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European Heart Journal Advance Access published online on June 11, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn253
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Randomized trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis

Julinda Mehilli, Robert A. Byrne, Anna Wieczorek, Raisuke Iijima, Stefanie Schulz, Olga Bruskina, Jürgen Pache, Rainer Wessely, Albert Schömig, Adnan Kastrati for the Intracoronary Stenting and Angiographic Restenosis Investigators – Test Efficacy of Rapamycin-eluting Stents with Different Polymer Coating Strategies (ISAR-TEST-3)*

Deutsches Herzzentrum and 1. Medizinische Klinik rechts der Isar, Technische Universität, Lazarettstrasse 36, 80636 Munich, Germany

Received 13 December 2007; revised 15 May 2008; accepted 23 May 2008.

* Corresponding author. Tel: +49 89 1218 4577, Fax: +49 89 1218 4053, Email: kastrati{at}dhm.mhn.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Aims: The objective of this study was to assess the non-inferiority, in terms of anti-restenotic efficacy, of both biodegradable-polymer (BP) and polymer-free (PF) stents compared with permanent-polymer rapamycin-eluting (PP; Cypher) stent.

Methods and results: Patients with de novo coronary lesions in native vessels were randomly assigned to receive a BP stent, a PF stent or a PP stent. The primary endpoint was in-stent late lumen loss at follow-up angiogram.

A total of 605 patients were enrolled: 202 patients received BP stents, 202 were treated with PP stents, and 201 received PF stents. Repeat angiography was available for 492 patients (81.3%). Mean late lumen loss at 6–8-month angiographic follow-up was 0.17 ± 0.45 mm in the BP stent group, 0.23 ± 0.46 mm in the PP cohort, and 0.47 ± 0.56 mm in the PF stent group. The BP stent met pre-specified criteria for non-inferiority (P < 0.001), whereas the PF stent did not (P = 0.94). There were no differences in safety outcomes.

Conclusion: Both BP and PF stents have a 1-year safety profile similar to that of the PP stent. Whereas the PF stent provided an inferior efficacy, the BP stent is at least as effective as the PP stent in terms of anti-restenotic efficacy.

Key Words: Biodegradable • Coronary restenosis • Drug-eluting stents • Polymer • Rapamycin


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Drug-eluting stents (DES) represent a breakthrough technology that has profoundly impacted the treatment of coronary artery disease.1,2 Their working principle consists of the local delivery of pharmacological agents with cytostatic or anti-mitotic properties at the implantation site, which leads to the suppression of neointimal proliferation, the main cause of lumen re-narrowing after stent implantation. Most DES are composed of the stent platform, anti-restenotic agent, and its carrier vehicle, most frequently a polymer, which serves for drug-loading and modification of release kinetics. Several pharmacological agents and different types of polymers, either durable or resorbable, have been employed. A large number of studies including patients with various clinical and angiographic characteristics have shown that DES markedly reduce restenosis risk, which has constituted the major limitation of long-term success of bare metal stents.3–9 The most studied DES are the rapamycin-eluting stent – Cypher - and the paclitaxel-eluting stent – Taxus - both of which use durable polymers. Although their mid-term efficacy has been well-established, there is an ongoing debate on the potential for an increased incidence of late-stent thrombosis,10–13 particularly after discontinuation of thienopyridine therapy, as well as on delayed onset of restenosis or DES "catch-up" phenomenon.14 Based on animal and human pathological data, investigators have linked the above-mentioned concerns to the presence of polymers in DES, which have proinflammatory and thrombogenic potential, and sometimes may induce a hypersensitivity reaction.15–21

Two strategies have been proposed and evaluated to avoid the potential negative influence of durable polymers in DES. One of these consists of the utilization of biodegradable-polymers (BPs) as a means for storage and controlled release of incorporated drugs. Although early work suggested little difference between non-BP and BP in terms of the inflammation response in the acute phase,15 their absorption after the completion of the elution process (typically 6–9 weeks), removes the potential nidus for inflammation and thrombogenicity over the medium to long-term. The first reports have shown promising results with DES using BPs in terms of their anti-restenotic efficacy.22,23 The second strategy consists of the utilization of polymer-free (PF) DES platforms. In this regard, it was recently shown that PF stents eluting rapamycin were effective in reducing neointimal hyperplasia and angiographic restenosis.24–26 At present, there are no data on the relative efficacy of DES which use the same pharmacological agent but differ with respect to the presence or type of polymers used.

We hypothesized that in patients treated with coronary stenting for de novo lesions located in native coronary vessels, rapamycin-eluting stent platforms—both PF and using BP—would have an equivalent effectiveness to the commercially available permanent-polymer (PP) rapamycin-eluting Cypher stent which is the current gold standard for the prevention of restenosis.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 References
 
Study population and protocol
Patients older than age 18 with ischaemic symptoms or evidence of myocardial ischaemia in the presence of ≥50% de novo stenosis located in native coronary vessels were considered eligible, provided that written, informed consent by the patient or her/his legally authorized representative for participation in the study was obtained. Patients with a target lesion located in the left main stem or in a bypass graft, in-stent restenosis, acute myocardial infarction (MI), cardiogenic shock, malignancies or other co-morbid conditions (e.g. severe liver, renal, and pancreatic disease) with life expectancy <12 months or that may result in protocol non-compliance, known allergy to the study medications (aspirin, clopidogrel, rapamycin, stainless steel), pregnancy (present, suspected or planned), or positive pregnancy test were considered ineligible for the study. The study protocol was approved by the institutional ethics committee responsible for both participating centres, the Deutsches Herzzentrum and the Medizinische Klinik I, Klinikum rechts der Isar, Munich, Germany. All patients gave their written, informed consent for participation in the study.

In each participating centre, allocation to treatment was made by means of sealed, opaque envelopes containing a computer-generated sequence; randomization was performed immediately after decision to proceed with percutaneous coronary intervention (PCI). Patients who met all of the inclusion criteria and none of the exclusion criteria were randomized in the order that they qualified. Patient allocation to each of the three treatment groups was in equal proportions. The three treatment groups were studied concurrently. Time zero was defined as the time of randomization. Patients were considered enrolled in the study at the time of randomization. The same randomly assigned stent had to be implanted in all lesions in those patients who required stenting in multiple lesions and the use of more than one stent per lesion was also allowed. Patients were assigned to receive the BP 0.4% rapamycin stent (180 µg rapamycin/cm2), the PF 2% rapamycin (479 µg rapamycin/cm2) stent, or the PP rapamycin-eluting stent (Cypher stent, Cordis; 140 µg rapamycin/cm2). The stent platform used for the BP and PF arms consists of a premounted, sand-blasted, 316L stainless steel microporous stent and the coating device. A detailed description for creating the micropores and its rationale, as well as the specifics of the coating process involved, have been reported previously.24,27 The BP matrix used in the BP stent arm is completely resorbed within ~6–9 weeks. The PF stent is coated with rapamycin without employing synthetic polymers. The rapamycin release profile of both the BP and PF stent platforms are shown in Figure 1. The elution characteristics of the PP stent are reported elsewhere.3,16


Figure 1
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  		Figure 1 Rapamycin-elution characteristics of BP RES (biodegradable-polymer rapamycin-eluting stent) and PF RES (polymer-free rapamycin-eluting stent).

 
An oral loading dose of 600 mg clopidogrel was administered to all patients at least 2 h prior to the intervention, regardless of whether the patient was taking clopidogrel prior to admission. During the procedure, patients were given intravenous aspirin, heparin or bivalirudin; glycoprotein IIb/IIIa inhibitor usage was at the discretion of the operators. After the intervention, all patients received 200 mg/day aspirin indefinitely, clopidogrel 150 mg for the first 3 days (or until discharge) followed by 75 mg/day for at least 6 months and other cardiac medications according to the judgment of patient’s physician [e.g. ß-blockers, ACE (angiotensin-converting enzyme)-inhibitors, statins, etc.]. After enrolment patients remained in hospital for at least 48 h. Blood samples were drawn every 8 h for the first 24 h after randomization and daily afterwards for the determination of cardiac markers (CK, CK-MB, Troponin T or I) and blood cell counts (haemoglobin, haematocrit, platelet count, white blood cell count). Daily recording of ECG was also performed until discharge. The occurrence of in-hospital bleeding or need for blood product transfusion was also monitored. All patients were evaluated at 1, 9, and 12 months by phone or office visit. Re-hospitalization for repeat coronary angiography was scheduled for 6–8 months.

Data management, endpoints, and definitions
Relevant data were collected and entered into a computer database by specialized personnel of the Clinical Data Management Centre. Clinical events were adjudicated upon by the Clinical Event Adjudication Committee. Patients were blinded to treatment allocation. The interventionalist performing the procedure was blinded to treatment allocation arm if the patient received a BP or PF stent, though not if a PP (Cypher) stent was implanted (due to distinctive packaging of this commercially available stent). Endpoint adjudication and quantitative coronary angiography analysis was fully blinded to randomly assigned stent type.

In the case of patients requiring multiple lesion intervention, the same assigned stent had to be implanted at each site. Baseline, post-procedural, and follow-up coronary angiograms were digitally recorded and assessed off-line in the quantitative angiographic core laboratory (Deutsches Herzzentrum ISAR Centre) with an automated edge-detection system (CMS version 7.1, Medis Medical Imaging Systems) by two independent experienced operators unaware of the treatment allocation. All measurements were performed on cineangiograms recorded after the intracoronary administration of nitroglycerin using the same single worst-view projection at all times. The contrast-filled non-tapered catheter tip was used for calibration. Quantitative analysis was performed on both the ‘in-stent’ and ‘in-segment’ area (including the stented segment, as well as both 5-mm margins proximal and distal to the stent). Qualitative morphological lesion characteristics were characterized by standard criteria.28

The primary endpoint of the study was in-stent late luminal loss, defined as the difference between the minimal luminal diameter at the end of the procedure and the minimal luminal diameter at follow-up angiography. Secondary endpoints were: in-segment binary angiographic restenosis (defined as diameter stenosis ≥50% in the in-segment area) at follow-up angiography; need for target lesion revascularization (TLR), defined as any revascularization procedure involving the target lesion due to luminal re-narrowing in the presence of symptoms or objective signs of ischaemia; the combined incidence of death or MI; incidence of stent thrombosis. The diagnosis of MI required the presence of new Q-waves on the ECG and/or elevation of creatinine kinase or its MB isoform to at least three times the upper limit of normal in no fewer than two blood samples. Restenosis morphology is categorized as described by Mehran et al.29 Stent thrombosis was classified according to recently agreed Academic Research Consortium criteria.30

Statistical analysis
The objective of the study was to assess the non-inferiority of both BP and PF stents to PP stents. Sample size calculation was based on a margin of non-inferiority for in-stent late luminal loss set at 0.16 mm for both comparisons.31 The assumed common standard deviation (SD) was 0.5 mm. This threshold allowed for the preservation of 80% of reduction in late lumen loss observed previously with rapamycin-eluting stent compared with bare-metal stent.6 With a power of 80% and a one-sided {alpha}-level of 0.025 due to two pre-specified comparisons, we estimated that 155 patients in each of the three groups were needed to show the non-inferiority of BP and PF stents. Expecting that up to 20% of patients would not return for follow-up angiography, we aimed to enrol a total of 600 patients (200 in each treatment arm). Sample size calculation was performed with nQuery Advisor (Statistical Solutions, Cork, Ireland) according to the method described by O'Brien and Muller.32 The analysis of primary and secondary endpoints was planned to be performed on an intention-to-treat basis. Although in a non-inferiority design, a per protocol analysis may be considered of equal importance, this issue is not of relevance where cross-over does not occur. The data are presented as means ± SD, or counts or percentages. The non-inferiority hypothesis was tested with EquivTest (Statistical Solutions, Cork, Ireland) according to the methods described by Chow and Liu.33


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
Baseline characteristics and procedural results
A total of 605 patients were enrolled in this study: 202 patients received the rapamycin stent with BP, 202 were treated with a PP rapamycin stent, and 201 received a PF rapamycin stent. Baseline clinical characteristics are shown in Table 1. Overall 27.4% of patients had diabetes mellitus. In all 712, lesions were treated. Lesion characteristics are shown in Table 2 and are notable for a high proportion of lesions with complex morphology, overall 74.1%. The treatment groups were well matched in terms of lesion and procedural characteristics (Table 3). Implantation of the assigned stent was successful in all patients. Study patient flow chart is shown in Figure 2.


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  		Table 1 Baseline patient characteristics

 

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  		Table 2 Angiographic characteristics

 

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  		Table 3 Lesion and procedural characteristics

 

Figure 2
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  		Figure 2 Patient study flow chart. BP RES, biodegradable-polymer rapamycin-eluting stent; FU, follow-up; PF RES, polymer-free rapamycin-eluting stent; PP RES, permanent-polymer rapamycin-eluting stent; uTLR, urgent target lesion revascularization.

 
Angiographic outcomes
Of 605 patients, 492 re-attended (81.3%) for follow-up angiography. There were no significant differences in follow-up rates between the treatment groups. With respect to the primary endpoint, mean late lumen loss at 6–8-month angiographic follow-up was 0.17 ± 0.45 mm in the cohort who received a BP stent, 0.23 ± 0.46 mm in those receiving a PP stent, and 0.47 ± 0.56 mm in patients treated using a PF stent (Figures 3 and 4). As a consequence, the BP stent met criteria for non-inferiority (P < 0.001), whereas the PF stent did not (P = 0.94) (Figure 5). As we adjusted our significance level for multiple comparisons, a one-sided {alpha}-level of 0.0125 may have been more appropriate for this non-inferiority analysis. We did perform a separate analysis of the data using such intervals and found no impact on the overall results (the upper one-sided 98.75% confidence interval for the difference was 0.03 mm for the BP stent and 0.37 mm for the PF stent).


Figure 3
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  		Figure 3 Primary endpoint. Late lumen loss at 6-month angiographic follow-up. BP RES, biodegradable-polymer rapamycin- eluting stent; PF RES, polymer-free rapamycin-eluting stent; PP RES, permanent-polymer rapamycin-eluting stent.

 

Figure 4
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  		Figure 4 Primary endpoint: Late lumen loss at follow-up angiography (mean ± SD). BP RES, biodegradable-polymer rapamycin- eluting stent; PF RES, polymer-free rapamycin-eluting stent; PP RES, permanent-polymer rapamycin-eluting stent.

 

Figure 5
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  		Figure 5 Differences in late lumen loss at 1 year. BP RES, biodegradable-polymer rapamycin-eluting stent; PF RES, polymer-free rapamycin-eluting stent; PP RES, permanent-polymer rapamycin-eluting stent.

 
In terms of secondary endpoints, there was a trend towards inferiority in terms of binary angiographic restenosis in-segment with the PF stent compared with the PP stent (Figure 6). This trend was not seen between the BP and PP stents. The distribution of patterns of restenosis observed across treatment arms is included in Table 4.


Figure 6
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  		Figure 6 Secondary endpoints. Binary angiographic restenosis at 6-month angiographic follow-up and target lesion revascularization (TLR) at 1 year. BP RES, biodegradable-polymer rapamycin-eluting stent; PF RES, polymer-free rapamycin-eluting stent; PP RES, permanent-polymer rapamycin-eluting stent.

 

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  		Table 4 Follow-up angiographic data (6–8 months)

 
Clinical outcomes
There were no significant differences in terms of early safety outcomes. Two patients treated with a PF stent suffered early complications. One patient required repeat PCI and another required surgical revascularization. At 30 days the combined endpoint of death or MI had occurred in three (1.5%), two (1.0%), and four (2.0%) of the patients treated with BP, PP, and PF, respectively.

One-year follow-up was complete for the study cohort (Table 5). There was a clear trend towards an excess of TLR procedures in the PF stent group with 26 cases as opposed to 16 in the PP group and 12 in the BP group. The incidence of death, non-fatal MI, and stent thrombosis was similar across all the three treatment arms (Tables 5 and 6).


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  		Table 5 One-year clinical events

 

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  		Table 6 Stent thrombosis at 1 year

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
In this prospective, randomized trial, we assessed the relative efficacy of PF and BP rapamycin-eluting microporous stents, with standard commercially available PP-based rapamycin stents (Cypher). The study population comprised a cohort of patients with complex coronary lesions (74.1% AHA/ACC type B2/C) and a high prevalence of diabetes mellitus (27.4%). The salient outcomes of our study are that (i) the treatment of complex de novo coronary lesions in native vessels with both BP and PF rapamycin stents is feasible and safe; (ii) in comparison with the PP rapamycin-eluting stent, a BP rapamycin-eluting stent shows equivalent anti-restenotic efficacy in terms of the primary endpoint of in-stent late luminal loss, whereas a PF rapamycin stent is associated with significantly higher luminal loss at follow-up angiography; and (iii) in terms of clinical outcomes, there was a trend towards an excess of TLR procedures at 12 months with the PF platform as compared with the PP platform. This parallels the differences seen in late luminal loss.

Several components of a DES platform contribute to its clinical efficacy, most notably stent design, active drug and the presence and type of polymer. We have previously shown that employing a rapamycin coating on a microporous PF stent platform results in superior clinical and angiographic outcomes than bare metal stent implantation and that a dose response exists up to 2% rapamycin.24,25 Furthermore, when this model was compared against a commercially available paclitaxel-eluting PP stent (Taxus) in a group of patients with similarly complex disease to this current cohort, outcomes were equivalent.26 In this current study, however, this platform proved inferior in terms of anti-restenotic efficacy, when compared with the PP stent. It seems clear that this significant inferiority is due to the use of a superior comparator (PP rapamycin stent) as the late luminal loss in the PF group was almost identical to that observed previously with this stent.26

In terms of choice of active drug for an optimal DES platform there is an accumulating literature suggesting a drug-specific effect in favour of rapamycin. There is well-documented evidence that rapamycin and paclitaxel differ significantly in terms of their anti-restenotic efficacy and cellular and molecular properties.34–37 In addition, a number of meta-analyses have confirmed that a potential safety and efficacy differential may exist in favour of sirolimus-eluting stents when compared with paclitaxel-eluting stents.5,38,39

The significant improvement in anti-restenotic efficacy derived from the delay in rapamycin release associated with the addition of a novel BP is noteworthy. An optimal release kinetic for any anti-restenotic compound used on a DES platform has thus far not been defined. This study is the first to make use of a novel stent coating comprised of a BP combined with a natural resin. Our previous experience with the PF rapamycin stent has shown that two-thirds of the rapamycin is released in the first week after implantation with the remainder eluting over the next 2 weeks. The BP used in this study typically remains in situ for ~6–9 weeks thereby delaying rapamycin release and enhancing primary stent efficacy. On the other hand, its absence from the vessel wall after this period removes a putative nidus for persistent inflammation and thrombosis. The potential safety implications both in terms of a reduced incidence of late acute stent thrombosis and an obviation of the need for prolonged thienopyridine therapy (and its attendant bleeding risks) are obvious and the concept inherently attractive.40 Previous preliminary experience using a BP on an everolimus-eluting stent was positive.22 Our trial, however, is the first to study a novel BP on this current DES platform and indeed the first to assess efficacy of such a model in a cohort of patients with complex coronary lesions. In this regard, the results were certainly encouraging. The 1-year safety profile, like that of the PF platform, is equivalent to that of the PP stent. Acute luminal gain at the time of index procedure was very well maintained at angiographic follow-up with a late luminal loss of 0.17 ± 0.45 mm comparing very favourably with that of 0.23 ± 0.46 mm seen with the PP. There were no differences in the observed rates of stent thrombosis between the three groups at 1-year follow-up. Whether the absence of PP from the coronary milieu over the mid- to long-term translates into significant differences in clinical outcomes remains to be seen.

Limitations of the study
This trial was not powered to detect differences in delayed clinical outcomes and clinical outcome data must be interpreted with this in mind. At this current time point, follow-up is only available for 1 year. Definitive assessment of the long-term performance of these novel platforms, and indeed of the accruement of potential clinical advantage in terms of a reduction in late thrombotic events, should be the objective of future studies. We should acknowledge the limitation that as we adjusted our significance level for multiple comparisons, a one-sided {alpha} of 0.0125 may have been more appropriate for this non-inferiority analysis. We did perform a separate analysis of the data using such significance levels (which we have reported in the results section) and found no impact on the overall results. The analysis of primary and secondary endpoints was planned to be performed on an intention-to-treat basis. We recognize the limitation of absence of angiographic follow-up in 18.3% of patients. Such a limitation is a feature of studies utilizing a primary angiographic endpoint. This is at least in part extenuated by the compatibility of findings from our secondary endpoint analysis, including TLR—an index of clinical restenosis—for which data were available on all patients.

In conclusion, we have demonstrated that in a cohort of patients with complex coronary lesion morphology, the implantation of both novel PF and BP DES platforms is feasible and that the 1-year safety data are similar to that of the Cypher stent. Whereas the PF rapamycin-eluting stent provided an inferior efficacy in terms of the primary endpoint of late luminal loss, the BP-based rapamycin-eluting stent is at least as effective as the Cypher stent. Definitive assessment of performance durability and the accruement of potential clinical advantage associated with the removal of PP from the coronary vessel wall will require further investigation.

Conflict of interest: R.A.B. was supported by a grant from the Irish Board for Training in Cardiovascular Medicine which was sponsored by A. Menarini Pharmaceuticals (Ireland). A.K. reports having received lecture fees from Bristol-Myers, Cordis, Lilly and Sanofi-Aventis. No other conflicts of interest declared.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
Study design and analysis were performed by Deutsches Herzzentrum, Munich, and funding was completely industry independent, provided in part by the Bavarian Research Foundation (BFS-ISAR Aktenzeichen AZ: 504/02 and BFS-DES Aktenzeichen AZ: 668/05).


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

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