea
from the SPIRIT Small Vessel trial that reported a
clinically indicated TLR of 5.1% after 1 year [78].
The recommendation for DAPT treatment was
1 month, and most of the patients received DAPT
for this periodwith a small proportion exceeding it
[43]. As older people in general are more at risk of
complications with prolonged DAPT treatment,
this study showed a low 6.1% MACE after
9 months despite the shortened DAPT duration,
highlighting the tempting aspects of DEB
treatment and thereby avoidance of prolonged
DAPT treatment in the elderly patients.
In short, while the planned combination of
DEB ? BMS does not seem promising, especially
in acute myocardial infarction, a DEB-only
approach seems interesting in a broad range of
different clinical scenarios. It has been
suggested that the disappointing outcome in
the scenario of acute myocardial infarction is
explained by the different drug uptake in the
acute ruptured plaque with high thrombus
burden or a hampering effect by the presence
of a BMS [12]. In bifurcation lesions, conflicting
results were reported, with DES treatment of MB
associated with a favorable outcome compared
to DEB ? BMS, whereas the DEB-only strategy in
bifurcation indicated potentially promising
results that warrant further investigation
[58, 63]. DEB in patients with diabetes, diffuse
lesions, and elderly also reveals interesting
results. Overall, the limited data makes it
difficult to draw any firm conclusions about
the use of DEB in these specific patient groups.
STENT THROMBOSIS AND DUALANTIPLATELET THERAPY
Data on the duration of DAPT treatment, early
or late stent thrombosis, geographical
mismatch, and duration of follow-up in the
studies are found in Table S1 the Appendix.
Substudies are not included in this table, nor are
studies where this information was insufficient
or difficult to interpret. Most studies with a
DEB-only strategy recommended 1–3 months of
DAPT, 3–12 months in the case of additional
BMS implantation, and 12 months in the case
of DES. Most studies took geographical
mismatch into consideration.
DISCUSSION
This review identified 52 studies of which 22
were randomized trials and 30 observational
registries investigating either DEBs alone or in
combination with a stent, mainly a BMS, in the
treatment of coronary de novo lesions. Overall,
the combination of DEB ? BMS treatment did
not seem to perform better than treatment with
a DES, with most studies showing results in
favor of DES or at best similar clinical or
angiographic outcomes. A DEB-only approach
on the other hand seems feasible and is
generally associated with outcomes close to
DES; however, some diverging evidence exists,
best reflected by the two randomized controlled
trials BELLO and PICCOLETO [48, 49]. Several
factors might have contributed to these
conflicting findings, including differences in
bailout rate, predilatation, geographical
mismatch, and the type of DEB used. For
example, bailout proportion varied between
6% and 36%, and in most cases bailout
stenting is associated with a less favorable
outcome [37, 46, 47, 49]; however, several
prospective registries using SeQuent Please
DEB did not find a difference between DEB
treatment with or without BMS implantation
[35, 39, 41]. Geographical mismatch between
the DEB-treated area and BMS implantation
Cardiol Ther (2016) 5:133–160 153
seems partly to account for the observed
differences, where especially the stent edges
are sites of restenosis, and thus geographical
mismatch should be avoided, and a BMS only
implanted as a part of a bailout strategy
[21, 24, 28, 37, 49]. The sequence of DEB
treatment, before or after BMS implantation,
was not found to significantly alter the outcome
[23, 32, 33]. When BMS is implanted prior to
DEB treatment a natural reference point for DEB
dilatation exists (i.e., the BMS); to avoid
geographical mismatch, extra caution should
be taken when DEB dilatation precedes BMS
implantation because the reference point for
BMS implantation might be missing [33].
Predilatation of the target lesion is thought to
create microdissections in the vessel wall, which
in turn facilitates the uptake of drug and is
therefore generally recommended prior to DEB
implantation [50]. Predilatation in the
PICCOLETO study was significantly higher in
the DES arm, and might also have favored DES
treatment in this study.
Most studies report on data from treatments
performed on relatively small vessels with a
reference diameter ranging from 2.48 to
3.30 mm in the planned DEB ? BMS strategy
and 1.95–2.80 mm in the DEB-only strategy,
and with a follow-up of maximum 12 months
except for five studies with at least 2 years of
follow-up. As a potential benefit of using DEB
was to avoid the late ST risk associated with DES
implantation, the follow-up periods were
generally too short to fully address this
question. Furthermore, none of the studies
included ST as a primary endpoint. Table S1 in
the appendix illustrates that only the study by
_Zurakowski et al. [27] and PEPCAD I [37] found
an excess of late ST in the DES group after a
clinical follow-up of 9 and 6 months,
respectively. However, _Zurakowski et al. found
more ST in the BMS ? DEB arm in total as a
result of more early ST in this group. In contrast,
the INDICOR study found one late ST in the
DEB ? BMS arm and no ST in the DES arm [33].
Generally, the very few ST events in these
studies yield potentially imprecise risk
estimates. In many of the studies, stent
thromboses, both early and late, were found to
be associated with early cessation of DAPT
treatment. In general, no conclusion can be
drawn about the hypothesis of increased late ST
associated with DES implantation from the
available body of evidence.
Another key point related to the hypothesis
of preventing ST is the need for prolonged DAPT
when using DESs as compared to DEBs.
Depending on the clinical setting, e.g.,
stable coronary artery disease or non-STEMI/
STEMI in patients undergoing PCI treatment,
current guidelines recommend DAPT treatment
for at least 6 and 12 months, respectively,
assuming no contraindications to DAPT
treatment [11]. With DEB and even
DEB ? BMS treatment, the duration of DAPT
treatment needed is thought to be shorter,
thereby limiting bleeding risk. The included
studies were not designed to investigate the
impact of different duration of DAPT treatment
on outcomes. Five studies differed in regard to
duration of DAPT treatment with a short period
of 1–3 month DAPT treatment in the DEB
(±BMS) arm compared to 12 months in the
DES arm. Table S1 in the Appendix
demonstrates no particular difference with
regard to early or late vessel/stent thrombosis
among these groups. Other endpoints such as
clinical outcomes and bleeding risk should be
considered. In general, studies using a DEB-only
strategy show minimal risk of vessel thrombosis
with only 1 month of DAPT. However, when
DEBs are used in combination with a BMS the
154 Cardiol Ther (2016) 5:133–160
risk increases. Although few studies have found
3 months of DAPT sufficient with additional
BMS implantation [38, 77], there is no current
consensus about duration of DAPT, and other
studies recommend 12 months of DAPT in case
of BMS implantation [10, 27, 33].
Most of the studies compared the paclitaxel
DEB to a paclitaxel DES in order to compare
treatment devices using the same drug. This
might be misleading as the sirolimus-eluting
DES was shown to perform better than
paclitaxel-eluting DES [7, 34]. Furthermore,
newer-generation limus DES (everolimus and
zotarolimus) perform even better than sirolimus
DES [79]. Thus, by using the best DES on the
market, even better DES results would be
expected, and the potential benefit of
treatment with a DEB might diminish. While
different drugs exist for DES, paclitaxel for now
seems the preferred drug and is to date the only
one used for DEB in the treatment of human
coronary arteries [17]. Also, the future impact of
using DEBs with drugs other than paclitaxel
remains to be investigated [19, 20].
CONCLUSIONS AND FUTUREPERSPECTIVES
The main indication for the use of DEB in the
treatment of denovo coronary lesions seems tobe
small vessel disease, and especially in patients
with high bleeding risk where a shorter time for
DAPT treatment is favorable. A DEB-only strategy
in bifurcations and in very high-risk patients, e.g.,
STEMI patients, also reveals promising results,
especially if a low bailout rate is achieved. In case
of DEB treatment the following is recommended:
thorough predilatation before DEB treatment, to
use aDEB-only strategyandonly implant aBMSas
part of a bailout strategy, and in case of need for
bailout BMS implantation it is advised to use a
shorter BMS and implant within the DEB-treated
area to avoid geographical mismatch. In cases of
doubt regarding geographical mismatch, post
DEB treatment should be performed to make
sure that the stent edges are fully coveredwith the
drug.
The available bodyof evidencedoesnot suggest
that aDEB (±BMS) treatment strategy is superior to
DESs with respect to preventing associated early or
late ST, but further studies with longer follow-up
are warranted to assess the optimal DAPT duration
across variouspopulations.Nonetheless, 3 months
of DAPT treatment in the case of DEB (±BMS)
implantation seems safe in an average risk
population.
No class effect exists among the different
paclitaxel DEBs, and DEBs with alternative
drugs might reveal even more promising
results, but such studies should be compared
with the contemporary gold standard of DESs.
Finally, most studies have investigated the use
of DEBs in small vessels. Studies investigating
the use of DEBs in large coronary vessels are
warranted.
ACKNOWLEDGMENTS
No funding or sponsorship was received for this
study or for the publication of this article. All
named authors meet the International
Committee of Medical Journal Editors (ICMJE)
criteria for authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval to the
version to be published.
Disclosures. Svend Eggert Jensen has
received an unrestricted research grant from
Aachen Resonance. Rasmus Kapalu Broge
Richelsen and Thure Filskov Overvad declare
no conflict of interests.
Cardiol Ther (2016) 5:133–160 155
Compliance with Ethics Guidelines. This
article is based on previously conducted
studies and does not involve any new studies
of human or animal subjects performed by any
of the authors.
Open Access. This article is distributed under
the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/
by-nc/4.0/), which permits any noncommercial
use, distribution, and reproduction in any
medium, provided you give appropriate credit to
the original author(s) and the source, provide a
link to the Creative Commons license, and
indicate if changes were made.
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