Prevention of restenosis by a novel drug-eluting stent system with a dose-adjustable, polymer-free, on-site stent coating
Jörg Hausleiter1,*,
Adnan Kastrati1,
Rainer Wessely1,
Alban Dibra1,
Julinda Mehilli1,
Thomas Schratzenstaller2,
Isolde Graf1,
Magdalena Renke-Gluszko2,
Boris Behnisch3,
Josef Dirschinger4,
Erich Wintermantel2,
Albert Schömig1,4 for the investigators of the Individualizable Drug-Eluting Stent System to Abrogate Restenosis Project
1Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Lazarettstrasse 36, 80636 Munich, Germany
2Zentralinstitut für Medizintechnik; Technische Universität München, Garching, Germany
3Translumina Labs, Munich, Germany
4I. Medizinische Klinik des Klinikums rechts der Isar, Technische Universität, Munich, Germany
Received 9 May 2005; revised 3 June 2005; accepted 16 June 2005; online publish-ahead-of-print 23 June 2005.
* Corresponding author. Tel: +49 89 1218 4038; fax: +49 89 1218 4013. E-mail address: hausleiter{at}dhm.mhn.de
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Abstract
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Aims Drug-eluting stents (DES) represent a major advance in interventional cardiology. Along with the success shown, current DES also present limitations related to the presence of polymer-coating, fixed drug, and dose used. With the ISAR (Individualized Drug-Eluting Stent System to Abrogate Restenosis) project, a DES system has been developed that permits individualized choice of the drug and dose to use for the given patient. The objective of this prospective dose finding study was to assess the feasibility, safety, and efficacy of a polymer-free on-site stent coating with increasing rapamycin doses.
Methods and results In this dose finding study, 602 patients were sequentially enrolled in four groups: microporous bare metal stent (BMS), DES stents coated with a 0.5, 1.0, and 2.0% rapamycin solution. The angiographic in-segment restenosis rate at follow-up angiography was the primary study endpoint. In-segment restenosis was significantly reduced from 25.9% with BMS to 18.9, 17.2, and 14.7% with 0.5, 1.0, and 2.0% rapamycin-eluting stents, respectively (P=0.024). Similarly, the need for target lesion revascularization at 1 year follow-up was reduced from 21.5% with BMS to 16.4, 12.6, and 8.8% with 0.5, 1.0, and 2.0% rapamycin-eluting stents, respectively (P=0.006).
Conclusion The placement of polymer-free stents coated on-site with rapamycin is feasible and safe. Furthermore, a dose-dependent efficacy in restenosis prevention is achievable with this new DES concept.
Key Words: Restenosis Stents Randomized Rapamycin Polymer
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Introduction
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When compared with conventional bare metal stents (BMS), the introduction of drug-eluting stents (DES) has resulted in a substantial reduction in the incidence of in-stent restenosis.1 DES systems eluting either sirolimus2 or paclitaxel3 from a polymer stent coating have been shown in randomized trials to effectively inhibit the process of neointimal proliferation resulting in restenosis reduction. Despite these advances, restenosis rates still remain substantial in patients with high-risk for restenosis, e.g. patients with long lesions and complex lesion morphologies4 or patients with lesions in bifurcations.5 Furthermore, the incidence of late occurring thrombotic vessel occlusions6,7 and the development of late restenosis8 have raised issues about the safety and the efficacy of DES in the long-term. Both late occurring complications have been related to a marked inflammatory response against the non-degradable polymer-coated stent surface and an incomplete re-endothelialization.
In the Individualized drug-eluting Stent system to Abrogate Restenosis (ISAR) project, we developed a novel DES system which allows for an individualizable, drug- and dose-adjustable stent coating without the obligate use of polymers. The system consists of two separate components, a balloon-mounted stainless steel stent with a unique microporous strut surface and a coating device, which can be operated in the catheterization laboratory. The purpose of the current study was to evaluate the feasibility, safety, and the efficacy of this novel DES system. For the proof-of-principle of this concept, stents were coated with increasing doses of rapamycin as the cytostatic compound which has been proven to inhibit neointima formation.
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Methods
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Study design
The present study was a prospective, open-label dose-finding study for the evaluation of four sequentially increasing rapamycin doses in a polymer-free stent coating for the prevention of restenosis. Patients were considered eligible for this study whether they complained of angina pectoris or had exercise-induced ischaemia in the presence of angiographically significant stenosis in native coronary arteries with a reference-vessel diameter between 2.5 and 3.5 mm. Excluded were patients suffering from an acute myocardial infarction (within the last 72 h before the intervention), lesions located in the left main stem, and lesions with in-stent restenosis. The placement of multiple rapamycin-eluting stents at the same dosage was allowed to cover one or more lesions. The control group consisted of patients treated with the same microporous BMS without drug coating. The protocol was approved by the institutional ethics committee and all patients gave written informed consent.
The DES platform
The DES platform (Yukon DES; Translumina, Hechingen, Germany) consists of two components, a pre-mounted, microstructured 316L stainless steel microporous stent in a disposable coating cartridge and the coating device. The detailed process of stent coating has been described elsewhere.9 The microporous stent surface increases the drug reservoir capacity and allows for a retarded drug release without obligatory application of a polymer. For stent coating, the cartridge holding the stent system is placed into the coating device and a 1 mL drug reservoir containing the dissolved drug in a pre-defined volume is connected to the cartridge. The coating process is initialized by the advancement of the drug into a mobile, positionable ring containing three jet units, which allow for uniform delivery of the drug onto the stent surface. Subsequently, to the termination of spray coating, the stent surface is dried by removing the solvent with pressured air and the stent is available for immediate use. The stents were coated in this study with 0.5, 1.0, and 2.0% rapamycin solutions. Specific analyses with high-performance liquid chromatography have shown that the spray coating with these rapamycin solutions resulted in 138±14, 313 ±59, and 479 ±26 µg rapamycin/mm2 stent surface area, respectively. Furthermore, pharmacokinetic assays revealed that rapamycin is released for >3 weeks with more than two-thirds released within the first week. The available stent sizes were 8, 12, 16, 20, 23, and 25 mm, with diameters of 2.0, 2.5, 3.0, and 3.5 mm.
Coronary procedures and medication
All patients received clopidogrel 600 mg at least 2 h and 500 mg i.v. of aspirin immediately before stent placement. Procedures completed with a residual diameter stenosis of the target lesion of <30% and a thrombolysis in myocardial infarction flow grade 3 were considered successful. Post-interventional therapy included aspirin 100 mg b.i.d. indefinitely, clopidogrel 75 mg b.i.d. until discharge but no longer than 3 days, followed by daily administration of 75 mg for at least 6 months as indicated, and other cardiac medications believed to be required by the patient's physician. The protocol provided for the performance of ECGs and collection of blood samples for the determination of creatine kinase and its MB isoenzyme, haemoglobin, and platelet count every 8 h for the first 24 h after the procedure and daily afterward, until discharge.
Angiographic evaluation
Qualitative and quantitative assessments in the core angiographic laboratory were performed by operators unaware of the treatment group. Lesions were classified by the modified American College of Cardiology/American Heart Association grading system.10 Digital angiograms were analysed offline with the automated edge detection system (CMS V6.0, Medis Medical Imaging Systems, Nuenen, The Netherlands). The in-segment analysis comprised the stent segment and the proximal and distal stent edges defined as 5 mm proximal or distal to the stent. The in-stent analysis was confined to the stented artery length. Matched views were selected for angiograms recorded before and immediately after the intervention and at follow-up. Each angiographic sequence was preceded by an intracoronary injection of nitroglycerin. The parameters obtained were minimum lumen diameter (MLD), vessel size, diameter stenosis, and diameter of the maximally inflated balloon. Late lumen loss was calculated as the difference in MLD noted between measurements after the procedure and at follow-up.
Definitions and endpoints of the study
Patients without adverse events within the first 30 days after the procedure were considered eligible for repeat angiography at 6 months. Angiographic in-segment restenosis at follow-up, defined as diameter stenosis
50%, was the primary endpoint. Secondary endpoints, which were assessed in all patients enrolled in this study, were the target lesion revascularization [TLR; percutaneous coronary intervention (PCI) or bypass surgery] and the combined incidence of death and myocardial infarction during 1 year follow-up. The diagnosis of myocardial infarction was based on typical chest pain combined with either new pathological Q waves or creatine kinase rise more than three times the upper limit of normal with concomitant increase in the MB isoenzyme. TLR was performed in the presence of angiographic restenosis and symptoms or signs of ischaemia. Adverse events were monitored throughout the follow-up period: by a clinical visit at 6 months and an additional telephone interview at 1 year after the intervention. If patients reported cardiac symptoms during the telephone interview, at least a clinical and electrocardiographic follow-up examinations were performed in the outpatient clinic or by the referring physician. All events were adjudicated and classified by an event-adjudication committee whose members were unaware of the patients' assigned treatment.
Statistical analysis
The number of patients included in the present study was based on the sample size estimation for the primary endpoint of angiographic restenosis on the basis of a test for trend analysis. Departing from an assumed restenosis rate of 24% in the BMS group, we hypothesized a stepwise reduction of 4% with each increase in rapamycin dose. We gave 80% power to the trial for detecting a significant doseeffect trend at a two-sided
level of 0.05. Accordingly, 560 lesions with repeat angiography were required.
The main analysis was performed on an intention-to-treat basis and the discrete variables are expressed as counts or per cent. Continuous variables are expressed as mean±SD. Differences in basal characteristics were tested for significance by the use of
2 test (discrete variables) or ANOVA test (continuous variables). The impact of rapamycin dose on angiographic and clinical results observed during follow-up was tested for significance by the use of test for trend (discrete variables) or linear regression analysis (continuous variables). Multivariable logistic regression analyses were used to investigate for the independent effect of risk factors on in-segment restenosis and the need for TLR. All variables describing the patient and the stenosis characteristics (Tables 1 and 2) as well as the rapamycin concentrations [0 (=BMS), 0.5, 1.0, and 2.0%] on the stent were entered into the models. The analysis was made per lesion. To eliminate a potential clustering effect in patients with multilesion intervention,11 bootstrapping with 1000 replications was applied for the calculation of regression coefficients, odds ratios, and 95% confidence intervals for each covariate in the models. Statistical significance was accepted for P<0.05.
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Results
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In total, 602 patients were sequentially assigned to receive a microporous BMS (155 patients) and a rapamycin-eluting stent with a dose of 0.5% rapamycin (139 patients), 1.0% rapamycin (161 patients), and 2.0% rapamycin (147 patients). Clinical characteristics were comparable between groups, as shown in Table 1. Notably, 29% of patients had diabetes mellitus and more than one-third of patients had already suffered from myocardial infarction. The angiographic and procedural characteristics are summarized in Tables 2 and 3, respectively. A total of 708 coronary stenoses were treated within this study with a higher prevalence of stenoses in the LAD in the 1% rapamycin-dose group. Additional differences between the sequential dose groups were seen for the incidence of complex lesions, chronic occlusions, and vessel size. No problems were encountered during on-site stent coating and the placement of coated stents was successful in all patients.
Clinical outcome
None of the patients died during the first 30 days after stent placement. Two patients (0.3%) of the overall study population suffered from a thrombotic stent occlusion: one lesion in the 0.5% and one lesion in the 2.0% rapamycin-dose groups, respectively. Both occlusions occurred within 24 h after rapamycin-eluting stent placement. The complication of non-fatal myocardial infarction within the first month after stenting was observed in 1.3% of the BMS patients and in 0.7, 2.5, and 2.0% of the 0.5, 1.0, and 2.0% rapamycin-eluting stent patients, respectively (P=0.64).
At 1 year follow-up, the combined rate of death or myocardial infarction did not differ between treatment groups. The incidence of death or non-fatal myocardial infarction at 1 year was 3.9% among the BMS patients and 1.4, 3.7, and 2.7% among the 0.5, 1.0, and 2.0% rapamycin-eluting stent patients, respectively (P=0.59).
Incidence of angiographic and clinical restenosis
Repeat angiography was performed in 484 of 598 (80.9%) eligible patients at a median time interval of 198 days (interquartile range: 175213 days). A total of five patients died before the scheduled angiographic follow-up; the remaining patients declined to undergo it. The angiographic results are summarized in Table 4. When compared with the BMS group, the in-stent restenosis rate demonstrated a significant dose-dependent reduction with increasing rapamycin doses (P=0.012). Similarly, the in-segment restenosis rate was reduced with increasing rapamycin doses (P=0.024) (Figure 1). Consequently, the in-segment late lumen loss was lowest with 0.36±0.55 mm in 2.0% rapamycin-eluting stents patients. TLR was necessary in 40 (21.5%) BMS lesions and in 28 (16.4%), 23 (12.6%), and 15 (8.8%) of the 0.5, 1.0, and 2.0% rapamycin-eluting stent patients, respectively (P=0.006) (Figure 1). Thus, the need for TLR was significantly reduced by 59% in the 2.0% rapamycin-eluting stent group.

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Figure 1 Bar graph demonstrating the angiographic restenosis rates and the need for TLR (repeat coronary intervention or bypass surgery) at follow-up for microporous stents coated with increasing rapamycin concentrations (0.52.0%).
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We applied a multivariable logistic regression model to correct for the possible influence of the differences in baseline patient and lesion characteristics on in-segment restenosis and on TLR. Table 5 summarizes the results of the regression model. In this analysis, the well-known variables among others, presence of diabetes, long lesions, and small vessel size, were identified as independent predictive risk factors for restenosis. In addition, the placement of rapamycin-eluting stents with increasing drug doses was independently associated with a reduced risk for restenosis (P=0.005) and for TLR (P<0.001).
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Discussion
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In this prospective, sequential dose-finding study, a high proportion of our patients presenting with acute coronary syndromes, multivessel disease, and complex lesions, was included. The study demonstrates that the placement of a polymer-free rapamycin-eluting stent with a microporous strut surface was feasible and safe. When compared with BMS, rapamycin-eluting stents markedly reduced the risk of restenosis in patients with a wide range of coronary lesions. All indices of restenosis improved with increasing rapamycin doses on the stent. When compared with the BMS group, the biologic potency of the polymer-free rapamycin-eluting stent was evidenced by a maximal 43% relative reduction in the risk of angiographic in-segment restenosis, with a corresponding 59% reduction in the need for TLR.
Since the introduction of DES in interventional cardiology, several large clinical trials consistently demonstrated an impressive reduction of in-stent restenosis in de novo coronary lesions by rapamycin- and paclitaxel-eluting stents.1,3,12,13 However, the restenosis rates still remain substantial in patients with high-risk for restenosis, such as patients with challenging interventional scenarios like long lesions with complex morphologies,4 lesions in bifurcations,5 or in-stent restenotic lesions.14 To overcome these limitations, dose adjustments may be desirable to enable an individual dosage for specific lesion or for patient subsets. In addition, the presently approved DES platforms use a polymer-based coating for retardation of drug release. Polymer-based DES have been associated with prolonged inflammatory reactions6,15 and several investigators believe that the polymer is the most likely mechanism.6 This hypersensitivity reaction may cause late stent thrombosis and restenosis.7,8 Therefore, we developed a novel concept for a drug-eluting stent platform, which allows for dose-adjustable coating of stents without the obligate use of a polymer.
This DES platform consists of two components, a microporous stainless steel stent and a coating device, which can be operated in the catheterization laboratory. When compared with a non-microporous stent, the microporosity may reduce neointima proliferation through an accelerated re-endothelialization;16 it allows for an increase in the drug reservoir and for a retardation of drug release. Indeed, pre-clinical investigations demonstrated that increasing doses of a chosen drug could be sprayed on a microporous stent surface and that the potential loss of the drug in the transition between insertion of the stent system into the guiding catheter and stent placement is negligible.9 Furthermore, studies in the porcine restenosis model demonstrated that the use of the microporous stent system is associated with a significant reduction in neointima proliferation when rapamycin is used as the active antiproliferative compound.9
So far, an optimal release kinetic has not been determined for any compound used on DES to obtain a most favourable balance between inhibition of neointima proliferation and re-endothelialization of the injured coronary artery. However, in a small study population, the slow- and fast-release kinetics of rapamycin from the polymer-based stent system have resulted in similar efficacies in the inhibition of neointima growth.12 In addition, short-term oral treatment with rapamycin has been shown to be effective for restenosis prevention in patients with recurrent in-stent restenosis.17 These results indicate that brief treatment duration may be sufficient to inhibit restenosis formation when rapamycin is the administered compound. With the current stent system, two-thirds of the stent-based rapamycin is eluted within the first week and the rest in the next 2 weeks, resulting in an effective inhibition of neointima proliferation. Although an even stronger inhibition may be obtainable with a retardation of rapamycin release, the achievement of the current results without the use of a polymer may have advantages in the event-free long-term follow-up of patients treated with rapamycin-eluting stents.
The efficacy of non-polymer-based DES has been questioned by the results of previous randomized trials. Although the placement of a non-polymer-based paclitaxel-coated stent has resulted in an effective, dose-dependent reduction of in-stent neointimal tissue proliferation,18 a similar non-polymer-based paclitaxel coating was only associated with a non-significant reduction of restenosis in the DELIVER trial.19 The differences in restenosis prevention between the non-polymer-based paclitaxel-coated stents and our polymer-free rapamycin-eluting stent might be explained by the differences in release kinetics of the drugs provided by the different strut surface and the drugs themselves.
Limitations
The groups of patients were enrolled in this study in a sequential manner; thus, we acknowledge the limitations of a non-randomized trial. Although the current dose-finding study shows that the on-site drug coating of stents is feasible and safe and that a doseresponse is obtainable with increasing drug doses on the stent surface, it did not investigate comprehensively the potentials of the system such as an individualized dosing regimen for different lesion morphologies or the use of different drug combinations on the stent system. Two (0.4%) of 447 patients receiving a rapamycin-eluting stent suffered from stent thrombosis within the first 24 h after stent placement. This rate of thrombotic stent occlusions is comparable to other DES trials.2,3 Nevertheless, we acknowledge the limitation that the sample size of this study is too small for a comprehensive investigation of the impact of rapamycin-eluting stents on events such as stent thrombosis. Current DES are an expensive treatment option with the potential of reducing medical care costs during follow-up.20 Although the rapamycin-eluting stent assessed in the present study might be a less expensive option, no formal cost-effectiveness analysis was done.
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Acknowledgement
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The ISAR project was supported by a research grant (AZ 504/02) from the Bayerische Forschungsstiftung, Munich, Germany.
Appendix: study organization
Steering Committee: A. Schömig (chair), E. Wintermantel, A. Kastrati; Data Coordinating Center: J. Mehilli (director), K. Hösl, H. Holle, F. Rodriguez, C. Peteler, M. Niemetz; Angiographic Core Laboratory: A. Dibra (director), S. Pinieck, S. Mayer; Deutsches Herzzentrum München: A. Schömig, A. Kastrati, J. Mehilli, H. Schühlen, J. Pache, C. Schmitt, R. Wessely, J. Hausleiter, B. Jaschke, C. Michaelis, I. Graf, I. Porwol; Klinikum rechts der Isar: A. Schömig, J. Dirschinger, M. Seyfarth, N. von Beckerath, M. Karch; Institut für Medizintechnik: E. Wintermantel, U. Steinseifer, T. Schratzenstaller, M. Renke-Gluszko, M. Stöver, M. Eblenkamp.
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