Coronary angioplasty was introduced to clinical practice by Andreas Grüntzig in 1977.1 In the coronary field, the most important improvement in angioplasty has been achieved with the introduction of stents. A significant proportion of the complex modern coronary interventional techniques rely on stenting. Stenting overcomes recoil and dissections but not restenosis due to neointimal proliferation. Local intravascular drug delivery by drug-eluting stents (DES) seemed to cross the last frontier in interventional procedures, namely restenosis. However, stents cannot be implanted at all sites as neointimal proliferation reduces the long-term benefit of angioplasty, and DES are not effective in the treatment of peripheral vascular disease. This article will review the potential applications of the drug-coated balloon (DCB) in coronary vascular disease.
Clinical Data – Coronary Applications
Paccocath® Prototype Balloon
The Paccocath in-stent-restenosis (ISR)-I trial was a German, controlled, randomised, first-in-human, multicentre study with blinded angiographic evaluation. It compared the efficacy and tolerance of Paccocath® paclitaxel-coated balloon catheters with conventional uncoated catheters for the treatment of coronary in-stent restenosis. Compared with patients treated with an uncoated balloon, patients in the Paccocath balloon group had significantly better angiographic results (in-segment late luminal loss 0.74±0.86 versus 0.03±0.48mm; p=0.002) and concomitant 12-month clinical outcomes.2 The subsequent Paccocath ISR-II trial confirmed the initial findings of the first ISR trial3 in an additional 56 patients with similar baseline clinical and angiographic data. The most surprising finding was that the beneficial effects of the Paccocath balloon catheter were maintained for up to two years after the intervention. Importantly, in contrast to DES, combined antiplatelet therapy was continued for only one month followed by treatment with aspirin alone. Figure 1 shows the results of a patient undergoing treatment of an occluded stent in the circumflex artery with the Paccocath balloon, including serial angiographic follow-up to 5.5 years.
In 2004, a second-generation coronary Paccocath balloon, the SeQuent® Please (B Braun Vascular Systems, Germany), was developed. SeQuent Please was studied in the Paclitaxel eluting PTCA–catheter in coronary artery disease (PEPCAD) clinical trial programme, which focused on criteria that are patient-related (e.g. diabetes mellitus, ethnicity, race), lesion-related (e.g. in-stent restenosis, small-vessel disease, bifurcations, chronic total occlusions), procedure-related (e.g. sequence of using the DCB and a BMS) and device-related (DCB combined with BMS or SeQuent Please with pre-mounted BMS). All studies were prospective, with late lumen loss of the target lesion as the primary end-point.
The PEPCAD I small vessel disease (SVD) trial was a German, non-randomised, single-arm, multicentre study including 120 patients with stenosis in the small coronary vessels (reference diameter 2.35±0.19 mm). Most of the patients (72%) could be treated with the SeQuent Please balloon only, while 28% of the patients required additional BMS implantation due to elastic recoil or severe dissections. Patients treated with the DCB demonstrated very low in-segment late lumen loss (0.16±0.38 mm) and a very low binary restenosis rate in the single digits (5.5%). However, in those patients with additional BMS implantation, geographical mismatch between coated balloon dilatation and stent implantation was frequently associated with the occurrence of restenosis.4
The PEPCAD II in stent restenosis (ISR) study was a German, randomised, non-blinded, two-arm, multicentre trial that included 131 patients and compared the safety and efficacy of the SeQuent Please balloon versus the paclitaxel-coated Taxus® stent (Boston Scientific, Natick, MA, US) in the treatment of coronary BMS restenosis. Compared with the DES, the DCB induced significantly less in-segment late lumen loss and binary restenosis at six-month follow-up and improved event-free survival at the 12-month visit.5 The results of this study are in good agreement with both the Paccocath ISR I study and the randomised intracoronary stenting and angiographic results: drug eluting stents for in-stent restenosis (ISAR-DESIRE) study comparing sirolimus- (Cypher® [Cordis, Miami]) and paclitaxel- (Taxus) eluting stents with plain balloon angioplasty in the treatment of in-stent restenosis.6
The PEPCAD III trial was a European randomised, single-blind (subject), two-arm multicentre study that compared an experimental device consisting of a cobalt–chromium stent pre-mounted on a paclitaxel-coated balloon (DCB+BMS) with the sirolimus-eluting Cypher stent in 637 patients with native coronary stenosis. The primary end-point in a non-inferiority design was late lumen loss at nine-month angiographic follow-up. Secondary end-points included major adverse cardiac events (MACE) – death, myocardial infarction and any revascularisation – at nine months. Clinical end-points were analysed on an intention-to-treat basis. For the per protocol analysis of the primary end-point, 477 patients (75%) were available. Quantitative coronary angiography demonstrated an effective inhibition of restenosis but not to the same extent or at the very high level of safety of the Cypher stent. The in-segment late lumen loss rate did not differ significantly between groups (0.20±0.52 versus 0.11±0.40mm; p=0.07), whereas in-stent analysis was significantly in favour of the DES (0.41±0.51 versus 0.16±0.39mm; p<0.001). The total MACE rate was 18.5% in the DCB+BMS group and 15.4% in the DES group (p=0.16). The DES group presented with a lower incidence of myocardial infarction (3.8 versus 0.6%; p<0.01) and target lesion revascularisation (8.1 versus 3.1%; p<0.01). The definite stent thrombosis rate was 1.3% (n=4) in the DCB+BMS group versus 0.3% (n=1) in the DES group (p=0.16). Detailed analysis revealed that most cases of stent thrombosis and myocardial infarction were not related to study device failure but to different reasons. However, this first DCB+BMS device did not meet the non-inferiority criteria compared with the sirolimus-eluting stent, which presented with very favourable results. Late lumen loss in both groups was comparable to published data on different DES. Restenosis in the DCB+BMS group was predominantly focal. Therefore, further design evolution seems to be possible to improve this new approach. DCBs are not a replacement for DES but rather a new platform in interventional cardiology and radiology to reduce the need for stents.7
PEPCAD V was a German small, prospective, one-arm, dual-centre study that included 28 patients with de novo bifurcational coronary artery lesions. The aim of this study was to investigate the feasibility of angioplasty using the SeQuent Please balloon in the main and side branch of the bifurcation followed by BMS implantation in the main branch. All procedures (primary end-point in this study) were successful. In-segment late lumen loss at nine months was 0.38mm in the main branch (DCB+BMS) and 0.21mm in the side branch (DCB only).
No MACE at 30-day follow-up and no deaths at nine-month follow-up were reported. Restenosis with target lesion revascularisation occurred in only one patient. However, in the main branch, where a DCB was used in combination with a BMS, two patients experienced late stent thrombosis.8
Further PEPCAD studies are ongoing. PEPCAD IV is an Asian, randomised, two-arm, multicentre study comparing the efficacy of the SeQuent Please balloon followed by cobalt–chromium stent (Coroflex® Blue) deployment versus the paclitaxel-eluting Taxus Liberté stent (Boston Scientific) in the treatment of de novo coronary stenosis in 84 diabetic patients. The primary end-point is late lumen loss in the target vessel at nine months. PEPCAD Chronic Total Occlusion (CTO) is a German, one-arm, dual-centre study assessing the safety and efficacy of the SeQuent Please balloon after BMS of a CTO in a native coronary artery. The PEPCAD-DES trial is a German, randomised, single-blind (subject), two-arm, multicentre efficacy study investigating vessel patency following treatment with either an uncoated balloon or a paclitaxel-coated SeQuent Please balloon in patients initially treated with a Cypher or Taxus stent. In both trials, the primary end-point is late lumen loss at six months. The PEPCAD-CTO and PEPCAD-DES studies are expected to be completed in 2014 and 2011, respectively. The SeQuent Please balloon catheter is also being investigated in the ISAR-DESIRE-3 study, which is currently recruiting patients (estimated number to be enrolled: 375). This German, randomised, single-blind (outcomes assessor), three-arm, dual-centre study aims to determine which treatment option – SeQuent Please balloon, Taxus stent or plain balloon angioplasty – is the most effective in the treatment of restenosis after initial implantation of a ‘-limus’-eluting stent. The INDICOR study is an Indian, randomised, single-blind (subject), two-arm, multicentre real-world study investigating the acute, six-month, 12-month and three-year outcome of using the SeQuent Please balloon and the bare-metal Coroflex Blue stent for the treatment of de novo and restenotic lesions in native coronary arteries in an estimated 125 patients. The primary end-point in the ISAR-DESIRE-3 study is per cent in-segment diameter stenosis at six to eight months, while that of the INDICOR study is late in-segment and in-stent lumen loss at six months. The ISAR-DESIRE-3 and INDICOR studies are expected to be completed in 2014 and 2012, respectively. Another German, randomised, single-blind (subject), two-arm trial investigated the combination of a paclitaxel-coated balloon and implantation of the Genous® stent (OrbusNeich, Hong Kong) in the prevention of restenosis in native coronary arteries.
The primary end-point, late lumen loss at six months, was significantly reduced from 0.61mm (Genous stent only) to 0.16mm (Genous stent followed by SeQuent Please) for the in-segment analysis (p<0.001). Clinical event rate was significantly lower with DCB post-dilatation (17.2 vs 4.8 %, p=0.03) (presented by Jochen Wöhrle at Transcatheter Cardiovascular Therapeutics [TCT] 2010).9
Comparison of two different paclitaxel-coated balloon catheters (Paccocath and DIOR®; Eurocor, Bonn, Germany) in the porcine model showed that inhibition of neointimal proliferation by paclitaxel depended on the coating composition. While the dose of paclitaxel is identical in the two devices, in the DIOR balloon catheter the adherence of paclitaxel is mediated by a rough membrane of the balloon without a hydrophilic matrix. A previous study of DIOR balloon catheters reported a measurable but very low tissue concentration in porcine arteries.10 No angiographic follow-up or histomorphometric data were reported. In a head-to-head comparison of the Paccocath and DIOR balloon catheters in the porcine coronary overstretch model, Cremers et al. showed that Paccocath balloons led to highly significant reduction of all parameters, including in-segment late lumen loss and minimal lumen diameter, compared with both uncoated and DIOR balloons at 28-day follow-up.11
The Italian, randomised, non-inferiority Piccoleto trial, which compared the paclitaxel-coated DIOR balloon versus the Taxus Liberté™ stent in 57 patients with small coronary vessel disease, showed that DIOR failed to meet the non-inferiority criteria versus the Taxus stent in terms of angiographic per cent stenosis (32 and 10% for the DIOR group and the Taxus group, respectively, at six-month follow-up). Other clinical outcomes (death, myocardial infarction) were found to be equivalent in both groups, except for a trend towards an increased rate of target lesion revascularisation in the balloon group for the balloon treatment arm and the Taxus treatment arm at nine-month follow-up, respectively.12
The Drug eluting balloon in bifurcation Utrecht (DEBUIT) registry is a Dutch, one-arm, monocentre registry assessing the short-term safety and efficacy of the DIOR paclitaxel-coated balloon in the treatment of coronary artery bifurcation lesions. Twenty patients were enrolled and sequentially treated with DIOR balloons in both the main and side branches, followed by provisional stenting of the main branch with a BMS. The group reported no major acute coronary events and no subacute vessel closure at four-month follow-up. Since no follow-up angiographies were performed, it is difficult to assess the efficacy of the DIOR balloon for this indication. Nevertheless, this study shows that the treatment of coronary artery bifurcation lesions with DIOR balloons was feasible and well-tolerated.13
The subsequent DEBIUT trial was a Dutch/Belgian/German, randomised, open-label, three-arm, multicentre study assessing the safety and efficacy of the DIOR drug-eluting balloon in coronary bifurcations in combination with a BMS, with a specific focus on the side branch using the provisional T-stenting technique with final kissing balloons. The primary end-points were angiographic late lumen loss in the main branch and the side branch after six months. However, in this trial the primary end-points were not reached.14
The Early re-endothelialization might not be the unique solution to prevent restenosis (EREMUS) trial is not yet open for recruitment. It is an Italian, randomised, investigator-initiated, three-arm study aimed at determining which treatment option – the Elutax® paclitaxel-coated balloon (Aachen Resonance, Aachen, Germany) combined with the Genous stent, an uncoated balloon combined with the Genous stent or an uncoated balloon combined with the Taxus stent – is the safest for patients undergoing percutaneous coronary intervention. In this study, with an estimated 75 patients to be enrolled, the primary end-point is late lumen loss at six-month follow-up.
Pre-clinical data for the IN.PACT® Falcon paclitaxel-coated balloon (Medtronic Invatec) show similar efficacy in animal experiments to the Paccocath coating. The IN.PACT CORO ISR first-in-man trial was a single-centre, one-arm study in 23 patients with 26 lesions for the treatment of bare-metal in-stent restenosis. Mean lesion length was 22.8±11.1mm, with a reference diameter of 2.64±0.31mm. After six months, late lumen loss in-stent was 0.07±0.37mm and in-segment was -0.02±0.50mm, with a binary restenosis rate of 4%.
The IN.PACT CORO I trial is a randomised, single-centre, three-arm pilot study comparing the entity of neointimal area and strut coverage as assessed by optical coherence tomography at six months following bare-metal stent implantation with pre- or post-dilatation with IN.PACT Falcon versus bare-metal stent alone (negative control). The Balloon Elution and Late Loss Optimization (BELLO) trial is a randomised, multicentre study on 182 patients randomised to treatment with either the IN.PACT Falcon balloon or the Taxus stent to assess late lumen loss at six months in the small coronary vessels.
The PEPPER trial is a German, non-randomised, open-label, one-arm, multicentre study evaluating the safety and efficacy of the Pantera® Lux paclitaxel-coated balloon (Biotronik AG, Germany) in patients with in-stent restenosis in a coronary artery. The majority of ISR lesions were focal. An interim analysis reported a late lumen loss in-stent of 0.07mm (presented by Christoph Hehrlein at TCT 2010).15
The potential of the Moxy paclitaxel-coated balloon (Lutonix, Inc, Maple Grove, MN, US) is currently being assessed in the De Novo Pilot Study for the treatment of coronary de novo stenosis and in the PREVIDEO I registry for the treatment of in-stent restenosis in BMS vessel segments. The De Novo Pilot Study is a Dutch, randomised, open-label, one-arm, multicentre study of 26 patients to be enrolled. The patients were treated with a Lutonix catheter either before or after BMS. Late lumen loss in the analysed segment at six months was 0.53 and 0.45mm respectively (presented by Patrick Serruys at TCT 2010).16 The PREVIDEO I registry is a European, prospective, non-randomised, open-label, one-arm study of 41 patients with BMS-ISR. Late lumen loss in-segment at six months was 0.16±0.40 mm (presented by Laura Mauri at TCT 2010).17
The currently available data on DCB angioplasty as a clinical treatment modality for coronary artery disease are limited but hold promise. The advantages of DCBs over standard angioplasty and stent technologies are: the potential for homogeneous drug delivery to the vessel wall, which is not accomplished using DES; immediate drug release without the use of a polymer, which can induce chronic inflammation and late thrombosis as observed with some DES; the option of using balloon catheters alone or in combination with a BMS; no foreign object such as DES left behind in the body; the potential of reducing antiplatelet therapy; and lower restenosis rates in several coronary lesion types compared with conventional treatment.
The results from several randomised controlled coronary clinical trials consistently show that paclitaxel in a matrix of soluble additive coated on balloons reduces neointimal formation, late lumen loss, restenosis and repeat revascularisation in patients with complex coronary artery lesions. It seems that in the coronary circulation, paclitaxel-coated balloon angioplasty holds the greatest promise for lesions in which stent deployment is not desirable or technically challenging (e.g. in-stent restenosis, long and distal lesions, very angulated segments, small vessels or bifurcation lesions).
The paclitaxel formulation is important since some balloon catheters coated with the same or a similar dose of paclitaxel failed to show efficacy in animal experiments and clinical trials. The current discussion on drug-coated balloons in coronary applications is based on several hundreds of coronary artery patients. We will still have to learn much more about the benefits but also the limitations of this technology. Even if the same drugs were taken as a coating material, there are considerable differences in the delivery efficacy of each balloon. It has to be pointed out that DCBs may be different even if the same drug and dose has been chosen. Therefore, there is a clear need for randomised clinical trials in different indications, pre-clinical studies on efficacy and tolerance and subsequent clinical trials on different coatings.
Although the use of DCBs appears to hold promise as a viable alternative to stand-alone balloon angioplasty and stent implantation for the treatment of coronary and peripheral arterial disease, it remains to be seen what place such a system will find in the treatment of the multitude of clinical problems addressable by vascular interventions. So far, data from randomised clinical trials in coronary applications identify the treatment of coronary in-stent restenosis as a viable option. Furthermore, results from the first non-randomised series and clinical experience identify the treatment of de novo lesions in small coronary vessels, bifurcation lesions, long lesions, paediatric interventions and cerebrovascular applications as potential beneficial indications for DCB catheters. In coronary applications, DCBs are not a replacement for DES. Their potential benefit is the reduced need for stents in complicated lesions. A strategy of DCB angioplasty with provisional spot stenting in the case of severe dissections may become a better alternative in long and complex lesions, bifurcations or patients with contraindications to DES (chronic anticoagulation, planned non-cardiac surgery, etc.; see Figure 2).