Randomized, Double-Blind, Multicenter Study of the Endeavor Zotarolimus-Eluting Phosphorylcholine-Encapsulated Stent for Treatment of Native Coronary Artery Lesions
Clinical and Angiographic Results of the ENDEAVOR II Trial
Background— The use of the Endeavor stent might reduce restenosis and stent thrombosis at 9 months.
Methods and Results— Patients (n=1197) treated for single coronary artery stenosis were enrolled in a prospective, randomized, double-blind study and randomly assigned to receive the Endeavor zotarolimus-eluting phosphorylcholine polymer–coated stent (n=598) or the same bare metal stent but without the drug or the polymer coating (n=599). The 2 groups were well matched in baseline characteristics. Diabetes was present in 20.1% of patients; the mean reference vessel diameter was 2.75 mm; and the mean lesion length was 14.2 mm. The primary end point of target vessel failure at 9 months was reduced from 15.1% with the bare metal stent to 7.9% with the Endeavor (P=0.0001), and the rate of major adverse cardiac events was reduced from 14.4% with the bare metal stent to 7.3% with the Endeavor (P=0.0001). Target lesion revascularization was 4.6% with Endeavor compared with 11.8% with the bare metal stent (P=0.0001). The rate of stent thrombosis was 0.5% with the Endeavor, which was not significantly different from 1.2% with the bare metal stent. In 531 patients submitted to angiographic follow-up, late loss was reduced from 1.03±0.58 to 0.61±0.46 (P<0.001) in stent and from 0.72±0.61 to 0.36±0.46 (P<0.001) in segment. The rate of in-segment restenosis was reduced from 35.0% to 13.2% with Endeavor (P<0.0001). There was no excessive edge stenosis, aneurysm formation, or late acquired malapposition by intravascular ultrasound imaging. Differences in clinical outcome were maintained at 12 and 24 months (P<0.0001).
Conclusions— Compared with bare metal stents, the Endeavor stent is safe and reduces the rates of clinical and angiographic restenosis at 9, 12, and 24 months.
Received November 7, 2005; revision received June 5, 2006; accepted June 14, 2006.
Endoluminal metallic stents became the default treatment for percutaneous coronary interventions after clinical trials indicated that stenting decreased reintervention rates compared with balloon angioplasty.1–3 With the use of bare metal stents, clinical and angiographic restenosis still occurs in a large number of patients, with rates as high as 20% to 40% in high-risk subgroups.4–6 The principal cause of in-stent restenosis is neointimal hyperplasia resulting from proliferation and migration of smooth muscle cells and extracellular matrix production.7 Stents coated with antiproliferative agents have successfully addressed these problems.
Clinical Perspective p 806
Indeed, polymer-based local delivery of sirolimus or paclitaxel from eluting stent platforms has drastically reduced restenosis rates.8–10 However, the antiproliferative properties of currently available drug-eluting stents prevent or delay vessel healing.11,12 Delayed healing and polymer degradation have been associated with stent malapposition, hypersensitivity reactions, and most important, late stent thrombosis.13–15 Concerns16,17 about mid- and long-term safety of drug-eluting stents have stimulated the development of new drug-eluting stents with equivalent antirestenosis capabilities but improved safety profile, one of which is the Endeavor zotarolimus-eluting stent. The potential for the zotarolimus-eluting stent to reduce target lesion revascularization (TLR) to 1% at 1 year has been demonstrated in a first-in-human study.18 The present study is a large-scale, prospective, randomized, double-blind, multicenter trial designed to examine the safety and efficacy of the Endeavor stent in reducing the risk of clinical and angiographic restenosis in patients/lesions with moderate restenosis risk compared with the same bare stent without the phosphorylcholine polymer or antiproliferative drug.
Patients and Protocol
Patients with clinical evidence of ischemia or a positive function study who were undergoing stenting of a single, previously untreated lesion in a native coronary were considered for enrollment. Major exclusion criteria were left ventricular ejection fraction <30%; significant (>50%) stenosis proximal or distal to the target lesion; myocardial infarction (MI) within the preceding 72 hours; contraindications or allergy to aspirin, heparin, clopidogrel, cobalt, nickel, or chromium; hypersensitivity to contrast media; serum creatinine level >2.0 mg/dL (177 μmol/L); leukocyte count <3000 cells/mm3 or platelet count <100 000 or >700 000 cells/mm3; current participation in other investigational trials; or any coronary interventional procedure within 30 days before or planned after the implantation of the study stent. Angiographic inclusion criteria were a reference vessel diameter of 2.25 to 3.50 mm and a lesion length >14 but ≤27 mm, as estimated by the investigator. Angiographic exclusion criteria included left main or ostial target lesion, severe calcification by angiography, bifurcation lesion, and location of the target lesion at a >45° bend. The study was conducted according to the Declaration of Helsinki. The medical ethics committees of all sites approved the study protocol, and written informed consent was obtained from every patient.
The Driver bare metal stent (Medtronic, Santa Rosa, Calif) received European CE Marking in November 2002 and approval from the US Food and Drug Administration in October 2003 for the treatment of coronary lesions. This cobalt-alloy stent has a low profile, with a strut thickness of 0.0036 in (91 μm), designed to improve tracking and crossing in tortuous anatomy. A prospective multicenter registry study of 297 patients confirmed the good performance of the Driver stent.19 The Endeavor stent system (Medtronic) consists of the same bare metal stent coated with phosphorylcholine, from which 10 μg zotarolimus per 1 mm stent length is eluted. The polymer phosphorylcholine coating is a synthetic copy of the predominant phospholipid in the outer membrane of red blood cells and shows high biovascular compatibility. In animal studies, phosphorylcholine-coated stents have demonstrated significantly less platelet adhesion compared with uncoated stents.20 A phosphorylcholine coating also was used by the BiodivYsio stent (Biocompatibles Ltd, Farnham, UK) and was found safe and effective in the Study of Phosphorylcholine Coating on Stents (SOPHOS) trial.21 Sirolimus and its analogs, including zotarolimus, block activation of the mammalian target of rapamycin. This blockage keeps smooth muscle cells from advancing from the G1 phase of cell cycle activity into DNA synthesis and cell division.22,23 The drug and polymer are asymmetrically distributed on the stent surface by a proprietary coating technique, so the drug is localized mainly on the ablumenal arterial wall side of the stent.24
Randomization and Stent Implantation
Randomization was performed by an interactive telephone system. Patients were assigned (1:1) to treatment with either the Endeavor zotarolimus-eluting stent or the visually indistinguishable Driver bare metal stent without drug and polymer.
Seventy-two sites in Europe, Asia Pacific, Israel, New Zealand, and Australia participated in this study. Stents were implanted according to a standardized procedure. Before catheterization, patients received a minimum of 75 mg aspirin and a 300-mg loading dose of clopidogrel; a baseline ECG was obtained; and creatinine kinase and isoenzyme levels were measured. Unfractionated heparin was administered to maintain activated clotting time >250 seconds or between 200 and 250 seconds if a glycoprotein IIb/IIIa inhibitor was administered at the operator’s discretion. Predilatation was mandatory. The predilatation balloon could be no longer than the stent intended for implantation, and selecting a stent long enough to completely cover the diseased vessel segment was recommended. Stents were available in lengths of 18, 24, and 30 mm and sizes of 2.25, 2.50, 3.00, and 3.50 mm. In the event of edge dissection or incomplete coverage, additional stents could be implanted at the operator’s discretion up to a maximum length of 48 mm. Postdilatation could be performed within the deployed stent as required to optimize stent expansion. After the procedure, an ECG was obtained, and cardiac enzymes were measured. Patients took aspirin daily indefinitely (at least 75 mg daily), and clopidogrel was prescribed for 12 weeks (75 mg daily). Clinical follow-up was scheduled for 30 days, 6 months, 9 months, and yearly thereafter for 5 years. In addition, the first 600 patients enrolled were scheduled to undergo angiographic follow-up at 8 months, among whom 300 patients were scheduled to undergo intravascular ultrasound after the procedure and at 8 months.
The study was monitored by an independent contract research organization (Quintiles Transnational, Research Triangle Park, NC), and the trial and data were coordinated and analyzed by the Harvard Clinical Research Institute (Boston, Mass). All major adverse cardiac events (MACE) were reviewed and adjudicated by an independent clinical events committee, whose members were unaware of treatment allocation. An independent data and safety monitoring board periodically reviewed blinded safety data.
End Points and Definitions
The primary end point was the 9-month rate of target vessel failure (TVF), defined as a composite of target vessel revascularization (TVR), recurrent Q-wave or non–Q-wave MI, or cardiac death that cannot be clearly attributed to a vessel other than the target vessel. TLR was defined as repeat revascularization for ischemia owing to stenosis ≥50% of the lumen diameter anywhere within the stent or within the 5-mm borders proximal or distal to the stent. Revascularization of ≥70% stenosis in the absence of ischemic signs or symptoms also was considered clinically driven. MI was defined either as the development of pathological Q waves in at least 2 contiguous leads with or without elevated cardiac enzymes or, in the absence of pathological Q waves, as an elevation in creatinine kinase levels to greater than twice the upper limit of normal in the presence of an elevated creatinine kinase-MB level. Enzyme levels were available in 581 of 592 Endeavor recipients and in 577 of 591 patients in the bare metal stent group.
Secondary end points were MACE, defined as death, MI (Q-wave and non–Q-wave MI), emergent cardiac bypass surgery, or TLR (repeat percutaneous transluminal coronary angioplasty or coronary artery bypass grafting); angiographic late loss; and binary restenosis, defined as stenosis of ≥50% of the lumen diameter of the treated lesion. Stent thrombosis was defined as an acute coronary syndrome with angiographic documentation of vessel occlusion or thrombus within or adjacent to a previously stented segment; in the absence of angiography, stent thrombosis could be confirmed by acute MI in the distribution of the treated vessel or death resulting from cardiac causes within 30 days.
Image acquisition was performed with ≥2 angiographic projections, intracoronary nitroglycerin to provide maximum coronary vasodilation, and repetition of identical angiographic projections at follow-up angiography. Cineangiograms were then forwarded to the Brigham and Women’s Hospital Angiographic Core Laboratory in Boston, Mass, for standardized review by observers blinded to treatment assignment. Lesion length was defined as the axial extent of the lesion that contained a shoulder-to-shoulder lumen reduction by ≥20%. Restenosis patterns were qualitatively assessed with the Mehran classification system.25 Coronary aneurysms were defined as a maximum lumen diameter within the treatment zone that was 1.2 times larger than the average reference diameter of the vessel. Using the contrast-filled injection catheter for calibration, we performed quantitative angiographic analysis with a validated automated edge detection algorithm (Medis CMS, Leiden, the Netherlands)26 on selected images demonstrating the stenosis in its “sharpest and tightest” view. A 5-mm segment of reference diameter proximal and distal to the stenosis was used to calculate the average reference vessel diameter; side branches and other anatomic landmarks were used to identify and maintain the consistency of the analysis. Angiographic measurements were reported separately for the vessel section within the stent (“in stent”), for the vessel portions extending 5 mm from the proximal and distal stent edges, and for the entire segment (“in segment”). Total occlusions were assigned a minimum lumen diameter of 0 mm and a 100% diameter stenosis. Late loss was defined as the difference between minimum lumen diameter after the procedure and at 8 months. Loss index was determined by dividing late loss by short-term gain.
The statistical analysis plan prespecified that the primary intention-to-treat population would consist of all patients in whom an attempt was made to implant a study stent. For the primary end point of TVF, we projected a 40% reduction at 9 months from an anticipated 16% with bare metal stenting to 9.5% with the Endeavor stent. Using a 2-sided test for differences in independent binomial proportions with an α level of 0.05 and assuming an 8% loss to clinical follow-up, we calculated that 1200 patients would have to undergo randomization to detect this relative reduction with 90% power. For the secondary end point of angiographic late loss, we assumed that the mean difference in in-stent late loss at 8 months would be >0.21 mm between the 2 arms using a standard deviation of 0.70 mm. A sample size of 600 subjects was needed for the 2-sided test for differences of the secondary end point of late loss, using an α level of 0.05 and a power of 90% and assuming a 20% loss to angiographic follow-up.
Categorical discrete variables were compared by the χ2 test or the Fisher exact test when appropriate. Continuous variables are presented as mean±SD and were compared with the use of the Student t test or the Wilcoxon 2-sample test for nonnormally distributed data. The interactions between 3 categorical variables (diabetes mellitus, vessel size, and lesion length) and treatment assignment were tested by logistic regression. All probability values are 2 sided.
The authors had full access to the data and take responsibility for their integrity. All authors have read and agree to the manuscript as written.
Baseline Characteristics and Procedural Results
Between July 14, 2003, and January 13, 2004, 1197 patients were assigned to receive either the Endeavor zotarolimus-eluting stent (598 patients) or a bare metal stent (599 patients). The baseline characteristics of the 2 groups were well matched (Table 1). The lesion, procedure, and device-deployment success rates approached 100% in the 2 groups; procedural variables and initial angiographic results were similar for the 2 groups (Table 2 and Figure 1).
Clinical follow-up at 9 months was completed for 1183 of 1197 patients (98.8%). Compared with the bare metal stent, implantation of the zotarolimus-eluting stent reduced the primary end point of TVF at 9 months by 47.7% and lowered TLR by 61.0% (Table 3). There was no significant difference between site-reported and adjudicated ischemia-driven revascularization. TLR rates for Endeavor were 3.9% by site and 4.6% by adjudication. TLR rates for bare metal stent were 9.8% by site and 11.8% by adjudication. The rates of death, MI, and stent thrombosis were low and similar in the 2 groups. At the 9-month follow-up, the TVR and MACE rates were significantly lower with the Endeavor stent compared with the bare metal stent (Table 3 and Figure 2). Stent thrombosis was very low in each group (0.5% for the zotarolimus-eluting stent, 1.2% for the bare metal stent). In the Endeavor group, no documented stent thrombosis was observed beyond 30 days up to 24 months after implantation. Clinical follow-up is available for 1179 patients (98.5%) and 1160 patients (96.9%) at 12 and 24 months, respectively. By 12 months, MACE rates remained significantly lower for the zotarolimus-eluting stent (8.8% versus 15.6%; P=0.0004), and TLR occurred in 5.9% compared with 13.1% (P<0.0001). By 24 months, MACE rates were 10.0% versus 18.7% (P<0.0001), and TLR was 6.5% versus 14.7% (P<0.0001) for the Endeavor versus the bare metal stent, respectively.
Angiographic and Intravascular Ultrasound Imaging Results
Angiography at 8 months was completed for 531 of the prespecified patients (88.5%). There was no significant difference in baseline characteristics, angiographic parameters, or procedural data between patients assigned to angiographic or clinical follow-up. In the angiographic cohort, average lesion length was 13.29 mm in patients assigned to Endeavor compared with 14.15 mm in patients receiving the bare metal stent (P=0.05).
In patients assigned to invasive follow-up, TLR rates were higher for both groups (15.8% and 5.8% for the bare metal and Endeavor stents, respectively) than for patients assigned to clinical follow-up (7.8% and 3.4% for the bare metal and Endeavor stents, respectively). Likewise, TVR rates were higher for both groups assigned to undergo systematic repeat angiography (Table 4).
Compared with the bare metal stent, patients who received the Endeavor stent had a significantly smaller late loss and a lower loss index. As a result, their mean minimum lumen diameters were greater, and they had a smaller mean degree of stenosis in stent, at both proximal and distal edges, and in segment (Table 5 and Figure 1). The use of an Endeavor stent reduced the risk of in-stent binary restenosis by 71.9% and in-segment binary restenosis by 62.3%. By intravascular ultrasound at 8 months for 132 patients who received the zotarolimus-eluting stent and 118 who received the bare metal stent, there was no late-acquired stent malapposition or coronary aneurysm. Evenly distributed coverage of the Endeavor stents by neointimal hyperplasia was observed.
As for the rates of clinical end points according to prespecified subgroups, treatment effect was similar across patient/lesion subsets, as indicated by the nonsignificant interaction term of the subgroup category and treatment assignment (Table 6 and Figure 3). In patients with non–insulin-dependent diabetes (n=168), TLR rates were reduced from 15.9% with the Driver to 6.3% with the zotarolimus-eluting stent (P=0.054). In patients with insulin-dependent diabetes (n=70), TLR rates were 13.6% and 11.5%, respectively (P=1.00). In patients assigned to invasive follow-up, the relative reduction in binary angiographic restenosis with the Endeavor stent was independent of diabetes mellitus status, the diameter of the reference vessel, and lesion length (Table 6).
Summary of Findings
In this prospective, randomized, double-blind, multicenter study of patients with previously untreated coronary lesions, implantation of the zotarolimus-eluting stent reduced the risk of angiographic restenosis at 8 months by 71.9% compared with a bare metal stent. The clinical efficacy and safety of the Endeavor stent were evidenced by a 47.7% relative reduction in TVF, a 61.0% reduction in TLR, and a 49.3% reduction in overall MACE at 9 months. Superior outcome was maintained at 2 years, and stent thrombosis was infrequent in both groups, with no documented late stent thrombosis. The rates of death from cardiac causes, including MI, also were low and were not significantly different between the 2 groups. No aneurysms were reported for any of the patients, and no late acquired stent malapposition was observed. Use of a biomimetic polymer as the drug-releasing platform might have contributed to the safety of this device.
Despite the large number of participating sites scattered over 4 continents, trial execution was carefully monitored, and quality of the data was ensured, as reflected in the high rates of clinical and angiographic follow-up. Systematic repeat angiography was restricted to half of the patient population. In this way, non–clinically driven redilatations are limited and the rates of repeat intervention are more likely to reflect real-life practice.27 Indeed, systematic repeat angiography resulted in an increase in TLR and TVR rates in both subgroups, reminiscent of previous observations.27 During the time period of patient enrollment, drug-eluting stents were not yet universally available at the participating sites, so randomization against a bare metal stent was still possible and ethically justifiable. Of note, the clinical outcome in patients randomized to bare metal stenting is satisfactory and was either superior8 or equivalent9 to the results obtained in the control arms of other pivotal drug-eluting stent trials.
Comparison With Other Drug-Eluting Stents
This randomized trial was powered for both the angiographic and the clinical end point.
Although neointimal hyperplasia was significantly reduced with the Endeavor stent, neointimal proliferation was not abolished as reported for other drug-eluting stents.28 A mathematical model describing the relation between in-stent late loss and binary angiographic restenosis was recently proposed by Mauri et al.29 Incremental steps in binary angiographic restenosis occur as in-stent late loss increases. When late loss increases from 0.2 to 0.4 mm, restenosis is predicted to increase by 3.1%, and when late loss increases from 0.4 to 0.6 mm, restenosis is expected to increase by 6.4%. The results observed in the present trial concur with that mathematical model. Along with the increasing values of late loss from SIRIUS (0.17 mm) to TAXUS IV (0.39 mm) to ENDEAVOR II (0.61 mm), observed restenosis rates were 3.2%, 5.5%, and 9.4%, respectively. However, establishing a new drug-eluting stent requires a large pivotal trial (>1000 to 2000 subjects) evaluating clinical end points. When these results are compared with either SIRIUS OR TAXUS IV, all metrics of clinical outcome show nearly identical single-digit figures.8,9 For instance, TVF rates were 8.6%, 7.6%, and 7.9% for SIRIUS, TAXUS IV, and ENDEAVOR II, respectively. This observation confirms the disconnect between clinical outcome and angiographic measures that was already noted in the ENDEAVOR I trial.18 It also raises important questions about the value of angiographic surrogate end points as predictors of clinical outcome.30 It appears that reducing neointimal proliferation below a critical threshold, as measured, for instance, by late loss, may be sufficient to sustain a good clinical outcome. This implies that abolishing tissue in-growth is not indispensable for a good clinical outcome, as was shown for drug-eluting stents,30 coated stents,31 or bare metal stents in combination with oral immunosuppressive drug treatment.32,33
Safety Versus Efficacy
Issues related to potential tradeoffs between efficacy and safety of drug-eluting stents have received increasing attention in recent years.16,17 The antiproliferative properties of drug-eluting stents are associated with delayed healing, which is setting the stage for prolonged biological interactions between the vessel wall and the permanent stent implantation. Side effects such as hypersensitivity reactions,13 acquired late malapposition,14 and most importantly, late stent thrombosis have been associated with delayed healing both in animal experiments12 and in human observations.11 Concerns about the prolonged risk of stent thrombosis have resulted in the empirical practice of extending dual antiplatelet therapy without alleviating the risk of abrupt thrombosis after treatment discontinuation.15,17 Accepting a mild degree of in-stent neointimal proliferation that is still compatible with a good clinical outcome might offer a reasonable compromise between safety and efficacy while we await the development of drug-eluting stents with both antiproliferative and prohealing properties.34
Conversely, the question should be raised whether the antiproliferative properties of the Endeavor stent are sufficient to portend equally good clinical outcome when used in patient/lesion subsets with even higher propensity for restenosis.35 The 3 principal determinants of restenosis after stenting are diabetes mellitus status, reference vessel diameter, and lesion length.4–6,36–38 The zotarolimus-eluting stent reduced the risk of TLR in patients with and those without diabetes, although the number of patients with diabetes who required insulin was too small to permit subgroup analysis. The Endeavor stent also reduced TLR rates across subgroups in terms of vessel size and lesion length. Compared with the bare metal stent, the Endeavor stent was particularly effective in reducing TLR rates in small coronary arteries <2.5 mm in diameter (relative reduction, 57.0%) and lesions >16 mm (relative reduction, 57.1%). Thus, subgroup analysis of this trial suggests that the zotarolimus-eluting stent was effective in the lesion/patient subsets at moderate risk for restenosis included in the present trial.
The Endeavor stent can be recommended as a valuable new tool for the percutaneous treatment of coronary artery stenoses. The device is highly deliverable, has significant antirestenosis properties, and has a favorable safety profile with short-term dual antiplatelet therapy. The results of ongoing and future trials in high-risk subsets will provide further insights into the interplay between clinical outcome, antiproliferative effects, and patient safety.
The successful completion of this trial was made possible thanks to the relentless dedication and highly professional support of the clinical research team headed by L. Hadjadjeba, MD, and F. Van Leeuwen, MD.
Source of Funding
ENDEAVOR II was supported by Medtronic Vascular, Santa Rosa, Calif.
After completion of study performance and analysis, Dr Kuntz became an employee of Medtronic. Dr Bonan is a medical advisor of Medtronic, and Dr Ormiston has been a member of the Guidant Physician Advisory Board. Dr Kuck is a consultant for St Jude and Stereotaxis. Dr Popma is a member of the Medtronic Speakers’ Bureau. Honoraria for lecturing at symposia have been received by Drs Fajadet (from Medtronic and Cordis J&J), Laarman (Medtronic and Cordis J&J), Kuck (St Jude and Biosense Webster), and Ormiston (Medtronic, Cordis J&J, Boston Scientific, and Guidant). Honoraria from Medtronic, Cordis J&J, Boston Scientific, Biotronik, and Conormed have been granted to the Cardiovascular Research Center Aalst on behalf of Dr Wijns. The institutions of Drs Wijns, Laarman, and Kuck are holding research grants from medical device companies. The other authors report no conflicts.
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The safety and efficacy of the Endeavor zotarolimus-eluting phosphorylcholine polymer-coated stent were tested in a pivotal randomized clinical trial against bare metal stenting. Patients (n=1197) treated for single coronary artery stenosis were randomly assigned (1:1) to receive the Endeavor stent (n=598) or the same bare metal stent but without the drug or the polymer coating (n=599). The primary clinical end point of target vessel failure at 9 months was reduced from 15.1% with the bare metal stent to 7.9% with the Endeavor (P=0.0001). The rate of major adverse cardiac events was reduced from 14.4% with the bare metal stent to 7.3% with the Endeavor stent (P=0.0001). The rate of stent thrombosis was 0.5% with the Endeavor, which was not significantly different from 1.2% with bare metal stent. Differences in clinical outcome were maintained at 12 and 24 months (P<0.0001). In 531 patients submitted to angiographic follow-up, late loss was reduced from 1.03±0.58 to 0.61±0.46 (P<0.001) in stent and from 0.72±0.61 to 0.36±0.46 (P<0.001) in segment. Compared with bare metal stents, the Endeavor stent is safe and reduces the rates of clinical and angiographic restenosis at 9, 12, and 24 months.
Guest Editor for this article was Kim M. Fox, MD.
The study investigators and participating institutions are listed in the Appendix, which is available in the online-only Data Supplement at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.591206/DC1.