European Heart Journal Advance Access originally published online on October 7, 2007
European Heart Journal 2007 28(22):2720-2725; doi:10.1093/eurheartj/ehm425
Randomized trial of rapamycin- and paclitaxel-eluting stents with identical biodegradable polymeric coating and design
Deutsches Herzzentrum and 1. Medizinische Klinik, Klinikum rechts der Isar, University of Technology, Lazarettstr. 36, 80636 Munich, Germany
Received 9 February 2007; revised 23 August 2007; accepted 30 August 2007; online publish-ahead-of-print 7 October 2007.
* Corresponding author. Tel: +49 89 1218 1514; fax: +49 89 1218 4013. E-mail address: rwessely{at}web.de
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Abstract |
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Aims: This prospective, randomized study sought to directly compare the performance of paclitaxel and rapamycin on an otherwise identical, polymer-coated drug-eluting stent (DES) platform.
Methods and results: Stents with identical design and biodegradable polymeric coating that elute either rapamycin or paclitaxel over a 2 months time period were utilized. In this pilot trial that included 91 patients, both stent platforms proved safe with no case of death, Q-wave myocardial infarction or stent thrombosis within a 9 months follow-up period. Late-lumen loss was markedly greater in the paclitaxel-eluting stent group compared with the rapamycin-eluting stent group (0.96 ± 0.75 vs. 0.33 ± 0.46 mm, P < 0.0001). Likewise, the rate of angiographic restenosis was higher in the paclitaxel-eluting stent group compared with the rapamycin-eluting stent group [39.0 vs. 12.2%; relative risk (RR) 3.20 (95% confidence interval, 1.29–7.92), P = 0.005]. Concomitantly, the need for target lesion revascularization was higher in the paclitaxel-eluting stent group compared with the rapamycin-eluting stent group [26.7 vs. 8.7%; RR 3.07 (1.07–8.80), P = 0.02].
Conclusion: The results of this clinical trial that is the first to directly compare the performance of paclitaxel and rapamycin on a DES platform otherwise identical in design and polymeric coating imply that rapamycin is more effective for the prevention of coronary restenosis on a DES platform with mid-term drug release and less dependent on release kinetics than paclitaxel. Thus, to ensure efficacy, drug release from a paclitaxel-coating stent platform must be prolonged and well controlled to achieve results that are comparable with the FDA-approved paclitaxel-eluting stent platform.
Key Words: Drug-eluting stents • Rapamycin • Sirolimus • Paclitaxel • Restenosis • Coronary artery disease
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Introduction |
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For decades, restenosis was considered the major problem of interventional cardiology. The introduction of drug-eluting stents (DESs) has greatly alleviated this problem. The majority of stents utilized in current clinical practice is polymer-based and elute either rapamycin (sirolimus) or paclitaxel. Both compounds have profound antiproliferative properties and interfere negatively with cell cycle progression: rapamycin imposes early cell cycle inhibition in G1. Paclitaxel, however, mainly abrogates cycle progression in the mitosis (M) phase.1
Differences in the performance of stent platforms that elute one of these compounds may be explained by differences in stent design, polymeric coating, and drug, including release kinetics. Since current DES platforms are diverse with respect to these parameters, no final conclusion can be drawn which of these parameters plays a pivotal role for differences that can be observed with different DESs. To partly overcome this obstacle, we examined stents identical in design and polymeric coating that elute either paclitaxel or rapamycin in a randomized clinical trial. Thus, possible differences in the clinical performance of these particular stents that are however distinct from commercially available, FDA-approved DESs, can be exclusively attributed to the drug compound and, importantly, its release kinetics.
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Study population
Patients eligible for this study were at least 18 years old and admitted with stable or unstable angina pectoris or a positive stress test and were undergoing coronary stenting for de novo lesions in a native coronary vessel. Patients with ST-elevation myocardial infarction within 48 h before admission, lesions involving the left main coronary artery, and patients with contraindications or allergies against aspirin, thienopyridines, heparin, rapamycin, paclitaxel, or stainless steel were excluded from the study. The study protocol was approved by the institutional Ethics Committee. The study was carried out in the Deutsches Herzzentrum, Munich, Germany. All patients that were included in the trial gave written, informed consent for participation in this study.
Stent platforms
The backbone stent for the DESs used in this study was the ArthosInert stent that has been previously evaluated as a bare-metal stent in humans.2 This stent was coated with either rapamycin or paclitaxel, respectively, including an identical biodegradable polymeric coating for both stents and was provided by AMG (Raesfeld-Erle, Germany). The polymer consists of a biodegradable, linear polyester with defined polylactid content and is typically degraded within 2 months after stent placement. Preceding animal studies provided by AMG revealed safety of both coated stent platforms. In brief, five pigs each were evaluated for both the rapamycin-coated as well as the paclitaxel-coated stent platform. Compared with their bare-metal counterparts, there was neither a difference in stent patency nor stent thrombosis. However, diameter stenosis was reduced from 44.7 ± 27.3% in non-coated ArthosInert stents to 25.2 ± 4.7% paclitaxel-coated ArthosInert stents and 27.3 ± 6.7%, respectively, in rapamycin-coated ArthosInert stents (n = 5 each) 30 days after stent placement. No statistically significant difference could be detected for stent endothelialization as assessed by light microscopy in this model. Available stent diameters included 2.25, 2.5 and 3.0 mm, available stent lengths ranged from 8–18 mm. Subsequently, these stents are referred to as either rapamycin-eluting or paclitaxel-eluting stents. Paclitaxel and rapamycin concentrations on the stent platform were 0.25 and 2.0 µg/mm2, respectively. Thus, the total amount of drug that is released from a stent platform over time is similar to the FDA-approved paclitaxel-eluting Taxus (Boston Scientific, Boston, MA) and the sirolimus-eluting Cypher stent (Cordis, Miami, FL), respectively. The Taxus stent platform is loaded with 1 µg/mm2 paclitaxel. However, only 10–30% are released into the vascular wall over time. The Cypher stent is loaded with 1.4 µg/mm2 rapamycin with the majority of drug release within the first 30 days. For determination of pharmacological release kinetics, paclitaxel or rapamycin-coated stents with biodegradable polymer (n = 3 for each DES group) were deployed ex vivo and submersed in 2 mL PBS (phosphate buffered saline) at 37°C. Samples harvested at distinct time points were subjected to UV spectrophotometry-based analysis by means of an MC1 UV–Vis-spectrophotometer (Safas, Monaco). Release kinetics are shown in Figure 1, illustrating a continuous drug release for up to approximately 3 months for both DES platforms with most of the drug liberated within the first 2 months.
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Study protocol
At least 2 h before PCI, patients received a loading dose with 600 mg clopidogrel, followed by 75 mg twice a day until discharge and continued clopidogrel administration of 75 mg once a day for at least 6 months. In this open-label study, randomization was performed with sealed, non-transparent envelopes containing a computer-generated random sequence. Patients were randomly assigned to receive either the rapamycin-eluting or the paclitaxel-eluting stent with identical biodegradable polymeric coating and design. Stenting of multiple lesions and the use of more than one stent per lesion were only allowed under the condition that the same randomly assigned stent had to be implanted in all lesions.
Data acquisition and management
Quantitative angiography was carried out at the Quantitative Angiographic Core (QCA) laboratory (Deutsches Herzzentrum, Munich, Germany) by specialized staff unaware of study arm assignment. QCA was carried out off-line and performed by an automatic edge-detection system (QCA-CMS V6.0, Medis Medical Imaging Systems, Nuenen, The Netherlands). Lesion complexity was analysed according to the modified AHA/ACC grading classification.3 The contrast-filled, non-tapered tip of the guiding catheter was used for calibration. Quantitative analysis was carried out within the stented area (in-stent analysis) as well as within the stent area including both 5 mm margins at the proximal and distal edges of the stent (in-segment analysis). The same projections were used at all times. The reference diameter was determined by QCA software-based extrapolation. Angiographic parameters measured included minimal lumen diameter, reference diameter of the vessel, percent diameter stenosis (difference between the reference diameter and minimal luminal diameter divided by the reference diameter and multiplied by 100), and late lumen loss (difference between minimal luminal diameter at the end of the procedure and minimal luminal diameter at follow-up).
Endpoints of the study
All patients were asked to return for follow-up angiography 6–8 months after stent placement or earlier, if anginal symptoms had developed. The primary endpoint of the study was in-stent late lumen loss at angiographic follow-up. Secondary endpoints included angiographic restenosis (diameter stenosis of at least 50% based on in-segment analysis) at follow-up angiography as well as the need for target lesion revascularization (TLR) due to restenosis in the presence of clinical ischaemic symptoms or a positive stress test. The incidence of all-cause death, angiographically proven stent thrombosis and myocardial infarction were also determined within the 9 months follow-up period.
Statistical methods
No sample size assumptions have been made for this pilot trial. The analyses were performed on a per patient basis; in patients with interventions in multiple lesions, only the first lesion for which randomization was done was included in the analysis. Continuous data are expressed as mean±SD. Discrete variable are expressed as counts (percentages). Differences in continuous variables were checked for statistical significance by t-test. Differences in discrete variables were checked for statistical significance by 
2 test or Fisher's exact test (if expected cell size was less than 5). P-values of less than 0.05 were considered significant.
General considerations
Study design, data analysis, and interpretation were performed exclusively within the Deutsches Herzzentrum, Munich and were, thus, completely industry-independent. Funding was equally industry-independent and provided, in part, by the Bavarian Research Foundation.
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Baseline characteristics and procedural results
A total of 91 patients were included into the study; 45 patients were assigned to paclitaxel-eluting stents, 46 patients to rapamycin-eluting stents (Figure 2). Baseline clinical and angiographic characteristics were evenly distributed among the study groups (Tables 1 and 2) with a high rate of complex lesions (B2/C) in both groups; approximately one-third of the patients had diabetes. Procedural characteristics are shown in Table 3. No significant differences were detected between the two study groups.
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During the 9 months study follow-up, which was available for all study patients, no patient died and there were no cases of stent thrombosis. One patient in the rapamycin-eluting group suffered a non-Q-wave myocardial infarction within 30 days after stent placement (P = 0.99 compared with the paclitaxel-eluting group).
Restenosis
Angiographic follow-up was available in 90.1% of study patients. Only four patients in the paclitaxel-eluting stent group and five patients in the rapamycin-eluting stent group did not consent to undergo follow-up angiography (Figure 2). However, clinical follow-up was available in all these patients and was uneventful. The primary endpoint of the study was in-stent late lumen loss at follow-up angiography. Figure 3 depicts the cumulative distribution curves for late lumen loss for the two stents. The quantitative angiographic results are comprehensively displayed in Table 4. As shown in this table, in-stent late lumen loss was considerably greater in the paclitaxel-eluting stent group compared with the rapamycin-eluting stent group (0.96 ± 0.75 vs. 0.33 ± 0.46 mm, P < 0.001). Thus, late lumen loss in the rapamycin-eluting stent group was approximately one-third in comparison to the paclitaxel-eluting stent group. Other quantitative parameters of angiographic restenosis were also in favour of the rapamycin-eluting stent (Table 4). Consequently, as shown in Figure 4, the rate of angiographic restenosis was higher in the paclitaxel-eluting stent group compared with rapamycin-eluting stent group [39.0 vs. 12.2%; relative risk (RR) 3.20 (95% confidence interval, 1.29–7.92), P = 0.005]. This did translate into a significantly higher rate of TLR in the paclitaxel-eluting stent group compared with rapamycin-eluting stent group [26.7 vs. 8.7%; RR 3.07 (1.07–8.80), P = 0.02].
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Discussion |
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Several components of a DES platform impact on outcome: the compound and its release kinetics, the polymer and the backbone stent. In addition to the observed differences in clinical trials, there is evidence that the pleiotropic anti-restenotic cellular and molecular properties differ significantly between paclitaxel and rapamycin.1 The precise clinical significance of rapamycin and paclitaxel and their release kinetics for the angiographic and clinical outcome is not yet defined. To directly compare the performance of local stent-based delivery of these particular drugs in a randomized clinical trial, we utilized specially designated stents identical in design and polymeric coating that elute either paclitaxel or rapamycin and are not commercially available.
Both DESs investigated in this study proved safe with no event of stent thrombosis or death within the 9 months clinical follow-up period. Whether the erodable polymeric coating will be more beneficial for vascular healing and re-endothelialization processes than non-erodable polymers remains to be determined in future studies.
The primary endpoint of the study, in-stent late lumen loss, was markedly lower in the group that received rapamycin-eluting stents compared with paclitaxel-eluting stents. Concomitantly, the observed rate secondary endpoints of this trial, angiographic and clinical restenosis (TLR), was significantly lower for rapamycin-eluting stents.
Consequently, the results of this trial suggest that the elution of rapamycin from a stent platform identical in design and biodegradable polymeric coating as it was utilized in our study is associated with a more favourable outcome than release of paclitaxel. There is no simple explanation to elucidate what accounts for the observed remarkable difference. There is unambiguous evidence that rapamycin and paclitaxel are different in their pleiotropic anti-restenotic effects and may impact on vascular healing processes in a different way.1,4 The late lumen loss observed with the paclitaxel-eluting stent is comparable with what was found in other trials that utilized a paclitaxel-eluting stent platform with short- or midterm drug release, compared with the FDA-approved polymer-based paclitaxel eluting Taxus stent. The DELIVER trial that reported a late lumen loss of 0.81 mm for non-polymeric stents loaded with 3.0 µg/mm2 paclitaxel that were implanted in patients with predominantly complex lesions, similar to our study.5 It is also comparable with the findings recently reported from the ASPECT trial, in which low dose (1.28 µg/mm2) and high dose (3.1 µg/mm2) non-polymeric paclitaxel-eluting stents were implanted. This study demonstrated a late ‘catch-up’ phenomenon with a late lumen loss 24 months after stent placement that was reported to range between 0.8 and 0.9 mm.6 Recently, the 9 months outcome of the COSTAR II study has been presented.7 In this trial, a total dosage of 10 µg paclitaxel per 17 mm stent length was delivered on the Conor stent platform by means of a bio-erodable polymer. The late lumen loss for this particular stent platform in this trial that comprised 1700 patients was 0.62 mm, significantly more compared with 0.24 mm for the paclitaxel-eluting, biostable polymer-based Taxus stent. In this trial, Taxus stents were associated with a more favourable MACE rate (comprising death, MI, and clinically driven TLR) of 6.9% compared with 11.0% for the Conor stent. Consequently, this questions, in conjunction with the findings of the our study, the widely held belief that a biodegradable polymer might be generally more beneficial than a biostable polymer.8 Conversely, in-stent and in-segment late lumen loss observed for the rapamycin-eluting stent in our study were higher but still within the range that is recognized for the FDA approved, non-erodable polymer-coated, rapamycin-eluting Cypher stent.9
The outcome of this randomized trial has several important implications. Besides the difference observed in angiographic and clinical results, the findings of this study implicate that kinetics of drug release from a paclitaxel coated DES platform is more crucial for the final outcome than it is for a rapamycin-eluting DES platform. This was also evident in the PISCES trial where stents that eluted identical dosages of paclitaxel but during different time periods achieved diverse outcomes.10 These data taken together with the findings of other clinical studies that investigated stents with short- to mid-term paclitaxel release5,6,11 implicate that accelerated paclitaxel release achieves a less beneficial outcome for the prevention of restenosis than prolonged drug elution on the slow-release, polymer-based Taxus stent platform.12 This device is currently the only paclitaxel-eluting stent platform that achieves reproducible clinical results in the range of the rapamycin-eluting Cypher stent. The results of this study strongly suggest that thorough evaluation of clinical efficacy and safety is needed, in particular, for novel paclitaxel-eluting stent platforms before their application outside clinical studies can be advised. This is of particular relevance since numerous paclitaxel-eluting stents with short- and mid-term drug release are currently entering the market outside the United States.
Limitations of the study
This pilot study was conducted to compare the performance of paclitaxel or rapamycin, respectively, on an otherwise identical stent platform with bio-erodable polymeric coating that is distinct from the FDA-approved DESs that elute the same compounds but on a different carrier stent and with distinct non-erodable polymeric coating. Therefore, the results of this study cannot be readily transferred to these existing stent platforms. Another limitation to be acknowledged is the open-label nature of the study. However, the assessment of the study endpoints was performed by individuals unaware of the treatment group assigned to the patients.
Conclusions
The results of this clinical trial that is the first to directly compare the performance of paclitaxel and rapamycin on a DES platform otherwise identical in polymeric coating and design imply that rapamycin is more efficient for the prevention of coronary restenosis on a stent platform with mid-term drug release. In addition, rapamycin efficacy appears to be less dependent on drug-adjusted release kinetics compared with paclitaxel. Therefore, paclitaxel release needs to be well controlled and demands sophisticated engineering capabilities in order to create a safe and effective stent platform. Thus, novel paclitaxel-eluting stents that are becoming increasingly available for clinical use may not necessarily reach the same level of efficacy and safety as the polymer-based Taxus stent.
Conflict of interest: none declared.
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Bayerische Forschungsstiftung (to R.W., A.K., and A.S.).
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