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Drug eluting balloon for the treatment of patients with coronary artery disease: Current perspectives
Drug Eluting Balloon for the treatment of patients with Coronary Artery Disease: current perspectives Mattia Lunardi, Carlo Zivelonghi, Floris S. van den Brink, Matteo Ghione, Giulia Vinco, Giovanni Benfari, Roberto Scarsini, Flavio Ribichini, Pierfrancesco Agostoni PII: DOI: Reference:
S1553-8389(17)30345-7 doi: 10.1016/j.carrev.2017.09.002 CARREV 1130
To appear in:
Cardiovascular Revascularization Medicine
Received date: Revised date: Accepted date:
3 July 2017 3 September 2017 5 September 2017
Please cite this article as: Lunardi Mattia, Zivelonghi Carlo, van den Brink Floris S., Ghione Matteo, Vinco Giulia, Benfari Giovanni, Scarsini Roberto, Ribichini Flavio, Agostoni Pierfrancesco, Drug Eluting Balloon for the treatment of patients with Coronary Artery Disease: current perspectives, Cardiovascular Revascularization Medicine (2017), doi: 10.1016/j.carrev.2017.09.002
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ACCEPTED MANUSCRIPT Drug Eluting Balloon for the treatment of patients with Coronary Artery Disease: current perspectives.
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Mattia Lunardi, MD1; Carlo Zivelonghi, MD1,2; Floris S. van den Brink, MD2; Matteo Ghione,
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MD3; Giulia Vinco, MD1; Giovanni Benfari, MD1; Roberto Scarsini, MD1; Flavio Ribichini, MD1;
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Pierfrancesco Agostoni, MD, PhD2
Department of Medicine, Division of Cardiology, University of Verona, Verona, Italy
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Department of Cardiology, St Antonius Hospital, Nieuwegein, The Netherlands
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Department of Cardiology, Ospedale San Paolo, Savona, Italy
profit sectors.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-
Total word count: 3211 (excluding references and tables)
Corresponding author: Pierfrancesco Agostoni St Antonius ziekenhuis Nieuwegein Postbus 2500 3430 EM Nieuwegein, the Netherlands Email: [email protected] Phone: +310306092774
ACCEPTED MANUSCRIPT Summary Despite the improvement of outcomes after the introduction of bare metal and drug eluting stents for the
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treatment of CAD, certain type of patients have still an increased risk of stent failure. An alternative is
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represented by drug-eluting balloons (DEB). This innovation could give potential benefits in particular for the in-stent restenosis (ISR) and the de-novo lesions. In the first setting DEB have shown results superior to
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those with plain-balloon angioplasty and similar to those with first generation DES. Their performance seems to be more evident in BMS-ISR than in DES-ISR, showing a reliable effectiveness in those cases of
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recalcitrant ISR or when dual antiplatelet therapy is not indicated. In the context of de-novo lesions the use of DEB as unique strategy results more safe and feasible than a strategy with combined BMS implantation. The results are comparable to DES in lesions limited to small coronary vessels. Other particular scenarios, like bifurcations, acute myocardial infarction and diffuse disease, have been approached with DEB resulting
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in very heterogeneous outcomes. At present, given the high efficacy of last generation DESs, DEBs should
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be considered where clinical and angiographic conditions require the avoidance of stent implantation.
ACCEPTED MANUSCRIPT Background The introduction of bare metal stents (BMS) for the treatment of coronary artery disease (CAD) has changed
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radically the prognosis of patients undergoing percutaneous coronary intervention (PCI), when compared
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with plain old balloon angioplasty (POBA)[1,2]. In addition, the introduction of drug eluting stents (DES), allowing for local cytostatic drug delivery, reduced the risk of restenosis and repeat revascularization.
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Despite this success, challenges remain, including the risk of stent restenosis and thrombosis and the requirement for dual antiplatelet therapy[3]. In particular, specific group of populations (e.g. diabetics,
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chronic kidney disease, previously failed revascularization with stent implantation)[4-6] and angiographic features (e.g. lesions involving bifurcations, small vessel disease, diffuse disease)[7,8] are known for predicting an increased risk of stent failure, thus representing an unfavourable condition for metallic layer positioning. Drug-eluting balloons (DEB) represent another finding, with a interessant applicability in the
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treatment of patients with CAD for both in-stent restenosis (ISR) and de-novo lesions. This review will clarify the potential benefits and possible clinical applications of DEB according to the most recent evidence.
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Mechanism of action
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DEB are semicompliant angioplasty balloons with an antirestenotic drug on their surface that is released locally into the vessel wall during balloon contact. Since the first proof-of-concept randomized clinical trial
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paclitaxel was chosen as drug for this technology [9], because it has an high lipophilicity and a particular tissue retention (Table 1). The development of novel limus-based DEB is still under investigation[10,11]. From a technical standpoint, most DEBs are coated with 3 µg/mm2 of paclitaxel, and, once reached the target lesion, require 60 to 90 seconds of balloon inflation to obtain an effective (8-18%) drug transfer to the vessel wall[12]. Of note, micro-injuries to the target lesion before treatment with DEB represent a key point for a proper drug absorption. For this reason, the importance of proper lesion preparation is crucial to achieve clinical success. Pre-dilation with conventional balloon is substantially mandatory in all cases, even by means of cutting or scoring balloons, in case of hard and calcified stenosis. Only once the lesion is adequately expanded and the angiographic result appears satisfying, the DEB could be adopted as a “drug delivery” device and applied to the pre-treated vessel segment[13]. Applications of DEB
ACCEPTED MANUSCRIPT In-Stent Restenosis (ISR) ISR represents the context with the widest experience and the most encouraging data until now for the use of
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DEB. Conceptually, DEB in this setting needs only to overcome the regrowth of neointimal hyperplasia in
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the stent, meanwhile recoil and dissections are taken care of by the stent already in place. BMS restenosis
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The first clinical application of DEB was described by Scheller et al., through the PACCOCATH-ISR trial
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where the effect of a paclitaxel-coated DEB (Sequent Please, B.Braun, Germany) were compared to those of an uncoated balloon in 52 patients presenting BMS-ISR[9] (see details of randomized trials in Table 2). The study showed mainly the significant reduction in-segment late lumen loss (LLL) at 6 months of FU in the arm treated with DEB (0.03±0.48 vs 0.74±0.86 mm respectively, p=0.002), associated with a significantly lower incidence of binary in-stent restenosis (5% vs 43% patients, p=0.002). The clinical long-term benefits
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of DEB were confirmed in the PACCOCATH-ISR II trial, that reported a 5-years follow up of more than 100
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patients[14,15]. Despite clearly-oriented results in the first trials, some researchers suggested that the same outcome cannot be expected by all devices. Agostoni P et al. investigated the effect of DEB by means of
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optical coherence tomography (OCT)[16] comparing urea-paclitaxel coated balloon (IN.Pact Falcon) with a different coating DEB (DIOR, EuroCor GmbH, Bonn, Germany). They found significantly different
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angiographic, OCT and functional results in favour to the urea-paclitaxel coated balloon[17], like the changes in neointimal volume during follow-up, revealing a 30 % increase for the DIOR verus a 16 % decrease for the IN.PACT Falcon. At present available data suggest that there is no class effect for DEB, so that outcome data for a given device should not be extrapolated to other DCB devices[18]. Afterwards the use of DEB in BMS-ISR was compared with DES. In the PEPCAD-II trial[19] the arm treated with a second-generation paclitaxel–iopromide DEB (SeQuent Please; B Braun, Melsungen, Germany) showed similar outcomes than the paclitaxel-eluting stent arm, (PES; Taxus Liberté, Boston Scientific, Natick, Massachusetts), showed similar clinical and angiographic outcomes. More recently, in the multicentre randomized RIBS V clinical trial, 189 patients were assigned to either DEB or to a secondgeneration everolimus-eluting stent (EES, Xience Prime, Abbott Vascular, Abbott Park, IL, USA)[20]. The primary endpoint of in-segment MLD at 9 months proved superior among the patients treated with EES (2.36
ACCEPTED MANUSCRIPT ± 0.6 mm vs. 2.01 ± 0.6 mm, respectively, p < 0.001; absolute mean difference: 0.35 mm, 95% CI: 0.16 to 0.53) with lower percent diameter stenosis (13 ± 17% vs. 25 ± 20%, respectively, p < 0.001). No difference was reported in the LLL and in MACEs were observed. The authors stated that both strategies demonstrated
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an excellent angiographic and clinical outcome. In conclusion, in the context of BMS-ISR DEB should be preferred to DES in selected cases, i.e. in the presence of multiple metal layers, in those with ISR encompassing large side branches (for the possibly increased risk of occlusion after stent implantation), and
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in those a prolonged dual antiplatelet regimen is not desiderable.
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DES restenosis
As with BMS-ISR, DEBs were compared to POBA in the first RCTs with patients presenting DES restenosis, showing that DEB had constantly better outcomes than plain old balloon angioplasty[21-23]. In addition, DEB versus first generation DES showed equivalent outcomes. In the 3-arm ISAR DESIRE III
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trial, 402 patients with any limus-eluting stent-ISR were randomly allocated to one of the following treatment: DEB (SeQuent Please), PES (Taxus Libertè) or POBA with conventional balloon[24]. DEB
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resulted non-inferior rather than PES in terms of diameter stenosis (DS) at 6-8 month follow-up , while not
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surprisingly, the incidence of adverse clinical events was higher in the POBA group, when compared with PEB and PES, difference mainly driven by a consistent TLR rate (43.5% vs 22.1% and 13.5% respectively,
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p<0.0001 for both comparisons). Of note, these results were confirmed by a large amount of registries that investigated the performance of DEB in real-life populations with DES-ISR[25-28], supporting DEB in presence of binary restenosis and TLR in non-focal type lesions and bifurcation lesions. Recently, however, a second generation DES (EES Xience Prime) was compared to DEB (SeQuent Please) in 309 patients in the RIBS-IV randomized clinical trial[29]. This trial proved the superiority of EES, obtaining a significantly larger in-segment MLD at follow-up (2.03 ± 0.7 mm vs. 1.80 ± 0.6
ACCEPTED MANUSCRIPT As deducible from the evidence described, DEB performance in DES-ISR is less pronounced than in BMSISR. Moreover, the clear benefits of this device tend to attenuate, if not disappear, when compared with last generation DES[20,29]. As a general indication, DEBs maintain a good profile and a reliable effectiveness in
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those patients with recalcitrant ISR or contraindications to prolonged dual antiplatelet therapy. At present, both BMS- and DES-ISR are approved indications for the utilization of DEB in the European Guidelines
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(IA)[30]. DEB in De Novo Lesions
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DEB in de-novo coronary lesions could minimize the necessity of prolonged DAPT and to minimize the implantation of metallic layers. Currently two strategies have been investigated: DEB associated with default BMS implantation and DEB as a stand-alone therapy (with bail-out only BMS).
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DEB + routine BMS
The main benefits of this option could derive from the absence of a permanent DES implantation, that means
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a limited DAPT period, with subsequent lower bleeding risk. With this strategy, DEB can provide rapid and homogeneous release of antiproliferative drug to the target lesion, while BMS prevents acute elastic recoil.
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This option has been investigated in several trials, showing superior outcomes in term of LLL at 6 months follow-up when compared against BMS implantation alone[31,32]. When compared with DES implantation,
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however, a strategy of DEB + BMS implantation resulted in most cases inferior, with only few reports describing comparable outcomes[33]. In the OCTOPUS trial, the procedural outcome of 90 patients undergoing either a DEB + BMS or a second generation DES (EES) implantation strategy were investigated with OCT[34]. Despite no significant differences in terms of struts coverage and clinical endpoints, the OCT analysis at 6-month follow-up suggested a relevant increase in neointimal proliferation in the study group (15.7±7.8 versus 11.0±5.2 mm3 proliferation volume/cm stent length; P=0.002). Moreover, an IVUS-based study from Fischer et al reported indeed augmented indexes of neointimal hyperplasia at 9 months follow-up, which also translated into a significantly higher incidence of in-stent restenosis rate (19.7 vs. 11 %, respectively; p<0.01)[35]. Striking evidence derived from the randomized trial of Liistro et al, prematurely interrupted for efficacy endpoints, in which a strategy of DEB+BMS was compared with implantation of a
ACCEPTED MANUSCRIPT second-generation DES (EES, Xience)[36]. TLR resulted five times higher in the study group than in the control group.
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In conclusion, the authors believe that a strategy of DEB associated with routine BMS implantation has
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currently no real indication, given the worse effect in terms of late luminal loss and need for TLR when compared with the now available DES, without a proven ability to reduce DAPT duration.
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DEB Alone (or with bailout BMS implantation)
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As far as concerns DEB as a stand-alone therapy, with the objective to minimize the implantation of metallic layer, first clinical studies have analyzed treatment of lesions in small coronary vessels. The implantation of a stent was allowed only when acute elastic recoils or dissections occured, the so-called “bailout stenting “. The hypothesis of this strategy in small vessels is the consequences of the placement of a stent there, as the effect of stent-associated neointimal hyperplasia is less tolerated in small-calibre vessels than in large ones.
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In the PEPCAD I (Paclitaxel-Eluting PTCA-Balloon Catheter to Treat Small Vessel Coronary Artery
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Disease) study[37] a SeQuent Please DEB was chosen for the angioplasty, and in 27% of the procedures a BMS deployment was necessary. The study showed significantly improved clinical and angiographical
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results when a DEB-only strategy was adopted, with TLR of 5% in the DEB-only group and 28% in the DEB + BMS group. Of note, the SeQuent Please World Wide Registry and the SeQuent Please Small Vessel
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‘‘PCB Only’’ Registry[38,39] reported lower and comparable rates of TLR and MACE in both groups[38]. A first comparison between DEB and DES in vessels with a diameter less than 2.75 mm derived by the PICCOLETTO trial[40]. This study was halted prematurely after enrolment of two-third of patients because of a clear superiority of the DES group, demonstrating less restenosis and a strong trend toward lower TLR (nearly three times than in the DEB group). A sample of 182 patients with vessels with a mean diameter of 2.15 mm was randomized in The Balloon Elution and Late Loss Optimization (BELLO) trial to compare the IN.PACT Falcon DEB with the Taxus Libertè[41]. The LLL was significantly lower in DEB compared with DES at 6 months (0.09 vs. 0.30 mm respectively, p=0.001). However, bailout BMS amounted at 21.1% of DEB patients; in this group, LLL was similar to that reported in DES group (0.33 mm). As far as MACE rates are concerned, no difference was observed at follow-up between DEB and DES groups (10% vs. 16.3%, p=0.18). Furthermore, the apparent superiority of DEB over DES persisted after 24 months of
ACCEPTED MANUSCRIPT BELLO study follow-up. The more promising results of BELLO study can be explained by different reasons. First of all, while the same device was adopted in both studies, a first-generation DEB was used in PICCOLETTO study, whereas the a second-generation one was employed in the BELLO study. Moreover,
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in the BELLO study the 96.8% of the procedures included predilatation before DEB application, while in PICCOLETTO trial this was performed only in 25% of patients. To conclude, a DEB-only strategy proves generally efficient, with results comparable to DES in a mixed population of patients with lesions limited to
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small coronary vessels (< 2.5 mm in diameter). Only two randomized controlled trials compared DEB
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against DES, which, however, reported on very heterogeneous outcomes. Bailout stenting rate ranges from 3% to 36% and seems to result in a worse clinical and angiographic outcome. Careful attention should be paid to avoid geographical mismatch. DEB in Complex Scenarios
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Subsets of clinical or angiographic more challenging conditions have also been approached with DEB.
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DEB in Acute Myocardial Infarction
The first results in this setting derived from the DEBAMI (Drug-Eluting Balloon in Acute Myocardial
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Infarction) trial[42,43], where patients with STEMI were randomly assigned to primary PCI with BMS (group A) vs DEB + BMS (group B) vs DES (group C). Discouraging results were registered in group B,
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showing a significant LLL at angiographic follow-up (0.64 ± 0.56 mm) and a relevant binary restenosis rate (28.6%), failing to prove superior than treatment with BMS alone. Given the promising DEB-only results from PEPCAD I and V, a fourth nonrandomized DEB-only arm was indaged[44]. In this case a predilatation was imperative before DEB application. Angiographic outcomes favoured DESs over DEB-only, but DEBonly was comparable to BMS alone and DEB + BMS. No thrombosis occurred, suggesting DEB-only as a valid treatment in STEMI patients with contraindication to DAPT. Analogue results were collected in the PAPPA study, which showed good clinical outcomes with a DEB-only strategy[45]. DEB in Bifurcation Lesions The optimal treatment for bifurcation lesions, aimed at sparing the side branch (SB) from acute effects after main branch (MB) angioplasty and preserving its patency at long term, is still a matter of debate among
ACCEPTED MANUSCRIPT interventionalists. At present, the most adopted technique is that of provisional stenting, which consists in implantation of a DES in the MB, and possible stenting of the SB according to the angiographic result (i.e. only in case of major SB dissection or clear suboptimal SB result). Possible roles of the DEB technology in
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this setting have been studied in the DEBIUT (Drug Eluting Balloon in Bifurcation Utrecht) registry, in which a DEB was used to treat both the main branch (MB) and SB before a T-stenting technique with BMS in the MB and final kissing post-dilation with normal balloons. No patients required additional BMS
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implantation in the SB, and 4 months follow-up reported no clinical relevant events. After this result, the
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same group of researchers set up the DEBIUT trial, which randomly assigned 117 patients to one of the following treatments: DEB in both MB and SB and BMS in MB (group A); BMS in MB and regular balloon angioplasty in SB (group B); or paclitaxel DES in MB and regular balloon in SB (group C)[46]. Although the DCB + BMS strategy achieved acceptable results in terms of LLL at 6 months, it failed to show angiographic and clinical superiority over conventional BMS, using a provisional T-stenting technique. The
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authors identified possible reasons for these findings in the unexpectedly good results of the normal balloon
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angioplasty-treated SB of both BMS and DES arms, and the inferior drug delivery attributes of the Dior-I DEB. The BABILON (Study of the Paclitaxel-Coated Balloon Catheter in Bifurcated Coronary Lesions)
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randomized trial compared provisional T stenting with BMS in the MB after MB/SB dilation with DEB (SeQuent Please) against provisional T stenting with everolimus-DES. This study confirmed the
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unsatisfactory results of the DEBIUT trial, with greater LLL and higher MACEs incidence in the study group[47]. Thereafter, in the BIOLUX-I study, a mixed strategy was adopted, using a second generation DES in the MB and a SB dilatation with DEB[48]. After pre-dilatation of MB, the SB was treated with a DEB (Pantera Lux, Biotronik AG, Buelach, Switzerland), and subsequently, a Xience Prime/Xience V DES was implanted in the MB. The rationale was to maintain the simplicity of provisional stenting technique with the advantage of reducing restenosis of the SB. The primary endpoint showed a low LLL in the SB of 0.10 mm at 9 months with good clinical outcome, proving this approach safe and effective. Is authors’ opinion that DEB treatment of the SB appears promising in a provisional SB stenting approach, but more robust randomized data are needed on the use of newer-generation DESs. DEB in CTO & Diffuse Disease
ACCEPTED MANUSCRIPT The use of DEB was investigated also in the context of chronic total occlusion. In the PEPCAD (PaclitaxelCoated Balloon With Bare-Metal Stenting in Patients With Chronic Total Occlusions in Native Coronary Arteries) CTO trial[49] 48 patients were treated, after successful recanalization of the lesion, with BMS and
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finally with DEB. These were compared with matched patients treated with a paclitaxel-eluting stent, showing similar clinical results and in-stent LLL. In the setting of diffuse disease, Costopoulos et al. compared a DEB-only strategy (IN.PACT Falcon or Pantera Lux) with the use of DES[50]. Despite a hybrid
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approach, combining DEB with DES implantation was necessary in one third of patients, long-term clinical
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follow up (median 26.1 months) demonstrated similar outcome with the two different strategies. CONLUSIONS
DEB catheters represent a valid tool in the armamentarium of the interventional cardiologist, especially useful in complex scenarios (ISR, bifurcations, small vessels and diffuse disease). Considering the advanced
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performance of last generation DESs, clinical indications of DEBs have been related to those scenarios where avoidance of a metallic layer implantation is most desirable. In the setting of ISR, evidence from
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RCTs with DEBs has disclosed results superior to those with plain-balloon angioplasty, and comparable to
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first generation DES, though slightly inferior to last generation DESs. By sparing metallic layer implantation, DEB angioplasty might be taken into account for these patients. Conversely, results with DEB angioplasty
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for de novo coronary disease have been relatively sub-optimal to date, and the use of DEBs in this settings should be carefully weighted in every single scenario (Table 3).
ACCEPTED MANUSCRIPT References [1] Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994;331:489-95.
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ACCEPTED MANUSCRIPT [18] Bondesson P, Lagerqvist B, James SK, et al. Comparison of two drug-eluting balloons: a report from the SCAAR registry. EuroIntervention 2012;8:444–449. [19] Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxel-coated balloon catheter versus paclitaxelcoated stent for the treatment of coronary in-stent restenosis. Circulation. 2009;119:2986-94.
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[20] Alfonso F, Pérez-Vizcayno MJ2, Cárdenas A, et al. A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent). J Am Coll Cardiol. 2014;63:1378-86.
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[21] Habara S, Mitsudo K, Kadota K, et al. Effectiveness of paclitaxel-eluting balloon catheter in patients with sirolimus-eluting stent restenosis. JACC Cardiovasc Interv. 2011;4:149-54.
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[22] Habara S, Iwabuchi M, Inoue N, et al. A multicenter randomized comparison of paclitaxel-coated balloon catheter with conventional balloon angioplasty in patients with bare-metal stent restenosis and drugeluting stent restenosis. Am Heart J. 2013;166:527-33. [23] Rittger H, Brachmann J, Sinha AM, et al. A randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon angioplasty in drug-eluting stent restenosis: the PEPCAD-DES study. J Am Coll Cardiol. 2012;59:1377-82.
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[24] Byrne RA, Neumann FJ, Mehilli J, et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet 2013; 381: 461–67
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[26] Habara S, Kadota K, Kanazawa T, et al. Paclitaxel-coated balloon catheter compared with drugeluting stent for drug-eluting stent restenosis in routine clinical practice. EuroIntervention. 2016;11(:1098105.
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[27] Stella PR, Belkacemi A, Waksman R, et al. The Valentines Trial: results of the first one week worldwide multicentre enrolment trial, evaluating the real world usage of the second generation DIOR paclitaxel drug-eluting balloon for in-stent restenosis treatment. EuroIntervention. 2011;7:705-10. [28] Kawamoto H, Ruparelia N, Latib A, et al. Drug-Coated Balloons Versus Second-Generation DrugEluting Stents for the Management of Recurrent Multimetal-Layered In-Stent Restenosis. JACC Cardiovasc Interv. 2015;8:1586-94. [29] Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, et al. A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial. J Am Coll Cardiol. 2015;66:23-33. [30] Windecker S, Kolh P, Alfonso F, Collet JP, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-619. [31] Herdeg C, Göhring-Frischholz K, Haase KK, et al. Catheter-based delivery of fluid paclitaxel for prevention of restenosis in native coronary artery lesions after stent implantation. Circ Cardiovasc Interv. 2009;2:294-301.
ACCEPTED MANUSCRIPT [32] Clever YP, Cremers B, Speck U, Dietz U, Böhm M, Scheller B. Influence of a paclitaxel coated balloon in combination with a bare metal stent on restenosis and endothelial function: comparison with a drug eluting stent and a bare metal stent. Catheter Cardiovasc Interv. 2014;84:323-31.
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[33] Żurakowski A, Buszman PP, Milewski KP et al. Stenting and Adjunctive Delivery of Paclitaxel Via Balloon Coating Versus Durable Polymeric Matrix for De Novo Coronary Lesions: Clinical and Angiographic Results from the Prospective Randomized Trial. J Interv Cardiol. 2015;28:348-57.
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[34] Poerner TC, Otto S, Gassdorf J, et al. Stent coverage and neointimal proliferation in bare metal stents postdilated with a Paclitaxel-eluting balloon versus everolimus-eluting stents: prospective randomized study using optical coherence tomography at 6-month follow-up. Circ Cardiovasc Interv. 2014;7:760-7.
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[35] Fischer D, Scheller B, Schäfer A, et al. Paclitaxcel-coated balloon plus bare metal stent vs. sirolimus-eluting stent in de novo lesions: an IVUS study. EuroIntervention. 2012;8:450-5. [36] Liistro F, Porto I, Angioli P, et al. Elutax paclitaxel-eluting balloon followed by bare-metal stent compared with Xience V drug-eluting stent in the treatment of de novo coronary stenosis: a randomized trial. Am Heart J. 2013;166:920-6. [37] Unverdorben M, Kleber FX, Heuer H, et al. Treatment of small coronary arteries with a paclitaxelcoated balloon catheter in the PEPCAD I study: are lesions clinically stable from 12 to 36 months? EuroIntervention. 2013;9:620-8.
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[38] Wöhrle J, Zadura M, Möbius-Winkler S, et al. SeQuentPlease World Wide Registry: clinical results of SeQuent please paclitaxel-coated balloon angioplasty in a large-scale, prospective registry study. J Am Coll Cardiol. 2012;60:1733-8. [39] Zeymer U, Waliszewski M, Spiecker M, et al. Prospective 'real world' registry for the use of the 'PCB only' strategy in small vessel de novo lesions. Heart. 2014;100:311-6.
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[40] Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study. Heart. 2010;96:1291-6.
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[41] Latib A, Colombo A, Castriota F, et al. A randomized multicenter study comparing a paclitaxel drugeluting balloon with a paclitaxel-eluting stent in small coronary vessels: the BELLO (Balloon Elution and Late Loss Optimization) study. J Am Coll Cardiol. 2012;60:2473-80. [42] Koh TH. Drug-eluting balloon in acute myocardial infarction (DEBAMI) trial. Paper presented at EuroPCR; May 18, 2011; Paris, France [43] Belkacemi A, Agostoni P, Nathoe HM, et al. First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial: a multicenter randomized comparison of drugeluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes. J Am Coll Cardiol. 2012;59:2327–37. [44] Nijhoff F, Agostoni P, Belkacemi A, et al. Primary percutaneous coronary intervention by drugeluting balloon angioplasty: the nonrandomized fourth arm of the DEB-AMI (drug-eluting balloon in STsegment elevation myocardial infarction) trial. Catheter Cardiovasc Interv. 2015;86(Suppl 1):S34–44. [45] Vos NS, Dirksen MT, Vink MA, et al. Safety and feasibility of a PAclitaxel-eluting balloon angioplasty in Primary Percutaneous coronary intervention in Amsterdam (PAPPA): one-year clinical outcome of a pilot study. EuroIntervention. 2014;10:584–90.
ACCEPTED MANUSCRIPT [46] Fanggiday JC, Stella PR, Guyomi SH, Doevendans PA. Safety and efficacy of drug-eluting balloons in percutaneous treatment of bifurcation lesions: the DEBIUT (Drug-Eluting Balloon in BIfurcaton UTrecht) registry. Catheter Cardiovasc Interv. 2008;71:629–35.
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[47] Lopez Mınguez JR, Nogales Asensio JM, Doncel Vecino LJ, et al. A prospective randomised study of the paclitaxel-coated balloon catheter in bifurcated coronary lesions (BABILON trial): 24-month clinical and angiographic results. EuroIntervention. 2014;10:50–7.
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[48] Worthley S, Hendriks R, Worthley M, et al. Paclitaxel-eluting balloon and everolimus-eluting stent for provisional stenting of coronary bifurcations: 12-month results of the multicentre BIOLUX-I study. Cardiovasc Revasc Med. 2015;16:413–7.
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[49] Whorle J, Werner GS, Wohrle J, Werner GS. Paclitaxel-coated balloon with bare-metal stenting in patients with chronic total occlusions in native coronary arteries. Catheter Cardiovasc Interv. 2013;81:793–9
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[50] Costopoulos C, Latib A, Naganuma T, et al. The role of drug-eluting balloons alone or in combination with drug-eluting stents in the treatment of de novo diffuse coronary disease. JACC Cardiovasc Interv. 2013;6:1153–9.
ACCEPTED MANUSCRIPT Table1: Commercially available drug-eluting balloons for coronary artery disease.
AgentTM Danubio® Dior® II
Paclitaxel
2.0
-
3.0 NA
-
Paclitaxel
3.0
Urea
Paclitaxel Paclitaxel Paclitaxel Paclitaxel
2.0 3.0 3.0 3.0
Polysorbate/sorbitol BTHC Shellac Shellac
Paclitaxel
3.0
Iopromide
Paclitaxel Paclitaxel
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Boston Scientific, USA Minvasys, Paris, France Eurocor, Bonn, Germany Aachen Resonance, Luxembourg, Elutax SV™ Luxembourg Essential iVascular, Spain GENIE Acrostak, Winterthur, Switzerland Medtronic Vascular, Santa Rosa, IN.PACT™ Falcon CA, USA Lutonix DCB® (Moxy) BARD, Murray Hill, NJ, USA Pantera Lux® Biotronik, Bülach, Switzerland Primus™ Cardionovum, Warsaw, Poland Restore DEB® Cardionovum, Germany B. Braun Melsungen AG, Berlin, SeQuent® Please Germany ATBC: acetyl-tributyl-citrate; BTHC: butyryl-tri-hexylcitrat.
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Paclitaxel Paclitaxel Paclitaxel
Drug Dose (µg/mm2) 2.2 2.5 3.0
Drug Eluted
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Company
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Device
Additive ATBC BTHC Shellac
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Table 2. Most relevant randomized clinical trial involving DEB for the treatment of coronary artery disease. CAD - Setting DEB
De novo - Bifurcation
SeQuent Please (+BMS)
Number of Patients
POBA POBA PES EES POBA POBA PES & POBA EES EES SES PES PES BMS & PES BMS & PES
52 108 131 189 50 110 402 309 90 55 60 182 150 117
EES
108
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Paccocath Paccocath SeQuent Please SeQuent Please SeQuent Please SeQuent Please SeQuent Please SeQuent Please SeQuent Please (+BMS) Coroflex DEBlue (+ BMS) Dior I IN.Pact Falcon Dior II Dior I
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BMS-ISR BMS-ISR BMS-ISR BMS-ISR DES-ISR DES-ISR DES-ISR DES-ISR De novo lesions De novo lesions De novo lesions De novo lesions De novo lesions - AMI De novo - Bifurcation
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PACCOCATH ISR9 PACCOCATH ISR II14 PEPCAD II19 RIBS V20 Habara et al 21 PEPCAD DES 23 ISAR-DESIRE III 24 RIBS IV29 OCTOPUS 34 Fischer et al 35 PICCOLETTO 40 BELLO 41 DEB-AMI 43 DEBIUT trial 46 BABILON 47
Treatment devices of Comparison Comparator(s)
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Trial
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BMS: bare metal stent; DES: drug-eluting stents; ISR: in-stent restenosis; POBA: plain-old balloon angioplasty; SES: sirolimus-eluting stent; PES: paclitaxel-eluting stent; EES: everolimus-eluting stents; EPC: endothelial progenitor-cell capturing; AMI: acute myocardial infarction.
ACCEPTED MANUSCRIPT Table3: Expert advices to obtain clinical success with DEB a. b.
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e.
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d.
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DEB is not a dilation balloon. It has been conceived as drug-carrier and should be used as such. Device class effect has not been demonstrated. DEB choice should be based on the evidence available for the specific subset of lesions. DEB can represent the first therapeutic choice in both BMS- and DES-ISR, especially when the lesion is included in the stent struts (focal or diffuse). Of note, adequate predilation with satisfactory result is mandatory before DEB treatment. DEB may be considered in the treatment of de novo lesions, provided that proper lesion predilation (Balloon-Artery ratio 1:1) is performed and angiographic result proves optimal (stenosis<30%, TIMI flow 3, no dissections). However indications for this strategy remain limited. Planned combination of DEB with BMS implantation should be avoided. If the strategy requires stent deployment, directly choose second generation DES.
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Clinical applications of Drug Eluting Balloons (DEBs) have focused on indications where avoidance of stent implantation is most desirable. DEBs could give potential benefits in particular for the in-stent restenosis (ISR) and the denovo lesions. In ISR scenario the performance of DEBs seems to be more evident in BMS-ISR than in DES-ISR. In the context of de-novo lesions the results are comparable to DES in lesions limited to coronary vessels less than 2.5 mm. Particular scenarios, like bifurcations, acute myocardial infarction and diffuse disease, have been approached with DEB resulting in very heterogeneous outcomes.
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S1553-8389(17)30345-7 doi: 10.1016/j.carrev.2017.09.002 CARREV 1130
To appear in:
Cardiovascular Revascularization Medicine
Received date: Revised date: Accepted date:
3 July 2017 3 September 2017 5 September 2017
Please cite this article as: Lunardi Mattia, Zivelonghi Carlo, van den Brink Floris S., Ghione Matteo, Vinco Giulia, Benfari Giovanni, Scarsini Roberto, Ribichini Flavio, Agostoni Pierfrancesco, Drug Eluting Balloon for the treatment of patients with Coronary Artery Disease: current perspectives, Cardiovascular Revascularization Medicine (2017), doi: 10.1016/j.carrev.2017.09.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Drug Eluting Balloon for the treatment of patients with Coronary Artery Disease: current perspectives.
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Mattia Lunardi, MD1; Carlo Zivelonghi, MD1,2; Floris S. van den Brink, MD2; Matteo Ghione,
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MD3; Giulia Vinco, MD1; Giovanni Benfari, MD1; Roberto Scarsini, MD1; Flavio Ribichini, MD1;
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Pierfrancesco Agostoni, MD, PhD2
Department of Medicine, Division of Cardiology, University of Verona, Verona, Italy
2
Department of Cardiology, St Antonius Hospital, Nieuwegein, The Netherlands
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3
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Department of Cardiology, Ospedale San Paolo, Savona, Italy
profit sectors.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-
Total word count: 3211 (excluding references and tables)
Corresponding author: Pierfrancesco Agostoni St Antonius ziekenhuis Nieuwegein Postbus 2500 3430 EM Nieuwegein, the Netherlands Email: [email protected] Phone: +310306092774
ACCEPTED MANUSCRIPT Summary Despite the improvement of outcomes after the introduction of bare metal and drug eluting stents for the
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treatment of CAD, certain type of patients have still an increased risk of stent failure. An alternative is
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represented by drug-eluting balloons (DEB). This innovation could give potential benefits in particular for the in-stent restenosis (ISR) and the de-novo lesions. In the first setting DEB have shown results superior to
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those with plain-balloon angioplasty and similar to those with first generation DES. Their performance seems to be more evident in BMS-ISR than in DES-ISR, showing a reliable effectiveness in those cases of
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recalcitrant ISR or when dual antiplatelet therapy is not indicated. In the context of de-novo lesions the use of DEB as unique strategy results more safe and feasible than a strategy with combined BMS implantation. The results are comparable to DES in lesions limited to small coronary vessels. Other particular scenarios, like bifurcations, acute myocardial infarction and diffuse disease, have been approached with DEB resulting
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in very heterogeneous outcomes. At present, given the high efficacy of last generation DESs, DEBs should
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be considered where clinical and angiographic conditions require the avoidance of stent implantation.
ACCEPTED MANUSCRIPT Background The introduction of bare metal stents (BMS) for the treatment of coronary artery disease (CAD) has changed
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radically the prognosis of patients undergoing percutaneous coronary intervention (PCI), when compared
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with plain old balloon angioplasty (POBA)[1,2]. In addition, the introduction of drug eluting stents (DES), allowing for local cytostatic drug delivery, reduced the risk of restenosis and repeat revascularization.
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Despite this success, challenges remain, including the risk of stent restenosis and thrombosis and the requirement for dual antiplatelet therapy[3]. In particular, specific group of populations (e.g. diabetics,
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chronic kidney disease, previously failed revascularization with stent implantation)[4-6] and angiographic features (e.g. lesions involving bifurcations, small vessel disease, diffuse disease)[7,8] are known for predicting an increased risk of stent failure, thus representing an unfavourable condition for metallic layer positioning. Drug-eluting balloons (DEB) represent another finding, with a interessant applicability in the
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treatment of patients with CAD for both in-stent restenosis (ISR) and de-novo lesions. This review will clarify the potential benefits and possible clinical applications of DEB according to the most recent evidence.
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Mechanism of action
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DEB are semicompliant angioplasty balloons with an antirestenotic drug on their surface that is released locally into the vessel wall during balloon contact. Since the first proof-of-concept randomized clinical trial
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paclitaxel was chosen as drug for this technology [9], because it has an high lipophilicity and a particular tissue retention (Table 1). The development of novel limus-based DEB is still under investigation[10,11]. From a technical standpoint, most DEBs are coated with 3 µg/mm2 of paclitaxel, and, once reached the target lesion, require 60 to 90 seconds of balloon inflation to obtain an effective (8-18%) drug transfer to the vessel wall[12]. Of note, micro-injuries to the target lesion before treatment with DEB represent a key point for a proper drug absorption. For this reason, the importance of proper lesion preparation is crucial to achieve clinical success. Pre-dilation with conventional balloon is substantially mandatory in all cases, even by means of cutting or scoring balloons, in case of hard and calcified stenosis. Only once the lesion is adequately expanded and the angiographic result appears satisfying, the DEB could be adopted as a “drug delivery” device and applied to the pre-treated vessel segment[13]. Applications of DEB
ACCEPTED MANUSCRIPT In-Stent Restenosis (ISR) ISR represents the context with the widest experience and the most encouraging data until now for the use of
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DEB. Conceptually, DEB in this setting needs only to overcome the regrowth of neointimal hyperplasia in
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the stent, meanwhile recoil and dissections are taken care of by the stent already in place. BMS restenosis
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The first clinical application of DEB was described by Scheller et al., through the PACCOCATH-ISR trial
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where the effect of a paclitaxel-coated DEB (Sequent Please, B.Braun, Germany) were compared to those of an uncoated balloon in 52 patients presenting BMS-ISR[9] (see details of randomized trials in Table 2). The study showed mainly the significant reduction in-segment late lumen loss (LLL) at 6 months of FU in the arm treated with DEB (0.03±0.48 vs 0.74±0.86 mm respectively, p=0.002), associated with a significantly lower incidence of binary in-stent restenosis (5% vs 43% patients, p=0.002). The clinical long-term benefits
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of DEB were confirmed in the PACCOCATH-ISR II trial, that reported a 5-years follow up of more than 100
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patients[14,15]. Despite clearly-oriented results in the first trials, some researchers suggested that the same outcome cannot be expected by all devices. Agostoni P et al. investigated the effect of DEB by means of
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optical coherence tomography (OCT)[16] comparing urea-paclitaxel coated balloon (IN.Pact Falcon) with a different coating DEB (DIOR, EuroCor GmbH, Bonn, Germany). They found significantly different
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angiographic, OCT and functional results in favour to the urea-paclitaxel coated balloon[17], like the changes in neointimal volume during follow-up, revealing a 30 % increase for the DIOR verus a 16 % decrease for the IN.PACT Falcon. At present available data suggest that there is no class effect for DEB, so that outcome data for a given device should not be extrapolated to other DCB devices[18]. Afterwards the use of DEB in BMS-ISR was compared with DES. In the PEPCAD-II trial[19] the arm treated with a second-generation paclitaxel–iopromide DEB (SeQuent Please; B Braun, Melsungen, Germany) showed similar outcomes than the paclitaxel-eluting stent arm, (PES; Taxus Liberté, Boston Scientific, Natick, Massachusetts), showed similar clinical and angiographic outcomes. More recently, in the multicentre randomized RIBS V clinical trial, 189 patients were assigned to either DEB or to a secondgeneration everolimus-eluting stent (EES, Xience Prime, Abbott Vascular, Abbott Park, IL, USA)[20]. The primary endpoint of in-segment MLD at 9 months proved superior among the patients treated with EES (2.36
ACCEPTED MANUSCRIPT ± 0.6 mm vs. 2.01 ± 0.6 mm, respectively, p < 0.001; absolute mean difference: 0.35 mm, 95% CI: 0.16 to 0.53) with lower percent diameter stenosis (13 ± 17% vs. 25 ± 20%, respectively, p < 0.001). No difference was reported in the LLL and in MACEs were observed. The authors stated that both strategies demonstrated
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an excellent angiographic and clinical outcome. In conclusion, in the context of BMS-ISR DEB should be preferred to DES in selected cases, i.e. in the presence of multiple metal layers, in those with ISR encompassing large side branches (for the possibly increased risk of occlusion after stent implantation), and
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in those a prolonged dual antiplatelet regimen is not desiderable.
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DES restenosis
As with BMS-ISR, DEBs were compared to POBA in the first RCTs with patients presenting DES restenosis, showing that DEB had constantly better outcomes than plain old balloon angioplasty[21-23]. In addition, DEB versus first generation DES showed equivalent outcomes. In the 3-arm ISAR DESIRE III
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trial, 402 patients with any limus-eluting stent-ISR were randomly allocated to one of the following treatment: DEB (SeQuent Please), PES (Taxus Libertè) or POBA with conventional balloon[24]. DEB
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resulted non-inferior rather than PES in terms of diameter stenosis (DS) at 6-8 month follow-up , while not
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surprisingly, the incidence of adverse clinical events was higher in the POBA group, when compared with PEB and PES, difference mainly driven by a consistent TLR rate (43.5% vs 22.1% and 13.5% respectively,
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p<0.0001 for both comparisons). Of note, these results were confirmed by a large amount of registries that investigated the performance of DEB in real-life populations with DES-ISR[25-28], supporting DEB in presence of binary restenosis and TLR in non-focal type lesions and bifurcation lesions. Recently, however, a second generation DES (EES Xience Prime) was compared to DEB (SeQuent Please) in 309 patients in the RIBS-IV randomized clinical trial[29]. This trial proved the superiority of EES, obtaining a significantly larger in-segment MLD at follow-up (2.03 ± 0.7 mm vs. 1.80 ± 0.6
ACCEPTED MANUSCRIPT As deducible from the evidence described, DEB performance in DES-ISR is less pronounced than in BMSISR. Moreover, the clear benefits of this device tend to attenuate, if not disappear, when compared with last generation DES[20,29]. As a general indication, DEBs maintain a good profile and a reliable effectiveness in
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those patients with recalcitrant ISR or contraindications to prolonged dual antiplatelet therapy. At present, both BMS- and DES-ISR are approved indications for the utilization of DEB in the European Guidelines
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(IA)[30]. DEB in De Novo Lesions
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DEB in de-novo coronary lesions could minimize the necessity of prolonged DAPT and to minimize the implantation of metallic layers. Currently two strategies have been investigated: DEB associated with default BMS implantation and DEB as a stand-alone therapy (with bail-out only BMS).
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DEB + routine BMS
The main benefits of this option could derive from the absence of a permanent DES implantation, that means
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a limited DAPT period, with subsequent lower bleeding risk. With this strategy, DEB can provide rapid and homogeneous release of antiproliferative drug to the target lesion, while BMS prevents acute elastic recoil.
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This option has been investigated in several trials, showing superior outcomes in term of LLL at 6 months follow-up when compared against BMS implantation alone[31,32]. When compared with DES implantation,
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however, a strategy of DEB + BMS implantation resulted in most cases inferior, with only few reports describing comparable outcomes[33]. In the OCTOPUS trial, the procedural outcome of 90 patients undergoing either a DEB + BMS or a second generation DES (EES) implantation strategy were investigated with OCT[34]. Despite no significant differences in terms of struts coverage and clinical endpoints, the OCT analysis at 6-month follow-up suggested a relevant increase in neointimal proliferation in the study group (15.7±7.8 versus 11.0±5.2 mm3 proliferation volume/cm stent length; P=0.002). Moreover, an IVUS-based study from Fischer et al reported indeed augmented indexes of neointimal hyperplasia at 9 months follow-up, which also translated into a significantly higher incidence of in-stent restenosis rate (19.7 vs. 11 %, respectively; p<0.01)[35]. Striking evidence derived from the randomized trial of Liistro et al, prematurely interrupted for efficacy endpoints, in which a strategy of DEB+BMS was compared with implantation of a
ACCEPTED MANUSCRIPT second-generation DES (EES, Xience)[36]. TLR resulted five times higher in the study group than in the control group.
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In conclusion, the authors believe that a strategy of DEB associated with routine BMS implantation has
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currently no real indication, given the worse effect in terms of late luminal loss and need for TLR when compared with the now available DES, without a proven ability to reduce DAPT duration.
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DEB Alone (or with bailout BMS implantation)
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As far as concerns DEB as a stand-alone therapy, with the objective to minimize the implantation of metallic layer, first clinical studies have analyzed treatment of lesions in small coronary vessels. The implantation of a stent was allowed only when acute elastic recoils or dissections occured, the so-called “bailout stenting “. The hypothesis of this strategy in small vessels is the consequences of the placement of a stent there, as the effect of stent-associated neointimal hyperplasia is less tolerated in small-calibre vessels than in large ones.
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In the PEPCAD I (Paclitaxel-Eluting PTCA-Balloon Catheter to Treat Small Vessel Coronary Artery
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Disease) study[37] a SeQuent Please DEB was chosen for the angioplasty, and in 27% of the procedures a BMS deployment was necessary. The study showed significantly improved clinical and angiographical
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results when a DEB-only strategy was adopted, with TLR of 5% in the DEB-only group and 28% in the DEB + BMS group. Of note, the SeQuent Please World Wide Registry and the SeQuent Please Small Vessel
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‘‘PCB Only’’ Registry[38,39] reported lower and comparable rates of TLR and MACE in both groups[38]. A first comparison between DEB and DES in vessels with a diameter less than 2.75 mm derived by the PICCOLETTO trial[40]. This study was halted prematurely after enrolment of two-third of patients because of a clear superiority of the DES group, demonstrating less restenosis and a strong trend toward lower TLR (nearly three times than in the DEB group). A sample of 182 patients with vessels with a mean diameter of 2.15 mm was randomized in The Balloon Elution and Late Loss Optimization (BELLO) trial to compare the IN.PACT Falcon DEB with the Taxus Libertè[41]. The LLL was significantly lower in DEB compared with DES at 6 months (0.09 vs. 0.30 mm respectively, p=0.001). However, bailout BMS amounted at 21.1% of DEB patients; in this group, LLL was similar to that reported in DES group (0.33 mm). As far as MACE rates are concerned, no difference was observed at follow-up between DEB and DES groups (10% vs. 16.3%, p=0.18). Furthermore, the apparent superiority of DEB over DES persisted after 24 months of
ACCEPTED MANUSCRIPT BELLO study follow-up. The more promising results of BELLO study can be explained by different reasons. First of all, while the same device was adopted in both studies, a first-generation DEB was used in PICCOLETTO study, whereas the a second-generation one was employed in the BELLO study. Moreover,
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in the BELLO study the 96.8% of the procedures included predilatation before DEB application, while in PICCOLETTO trial this was performed only in 25% of patients. To conclude, a DEB-only strategy proves generally efficient, with results comparable to DES in a mixed population of patients with lesions limited to
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small coronary vessels (< 2.5 mm in diameter). Only two randomized controlled trials compared DEB
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against DES, which, however, reported on very heterogeneous outcomes. Bailout stenting rate ranges from 3% to 36% and seems to result in a worse clinical and angiographic outcome. Careful attention should be paid to avoid geographical mismatch. DEB in Complex Scenarios
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Subsets of clinical or angiographic more challenging conditions have also been approached with DEB.
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DEB in Acute Myocardial Infarction
The first results in this setting derived from the DEBAMI (Drug-Eluting Balloon in Acute Myocardial
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Infarction) trial[42,43], where patients with STEMI were randomly assigned to primary PCI with BMS (group A) vs DEB + BMS (group B) vs DES (group C). Discouraging results were registered in group B,
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showing a significant LLL at angiographic follow-up (0.64 ± 0.56 mm) and a relevant binary restenosis rate (28.6%), failing to prove superior than treatment with BMS alone. Given the promising DEB-only results from PEPCAD I and V, a fourth nonrandomized DEB-only arm was indaged[44]. In this case a predilatation was imperative before DEB application. Angiographic outcomes favoured DESs over DEB-only, but DEBonly was comparable to BMS alone and DEB + BMS. No thrombosis occurred, suggesting DEB-only as a valid treatment in STEMI patients with contraindication to DAPT. Analogue results were collected in the PAPPA study, which showed good clinical outcomes with a DEB-only strategy[45]. DEB in Bifurcation Lesions The optimal treatment for bifurcation lesions, aimed at sparing the side branch (SB) from acute effects after main branch (MB) angioplasty and preserving its patency at long term, is still a matter of debate among
ACCEPTED MANUSCRIPT interventionalists. At present, the most adopted technique is that of provisional stenting, which consists in implantation of a DES in the MB, and possible stenting of the SB according to the angiographic result (i.e. only in case of major SB dissection or clear suboptimal SB result). Possible roles of the DEB technology in
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this setting have been studied in the DEBIUT (Drug Eluting Balloon in Bifurcation Utrecht) registry, in which a DEB was used to treat both the main branch (MB) and SB before a T-stenting technique with BMS in the MB and final kissing post-dilation with normal balloons. No patients required additional BMS
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implantation in the SB, and 4 months follow-up reported no clinical relevant events. After this result, the
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same group of researchers set up the DEBIUT trial, which randomly assigned 117 patients to one of the following treatments: DEB in both MB and SB and BMS in MB (group A); BMS in MB and regular balloon angioplasty in SB (group B); or paclitaxel DES in MB and regular balloon in SB (group C)[46]. Although the DCB + BMS strategy achieved acceptable results in terms of LLL at 6 months, it failed to show angiographic and clinical superiority over conventional BMS, using a provisional T-stenting technique. The
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authors identified possible reasons for these findings in the unexpectedly good results of the normal balloon
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angioplasty-treated SB of both BMS and DES arms, and the inferior drug delivery attributes of the Dior-I DEB. The BABILON (Study of the Paclitaxel-Coated Balloon Catheter in Bifurcated Coronary Lesions)
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randomized trial compared provisional T stenting with BMS in the MB after MB/SB dilation with DEB (SeQuent Please) against provisional T stenting with everolimus-DES. This study confirmed the
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unsatisfactory results of the DEBIUT trial, with greater LLL and higher MACEs incidence in the study group[47]. Thereafter, in the BIOLUX-I study, a mixed strategy was adopted, using a second generation DES in the MB and a SB dilatation with DEB[48]. After pre-dilatation of MB, the SB was treated with a DEB (Pantera Lux, Biotronik AG, Buelach, Switzerland), and subsequently, a Xience Prime/Xience V DES was implanted in the MB. The rationale was to maintain the simplicity of provisional stenting technique with the advantage of reducing restenosis of the SB. The primary endpoint showed a low LLL in the SB of 0.10 mm at 9 months with good clinical outcome, proving this approach safe and effective. Is authors’ opinion that DEB treatment of the SB appears promising in a provisional SB stenting approach, but more robust randomized data are needed on the use of newer-generation DESs. DEB in CTO & Diffuse Disease
ACCEPTED MANUSCRIPT The use of DEB was investigated also in the context of chronic total occlusion. In the PEPCAD (PaclitaxelCoated Balloon With Bare-Metal Stenting in Patients With Chronic Total Occlusions in Native Coronary Arteries) CTO trial[49] 48 patients were treated, after successful recanalization of the lesion, with BMS and
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finally with DEB. These were compared with matched patients treated with a paclitaxel-eluting stent, showing similar clinical results and in-stent LLL. In the setting of diffuse disease, Costopoulos et al. compared a DEB-only strategy (IN.PACT Falcon or Pantera Lux) with the use of DES[50]. Despite a hybrid
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approach, combining DEB with DES implantation was necessary in one third of patients, long-term clinical
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follow up (median 26.1 months) demonstrated similar outcome with the two different strategies. CONLUSIONS
DEB catheters represent a valid tool in the armamentarium of the interventional cardiologist, especially useful in complex scenarios (ISR, bifurcations, small vessels and diffuse disease). Considering the advanced
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performance of last generation DESs, clinical indications of DEBs have been related to those scenarios where avoidance of a metallic layer implantation is most desirable. In the setting of ISR, evidence from
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RCTs with DEBs has disclosed results superior to those with plain-balloon angioplasty, and comparable to
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first generation DES, though slightly inferior to last generation DESs. By sparing metallic layer implantation, DEB angioplasty might be taken into account for these patients. Conversely, results with DEB angioplasty
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for de novo coronary disease have been relatively sub-optimal to date, and the use of DEBs in this settings should be carefully weighted in every single scenario (Table 3).
ACCEPTED MANUSCRIPT References [1] Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994;331:489-95.
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[10] Cremers B, Toner JL, Schwartz LB, et al. Inhibition of neointimal hyperplasia with a novel zotarolimus coated balloon catheter. Clin Res Cardiol. 2012;101:469-76.
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ACCEPTED MANUSCRIPT [18] Bondesson P, Lagerqvist B, James SK, et al. Comparison of two drug-eluting balloons: a report from the SCAAR registry. EuroIntervention 2012;8:444–449. [19] Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxel-coated balloon catheter versus paclitaxelcoated stent for the treatment of coronary in-stent restenosis. Circulation. 2009;119:2986-94.
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[20] Alfonso F, Pérez-Vizcayno MJ2, Cárdenas A, et al. A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent). J Am Coll Cardiol. 2014;63:1378-86.
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[21] Habara S, Mitsudo K, Kadota K, et al. Effectiveness of paclitaxel-eluting balloon catheter in patients with sirolimus-eluting stent restenosis. JACC Cardiovasc Interv. 2011;4:149-54.
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[22] Habara S, Iwabuchi M, Inoue N, et al. A multicenter randomized comparison of paclitaxel-coated balloon catheter with conventional balloon angioplasty in patients with bare-metal stent restenosis and drugeluting stent restenosis. Am Heart J. 2013;166:527-33. [23] Rittger H, Brachmann J, Sinha AM, et al. A randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon angioplasty in drug-eluting stent restenosis: the PEPCAD-DES study. J Am Coll Cardiol. 2012;59:1377-82.
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[24] Byrne RA, Neumann FJ, Mehilli J, et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet 2013; 381: 461–67
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[25] Wöhrle J, Zadura M, Möbius-Winkler S, et al. SeQuentPlease World Wide Registry: clinical results of SeQuent please paclitaxel-coated balloon angioplasty in a large-scale, prospective registry study. J Am Coll Cardiol. 2012;60:1733-8.
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[26] Habara S, Kadota K, Kanazawa T, et al. Paclitaxel-coated balloon catheter compared with drugeluting stent for drug-eluting stent restenosis in routine clinical practice. EuroIntervention. 2016;11(:1098105.
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[27] Stella PR, Belkacemi A, Waksman R, et al. The Valentines Trial: results of the first one week worldwide multicentre enrolment trial, evaluating the real world usage of the second generation DIOR paclitaxel drug-eluting balloon for in-stent restenosis treatment. EuroIntervention. 2011;7:705-10. [28] Kawamoto H, Ruparelia N, Latib A, et al. Drug-Coated Balloons Versus Second-Generation DrugEluting Stents for the Management of Recurrent Multimetal-Layered In-Stent Restenosis. JACC Cardiovasc Interv. 2015;8:1586-94. [29] Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, et al. A Prospective Randomized Trial of Drug-Eluting Balloons Versus Everolimus-Eluting Stents in Patients With In-Stent Restenosis of Drug-Eluting Stents: The RIBS IV Randomized Clinical Trial. J Am Coll Cardiol. 2015;66:23-33. [30] Windecker S, Kolh P, Alfonso F, Collet JP, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-619. [31] Herdeg C, Göhring-Frischholz K, Haase KK, et al. Catheter-based delivery of fluid paclitaxel for prevention of restenosis in native coronary artery lesions after stent implantation. Circ Cardiovasc Interv. 2009;2:294-301.
ACCEPTED MANUSCRIPT [32] Clever YP, Cremers B, Speck U, Dietz U, Böhm M, Scheller B. Influence of a paclitaxel coated balloon in combination with a bare metal stent on restenosis and endothelial function: comparison with a drug eluting stent and a bare metal stent. Catheter Cardiovasc Interv. 2014;84:323-31.
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[33] Żurakowski A, Buszman PP, Milewski KP et al. Stenting and Adjunctive Delivery of Paclitaxel Via Balloon Coating Versus Durable Polymeric Matrix for De Novo Coronary Lesions: Clinical and Angiographic Results from the Prospective Randomized Trial. J Interv Cardiol. 2015;28:348-57.
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[34] Poerner TC, Otto S, Gassdorf J, et al. Stent coverage and neointimal proliferation in bare metal stents postdilated with a Paclitaxel-eluting balloon versus everolimus-eluting stents: prospective randomized study using optical coherence tomography at 6-month follow-up. Circ Cardiovasc Interv. 2014;7:760-7.
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[35] Fischer D, Scheller B, Schäfer A, et al. Paclitaxcel-coated balloon plus bare metal stent vs. sirolimus-eluting stent in de novo lesions: an IVUS study. EuroIntervention. 2012;8:450-5. [36] Liistro F, Porto I, Angioli P, et al. Elutax paclitaxel-eluting balloon followed by bare-metal stent compared with Xience V drug-eluting stent in the treatment of de novo coronary stenosis: a randomized trial. Am Heart J. 2013;166:920-6. [37] Unverdorben M, Kleber FX, Heuer H, et al. Treatment of small coronary arteries with a paclitaxelcoated balloon catheter in the PEPCAD I study: are lesions clinically stable from 12 to 36 months? EuroIntervention. 2013;9:620-8.
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[38] Wöhrle J, Zadura M, Möbius-Winkler S, et al. SeQuentPlease World Wide Registry: clinical results of SeQuent please paclitaxel-coated balloon angioplasty in a large-scale, prospective registry study. J Am Coll Cardiol. 2012;60:1733-8. [39] Zeymer U, Waliszewski M, Spiecker M, et al. Prospective 'real world' registry for the use of the 'PCB only' strategy in small vessel de novo lesions. Heart. 2014;100:311-6.
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[40] Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study. Heart. 2010;96:1291-6.
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[41] Latib A, Colombo A, Castriota F, et al. A randomized multicenter study comparing a paclitaxel drugeluting balloon with a paclitaxel-eluting stent in small coronary vessels: the BELLO (Balloon Elution and Late Loss Optimization) study. J Am Coll Cardiol. 2012;60:2473-80. [42] Koh TH. Drug-eluting balloon in acute myocardial infarction (DEBAMI) trial. Paper presented at EuroPCR; May 18, 2011; Paris, France [43] Belkacemi A, Agostoni P, Nathoe HM, et al. First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial: a multicenter randomized comparison of drugeluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes. J Am Coll Cardiol. 2012;59:2327–37. [44] Nijhoff F, Agostoni P, Belkacemi A, et al. Primary percutaneous coronary intervention by drugeluting balloon angioplasty: the nonrandomized fourth arm of the DEB-AMI (drug-eluting balloon in STsegment elevation myocardial infarction) trial. Catheter Cardiovasc Interv. 2015;86(Suppl 1):S34–44. [45] Vos NS, Dirksen MT, Vink MA, et al. Safety and feasibility of a PAclitaxel-eluting balloon angioplasty in Primary Percutaneous coronary intervention in Amsterdam (PAPPA): one-year clinical outcome of a pilot study. EuroIntervention. 2014;10:584–90.
ACCEPTED MANUSCRIPT [46] Fanggiday JC, Stella PR, Guyomi SH, Doevendans PA. Safety and efficacy of drug-eluting balloons in percutaneous treatment of bifurcation lesions: the DEBIUT (Drug-Eluting Balloon in BIfurcaton UTrecht) registry. Catheter Cardiovasc Interv. 2008;71:629–35.
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[47] Lopez Mınguez JR, Nogales Asensio JM, Doncel Vecino LJ, et al. A prospective randomised study of the paclitaxel-coated balloon catheter in bifurcated coronary lesions (BABILON trial): 24-month clinical and angiographic results. EuroIntervention. 2014;10:50–7.
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[48] Worthley S, Hendriks R, Worthley M, et al. Paclitaxel-eluting balloon and everolimus-eluting stent for provisional stenting of coronary bifurcations: 12-month results of the multicentre BIOLUX-I study. Cardiovasc Revasc Med. 2015;16:413–7.
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[49] Whorle J, Werner GS, Wohrle J, Werner GS. Paclitaxel-coated balloon with bare-metal stenting in patients with chronic total occlusions in native coronary arteries. Catheter Cardiovasc Interv. 2013;81:793–9
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[50] Costopoulos C, Latib A, Naganuma T, et al. The role of drug-eluting balloons alone or in combination with drug-eluting stents in the treatment of de novo diffuse coronary disease. JACC Cardiovasc Interv. 2013;6:1153–9.
ACCEPTED MANUSCRIPT Table1: Commercially available drug-eluting balloons for coronary artery disease.
AgentTM Danubio® Dior® II
Paclitaxel
2.0
-
3.0 NA
-
Paclitaxel
3.0
Urea
Paclitaxel Paclitaxel Paclitaxel Paclitaxel
2.0 3.0 3.0 3.0
Polysorbate/sorbitol BTHC Shellac Shellac
Paclitaxel
3.0
Iopromide
Paclitaxel Paclitaxel
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Boston Scientific, USA Minvasys, Paris, France Eurocor, Bonn, Germany Aachen Resonance, Luxembourg, Elutax SV™ Luxembourg Essential iVascular, Spain GENIE Acrostak, Winterthur, Switzerland Medtronic Vascular, Santa Rosa, IN.PACT™ Falcon CA, USA Lutonix DCB® (Moxy) BARD, Murray Hill, NJ, USA Pantera Lux® Biotronik, Bülach, Switzerland Primus™ Cardionovum, Warsaw, Poland Restore DEB® Cardionovum, Germany B. Braun Melsungen AG, Berlin, SeQuent® Please Germany ATBC: acetyl-tributyl-citrate; BTHC: butyryl-tri-hexylcitrat.
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Paclitaxel Paclitaxel Paclitaxel
Drug Dose (µg/mm2) 2.2 2.5 3.0
Drug Eluted
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Device
Additive ATBC BTHC Shellac
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Table 2. Most relevant randomized clinical trial involving DEB for the treatment of coronary artery disease. CAD - Setting DEB
De novo - Bifurcation
SeQuent Please (+BMS)
Number of Patients
POBA POBA PES EES POBA POBA PES & POBA EES EES SES PES PES BMS & PES BMS & PES
52 108 131 189 50 110 402 309 90 55 60 182 150 117
EES
108
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Paccocath Paccocath SeQuent Please SeQuent Please SeQuent Please SeQuent Please SeQuent Please SeQuent Please SeQuent Please (+BMS) Coroflex DEBlue (+ BMS) Dior I IN.Pact Falcon Dior II Dior I
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BMS-ISR BMS-ISR BMS-ISR BMS-ISR DES-ISR DES-ISR DES-ISR DES-ISR De novo lesions De novo lesions De novo lesions De novo lesions De novo lesions - AMI De novo - Bifurcation
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PACCOCATH ISR9 PACCOCATH ISR II14 PEPCAD II19 RIBS V20 Habara et al 21 PEPCAD DES 23 ISAR-DESIRE III 24 RIBS IV29 OCTOPUS 34 Fischer et al 35 PICCOLETTO 40 BELLO 41 DEB-AMI 43 DEBIUT trial 46 BABILON 47
Treatment devices of Comparison Comparator(s)
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Trial
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BMS: bare metal stent; DES: drug-eluting stents; ISR: in-stent restenosis; POBA: plain-old balloon angioplasty; SES: sirolimus-eluting stent; PES: paclitaxel-eluting stent; EES: everolimus-eluting stents; EPC: endothelial progenitor-cell capturing; AMI: acute myocardial infarction.
ACCEPTED MANUSCRIPT Table3: Expert advices to obtain clinical success with DEB a. b.
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e.
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d.
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c.
DEB is not a dilation balloon. It has been conceived as drug-carrier and should be used as such. Device class effect has not been demonstrated. DEB choice should be based on the evidence available for the specific subset of lesions. DEB can represent the first therapeutic choice in both BMS- and DES-ISR, especially when the lesion is included in the stent struts (focal or diffuse). Of note, adequate predilation with satisfactory result is mandatory before DEB treatment. DEB may be considered in the treatment of de novo lesions, provided that proper lesion predilation (Balloon-Artery ratio 1:1) is performed and angiographic result proves optimal (stenosis<30%, TIMI flow 3, no dissections). However indications for this strategy remain limited. Planned combination of DEB with BMS implantation should be avoided. If the strategy requires stent deployment, directly choose second generation DES.
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Clinical applications of Drug Eluting Balloons (DEBs) have focused on indications where avoidance of stent implantation is most desirable. DEBs could give potential benefits in particular for the in-stent restenosis (ISR) and the denovo lesions. In ISR scenario the performance of DEBs seems to be more evident in BMS-ISR than in DES-ISR. In the context of de-novo lesions the results are comparable to DES in lesions limited to coronary vessels less than 2.5 mm. Particular scenarios, like bifurcations, acute myocardial infarction and diffuse disease, have been approached with DEB resulting in very heterogeneous outcomes.
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