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.
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.
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 . 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).
| DCB | DES | |
|---|---|---|
| Drug type | Mostly paclitaxel | Various |
| Drug dose | High: 300–600 μg | Low: < 100–200 μg |
| Retention | Embedded imprinted | Polymer based |
| Platform of drug delivery | Balloon | Stent scaffold |
| Distribution | Balloon surface distribution | Strut-based vascular penetration |
| Release kinetics | Fast release | Slow and controlled |
| Advantages | Respectful of the original artery anatomy with no implant | Mechanical support decreasing recoil |
| Homogenous drug transfer to the vessel wall | Less drug spillage in the circulation | |
| Highest drug concentrations at injury time | Proven efficacy in multiple indications | |
| Local drug delivery over very short period of time | Able to treat dissections | |
| Avoid chronic inflammation because of absence of polymers | ||
| Reduced DAPT duration | ||
| Better profile in small arteries | ||
| Easy lesion crossing/deliverability by balloon only |
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 . 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 . The optimal concentration of paclitaxel has been studied in animal models, with increasing doses ranging from 1 to 9 μg/mm 2 , with an optimal efficacy at the 3 μg/mm 2 dose, without any further benefit at higher doses . Moreover, high doses (3 × 9 μg/mm 2 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 .
Therefore, not all DCBs are created equal. The pharmacological properties and clinical outcomes of the resulting DCB can also be quite different . 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 .
| Name; manufacturer | Drug delivery technology & excipient | Paclitaxel dosage | Main clinical studies |
|---|---|---|---|
| PACCOCATH ® ; Bayer, Leverkusen, Germany | PACCOCATH ® technology (paclitaxel embedded in hydrophilic iopromide coating); matrix coating (paclitaxel + iopromide) | 3 μg/mm 2 | PACCOCATH ISR I (R, ISR); PACCOCATH ISR II (ISR) |
| SeQuent ® Please; B. Braun Melsungen, Berlin, Germany | Improved PACCOCATH ® technology (paclitaxel embedded in hydrophilic iopromide coating); matrix coating (paclitaxel + iopromide) | 3 μg/mm 2 | PEPCAD SVD (SVD); PEPCAD II (R, ISR); PEPCAD III (R, DNL); PEPCAD IV (DNL); PEPCAD V (B); PEPCAD DES (R, ISR); PEPCAD CTO (CTO); PERfECT, ISAR-DESIRE 3 (R, ISR); SeQuent ® Please World Wide Registry, SeQuent ® Please Small Vessel ‘PCB only’ Registry (SVD); BABILON trial (R, B); OCTOPUS (R, DNL); INDICOR (R, DNL); DEB-AMI (AMI); PEPCAD BIF (R, B); PEPCAD China ISR trial (R, ISR); The Treatment of In-Stent Restenosis Study (R, ISR) |
| DIOR ® I; Eurocor, Bonn, Germany | Paclitaxel-coated onto microporous balloon surface and folded–delivery by simple diffusion; crystalline coating (paclitaxel + dimethyl sulphoxide) | 3 μg/mm 2 | PICCOLETO (R, SVD); DEBIUT (B) |
| DIOR ® II; Eurocor, Bonn, Germany | Paclitaxel-coated onto microporous balloon surface with bioabsorbable polymer coating; 1:1 mixture of aleuritic and shellolic acid with paclitaxel (shellac coating) | 3 μg/mm 2 | VALENTINES I (ISR) & II (DNL); Spanish DIOR ® registry (various settings); DEAR, DEB-AMI (R, AMI) |
| IN-PACT Falcon™; Medtronic, Santa Rosa, CA, USA | Delivery by simple diffusion; crystalline coating (paclitaxel + urea: FreePac™) | 3 μg/mm 2 | BELLO (R, SVD); IN-PACT CORO (R, DNL) |
| Genie™; Acrostak, Geneva, Switzerland | Nanoporous double balloon liquid release; no excipient | 10 μmol/L | LOCAL TAX (R, DNL) |
| Pantera ® Lux; Biotronik, Bulach, Switzerland | Paclitaxel + BTHC | 3 μg/mm 2 | PEPPER (ISR); PAPP-A (AMI); DELUX registry (ISR, DNL) |
| Moxy ® ; Lutonix, Maple Grove, MN, USA | Paclitaxel + non-polymeric | 3 μg/mm 2 | De novo pilot study (R, DNL) |
| Elutax ® ; Aachen Resonance, Aachen, Germany | Two layers of paclitaxel (the first on the inflated balloon; the second as a crystal power); no excipient | 2 μg/mm 2 | Elutax ® paclitaxel-eluting balloon followed by BMS compared with Xience V DES in the treatment of de novo coronary stenosis: a randomized trial. Listro et al. (R, DNL) |
| Danubio ® ; Minvasys, Gennevilliers, France | Paclitaxel + BTHC | 2.5 μg/mm 2 | DEBSIDE trial (B) |
| RESTORE ® DEB; Cardionovum, Bonn, Germany | Shellac | 3 μg/mm 2 | Efficacy and safety of paclitaxel-coated balloon for the treatment of in-stent restenosis in high-risk patients (ISR) |
| Protégé ® & Protégé ® NC; Blue Medical, Helmond, Netherlands | Paclitaxel + BTHC | 3 μg/mm 2 | – |
| MagicTouch™; Concept Medical, Surat, India | Sirolimus + nanocarriers | 1.27 μg/mm 2 | – |
Potential applications of DCBs
In-stent restenosis (ISR)
The first clinical application of a DCB in humans was described by Scheller et al. 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) . The SEDUCE trial 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 , 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. 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 ± 0.44 mm vs. 0.44 ± 0.73 mm; 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) 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 , 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) . 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 demonstrated sustained long-term clinical efficacy for both devices. Even if the recent RIBS IV trial 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 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 . 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 . 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 3.0 mm). A few studies have evaluated the use of DCBs in SVD, and these are summarized in Table 3 . The PEPCAD I study evaluated the efficacy of the SeQuent ® Please DCB in 118 patients with 2.35 ± 0.19 mm 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 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 (< 2.75 mm 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.
