Review

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Drug-eluting balloon:
new tool in the box
Expert Rev. Med. Devices 7(3), 381–388 (2010)

Sumeet Sharma†1, Percutaneous coronary intervention has revolutionized coronary revascularization therapy. It is
Expert Review of Medical Devices Downloaded from informahealthcare.com by Nyu Medical Center on 05/14/15

Neville Kukreja­1, increasingly becoming an attractive alternative to medical therapy and surgical revascularization
Christos Christopoulos1 in the treatment of coronary artery disease. Restenosis is a major challenge, and has been
described as the Achilles heel of the procedure. It is a serious occurrence that can lead not only
and Diana A Gorog1,2
to recurrent angina and repeat revascularization, but also to acute coronary syndromes. Newer
1
East & North Herts NHS Trust,
devices and strategies are being continuously sought to try and overcome these hurdles.
Department of Cardiology,
QE II Hospital, Howlands, Welwyn Drug-eluting balloon technology is one such device that can potentially provide the solutions
Garden City, AL7 4HQ, UK to these problems. This review focuses on the limitations associated with the use of drug-
2
Imperial College, London, UK eluting stents in treating in-stent restenosis, and the concept and the available evidence for the
†
Author for correspondence: use of  drug-eluting balloons, particularly the paclitaxel-eluting balloons, in coronary and
Tel.: +44 170 722 4909
peripheral revascularization.
Fax: +44 170 736 9068
sumeetsharma@nhs.net
Keywords : drug-eluting balloon • drug-eluting stent • in-stent restenosis • paclitaxel • percutaneous
coronary intervention
For personal use only.

Andreas Grüntzig performed the first successful
percutaneous transluminal coronary angioplasty
(PTCA) on a human on September 16, 1977,
at University Hospital, Zurich, Switzerland [1] .
Since then, many improvements have been made
in both balloon and stent technology. Many new
devices were introduced, some of which are still
in use today, while many more have fallen into
disuse. With the technology came the compli-
cations. In the initial years of PTCA, major
complications included abrupt vessel closure,
vessel dissection and restenosis. Early restenosis
occurred in as many as 30% of patients under-
going PTCA. The pathomechanism of reste-
nosis that occurs following balloon angioplasty
involves negative vascular remodeling, elastic
recoil and thrombus at the site of injury [2] . In
1986, the first intracoronary stents were suc-
cessfully deployed in coronary arteries [3,4] , and
stenting came into routine use in the 1990s.
Although stenting largely eliminated the prob-
lems related to coronary dissection, elastic recoil
and abrupt vessel closure, two major complica-
tions remained – namely, stent-thrombosis and
restenosis. Several factors are associated with
an increased risk of stent thrombosis, including
procedure-related factors (stent malapposition
and/or underexpansion, number of implanted
stents, stent length, persistent slow coronary
blood flow and dissection), patient and lesion
characteristics, stent design and premature
cessation of antiplatelet drugs [5] .
The increased use of intracoronary stents
brought a new realization into light – the problem
of in-stent restenosis (ISR). ISR is a pathobiologic
process, histologically distinct from restenosis,
mainly due to neointima formation  [6–9] that is
principally composed of proliferating smooth
muscle cells (SMC) and extracellular matrix [2,10] .
Stenting may generate a hyperplastic response
and, consequently, risk restenosis [11,12] . By the
late 1990s, it was acknowledged that although the
incidence of ISR was lower than that of restenosis
following balloon angioplasty [13] , it occurred in
15–30% of patients, and possibly more frequently
in certain subgroups [14] .
Early treatment modalities for ISR
Strategies to treat ISR have included balloon
angioplasty, atherectomy and repeat stenting.
Brachytherapy significantly reduced revas-
cularization, but was limited by the need for
multi­d isciplinary expertise, expensive equip-
ment and radiation, and the long-term efficacy
remained limited by stent edge restenosis and
late thrombosis [15–17] .
Drug-eluting stents
The focus of treatment for coronary artery dis-
ease changed from gaining procedural success,

www.expert-reviews.com 10.1586/ERD.10.5 © 2010 Expert Reviews Ltd ISSN 1743-4440 381

 Review Sharma, Kukreja, Christopoulos & Gorog
to the prevention of ISR and stent thrombosis. The early heparin-
coated Palmaz-Schatz stent demonstrated a lower incidence of
subacute thrombosis than bare metal stents (BMS), albeit with
more frequent bleeding [18,19] . At approximately the same time,
the first drug-eluting stent (DES) was developed. Restenosis
rates with the sirolimus-eluting CYPHER® (Cordis, Johnson &
Johnson Co., NJ, USA) stent were significantly lower than with
bare BMS (3.2 vs 35.4%) [20] . Later, several large clinical trials
proved the superiority of DES in reducing restenosis [21–23] . By the
end of 2004, DESs were used in nearly 80% of all percutaneous
coronary intervention (PCI) procedures in the USA [24] .
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Limitations of DES
Although they represent a major advantage over previous tech-
nologies, there remain limitations to the use of DESs. DESs have
not overcome many challenges of PCI (Box 1) , and additionally
necessitate the need for prolonged dual antiplatelet medication.
Restenosis rates remain relatively high in small vessels, long lesions
and with bifurcation stenting.
In 2007, Serruys et al. demonstrated that late stent thrombo-
sis was encountered steadily, irrespective of the type of DES,
with no evidence of diminution up to 3 years after implanta-
tion  [25] . Furthermore, transfer of the drug to the vessel wall is
non­homogenous, as the drug concentration is highest at the stent
For personal use only.
struts [26] . Only 15% of the stented vessel wall area is covered
with stent struts, resulting in reduced drug concentration in the
remaining 85% area. In  vitro studies indicate that achieving
sufficient inhibition of cell proliferation is dose-dependent [27] .
Therefore, high drug concentrations on the stent struts, including
a controlled and sustained release mechanism, are mandatory for
stent-based local drug delivery [28] . This has required the use of
polymeric matrices, which have been associated with delayed and
incomplete endothelialization of the stent struts, thought to be the
mechanism underlying late stent thrombosis. The polymer used
for sustained drug release could in itself induce inflammation and
act as a trigger for late thrombosis [29] .
Box 1. Current challenges in percutaneous
intervention.
• Calcified vessels
• Tortuous vessels
• Small-diameter vessels
• Bifurcation lesions:
– Those treated with bifurcation stenting – in-stent restenosis
at the bifurcation
– Those treated with single stent – plaque shift and stenosis
at the ostium of the side-branch
• Stent thrombosis
– Related to delayed endothelialization
• In-stent restenosis in drug-eluting stent
– Further drug-eluting stent implantation carries nearly 50%
risk of further in-stent restenosis
• Need for prolonged dual antiplatelet medication
382
Although less frequent, ISR continues to occur with DESs,
and when it occurs, treatment is challenging. Treatment of a
restenosed DES with a second DES is associated with a risk of
subsequent restenosis of up to 43% [30] .
Alternatives to stenting
The limitations of PCI, some of which are not overcome even by
DESs, are shown in Box 1. These limitations either pertain due to
the stent itself, causing problems with deliverability, or acting as
a persistent stimulus for neointimal proliferation and restenosis,
or are due to the polymer, causing delayed endothelialization
with the risk of stent thrombosis and mandating prolonged dual
antiplatelet medication.
Therefore, the ideal treatment of a coronary stenosis would
eliminate both the stent and the polymer, while at the same time
delivering an antiproliferative agent to reduce the risk of restenosis.
Thus, local drug delivery may offer a possible solution. It offers
a unique opportunity to provide site-specific drug treatment,
achieving high local concentration without systemic elution or
side effects. However, there are important obstacles that must be
overcome before local drug delivery can be applied to clinical situ-
ations. Among other things, these challenges include the delivery
and maintenance of the drug at the desired location, overcoming
the potentially deleterious effects of inhibition of wound healing
and overcoming the potential regulatory inhibitions to bringing
a novel treatment to clinical practice [31] .
Goldman et al. studied catheter-based drug delivery for the
first time in 1987 [32] . In the 1990s, despite extensive research to
improve catheter based, site-specific (or local) intra-arterial delivery
of drugs, studies in animals and humans demonstrated marked
variability of site-specific uptake in the arterial wall and a quick
washout of the compounds so that clinically convincing results
could not be demonstrated [33–35] . This was likely due to insuf-
ficient concentration and lack of chronic dosing at the site. It also
highlights the fact that animal models may not represent human
conditions very accurately due to species differences in the response
to vascular injury, or because doses effective in animals may not
always be achieved safely in humans owing to potential toxicity.
Various other approaches for local drug delivery have been pro-
posed, including the use of nanoparticles, contrast media and
drug-delivery balloons, such as porous [36] and double balloons [37] .
Most of these approaches were developed before the introduction
of DES, with little known regarding drugs like sirolimus and
paclitaxel. However, stent implantation prior to or following local
drug delivery did not result in improved efficiency of drug delivery
in a study by Baumbach et al. [38] . Stent-based local drug delivery
is still considered the treatment of choice for coronary restenosis.
Old-style balloon angioplasty married to the latest in drug-­
eluting technology, producing a drug-eluting balloon (DEB), may
be an effective alternative to stenting, in particular to overcome
the problems of restenosis and ISR. Such a device would poten-
tially overcome the drawbacks of stenting, polymer-related delayed
endothelialization and stent delivery, while at the same time pro-
viding homogenous drug delivery to the vessel wall, allowing
earlier endothelialization and flexibility of use in complex lesions.
Expert Rev. Med. Devices 7(3), (2010)

However, its limitations include the failure to provide a mechani-
cal scaffold for the prevention of acute recoil, and the problem of
not being able to treat dissection flaps.
Choice of drug
The ideal drugs for local delivery should be lipophilic in nature,
rapidly adsorbed and have a high retention rate by the vessel
intima, in order to exert maximal beneficial effects [38] . Anti-
inflammatory compounds, such as colchicine and methotrex-
ate, failed to inhibit restenosis [39,40] . Many pharmacological
agents with antiproliferative properties have been tested, but
the results have mostly been disappointing [31] . Other agents,
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such as the naturally occurring MAPK inhibitor genistein and
Ca 2+ activated K+ channel inhibitor, have been tested for use
as a coating on DEBs. In 2008, Sheiban et al. reported that
although the application of a genistein-coated angioplasty bal-
loon prior to bare-metal stenting in a porcine model of cor-
onary stenosis resulted in significant reduction of peri-stent
mononucleocyte count at 4 weeks, this did not translate into
reduced neointimal hyperplasia at 6–8  weeks [41] . Taxanes
such as paclitaxel have high lipophilicity and bind tightly to
various cell constituents [42] , resulting in effective local reten-
tion at the site of delivery [43] . Paclitaxel has been shown to
have an antiproliferative effect on rat SMCs in vitro, as well as
For personal use only.
in vivo [44] . Paclitaxel exerts a long-lasting effect in the cell due
to structural alteration of the cytoskeleton. Goggelmann and
colleagues showed that even after a short single-dose applica-
tion to human SMC culture, paclitaxel exerted a potent and
sustained inhibitory effect on SMC proliferation and migration
over a period of 14 days without showing rebound or cytotoxic
effects [27] . Thus, paclitaxel, with its lipophilic nature, com-
bined with the fact that its solubility is enhanced by adding
a small amount of hydrophilic contrast medium [45], makes it
well suited for delivery on a DEB. Various other drugs, such as
sirolimus when delivered on a stent platform [20] , have greatly
reduced restenosis compared with BMS. Sirolimus is a natu-
ral macrocyclic lactone with potent immunosuppressive and
anitimitotic action. Sirolimus blocks cell-cycle progression and
expression of inflammatory cytokines, thus inhibiting cellular
proliferation. It is a potential candidate for use in DEB and is
currently under investigation in this setting. A number of com-
panies are investigating the use of alternative anti-restenotic
drugs, such as Caliber Therapeutics Inc.’s (NJ, USA) rapalog-
based DEB technology, which is being developed in combi-
nation with DSM Biomedical (The Netherlands). In theory,
everolimus, a derivative of sirolimus, and zotarolimus (synthetic
analogue of sirolimus) may also be suitable due to their lipo-
philic nature, but clinical data are lacking. Drugs other than
the ‘limus’ drugs could also be used to coat a DEB. Further
studies are warranted to test the efficacy and safety of the use of
drugs other than paclitaxel to coat the DEB. The optimization
of the drug-eluting formulation to prevent premature release
of the drug prior to balloon placement and to maximize rapid
uptake of the drug into the vessel wall upon inflation is also
being investigated.
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Drug-eluting balloon Review
Preclinical data
In 2004, Scheller et al. implanted stainless steel stents (n = 40; diam-
eter: 3.0–3.5 mm; length: 18 mm) in the left anterior descending and
circumflex coronary arteries of pigs. Both conventional uncoated
and three different types of paclitaxel-coated coronary angioplasty
balloons were used, and contact with vessel wall was maintained for
1 min. The results were asserted by quantitative angiography and
histomorphometric studies of the stented arteries. They showed a
marked reduction (up to 63%) of parameters characterizing ISR in
the paclitaxel-coated balloon group, without evidence of increased
inflammation in proximity to the stent struts or any effect on re-
endothelialization of the struts [46] . They also showed that paclitaxel-
coated balloons lose only 6% of the drug when introduced into the
coronary circulation and retracted without inflation. Approximately
80% of the drug is released during inflation, suggesting rapid trans-
fer of the drug from the balloon to the vessel wall without much loss.
In this study they found that the percentage of drug recovered from
the vessel wall was at a maximum (17.3%) when a premounted stent
on a coated balloon was used, compared with postdilatation using
a coated balloon (15.6%) or the coated balloon on its own (8.7%).
Speck et al. conducted studies in porcine coronary arteries com-
paring non-stent-based drug delivery with a DES in reducing
neointimal proliferation. The study group was divided into four
groups as follows. Group A was the control group with uncoated
balloons, BMS and ‘plain’ contrast medium. Group B was the
same treatment as A, but with paclitaxel in the contrast medium.
Group C was paclitaxel-coated balloons, with premounted BMS
and plain contrast medium. Finally, Group D was sirolimus-
eluting stents, noncoated balloons, and plain contrast medium.
At 4 weeks, assessment of stenosis was carried out using angiog-
raphy and histomorphometry. The most impressive inhibition
of neointimal proliferation was achieved in the coated balloon
group – the neointimal area was 2.4 mm 2 ± 0.3 (p < 0.01 vs
all other groups), compared with 5.2 mm 2 ± 0.3 in Group A,
4.3 mm2 ± 0.3 in Group B and 3.8 mm2 ± 0.3 in Group D [47] .
Cremers et al. studied the relationship between the inflation
time and the dose of paclitaxel on the DEB on effectiveness in
reducing neo-intimal proliferation in a porcine model [48] . DEB
technology was shown to be effective in reducing neointimal
proliferation regardless of the balloon inflation time (10 s, 60 s
and two 60 s inflations) and dose (up to a total amount of 10 µg
paclitaxel/mm² balloon surface) within the tested range.
The same group performed a comparative study of two different
types of DEB (Original Paccocath-coating, similar to SeQuent®
Please, B. Braun, Germany and DIOR®, Eurocor, Germany) on
a porcine coronary overstretch model. This study demonstrated
much better results with the matrix-coated Paccocath DEB com-
pared with the roughened surface DIOR balloon, suggesting that
inhibition of neointimal proliferation is dependent on the coating
method used [49] , as shown in Figure 1.
Clinical evidence
The Paccocath I and II studies were randomized, double-blind
German multicenter clinical trials to assess the efficacy and toler-
ability of a paclitaxel-coated balloon catheter in the treatment of
383
 Review Sharma, Kukreja, Christopoulos & Gorog

balloon and stent groups, respectively  [53] .

These findings suggest that DEB is at least
as effective as DES in treating ISR.
PEPCAD  III was a prospective, multi-
center, Phase II pilot study that compared the
combination of paclitaxel-coated DEB plus
Roughened Matrix-coated BMS (Coroflex® DEBlue, B. Braun) with the
Control surface DEB DEB
sirolimus-eluting CYPHER stent in the treat-
Figure 1. Representative examples of histological findings in porcine coronary ment of de novo native coronary stenoses with
arteries 4 weeks post-stent implantation. Bare metal stents with uncoated balloon stent diameters between 2.5 and 3.5 mm and
(A), bare metal stents with DIOR® balloon (B), bare metal stents with Paccocath (C). less than 24 m length [54] . The primary end
DEB: Drug-eluting balloon. point was defined as late lumen loss in treated
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Adapted with permission from [49] . © Springer-Verlag 2009. segment at 9 months assessed angiographi-
cally. The 637 patients with stable or unstable
coronary ISR [50,51] . Scheller et al. enrolled 108 patients (52 and angina or documented ischemia (ST-elevation myocardial infarction
56 patients in each study) with a single ISR lesion to undergo and non-ST-elevation myocardial infarction excluded) were rand-
balloon angioplasty either using a DEB (Paccocath paclitaxel- omized to undergo PCI with either the paclitaxel DEB plus BMS
coated balloon) or an uncoated balloon of the same type. The (n = 312) or the sirolimus DES (n = 325). The in-stent late lumen
primary end point was angiographic in-segment late lumen loss. loss was 0.41 ± 0.51 mm in the DEB plus BMS group, compared
They reported that at 6-month follow-up, in-segment late lumen with 0.16 ± 0.39 mm in the DES group (p < 0.001). The values for
loss was 0.81 ± 0.79 mm in the uncoated balloon group, versus in-segment late lumen loss in the two groups were 0.20 ± 0.52 mm
0.11 ± 0.45 mm (p < 0.001) in the drug-coated balloon group. By and 0.11 ± 0.40 mm (p = 0.06), respectively. Target-vessel revascu-
12 months, only two patients in the coated balloon group required larization (13.8 vs 6.9%, p < 0.01) and TLR (10.5 vs 4.7%, p < 0.01)
target vessel re-vascularization (p = 0.001), compared with 20 in rates were also significantly higher in the DEB plus BMS subgroup at
For personal use only.

the control group. 9 months. Of the safety end points, the rate of myocardial infarction
Paclitaxel-eluting PTCA-balloon Catheter in Coronary Artery at 9 months was 4.6 and 0.3% (p < 0.001) in the DEB plus BMS
Disease (PEPCAD I-SVD) was a Phase  II nonrandomized, and DES groups, respectively. Aditionally, stent thrombosis rates by
open-label, uncontrolled, single group (one arm) assignment, Academic Research Consortium criteria were 2.0 and 0.3%, respec-
efficacy study evaluating the use of a DEB catheter (SeQuent tively (p < 0.05). These results show that the DEB-stent system did
Please) for the treatment of small vessel coronary artery disease in not meet the noninferiority criteria versus the CYPHER stent, and
120 patients (reference diameter of 2.25–2.8 mm). If the angio- the safety aspects need further investigation.
graphic result was not satisfactory at the end of the procedure, the In a small study of 20 patients (DEB in bifurcation Utrecht
subjects could be treated with any device, but a bare metal stent [DEBIUT] registry), Fanggiday et al. showed the efficacy and
was recommended. After 6 months, de novo lesions treated solely safety of DEB in treating bifurcation lesions [55] . They treated the
with the DEB or in combination with BMS (28% of patients) bifurcation lesions (main and side branch) with paclitaxel-coated
showed a 17.3% binary restenosis rate, and at 1 year 11.7% target DIOR balloon followed by BMS implantation of only the main
lesion revascularization (TLR) and 15% major adverse cardio- branch. At 4-month follow-up no major acute coronary events
vascular event rate [52] . However, in the patients who received and no subacute vessel closure were reported. There was no angio-
DEB alone (n = 82) without additional stent insertion, the binary graphic follow-up performed in this study, making it difficult to
re­stenosis rate was only 5.5%. The somewhat higher restenosis rate assess the results, although the fact that major adverse cardiovas-
in the total population may have been attributable to ‘geographic cular event rates were not elevated after 4 months indicates that
mismatch’ between the DEB-treated area and the subsequently the coating of this balloon is well tolerated.
stented surface area. Recently, The Piccoleto Trial failed to show the ‘non­inferiority’
The PEPCAD II-ISR trial was a prospective, randomized study of a paclitaxel-eluting balloon (DIOR) compared with a paclitaxel-
directly comparing the DEB catheter (SeQuent Please) to the eluting stent (Taxus Liberte, Boston Scientific) in terms of reste-
paclitaxel-eluting Taxus® stent (Boston Scientific, MA, USA) in nosis for the treatment of small coronary arteries (≤2.75 mm) [56] .
131 patients with ISR, followed up for 6 months. In 6.2% of This was a small, single-center, randomized controlled study that
the Taxus stent group, the stent was undeliverable and a bal- randomized patients with stable or unstable angina and an indica-
loon catheter had to be used instead. Clopidogrel was given for tion to undergo PCI in small vessels (≤2.75 mm) to receive either a
3 months post treatment to the balloon group and 6 months to DES (Taxus Liberte) or a DEB (DIOR). At 6-month angiographic
the stent group. Patients treated with the DEB experienced a follow-up, the rate of binary restenosis was 32.1% in the balloon
7.0% ISR compared with 20.3% in the other group. Adverse group and 10.3% in the stent group (p = 0.043).
cardiac events occurred in 22% of the stent group and in 9% The THUNDER trial showed that the use of paclitaxel-coated
of the coated-balloon group (p = 0.08), driven predominantly angioplasty balloons in the treatment of femoropopliteal disease
by a reduced need for TLR, which was 6.3 and 15.4% in the is associated with significant reduction in late lumen loss and

384 Expert Rev. Med. Devices 7(3), (2010)


target-lesion revascularization compared with uncoated balloons
without paclitaxel [57] . In this multicenter trial, 154 patients with
femoropopliteal disease were randomized to treatment with stan-
dard balloon catheters coated with paclitaxel, uncoated balloons
with paclitaxel dissolved in the contrast medium or uncoated bal-
loons without paclitaxel (control). At 6 months, the mean angio-
graphic late lumen loss was 1.7 ± 1.8 mm in the control group
compared with 0.4 ± 1.2 mm (p < 0.001) in the group treated
with paclitaxel-coated balloons. The rate of revascularization of
target lesions at 6 months was 37% in the control group, 4%
in the group treated with paclitaxel-coated balloons (p < 0.001
vs control) and 29% in the group treated with paclitaxel in the
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contrast medium (p = 0.41 vs control); at 24 months, the rates
increased to 52, 15 and 40%, respectively.
Similar efficacy of the paclitaxel-coated balloon, compared
with the uncoated balloon, was reported in the FemPac trial for
reduction in TLR when treating femoropopliteal lesions [58] . In
this trial 87 patients with superficial femoral and/or popliteal
artery disease with clinical Rutherford stage 1–5 were random-
ized to receive treatment with either conventional uncoated or
paclitaxel-coated balloon catheters. At 6-month follow-up angi-
ography, there was reduced late lumen loss in the coated balloon
group (0.5 ± 1.1 vs 1.0 ± 1.1 mm; p = 0.031). The number of target
lesion revascularizations was also lower in the paclitaxel-coated
For personal use only.
balloon group than in control subjects (p = 0.002). Several other
studies using different devices are currently ongoing, as recently
listed by Waksmann et al. in their reviews [59,60] .
DEB catheters
Several manufacturers are either selling or developing paclitaxel-
eluting balloon catheters for use in coronary or peripheral revas-
cularization procedures. Table 1 shows a list of such products.
Expert commentary & five-year view
Percutaneous intervention has become an increasingly attractive
alternative to medical therapy and surgical revascularization for
the treatment of coronary artery disease. Millions of interven-
tional procedures are performed annually worldwide, with the
Table 1. Drug-eluting balloon devices currently available or in development.
Name of company Name of device
Aachen Resonance GmbH, Aachen, Germany Elutax
B. Braun, Melsungen, Germany SeQuent® Please
Cook Group, Inc. Advance 18PTX
® ®
DSM Biomedical, Geleen, The Netherlands Undisclosed
EuroCor (subsidiary of Opto Circuits), Bonn, Germany DIOR ®
Genesis Technologies, LLC, CA, USA Genesis DESA
Invatec, Roncadelle, Italy IN.PACT™ Amphirion/Admiral/Pacific
Invatec, Roncadelle, Italy IN.PACT Falcon
™
Lutonix, Inc., MN, USA Undisclosed
Medrad/Possis Medical, PA, USA Cotavance
www.expert-reviews.com
Drug-eluting balloon Review
numbers continuing to rise. Restenosis is a major challenge and
has been described as the Achilles heel of the procedure. It is a
serious occurrence that can lead not only to recurrent angina and
repeat revascularization, but also to acute coronary syndromes.
Early attempts at prevention of restenosis with oral pharmaco-
logic agents failed to show benefit in clinical trials. The intro-
duction of intracoronary stents resulted in a 30% reduction in
re­stenosis by abolishing the early vessel recoil that occurred fol-
lowing balloon angioplasty. However, stenting brought with it its
own limitation – that of ISR. With advances in technology and
better understanding of vascular pathobiology, novel therapeutic
strategies, such as brachytherapy, immunosuppressive agents and
gene therapy, have been deployed to prevent coronary restenosis.
Unfortunately, none of these efforts were fruitful, and to date
DESs remain the tool available to overcome this problem, albeit
with their own disadvantages and limitations.
The concept of a DEB is very promising and the preclinical and
early clinical data makes it appealing as a potential new tool in the
box for coronary revascularization. The data so far are very limited
and in their infancy. Long-term follow-up and further randomized,
blinded, comparative studies are required before any large-scale use
of this technology. DEB surely seems to have a favorable outlook
in the treatment of ISR, and possibly in de novo lesions in small
coronary vessels and in peripheral vascular disease. In such sce-
narios it has several advantages over DES: it helps to avoid double/
triple metal layer and making the coronary vasculature into a metal
jacket, thereby distorting the anatomy; it has potential to provide
homogenous drug distribution onto the vessel wall, thus reducing
the effects of delayed endothelialization of stent struts; it is free of
the polymer matrix used in DESs, thus removing the stimulus for
late thrombosis; advantages are observed despite a shorter period
of dual antiplatelet therapy usage, thus probably reducing costs and
problems associated with prolonged dual antiplatelet treatment; and
it is suitable for lesions in small, tortuous or heavily calcified vessels
or bifurcation lesion, where DESs continue to underperform.
There are limitations and potential concerns regarding the
use of DEBs. The inability to tackle acute vessel recoil and deal
with dissection flaps may result in acute coronary thrombosis.
Status
Available in Europe
Available
Trials – for peripheral use
In development
Available
Trials
Available in Europe – peripheral use
Available in Europe – coronary use
Trials
™
In development for peripheral use
385
 Review Sharma, Kukreja, Christopoulos & Gorog

The safety of the methods used to coat the balloon with the
anti­proliferative agent has not been evaluated, and the different
methods have not been compared. We do not yet know whether
adverse positive remodeling, which may result in coronary
ectasia or aneurysm formation, and is well documented with
DESs [61,62] , is going to be a problem that haunts DEB technol-
ogy. Allergic reaction to sirolimus-eluting stents has previously
been documented, and although extremely rare, such a reaction
may also be possible with DEBs [63] . It is not known whether
there is any long-term effect of the drug lost systemically. DEBs
are bulkier compared with a non-coated balloon, making it
sometimes difficult to achieve good vessel wall–balloon contact
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some situations may require multiple inflations either for long
lesions or because of balloon undersizing, necessitating the use
of multiple balloons.
Early data are promising, and we expect an increased uptake of
DEB technology over the next few years, at least in the treatment
of ISR. Whether these preliminary observations can be expected
to translate into a significant clinical benefit is not clear, and fur-
ther large-scale clinical trials are warranted.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with

to gain the desired outcome, and it is not known whether an the subject matter or materials discussed in the manuscript. This includes
edge effect similar to DESs will be seen at angiographic follow- employment, consultancies, honoraria, stock ownership or options, expert
up. The DEB technology may not be cost-effective compared testimony, grants or patents received or pending, or royalties.
with stenting, as they are designed for single inflation only and No writing assistance was utilized in the production of this manuscript.

Key issues
• Percutaneous coronary intervention is becoming a mainstay of treatment in coronary artery disease.
• Drug-eluting stents are implanted in millions of coronary arteries around the world each year.
• Stent thrombosis and in-stent restenosis remain a major problem in percutaneous coronary intervention with stents.
• Various treatment modalities have been used to treat in-stent restenosis, but with limited success.
• Drug-eluting balloons have shown promising results in the early data for use in treating in-stent restenosis.
For personal use only.

8 Hoffman R, Mintz GS, Dussaillant RG 15 Leon MB, Teirstein PS, Moses JW et al.
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