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Archives of cardiovascular diseases
Volume 110, n° 4
pages 259-272 (avril 2017)
Doi : 10.1016/j.acvd.2017.01.005
Received : 20 November 2016 ;  accepted : 4 January 2017
Reviews

Contemporary use of drug-coated balloons in coronary artery disease: Where are we now?
Utilisation du ballon actif dans la maladie coronaire : où en sommes-nous actuellement ?
 

Fabien Picard a, b, Serge Doucet a, Anita W. Asgar a,
a Interventional cardiology division, department of medicine, Montreal heart institute, université de Montréal, 5000 Bélanger, H1T 1C8 Montréal, QC, Canada 
b Interventional cardiology department, Cochin hospital, Assistance publique–Hôpitaux de Paris, Paris, France 

Corresponding author.
Summary

The drug-coated balloon (DCB) has emerged as an additional tool in the arsenal of interventional cardiology devices; it delivers antiproliferative drugs to local arterial tissue by single prolonged coated balloon angioplasty inflation, and prevents restenosis, leaving no implant behind. This strategy theoretically decreases the risk of late inflammatory response to device components, without preventing positive remodelling. DCBs, when used carefully and with a good technique, may have a role in the treatment of lesion subsets, such as in-stent restenosis, small vessel disease or side branch bifurcations, in which the implantation of a drug-eluting stent is not desirable or is technically challenging. Using the latest evidence regarding the effectiveness of the currently available DCBs, this review will discuss the rationale for DCB use, and the effectiveness of DCBs in different clinical and lesion settings, and will give practical tips for their correct use in everyday clinical practice.

The full text of this article is available in PDF format.
Résumé

Les ballons actifs sont un outil supplémentaire dans l’arsenal thérapeutique du cardiologue interventionnel. Ils permettent de délivrer localement au tissu artériel un agent anti-proliférant par inflation prolongée d’un ballon d’angioplastie recouvert de celui-ci, prévenant la resténose et ne laissant pas d’implant dans l’artère. Cette stratégie diminue de manière théorique le risque de réponse inflammatoire tardive liée aux composants de l’endoprothèse sans compromettre le remodelage positive. Les ballons actifs, lorsqu’ils sont utilisés avec une bonne technique, pourraient avoir un rôle dans le traitement de certains types de lésions coronaires, où l’implantation d’un stent actif n’est pas souhaitable ou difficile techniquement, comme dans la resténose intra-stent, les petits vaisseaux ou les branches filles de bifurcations. En utilisant la littérature la plus récente concernant l’efficacité des ballons actifs actuellement disponibles, cette revue de la littérature fait le point sur rationnel de l’utilisation des ballons actifs, de leur efficacité dans différentes situations cliniques et types de lésions particuliers, et donnera les astuces pratiques pour une utilisation optimale dans le laboratoire de cathétérisme cardiaque au quotidien.

The full text of this article is available in PDF format.

Keywords : Drug-coated balloon, Drug-eluting balloon, In-stent restenosis, Percutaneous coronary intervention, Paclitaxel

Mots clés : Ballon médicamenté, Athérosclérose, Resténose intra-stent, Angioplastie percutanée, Paclitaxel

Abbreviations : AMI, BMS, DAPT, DCB, DES, EES, ISR, LLL, MACE, MB, MI, PCI, SB, SVD, TLR, TVR


Background

Drug-eluting stents (DESs) have improved the clinical outcomes of patients undergoing percutaneous coronary intervention (PCI) by reducing the risk of restenosis and repeat revascularization [1]. Despite this success, challenges remain, including the risk of stent thrombosis and the requirement for dual antiplatelet therapy. Drug-coated balloons (DCBs) represent another innovation, with a significant potential impact in the treatment of patients with coronary artery disease. Using the same principles as DESs, the goal of DCBs is to quickly and homogeneously deliver an antiproliferative drug to the vessel wall, restricting its activity to a limited time, when the neointimal proliferation response to angioplasty is the highest. Despite numerous publications, current knowledge on DCBs is limited to a few well-performed trials and several confounding studies. This review will discuss the rationale for DCB use, and will provide simple and direct clarification of the main indications for DCBs and practical tips for their correct use in everyday clinical practice.

Rationale for DCB use

Since the beginning of PCI, the interventional cardiovascular community has made a great effort to understand how to provide the best treatment to patients presenting with coronary artery stenosis, and how to best fight restenosis. Initial attempts were focused on elastic recoil and late negative remodelling, which were drastically diminished by using bare-metal stents (BMSs). However, BMSs were associated with increased neointima formation and acute stent thrombosis. Therefore, efforts were made to develop technologies to reduce post-stenting neointima formation, such as improvements in-stent design and the use of mechanical ablation devices and systemic or local pharmacological therapies. DESs were more optimal to win this battle. Nevertheless, despite the significant reduction in restenosis, there are still subsets of patients in which DES restenosis persists, particularly diabetic patients or those with complex lesions. Moreover, DESs present other limitations, including stent thrombosis – particularly late stent thrombosis – which is probably caused by using a polymeric matrix on the stent in which the antiproliferative drug is embedded. To overcome this limitation, new generations of biocompatible-polymer DESs, biodegradable-polymer DESs, polymer-free DESs and fully bioabsorbable devices are now available. Nevertheless, the latest generations of biodegradable-polymer, polymer-free and fully bioabsorbable scaffolds still have to prove their long-term efficacy compared with the best-in-class DESs. Another pitfall of the DES is the non-uniform delivery of the drug on the arterial wall, with the highest concentrations at the stent struts and the lowest between the struts and at the margins. Lastly, other limitations include small vessel disease (SVD) treatment, because of stent thickness, stent layers left in place in the artery, with arterial vasomotricity abnormalities after multiple layers, and issues related to the duration of dual antiplatelet therapy (DAPT).

These limitations spawned the idea of direct local delivery of an antiproliferative drug by conventional angioplasty balloons, which sound very attractive, as it could fulfill the goal of the DES without duplicating the limitations encountered with this device. The theoretical advantages, summarized in Table 1, include homogenous drug transfer to the arterial wall, which could enhance the effect of the drug on neointima formation, highest drug concentrations at the time of intimal injury, with more effect on initial neointima process, absence of polymer, which could decrease chronic inflammation and thrombosis (therefore decreasing the need of long DAPT), respectful of original arterial anatomy, and treatment of lesions where stent deployment is not possible (small vessels).

Nevertheless, DCBs also have multiple drawbacks. First, a DCB has the mechanical limitation of acute recoil seen after balloon angioplasty. Second, it is unclear if DCBs can evict the late negative remodelling seen with standard balloons. Third, the safety and efficacy of bailout stenting with an adjunctive BMS or DES still has to be proved in case of acute closure caused by occlusive dissection with DCB angioplasty. Lastly, the variability of excipients and different coating methods of the different DCBs offer less efficacy reproducibility compared with DESs.

Mechanisms of action and available devices

Initially, extensive research was performed to develop site-specific intra-arterial delivery of antiproliferative drugs, but clinical results were unsatisfying, because of arterial wall drug absorption variability and quick washout of the drugs being studied [1]. The emergence of sirolimus and paclitaxel, both highly lipophilic drugs absorbed rapidly by the arterial tissue, reingnited the interest in non-stent-based local drug delivery therapy. DCBs are semicompliant angioplasty balloons covered with an antirestenotic drug that is released locally into the vessel wall during balloon contact. Now, most of the CE-marked manufactured DCBs use paclitaxel, because of its lipophilicity and tissue retention characteristics.

Paclitaxel is highly antiproliferative; it binds to the β-tubuline microtubule subunit and exerts locally very potent, dose-dependent, inhibitory effects on human arterial smooth muscle cell proliferation and migration, thereby fighting neointimal hyperplasia [2]. The optimal concentration of paclitaxel has been studied in animal models, with increasing doses ranging from 1 to 9μg/mm2, with an optimal efficacy at the 3μg/mm2 dose, without any further benefit at higher doses [3]. Moreover, high doses (3×9μg/mm2 balloon applications) were leading to acute thrombotic events. Although paclitaxel was, until recently, the only drug used for eluting balloons, multiple excipients have been used to increase its solubility.

As most DCBs for human use release paclitaxel, the main differences result from the different combinations of balloon, molecule drug load and coating methods. Methodologies to load the drug onto the balloon include spraying, dipping, nanoparticles and imprinting the drug on the rough surface of the balloon. With the use of different excipients and different coating methods, the pharmacological properties of the resulting DCBs can be quite different [4, 5, 6].

Therefore, not all DCBs are created equal. The pharmacological properties and clinical outcomes of the resulting DCB can also be quite different [4, 5, 6]. We therefore advise a good understanding of the specific DCBs used in your catheterization laboratory, and their individual results in the literature. The current approved DCBs are listed in Table 2.

Potential applications of DCBs
In-stent restenosis (ISR)

The first clinical application of a DCB in humans was described by Scheller et al. [7] for BMS-ISR. In their multicentre, randomized trial, the effects of a paclitaxel DCB (PACCOCATH®) were compared with those of an uncoated balloon in 52 patients with BMS-ISR. At follow-up, 10 of 23 (43%) patients in the uncoated balloon group had restenosis, compared with 1 of 22 (5%) patients in the coated balloon group (P =0.002).

The use of DCBs has also been compared with second-generation DESs for the treatment of BMS-ISR in three major randomized trials of DCBs versus everolimus-eluting stents (EESs) [8, 9]. The SEDUCE trial [8] randomized 50 patients with BMS-ISR to treatment with either a DCB (SeQuent® Please) or an EES, with optical coherence tomography evaluation at 9 months. DCBs appeared to be associated with better healing characteristics, as assessed by stent strut coverage, but tended to be slightly less effective compared with EESs. In the Spanish multicentre RIBS V clinical trial [9], 189 patients with BMS-ISR were randomized to a DCB or an EES. Although both the DCBs and EESs provided excellent clinical results, with a very low rate of clinical and angiographic recurrences, compared with DCBs, the EESs provided superior late angiographic findings and a lower percentage of diameter stenosis. More recently, Pleva et al. [10] reported the results of a study randomizing 136 patients with BMS-ISR to treatment with a DCB (SeQuent® Please) or an EES (Promus Element; Boston Scientific, Marlborough, MA, USA). The primary endpoint, late lumen loss (LLL) at 12 months, was lower in the DCB group (0.09±0.44mm vs. 0.44±0.73mm; P =0.0004). However, the net gain was not reported, and the difference in the incidence of repeated binary restenosis and target vessel revascularization (TVR) did not reach significance.

Both strategies (DCB or EES) are associated with an excellent 1-year outcome, and are effective. The 2014 European Society of Cardiology guidelines on myocardial revascularization for the treatment of ISR (within a BMS or a DES) [11] give both strategies a Class I indication (level of evidence: A).

Recommendations for the treatment of DES-ISR were based on the first randomized, controlled studies published comparing a DCB versus plain old balloon angioplasty or a first-generation DES [12, 13], in which DCBs had constantly better outcomes than plain old balloon angioplasty, and were equivalent to first-generation DESs. Therefore, DCB use may be more attractive, as it would permit avoiding another layer of stent in the artery. The 3-year follow-up of the ISAR-DESIRE 3 trial (DCB versus paclitaxel-eluting stent in DES-ISR) found that the risk of death/myocardial infarction (MI) tended to be lower with DCBs versus paclitaxel-eluting stents (hazard ratio: 0.55, 95% CI: 0.28 to 1.07; P =0.708), because of a lower risk of death (hazard ratio: 0.38, 95% CI: 0.17 to 0.87; P =0.02) [14]. These results could be related to an elevated stent thrombosis risk in “sandwich DESs”. Consistent with these findings, the 2-year follow-up results of the PEPCAD China ISR trial [15] demonstrated sustained long-term clinical efficacy for both devices. Even if the recent RIBS IV trial [16, 17] demonstrated better clinical outcomes (composite of cardiac death, MI and TVR) with EESs at 1 year (10% vs. 18%; P =0.04), we should wait for long-term safety and efficacy information from these trials before considering multiple layers of DESs.

In addition to these studies, recent meta-analyses [18, 19] suggest that these two strategies could be considered for treatment of ISR: PCI with EESs because of the best angiographic and clinical outcomes, and DCBs because of their ability to provide favourable results without adding a new stent layer. Further studies should focus on patient subgroups or restenosis patterns that could benefit most from one or the other strategy. Nevertheless, with the arrival of limus DCBs and bioabsorbable vascular scaffolds, the debate is likely to be revived again.

De novo coronary artery stenosis treatment
Small native vessels

PCI of small coronary vessels still represents a challenge for myocardial revascularization, because of the high-risk of stent restenosis and the increased risk of adverse clinical events [20]. This is because of the limited ability of the vessel to adapt to neointima formation that might develop after stent implantation, although this is less apparent with second-generation DESs [21]. DCBs may be advantageous in this setting, because of: less vessel inflammation in the absence of metallic stents and polymer; original anatomy with no stent left in the artery, reducing abnormal flow and permitting positive remodelling of the vessel; and better crossing profile.

The definition of SVD is variable in the literature, but is mainly based on the pre-PCI angiographic estimation of reference vessel diameter (<2.8 to 3.0mm). A few studies have evaluated the use of DCBs in SVD, and these are summarized in Table 3. The PEPCAD I study [22] evaluated the efficacy of the SeQuent® Please DCB in 118 patients with 2.35±0.19mm mean diameter vessels. In total, 82/120 (68.3%) patients were treated with the DCB-only, and 32/120 (26.7%) patients required additional BMS deployment. Overall, treatment of SVD with a paclitaxel-coated balloon exhibited good 6-month angiographic and 1-year clinical data that persisted during the 3-year follow-up period. Subsequently, the PICCOLETTO trial [23] was the first randomized study to compare the first-generation Dior® I DCB (28 patients) with the Taxus® Liberté® paclitaxel-eluting stent (Boston Scientific, Marlborough, MA, USA) (29 patients) in patients with stable or unstable angina undergoing PCI of small coronary vessels (<2.75mm diameter). However, this study was halted after enrolment of two-thirds of the patients, because of the clear superiority of the Taxus® group regarding angiographic endpoints. Compared with the PEPCAD I study, the poor results of the DCB were attributed to the lower tissue drug dosage in the Dior® I DCB, and to procedural differences, such as lower predilation rates and lower inflation pressures employed in the DCB group.

The 3-year clinical follow-up of the BELLO study [24], in which 182 patients undergoing PCI of SVD were randomly assigned to either IN-PACT Falcon™ DCB dilation and provisional BMS (n =90) or paclitaxel-eluting stent (Taxus® Liberté®) implantation (n =92), was published recently. At the 3-year follow-up, there was no difference between these two groups in terms of TVR or target lesion revascularization (TLR), and no target stent (or vessel) thrombosis was reported in either group. Interestingly, there was a statistically significant benefit regarding major adverse cardiac events (MACE) at 3 years with the DCB compared with the DES (6 [15.4%] vs. 14 [38.9%]; P =0.02). Whereas this study was not adequately powered for this endpoint, it does raise the interesting hypothesis that treatment of SVD with a DCB might be associated with an outcome benefit. Nevertheless, further larger studies are required to evaluate whether there is an additional outcome benefit associated with this approach. In addition to this randomized trial, two large registries [25, 26] also demonstrated low rates of TLR and MACE associated with DCB use.

Diffuse disease

PCI strategy for long, diffuse lesions in native coronary arteries is still a challenge. Whereas stent length was initially presumed to independently predict restenosis and stent thrombosis, it seems to be less clear with newer-generation DESs [27]. Few data exist about full lesion coverage with long multiple overlapping stents, also called “full-metal jacket”, but long-term follow-up seems acceptable given the complexity of the lesions treated [28]. However, such a strategy can preclude future surgical revascularization, and restenosis is often difficult to treat. One of the potential advantages of a DCB approach with spot stenting is that it can lessen the amount of metal in the vessels without removing the possibility of future coronary artery bypass grafting. Data are scarce on this strategy. Costopoulos et al. [29] retrospectively evaluated 69 patients (93 lesions) treated with DCB±DES, and 93 patients (93 lesions) treated with DES alone. Of the DCB-treated lesions, 56.0% were treated with DCB alone, 7.4% with DCB and DES as bailout, and 36.6% with DES and DCB as part of a hybrid approach for very long disease. Outcome rates with DCB±DES were similar to those with DES alone at 2-year follow-up (MACE 20.8% vs. 22.7% [P =0.74]; TVR 14.8% vs. 11.5% [P =0.44]; TLR 9.6% vs. 9.3% [P =0.84]). DCB may have a role in the treatment of de novo long diffuse disease, either alone in smaller vessels or in combination with DESs in very long disease, but there is a lack of data on this hybrid strategy. Therefore, randomized studies are needed before taking such an approach.

Bifurcation lesions

Bifurcation lesion treatment is a serious challenge in coronary bifurcation PCI, mainly driven by suboptimal side branch (SB) results. Based on recent literature, the approach of main branch (MB) stenting with provisional SB stenting remains the default approach for most bifurcation lesions [30]. The use of DCBs in the SB may be preferable to regular balloon angioplasty, and multiple strategies have been studied to assess the efficacy of DCBs in bifurcation lesions (Table 4).

The DEBIUT trial [31] randomized 117 patients in three arms: Dior® I DCB pretreatment+BMS; BMS+uncoated balloon; and paclitaxel DES+uncoated balloon. 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. This may have been caused by unexpectedly good results in the plain balloon angioplasty-treated SB in both the BMS and the DES arms, or by the use of the first-generation Dior® DCB, with inferior drug delivery attributes (no carrier matrix).

Despite these deceptive results, the BABILON trial [32] randomized 108 patients, and compared angiographic and clinical outcomes between sequential MB/SB-DCB+MB-BMS versus EES in de novo bifurcated lesions. In this study, both strategies showed similar results in the SB, but an increased incidence of MACE in the DCB+BMS group, probably because of the BMS use.

Thereafter, the strategy was switched to SB-DCB+MB-DES. Three observational studies evaluated a SB-DCB+MB-DES strategy [33, 34, 35]. In the BIOLUX-I study [35], Worthley et al. evaluated the feasibility and safety of the combination of MB-EES and SB-Pantera® Lux DCB followed by final kissing balloon inflation for the treatment of symptomatic single de novo bifurcation lesions, which were suitable for a provisional stenting technique. At 9 months, SB LLL was 0.10±0.43mm, with no binary restenosis observed. At 1-year follow-up, one patient had died and three MIs (one suspected and two in non-target vessels) and one TLR had occurred. No probable or definite stent thrombosis was observed. Consistent with these findings, the DEBSIDE trial (n =50) [33], using the same strategy with the Danubio® DCB in a different order, also showed good results in terms of SB LLL. The possibility of using a DCB-only strategy in bifurcations has also been considered. Schulz et al. [36] reported a series of 39 consecutive DCB-only interventions in de novo bifurcation lesions with SB2 mm indicating low rates of restenosis and TLR, but within a very short follow-up period.

As of now, DCB 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.

DCB-only strategy in de novo coronary lesions

Data on DCB treatment of native vessels with a normal calibre (i.e. calibre>2.75mm) are sparse. In this setting, stenting has been associated with excellent results, in terms of both efficacy and safety. Nevertheless, there is emerging evidence that suggests that a DCB-only strategy could achieve superior LLL, and could be considered when DES use is not wanted. The “DCB-only” concept involves careful lesion preparation and DCB application (acceptable angiographic result) or bailout stenting (major dissection [type C or higher], reduced flow or significant residual stenosis). This approach aims to avoid the use of unnecessary stents, and to shorten the duration of DAPT, compared with DES implantation. In this setting, the Valentines II registry [37] was designed as a prospective, multicentre study that enrolled 103 patients in whom DCB was used as an adjunct to balloon angioplasty to treat de novo coronary stenosis. The primary endpoint of cumulative MACE at 8 months was 8.7%, with 1% all-cause death, 1% MI, 6.9% overall TVR (of which 2.9% were TLR) and no vessel thrombosis. In this study, despite high predilatation rates (85%), bailout stenting was only 11.3%. Nevertheless, although the use of DCB in de novo lesions was demonstrated to be technically feasible and theoretically appealing, with the lack of clear direct comparison and the fact that these studies are underpowered, their use must be reserved for patients in whom the use of a DES is deemed to be controversial (i.e. small vessels, bifurcations, ISR).

DCBs in acute MI (AMI)

The use of DESs in MI has reduced restenosis, but still has a risk of uncovered stent struts and late malapposition, which increases the risk of stent thrombosis. In this setting, DCBs could be an attractive treatment option in STEMI, because of the absence of stent implantation in the artery. A DCB-only approach was evaluated recently in three studies [38, 39, 40]. The PAPP-A pilot study [40] evaluated the safety and feasibility of a strategy of Pantera® Lux DCB angioplasty, after thrombus aspiration and adequate predilation, without stenting, in primary PCI for STEMI. Additional stenting was allowed only in case of type C to F coronary dissection or residual stenosis>50%. At 1-year follow-up, out of the 100 enrolled patients, only five MACE were reported (5%): two cardiac deaths and three TLRs. In a similar fashion, the DEB-AMI research group published the results of the non-randomized fourth arm of the DEB-AMI trial [39]: 40 patients who underwent a Dior® II DCB-only strategy in primary PCI. In this highly selected population, the DCB-only strategy yielded an angiographic outcome that was similar to BMS alone and DCB+BMS, but inferior to DES. Lastly, Ho et al. [38] reported a series of 89 STEMI patients in whom DCB-only PCI was performed in 96% of cases, with the remaining 4% of patients receiving bailout stenting. No patients experienced abrupt closure of the infarct-related artery, and there was no reported target lesion failure at 30-day follow-up, but no data on longer-term follow-up were reported.

A DCB-only strategy could be an alternative treatment during primary PCI in patients with contraindications to DES, but this approach is, however, limited by a dependence on bailout stenting, which may hamper long-term efficacy, and the fact that with most recent DESs, DAPT can be safely shortened to 3–6 months, which may reduce the DCB strategy benefit. Nevertheless, further randomized studies are required to increase the body of evidence for the potential role of DCBs in patients with STEMI. Moreover, only little is known about drug uptake in ruptured plaques with high thrombus burden, so further pharmacokinetic studies are required.

Tips and tricks for DCB use

First, lesion preparation is mandatory. This is the required first step of this treatment approach to identify patients with procedure-related flow-limiting dissections necessitating bailout stenting, and to facilitate homogeneous drug delivery. Lesion preparation can be performed either with uncoated semicompliant balloons (balloon-to-vessel ratio 0.8–1.0) or non-compliant high-pressure balloons, cutting or scoring balloons in cases of more complex and calcified lesions. Additional intravascular imaging or functional measurements are advised in cases of doubtful results. The balloon size should be in the range of –0.5 to 0mm of the DCB size [41, 42].

Second, the use of the DCB carries special precautions that differ from a conventional angioplasty balloon. Manipulation of the balloon must be avoided during flushing and preparation of the DCB catheter to prevent drug loss during handling. In addition, careful attention should be paid when crossing the Y-connector, navigating through the guiding catheter and the proximal parts of the coronary artery up to the lesion. The DCB balloon should be brought rapidly to and gently inflated at the lesion site to avoid drug loss in the bloodstream during the transit time. Prolonged inflation is advised (60seconds), although single 30-second inflation is usually considered enough with the newest-generation DCBs. As they generally present poor mechanical properties, the inflation pressure should not exceed the nominal pressure, to reduce the risk of dissection.

Lastly, one should not expect a stent-like result, as residual stenosis caused by elastic recoil often occurs. Residual stenosis<30% and minor dissection (A or B type) are deemed acceptable, and can be left unstented. However, in case of additional BMS stent need, it is critical that the entire vessel surface covered by the stent has been previously treated with a DCB to avoid the so-called “geographical mismatch”. Indeed, in patients with adjunctive BMS implantation, geographical mismatch was reported to be a strong predictor of future ISR [22]. Tips and tricks for DCB use are summarized in Figure 1.



Figure 1


Figure 1. 

Decision tree and practical tips and tricks for drug-coated balloon (DCB) use. DES: drug-eluting stent; BMS: bare-metal stent.

Zoom

Antiplatelet therapy

The goal of DAPT after PCI is to ensure maximal protection against stent or vessel thrombosis while limiting the bleeding risk. The opportunity to shorten the duration of DAPT compared with the necessary prolonged length when a DES is implanted represents one of the greatest advantages of DCBs. The lack of a metallic scaffold virtually cancels the threat of thrombosis in both the short- and long-term, because of implantation concerns or delayed inflammatory response, respectively. Moreover, even if there is a need for stenting, the absence of polymer and the short persistence of the antiproliferative drug in the vessel wall reduce the risk of delayed endothelization and, thus, of thrombotic events.

In most studies on ISR and SVD [7, 22, 23], with the DCB-only strategy, the duration of DAPT was only 1 month, without occurrence of any thrombotic events. These data are reassuring, and suggest the safety of DCBs, even with short DAPT. Nevertheless, whereas a DCB-only approach confers little risk of vessel thrombosis, this risk increases when coupled with a BMS. Currently, manufacturers advise 3 months of DAPT following DCB treatment. These recommendations are derived directly from clinical trials in which a BMS has been implanted following DCB angioplasty. However, there are still reports of thrombosis occurring beyond 6 months, and perhaps the DCB+BMS combination should be treated like DES implantation, with 6–12 months of DAPT. This should be even more relevant in high-thrombotic-risk lesion subsets, where DAPT should be considered for a full 12 months. Yet, the lack of studies focusing on DAPT duration with DCB use does not allow definitive conclusions to be drawn regarding its best duration.

Conclusions and future perspectives

Drug-coated technologies are still evolving and trying to find their role in coronary artery disease treatment. Current data support the use of a DCB-only strategy in ISR and SVD, with acceptable efficacy and good safety results, but do not suggest superiority over the best-in-class DES. Similarly, DCB use in bifurcation SB lesions sounds promising, although the technical aspects of this procedure are still being evaluated. The potential applications of DCB are summarized in Table 5, with their rationale, evidence and recommendations. The limitations of the currently available evidence are that these studies are mainly based on registries and a few small, randomized trials, which were mostly performed during the first-generation DES era. Moreover, in most of these studies, LLL was systematically used as primary endpoint, instead of clinical outcomes, such as MACE or TLR. Indeed, the use of LLL for DCB and DES comparison can be misleading, because of the immediate recoil sometimes present with DCB, which will not be considered at follow-up. In addition, net gain, which is often greater with DES compared with DCB because of the absence of immediate recoil, is not always reported in DCB studies. To date, the first long-term follow-up data are just emerging, with no positive or negative signal in terms of results. Indeed, most of the studies performed sought to evaluate different indications with different DCB techniques and different DCB balloons, which are now known not to be perfectly equal. Nevertheless, we have now identified what should be attempted with acceptable results (mainly lesion subsets in which implanting a DES is not desirable or technically challenging), and what should be avoided (primary DCB+BMS association). Therefore, using a DCB-only strategy with bailout stenting, further studies should keep on determining in which situation DCBs could demonstrate non-inferiority, in terms of clinical outcomes, or decrease complications, such as stent thrombosis or DAPT bleeding complications, compared with DESs.

In addition, actual research has recently focused on different coating and drug delivery technologies. Zotarolimus and sirolimus DCB use have been reported in preclinical studies, but it still has to be determined if such a formulation will result in a relevant clinical effect [43, 44, 45]. Lemos et al. [45] recently described the structure and preclinical validation profile of a novel phospholipid-encapsulated sirolimus nanocarrier, used as a coating in two formulations: a coronary stent-plus-balloon system and a stand-alone balloon catheter. The nanoparticles provided a stable, even and homogeneous coating to the devices in both formulations. Dose-finding studies allowed the most appropriate identification of the best nanoparticle structure associated with an extremely efficient transfer of drug to all layers of the vessel wall, achieving high tissue concentrations that persisted days after the application, with low systemic drug leaks [45]. Moreover, a recently published preclinical study indicated that the vascular effects of sirolimus nanoparticles delivered through a porous angioplasty balloon (Virtue™; Caliber Therapeutics, New Hope, PA, USA) in a porcine model achieved therapeutic long-term intra-arterial drug concentrations without significant systemic residual exposure [46].

In conclusion, when used carefully and with a good technique, DCBs may have a role in the treatment of lesions not suitable for DES implantation, such as ISR, SVD or SB bifurcations. Nevertheless, larger randomized clinical trials, adequately powered and rigorously performed, with clinical endpoints, are clearly required to further elucidate the role of this technology, including the evaluation of new limus-based DCBs.

Funding

F.P. was supported by a grant from the French Federation of Cardiology. A.W.A. receives funding from the Desgroseillers – Bérard Research Chair in Interventional Cardiology at the Montreal Heart Institute.

Authors’ contributions

All of the authors contributed to the literature review and manuscript drafts, and reviewed and approved the final manuscript.

Disclosure of interest

The authors declare that they have no competing interest.

References

Mennuni M.G., Pagnotta P.A., Stefanini G.G. Coronary stents: the impact of technological advances on clinical outcomes Ann Biomed Eng 2016 ;  44 : 488-496 [cross-ref]
Axel D.I., Kunert W., Goggelmann C., and al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery Circulation 1997 ;  96 : 636-645 [cross-ref]
Kelsch B., Scheller B., Biedermann M., and al. Dose response to paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model Invest Radiol 2011 ;  46 : 255-263 [cross-ref]
Benezet J., Agarrado A., Gutierrez-Barrios A., Ruiz-Fernandez D., Del Rio A., Canadas D. Comparison of two different drug-coated balloons for the treatment of in-stent restenosis: a long-term single-centre experience Cardiovasc Revasc Med 2016 ;  17 : 176-180 [cross-ref]
Bondesson P., Lagerqvist B., James S.K., Olivecrona G.K., Venetsanos D., Harnek J. Comparison of two drug-eluting balloons: a report from the SCAAR registry EuroIntervention 2012 ;  8 : 444-449 [cross-ref]
Nijhoff F., Stella P.R., Troost M.S., and al. Comparative assessment of the antirestenotic efficacy of two paclitaxel drug-eluting balloons with different coatings in the treatment of in-stent restenosis Clin Res Cardiol 2016 ;  105 : 401-411 [cross-ref]
Scheller B., Hehrlein C., Bocksch W., and al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter N Engl J Med 2006 ;  355 : 2113-2124 [cross-ref]
Adriaenssens T., Dens J., Ughi G., and al. Optical coherence tomography study of healing characteristics of paclitaxel-eluting balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in Coronary artery rEstenosis) randomised clinical trial EuroIntervention 2014 ;  10 : 439-448 [cross-ref]
Alfonso F., Perez-Vizcayno M.J., Cardenas A., and 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 : 1378-1386 [cross-ref]
Pleva L., Kukla P., Kusnierova P., Zapletalova J., Hlinomaz O. Comparison of the efficacy of paclitaxel-eluting balloon catheters and everolimus-eluting stents in the treatment of coronary in-stent restenosis: the treatment of in-stent restenosis study Circ Cardiovasc Interv 2016 ;  9 : e003316
Windecker S., Kolh P., Alfonso F., and al. Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Eur Heart J 2014 ;  35 : 2541-2619
Byrne R.A., Neumann F.J., Mehilli J., and 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 : 461-467 [cross-ref]
Indermuehle A., Bahl R., Lansky A.J., and al. Drug-eluting balloon angioplasty for in-stent restenosis: a systematic review and meta-analysis of randomised controlled trials Heart 2013 ;  99 : 327-333 [cross-ref]
Kufner S., Cassese S., Valeskini M., and al. Long-term efficacy and safety of paclitaxel-eluting balloon for the treatment of drug-eluting stent restenosis: 3-year results of a randomized controlled trial JACC Cardiovasc Interv 2015 ;  8 : 877-884 [cross-ref]
Xu B., Qian J., Ge J., and al. Two-year results and subgroup analyses of the PEPCAD China in-stent restenosis trial: a prospective, multicenter, randomized trial for the treatment of drug-eluting stent in-stent restenosis Catheter Cardiovasc Interv 2016 ;  87 (Suppl. 1) : 624-629 [cross-ref]
Alfonso F., Perez-Vizcayno M.J., Cardenas A., and 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 [cross-ref]
Alfonso F., Perez-Vizcayno M.J., Garcia Del Blanco B., and al. Comparison of the efficacy of everolimus-eluting stents versus drug-eluting balloons in patients with in-stent restenosis (from the RIBS IV and V randomized clinical trials) Am J Cardiol 2016 ;  117 : 546-554 [inter-ref]
Giacoppo D., Gargiulo G., Aruta P., Capranzano P., Tamburino C., Capodanno D. Treatment strategies for coronary in-stent restenosis: systematic review and hierarchical Bayesian network meta-analysis of 24 randomised trials and 4880 patients BMJ 2015 ;  351 : h5392
Siontis G.C., Stefanini G.G., Mavridis D., and al. Percutaneous coronary interventional strategies for treatment of in-stent restenosis: a network meta-analysis Lancet 2015 ;  386 : 655-664 [cross-ref]
Puymirat E., Barbato E. Percutaneous revascularization strategies in small-vessel disease Ann Cardiol Angeiol (Paris) 2014 ;  63 : 28-31 [cross-ref]
Caputo R., Leon M., Serruys P., and al. Performance of the resolute zotarolimus-eluting stent in small vessels Catheter Cardiovasc Interv 2014 ;  84 : 17-23 [cross-ref]
Unverdorben M., Kleber F.X., Heuer H., and al. Treatment of small coronary arteries with a paclitaxel-coated balloon catheter in the PEPCAD I study: are lesions clinically stable from 12 to 36 months? EuroIntervention 2013 ;  9 : 620-628 [cross-ref]
Cortese B., Micheli A., Picchi A., and 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 : 1291-1296 [cross-ref]
Latib A., Ruparelia N., Menozzi A., and al. 3-year follow-up of the Balloon Elution and Late Loss Optimization Study (BELLO) JACC Cardiovasc Interv 2015 ;  8 : 1132-1134 [cross-ref]
Vaquerizo B., Miranda-Guardiola F., Fernandez E., and al. Treatment of small vessel disease with the paclitaxel drug-eluting balloon: 6-month angiographic and 1-year clinical outcomes of the Spanish multicenter registry J Interv Cardiol 2015 ;  28 : 430-438 [cross-ref]
Zeymer U., Waliszewski M., Spiecker M., and al. Prospective ‘real world’ registry for the use of the ‘PCB only’ strategy in small vessel de novo lesions Heart 2014 ;  100 : 311-316 [cross-ref]
Choi I.J., Koh Y.S., Lim S., and al. Impact of the stent length on long-term clinical outcomes following newer-generation drug-eluting stent implantation Am J Cardiol 2014 ;  113 : 457-464 [inter-ref]
Basavarajaiah S., Naganuma T., Latib A., and al. Extended follow-up following “full-metal jacket” percutaneous coronary interventions with drug-eluting stents Catheter Cardiovasc Interv 2014 ;  84 : 1042-1050 [cross-ref]
Costopoulos C., Latib A., Naganuma T., and 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 : 1153-1159 [cross-ref]
Alomari I., Seto A. Approach to treatment of bifurcation lesions Curr Treat Options Cardiovasc Med 2016 ;  18 : 5 [cross-ref]
Stella P.R., Belkacemi A., Dubois C., and al. A multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in bifurcation lesions treated with a single-stenting technique: six-month angiographic and 12-month clinical results of the drug-eluting balloon in bifurcations trial Catheter Cardiovasc Interv 2012 ;  80 : 1138-1146 [cross-ref]
Lopez Minguez J.R., Nogales Asensio J.M., Doncel Vecino L.J., and 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 : 50-57 [cross-ref]
Berland J., Lefevre T., Brenot P., and al. DANUBIO – a new drug-eluting balloon for the treatment of side branches in bifurcation lesions: six-month angiographic follow-up results of the DEBSIDE trial EuroIntervention 2015 ;  11 : 868-876 [cross-ref]
Jim M.H., Lee M.K., Fung R.C., Chan A.K., Chan K.T., Yiu K.H. Six month angiographic result of supplementary paclitaxel-eluting balloon deployment to treat side branch ostium narrowing (SARPEDON) Int J Cardiol 2015 ;  187 : 594-597 [cross-ref]
Worthley S., Hendriks R., Worthley M., and al. Paclitaxel-eluting balloon and everolimus-eluting stent for provisional stenting of coronary bifurcations: 12-month results of the multicenter BIOLUX-I study Cardiovasc Revasc Med 2015 ;  16 : 413-417 [cross-ref]
Schulz A., Hauschild T., Kleber F.X. Treatment of coronary de novo bifurcation lesions with DCB only strategy Clin Res Cardiol 2014 ;  103 : 451-456 [cross-ref]
Waksman R., Serra A., Loh J.P., and al. Drug-coated balloons for de novo coronary lesions: results from the Valentines II trial EuroIntervention 2013 ;  9 : 613-619 [cross-ref]
Ho H.H., Tan J., Ooi Y.W., and al. Preliminary experience with drug-coated balloon angioplasty in primary percutaneous coronary intervention World J Cardiol 2015 ;  7 : 311-314 [cross-ref]
Nijhoff F., Agostoni P., Belkacemi A., and al. Primary percutaneous coronary intervention by drug-eluting balloon angioplasty: the nonrandomized fourth arm of the DEB-AMI (drug-eluting balloon in ST-segment elevation myocardial infarction) trial Catheter Cardiovasc Interv 2015 ;  86 (Suppl. 1) : S34-S44
Vos N.S., Dirksen M.T., Vink M.A., and 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 : 584-590 [cross-ref]
Cortese B., Berti S., Biondi-Zoccai G., and al. Drug-coated balloon treatment of coronary artery disease: a position paper of the Italian Society of Interventional Cardiology Catheter Cardiovasc Interv 2014 ;  83 : 427-435 [cross-ref]
Kleber F.X., Rittger H., Bonaventura K., and al. Drug-coated balloons for treatment of coronary artery disease: updated recommendations from a consensus group Clin Res Cardiol 2013 ;  102 : 785-797 [cross-ref]
Clever Y.P., Peters D., Calisse J., and al. Novel sirolimus-coated balloon catheter: in vivo evaluation in a porcine coronary model Circ Cardiovasc Interv 2016 ;  9 : e003543
Cremers B., Toner J.L., Schwartz L.B., and al. Inhibition of neointimal hyperplasia with a novel zotarolimus coated balloon catheter Clin Res Cardiol 2012 ;  101 : 469-476 [cross-ref]
Lemos P.A., Farooq V., Takimura C.K., and al. Emerging technologies: polymer-free phospholipid encapsulated sirolimus nanocarriers for the controlled release of drug from a stent-plus-balloon or a stand-alone balloon catheter EuroIntervention 2013 ;  9 : 148-156 [cross-ref]
Granada J.F., Tellez A., Baumbach W.R., and al. In vivo delivery and long-term tissue retention of nano-encapsulated sirolimus using a novel porous balloon angioplasty system EuroIntervention 2016 ;  12 : 740-747 [cross-ref]



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