CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Comparison of Zotarolimus-Eluting and Sirolimus-Eluting Stents in Patients With Native Coronary Artery Disease
A Randomized Controlled Trial
David E. Kandzari, MD, FACC*,*,
Martin B. Leon, MD, FACC ,
Jeffrey J. Popma, MD, FACC ,
Peter J. Fitzgerald, MD, FACC||,
Charles O’Shaughnessy, MD, FACC#,
Michael W. Ball, MD, FACC**,
Mark Turco, MD, FACC ,
Robert J. Applegate, MD, FACC,
Paul A. Gurbel, MD, FACC,
Mark G. Midei, MD, FACC,
Sejal S. Badre, MS,
Laura Mauri, MD, MSc, FACC,
Kweli P. Thompson, MD¶,
LeRoy A. LeNarz, MD¶,
Richard E. Kuntz, MD, FACC¶ for the ENDEAVOR III Investigators
* Duke Clinical Research Institute, Durham, North Carolina
Baptist Medical Center and Wake Forest University, Winston-Salem, North Carolina
Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York
Harvard Clinical Research Institute and Brigham and Women’s Hospital, Boston, Massachusetts
|| Stanford University Medical Center, Palo Alto, California
¶ Medtronic, Inc., Santa Rosa, California
# North Ohio Heart Center, Elyria, Ohio
** St. Vincent’s Hospital, Indianapolis, Indiana
Washington Adventist Hospital, Takoma Park, Maryland
Sinai Center for Thrombosis Research, Baltimore, Maryland
St. Joseph’s Medical Center, Towson, Maryland.
Manuscript received March 24, 2006;
revised manuscript received August 7, 2006,
accepted August 7, 2006.
* Reprint requests and correspondence: Dr. David E. Kandzari, Room 7063, Duke Clinical Research Institute, 2400 Pratt Street, Durham, North Carolina 27705. (Email: david.kandzari{at}duke.edu).
 |
Abstract
|
|---|
OBJECTIVES: This trial examined the relative clinical efficacy, angiographic outcomes, and safety of zotarolimus-eluting coronary stents (ZES) with a phosphorylcholine polymer versus sirolimus-eluting stents (SES).
BACKGROUND: Whether a cobalt-based alloy stent coated with the novel antiproliferative agent, zotarolimus, and a phosphorylcholine polymer may provide similar angiographic and clinical benefit compared with SES is undetermined.
METHODS: A prospective, multicenter, 3:1 randomized trial was conducted to evaluate the safety and efficacy of ZES (n = 323) relative to SES (n = 113) in 436 patients undergoing elective percutaneous revascularization of de novo native coronary lesions with reference vessel diameters between 2.5 mm and 3.5 mm and lesion length  14 mm and  27 mm. The primary end point was 8-month angiographic in-segment late lumen loss.
RESULTS: Angiographic in-segment late lumen loss was significantly higher among patients treated with ZES compared with SES (0.34 ± 0.44 mm vs. 0.13 ± 0.32 mm, respectively; p < 0.001). In-hospital major adverse cardiac events were significantly lower among patients treated with ZES (0.6% vs. 3.5%, p = 0.04). In-segment binary angiographic restenosis was also higher in the ZES cohort (11.7% vs. 4.3%, p = 0.04). Total (clinically and non-clinically driven) target lesion revascularization rates at 9 months were 9.8% and 3.5% for the ZES and SES groups, respectively (p = 0.04). However, neither clinically driven target lesion revascularization (6.3% zotarolimus vs. 3.5% sirolimus, p = 0.34) nor target vessel failure (12.0% zotarolimus vs. 11.5% sirolimus, p = 1.0) differed significantly.
CONCLUSIONS: Compared with SES, treatment with a phosphorylcholine polymer-based ZES is associated with significantly higher late lumen loss and binary restenosis at 8-month angiographic follow-up.
(The Endeavor III CR; http://clinicaltrials.gov/ct/show/
NCT00265668
[ClinicalTrials.gov]
?order=1?)
|
Abbreviations and Acronyms
| | CK = creatine kinase | | IVUS = intravascular ultrasound | | MACE = major adverse cardiac events | | MLD = minimal lumen diameter | | SES = sirolimus-eluting stent | | ZES = zotarolimus-eluting stent |
|
Compared with bare metal coronary stents, the beneficial treatment with drug-eluting stents to avoid restenosis and the need for repeat revascularization has been consistently demonstrated in systematic, randomized clinical trials (1–8) and observational studies (9–11) that have included both selected and broad patient populations with varying clinical and angiographic characteristics. Because of their efficacy in limiting neointimal hyperplasia after percutaneous coronary revascularization, drug-eluting stents have become routine therapy in clinical practice, and currently available paclitaxel- eluting stents and sirolimus-eluting stents (SES) have become the comparative standard for evaluation of novel anti-proliferative therapies and stent technologies.
Whether safety, clinical efficacy, and angiographic outcomes are similar between differing drug-eluting stents has only been recently examined (12–18). An important emerging controversy in clinical trials comparing drug-eluting stent therapies has been the relationship of clinical end points such as target lesion revascularization or target vessel failure (generally considered the "gold standards" for assessing safety and efficacy) and surrogate angiographic end points such as late lumen loss, which measure more precisely the biological effects of these novel anti-restenosis therapies on intimal hyperplasia (19,20).
Zotarolimus (ABT-578, Abbott Pharmaceuticals, Abbott Park, Illinois) is a novel pharmacologic therapy with both anti-proliferative and anti-inflammatory effects. A tetrazole-containing macrocyclic immunosuppressant, zotarolimus shares structural homology and biological activity with the anti-restenotic agent sirolimus. Recently, in a randomized trial comparing coronary revascularization with zotarolimus-eluting (ZES) and bare metal stents, treatment with ZES was associated with significant reductions in angiographic restenosis and repeat target lesion revascularization (8). Despite this marked benefit relative to conventional bare metal stents, the comparative efficacy between ZES and other effective drug-eluting stents, such as SES, is undetermined. We therefore performed a randomized, multicenter trial to examine the relative safety, clinical efficacy, and angiographic outcomes of a phosphorylcholine polymer-based coronary stent eluting zotarolimus versus sirolimus in patients with native coronary lesions.
|
Methods
|
|---|
Trial overview and study population.
The ENDEAVOR III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) trial was a prospective, randomized, single-blinded multicenter trial comparing ZES and SES in elective percutaneous coronary revascularization at 29 hospitals in the U.S. Individuals eligible for enrollment were consecutive patients age 18 years or older with symptomatic ischemic heart disease due to de novo stenotic lesions (>50% angiographic diameter stenosis by visual estimate) in native coronary arteries. Angiographic inclusion criteria were a reference vessel diameter between 2.5 mm and 3.5 mm and lesion length 14 mm and 27 mm. Patients were excluded if they experienced recent (<72 h) myocardial infarction, underwent prior stent placement within the target vessel or any other vessel within 30 days of the index procedure, or had any general contraindication to the revascularization procedure and routine pharmacologic therapies. Principal angiographic exclusion criteria were a left ventricular ejection fraction <30%, stenosis >40% elsewhere in the target vessel (other than the target lesion), involvement of a sidebranch 2.0 mm in diameter, unprotected left main coronary disease, chronic total occlusions, and Thrombolysis In Myocardial Infarction flow grade <2 in the treatment vessel. The study was approved by the institutional review board at each enrolling site, and consecutive, eligible patients signed written informed consent before the interventional procedure.
Device description.
The Endeavor drug-eluting coronary stent (Medtronic Vascular, Inc., Santa Rosa, California) is a cobalt-based alloy stent with a phosphorylcholine polymer (21) and zotarolimus dose concentration of 10 µg/mm stent length. In a porcine coronary model, stents coated with a phosphorylcholine polymer and zotarolimus were associated with significant reductions in neointimal area and percent area stenosis (22). In a similar preclinical study, approximately 95% of zotarolimus is eluted from the stent within 15 days of implantation, although drug concentrations within surrounding vascular tissue may be detected as late as 30 days after stent deployment (23). Zotarolimus-eluting stents were available in diameters ranging from 2.5 mm to 3.5 mm and in lengths from 9 mm to 30 mm. The control SES stent (Cypher, Cordis Corporation, Miami Lakes, Florida) was available in diameters ranging from 2.5 mm to 3.5 mm and in lengths from 8 mm to 33 mm.
Randomization, interventional procedure, and adjunctive drug therapies.
Patients were blinded to treatment assignment and randomized to the ZES or SES in a 3:1 fashion. Revascularization was to be performed with no more than 1 study stent except in instances of insufficient lesion coverage or as a "bailout" procedure for dissection or thrombus. All lesions were pre-dilated with balloon angioplasty, and the protocol specified that stent length should be 3 to 5 mm longer than the lesion for adequate coverage. Both the ZES and SES were expanded to achieve <10% residual stenosis by visual estimate in the treated segment, with a combination of the stent deployment balloon and, at the operator’s discretion, subsequent post-dilatation balloons. After stent implantation was optimized by angiographic criteria, routine intravascular ultrasound (IVUS) of the target lesion was performed.
Before revascularization, all patients received treatment with aspirin (325 mg/day) and clopidogrel (75 mg/day) for at least 48 h, followed by dual antiplatelet therapy for a minimum of 3 months after the procedure and indefinite aspirin therapy. In those patients not receiving at least 48 h of dual anti-platelet therapy before the procedure, a loading dose of clopidogrel (300 to 600 mg) was given immediately before or during the procedure. Unfractionated heparin was administered to achieve an activated clotting time 250 s or 200 to 250 s if an intravenous glycoprotein IIb/IIIa inhibitor was used. Treatment with additional device therapies (e.g., atherectomy) was not permitted.
Clinical events were assessed during hospital stay and at clinic visits at 30 days and at 9 months after the index procedure. All patients were scheduled to undergo follow-up angiography and IVUS at 8 months or sooner if the patient developed angina or objective evidence of target vessel ischemia.
Data management and core laboratories.
All data were submitted to a central data coordinating facility (Cardiovascular Data Analysis Center, Harvard Clinical Research Institute, Harvard Medical School, Boston, Massachusetts). Coronary angiograms performed at baseline and at follow-up were reviewed by an independent angiographic core laboratory (Brigham and Women’s Angiographic Core Laboratory, Boston, Massachusetts). Standard image acquisition was performed with 2 or more angiographic projections of the stenosis before and after stent placement. Compulsory angiography was planned 240 ± 30 days after the procedure with identical angiographic projections. Qualitative analysis was performed with the modified American College of Cardiology (ACC)/American Heart Association (AHA) classification (24). Quantitative angiographic analysis was performed with a validated automated edge detection algorithm (Medis CMS, Leiden, the Netherlands) (25). Frames were selected for analysis in the 2 "sharpest and tightest" views that minimized foreshortening and vessel overlap. The contrast-filled injection catheter was used as the calibration source. A 5- to 10-mm segment of reference diameter proximal and distal to the stenosis was used to calculate the average reference vessel diameter at baseline, after stent implantation, and at follow-up. Similarly, IVUS images were examined by an independent core laboratory (Cardiovascular Core Analysis Laboratory, Stanford University, Stanford, California) (26,27). Reviewers from each core laboratory were unaware of the type of stent implanted. For both coronary angiograms and IVUS images, quantitative analysis was performed to evaluate the in-stent region (bordered by the stent margins) as well as the in-segment region (in-stent region plus 5-mm margins proximal and distal to the stent).
Study end points and definitions.
The primary end point of in-segment late lumen loss was examined by quantitative coronary angiography at 8-month angiographic follow-up. Late lumen loss was defined as the difference between the in-segment minimal lumen diameter (MLD) at the completion of the stenting procedure and the in-segment MLD measured at angiographic follow-up.
Secondary clinical safety and efficacy end points included major adverse cardiac events (MACE: all-cause death, myocardial infarction, and clinically driven target lesion revascularization); the individual components of the composite end point in-hospital, at 30 days, and at 9 months; stent thrombosis (acute, <1 day; subacute, 1 to 30 days; and late, >30 days); clinically driven target vessel revascularization at 9 months; and target vessel failure (cardiovascular death, myocardial infarction, and clinically driven target vessel revascularization) at 9 months. Device success was defined as a <50% diameter stenosis of the target lesion (determined by the core angiographic laboratory) with the assigned study stent, and procedure success was defined as device success and no in-hospital MACEs. Myocardial infarction was defined as a creatine kinase (CK) elevation 2 times above the upper limit of normal with any associated elevation in the CK myocardial band or the development of new pathologic Q waves in 2 contiguous electrocardiographic leads. Clinically driven revascularization was identified as any repeat revascularization of the target lesion or target vessel associated with either: 1) ischemic symptoms and/or an abnormal functional study and a 50% coronary stenosis by quantitative angiography; or 2) any revascularization of a 70% diameter stenosis. All primary and secondary clinical end points were adjudicated by an independent clinical events committee blinded to the patient’s treatment assignment.
Secondary angiographic and IVUS efficacy end points included in-stent late lumen loss at 8 months, angiographic binary restenosis (both in-stent and in-segment) at 8 months, and percent volume obstruction assessed by IVUS at 8 months. Development of acquired incomplete late stent apposition at IVUS follow-up was identified according to previously described methods (28). Angiographic binary restenosis was defined as a stenosis 50% of the lumen diameter of the target lesion (determined by the core angiographic laboratory). Percent diameter stenosis was defined as (1 – [MLD/reference vessel diameter]) x 100, and acute gain was defined as the MLD immediately after the procedure minus the MLD before the procedure. Restenosis patterns were characterized according to established criteria (29).
Statistical methods.
This randomized study was designed to determine the equivalence (non-inferiority) of 8-month in-segment late lumen loss with an equivalence definition (delta) such that the ZES would have a mean in-segment late lumen loss 0.2 mm plus the control SES in-segment late lumen loss. With a 3:1 (ZES/SES) randomization and assuming a common SD of 0.55 mm, a sample size of 436 patients (323 ZES, 113 SES) with at least 80% angiographic follow-up was required for the trial to have 90% statistical power to detect a significant difference at an alpha level of 0.05. Patients were analyzed for all primary and secondary efficacy and safety end points on the basis of the intent-to-treat principle. Baseline characteristics of study patients were summarized in terms of frequencies and percentages for categorical variables and by means with SDs for continuous variables. Categorical variables were compared by Fisher exact test. Continuous variables were compared by the 2-sample t test. Cumulative event-free survival was summarized as Kaplan-Meier estimates. A p value of 0.05 was established as the level of statistical significance for all tests. All analyses were performed with SAS software (version 8.2 or higher, SAS Institute, Cary, North Carolina).
|
Results
|
|---|
Patient characteristics.
Among 436 patients undergoing elective percutaneous coronary revascularization, 323 patients were randomized to treatment with ZES and 113 patients were treated with SES. No significant differences were present in the baseline clinical or demographic characteristics between patients randomized to receive ZES versus the control SES, except that fewer patients assigned to ZES were male (65.3% vs. 81.4%, p = 0.001) (Table 1). Overall, the mean age was 61.5 years, 21.1% underwent prior percutaneous coronary intervention, 68.8% had a history of smoking, and 29.4% had diabetes mellitus. Most patients (61.2%) had single-vessel coronary disease, and 20.1% of patients had a history of prior myocardial infarction.
Baseline angiographic characteristics were also similar (Table 1), except for a higher frequency of moderate complexity lesions characterized as type B2 or C according to the modified ACC/AHA classification (24) in the ZES group (67.4% vs. 56.6%, p = 0.047). Overall, the mean lesion length was 14.97 mm, the average reference vessel diameter was 2.76 mm, and most lesions (40.9%) were located in the left anterior descending artery.
Procedural and in-hospital outcomes.
The number, length, and diameter of stents implanted were similar in patients assigned to each treatment group (Table 2). The average number of stents/target lesion was 1.15, with overlapping stents in 23.6% of patients. Importantly, device success was significantly higher among patients treated with ZES (98.8% vs. 94.7%, p = 0.02). By intention to treat analysis, the reason for device failure in SES cases was an inability to deliver the assigned study stent to the target lesion, except for 1 instance of an inadvertent protocol exclusion, in which a patient was treated with a non-study stent.
In-hospital major adverse events were higher among patients randomized to SES, principally owing to a significantly higher incidence of non–Q-wave myocardial infarction (0.6% with ZES vs. 3.5% with SES for both non–Q-wave myocardial infarction and in-hospital MACE; p = 0.04) (Table 2). Among patients with myocardial infarction, a CK-MB elevation >3 times the upper normal limit occurred in all patients except 1 ZES patient, and a CK elevation >3 times the upper normal limit occurred in only 1 patient, who was treated with SES. Administration of intravenous glycoprotein IIb/IIIa inhibitors did not differ between groups (44.0% with ZES vs. 44.6% with SES, p = 0.91). Among patients with myocardial infarction, 2 of the 4 events in the SES group and none in the ZES group were related to sidebranch occlusion. There were no differences in the frequency of myocardial infarction between patients receiving multiple and/or overlapping stents in either treatment group. Procedure success was significantly higher with ZES than with SES (98.1% vs. 91.2%, p = 0.002).
Angiographic and IVUS outcomes.
Eight-month follow-up angiography was performed in 282 (87.3%) of patients in the ZES group and 94 (83.2%) patients in the SES group. There were no differences in baseline characteristics and clinical outcomes in patients who did and those who did not undergo follow-up angiography. Both in-stent late lumen loss and in-stent binary restenosis were significantly higher after ZES versus SES therapy (Table 3). The primary end point, in-segment late lumen loss, was also significantly higher among patients treated with ZES versus SES (0.34 ± 0.44 mm vs. 0.13 ± 0.32 mm, p < 0.001; p = 0.65 for non-inferiority), corresponding to a higher frequency of in-segment binary restenosis (11.7% vs. 4.3%, p = 0.04) (Table 3). Although the pattern of in-stent restenosis was most frequently focal in both ZES- and SES-treated patients, the restenosis lesion length was significantly greater in patients treated with ZES (12.94 mm with ZES vs. 6.46 mm with SES, p < 0.001). There were no differences in restenosis within the proximal or distal margins of the stents comparing ZES versus SES patients.
Immediate post-procedural IVUS measurements did not differ significantly among the 2 study groups. Follow-up IVUS at 8 months (with images suitable for analysis) was performed in 187 (59.2%) patients in the ZES group and 61 (54.0%) patients in the SES group. At 8 months, percent volume obstruction (16.1 ± 11% vs. 2.7 ± 3%, p < 0.001) was significantly greater with ZES compared with SES (Table 3). Importantly, newly observed incomplete late stent apposition with abnormal remodeling and vessel expansion occurred in 4 patients (5.9%) treated with SES and in only 1 (0.5%) patient receiving ZES (p = 0.02) (Table 3).
Nine-month clinical outcomes.
Clinical follow-up was completed in 316 patients (97.8%) in the ZES group and in 113 patients (100%) in the SES group (Table 4). There were no episodes of acute, subacute, or late stent thrombosis in either treatment group. There were 2 (0.6%) deaths in the ZES group and none in the SES group. The deaths in the ZES group were due to stroke in 1 patient and pancreatic cancer in the other patient. There were no out-of-hospital myocardial infarctions in either group, such that the early lower frequency of myocardial infarctions with ZES persisted during the follow-up period. The occurrence of clinically driven target lesion revascularization did not significantly vary between the ZES and SES groups (6.3% ZES vs. 3.5% SES, p = 0.34) (Table 4). Target vessel revascularization unrelated to the target lesion was also similar between ZES and SES groups (6.0% with ZES vs. 5.3% with SES, p = 1.0). Target lesion revascularization adjudicated as non-clinically driven (i.e., occurring without an abnormal functional study or 70% stenosis) occurred in an additional 11 (3.5%) patients treated with ZES; therefore, the total (clinically and non-clinically driven) target lesion revascularization rates were 9.8% and 3.5% for the ZES and SES groups, respectively (p = 0.04). There were no significant differences between ZES and SES in the occurrence of MACEs (7.6% vs. 7.1%, p = 1.0) and target vessel failure (12.0% vs. 11.5%, p = 1.0). Actuarial event-free survival at 9 months for clinically driven target lesion revascularization, MACEs, and target vessel failure did not significantly differ among ZES and SES patients (Fig. 1).
View larger version (25K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Kaplan-Meier event-free survival to 9 months for patients treated with zotarolimus- (ZES) and sirolimus-eluting (SES) stents. MACE = major adverse cardiac events; TLR = target lesion revascularization; TVF = target vessel failure.
|
|
|
Discussion
|
|---|
In this prospective, randomized trial comparing the clinical efficacy, safety, and angiographic outcomes among patients treated with ZES and SES, treatment with ZES was associated with increased neointimal hyperplasia resulting in greater angiographic late lumen loss.
The reasons for higher late lumen loss observed with ZES in this trial compared with SES (the primary end point) and other studies are incompletely understood. Among patients treated with ZES in the first-in-man ENDEAVOR I (100-patient) and large (1,200-patient), randomized ENDEAVOR II trials (8,30), for example, angiographic measurement of in-stent late lumen loss was 0.61 mm in both studies, compared with 0.60 mm in the current study. Increased neointimal hyperplasia with ZES might be due to differences in biological activity of zotarolimus compared with sirolimus, although in vitro cell culture experiments and animal studies would suggest equivalent nanomolar potencies in suppressing smooth muscle cell proliferation (23). Another potential reason for the observed differences is that the more rapid elution kinetics of zotarolimus from the phosphorylcholine polymer—95% eluted in approximately 2 weeks (23)—compared with the slower release of sirolimus from the polyethylene-co-vinyl acetate/poly n-butyl methacrylate co-polymer—95% eluted in approximately 6 weeks—might significantly influence biological efficacy. Optimal suppression of procedural-induced injury responses resulting in inflammation and subsequent intimal hyperplasia might require more prolonged tissue exposure to the therapeutic agent. Lastly, there might be differences in biological responses to either the stent or the phosphorylcholine polymer itself.
Regarding secondary end points, the results from this trial are the first among comparative drug-eluting stent trials to demonstrate a statistically significant difference in both procedural device success and in-hospital clinical outcome. First, device success was significantly higher with ZES, owing to enhanced stent deliverability likely associated with a more flexible, low profile thin-strut cobalt alloy stent. Second, although infrequent in both groups, the occurrence of in-hospital non–Q-wave myocardial infarctions was significantly lower with ZES compared with SES. This observation is more difficult to reconcile, given that most procedural, demographic, and baseline angiographic characteristics did not differ between the 2 groups.
Although the angiographic and IVUS follow-up analyses favored SES compared with ZES, differences in clinical outcome were less consistent. Most clinical end points did not statistically differ between these 2 drug-eluting stents (Table 4), including clinically driven target lesion revascularization (6.3% for ZES vs. 3.5% for SES, p = 0.34). However, overall target lesion revascularization (clinically and non-clinically driven) was significantly more common in the ZES group. The modest but statistically significant benefit associated with lower peri-procedural myocardial infarction rates with ZES was offset by the slightly higher follow-up target lesion revascularization frequencies, such that the composite target vessel failure and MACE values for ZES and SES were similar. As with previous studies using paclitaxel-eluting stents (3,6,7), a discordance might exist between angiographic and clinical outcomes in this ZES trial, suggesting that there might be an angiographic late lumen loss threshold or "window" below which the occurrence of repeat clinically driven revascularization events is unlikely (Fig. 2). In low- or medium-complexity lesions, an in-stent late loss of 0.60 mm and an in-segment late loss of 0.34 mm were in most instances well tolerated and not sufficient to induce important changes in clinically driven target lesion revascularization compared with SES. Of course, in higher complexity lesions (such as diffuse disease, in-stent restenosis, or small vessels), where there is the potential for an upward drift in late lumen loss, greater differences between ZES and SES might become apparent. At present, an international "open" registry with ZES is ongoing to provide insights regarding the clinical efficacy of ZES in a broad, unselected patient population with greater lesion complexity and in varied clinical settings.
Study limitations.
There are several limitations of this study. Because the primary objective of the study was to compare an angiographic surrogate end point—follow-up in-segment late lumen loss—between 2 drug-eluting stents, the sample size did not enable adequate statistical power to rigorously examine differences among pertinent clinical end points. Moreover, the unbalanced randomization resulted in a very small SES comparison group, such that results for SES were subject to potential over-interpretation due to broad confidence intervals. It is also noteworthy that the differences between ZES and SES were somewhat exaggerated in this clinical trial, owing to an unexpectedly low SES in-segment late lumen loss compared with other recent SES clinical trials (1,2,17). Unlike previous double-blinded drug-eluting stent versus bare metal stent clinical trials, this study was single-blinded, and the identity of the treatment stent was known to the interventional operator, which could introduce bias in procedural outcomes and the performance of repeat revascularization. As stated, the results from this trial are specific to the patient population studied and cannot be generalized to the much broader population of patients with more complex lesion morphologies.
Conclusions.
As demonstrated in this ZES versus SES clinical trial, ZES was shown to have significantly higher angiographic late lumen loss. Although most other angiographic outcomes favored SES, differences in secondary clinical end points were not consistent between the 2 stent groups. Clinical interventional operators will have to consider the overall attributes of ZES versus SES in making decisions concerning preferential device use under specific clinical circumstances.
|
Appendix
|
|---|
For a list of the ENDEAVOR III trial study sites and principal investigators, please see the online version of this article.
|
Footnotes
|
|---|
Study support provided by Medtronic Vascular, Inc. Santa Rosa, California.
|
References
|
|---|
1. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization N Engl J Med 2002;346:1773-1780.[Abstract/Free Full Text]2. Moses JW, Leon MB, Popma JJ, et al. SIRIUS Investigators Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery N Engl J Med 2003;349:1315-1323.[Abstract/Free Full Text] 3. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease N Engl J Med 2004;350:221-231.[Abstract/Free Full Text] 4. Schampaert E, Cohen EA, Schluter M, et al. C-SIRIUS Investigators The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS) J Am Coll Cardiol 2004;43:1110-1115.[Abstract/Free Full Text] 5. Schofer J, Schluter M, Gershlick AH, et al. E-SIRIUS Investigators Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS) Lancet 2003;362:1093-1099.[CrossRef][Web of Science][Medline] 6. Stone GW, Ellis SG, Cannon L, et al. TAXUS V Investigators Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial JAMA 2005;294:1215-1223.[Abstract/Free Full Text] 7. Dawkins KD, Grube E, Guagliumi G, et al. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trialSupport for the use of drug-eluting stents in contemporary clinical practice. Circulation 2005;112;:3306-3313. 8. Fajadet J, Wijns W, Laarman GJ, et al. 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 Circulation 2006;114:798-806. 9. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the "real world": the rapamycin-eluting stent evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry Circulation 2004;109:190-195. 10. Ong ATL, Serruys PW, Aoki J, et al. The unrestricted use of paclitaxel-versus sirolimus-eluting stents for coronary artery disease in an unselected population: one-year results of the Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry J Am Coll Cardiol 2005;45:1135-1141.[Abstract/Free Full Text] 11. Lemos PA, Hoye A, Goedhart D, et al. Clinical, angiographic, and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation in complex patients Circulation 2004;109:1366-1370. 12. Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization N Engl J Med 2005;353:653-662.[Abstract/Free Full Text] 13. Dibra A, Kastrati A, Mehillia J, et al. ISAR-DIABETES Study Investigators Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients N Engl J Med 2005;353:663-670.[Abstract/Free Full Text] 14. Goy JJ, Stauffer JC, Siegenthaler M, Benoit A, Seydoux C. A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology: the TAXI trial J Am Coll Cardiol 2005;45:308-311.[Abstract/Free Full Text] 15. Kastrati A, Mehilli J, von Beckerath N, et al. ISAR-DESIRE Study Investigators Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial JAMA 2005;293:165-171.[Abstract/Free Full Text] 16. Kastrati A, Dibra A, Eberle S, et al. Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artery disease: meta-analysis of randomized trials JAMA 2005;294:819-825.[Abstract/Free Full Text] 17. Morice MC, Colombo A, Meier B, et al. REALITY trial Investigators Sirolimus-versus paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial JAMA 2006;295:895-904.[Abstract/Free Full Text] 18. de Lezo JS, Medina A, Pan M, et al. Drug-eluting stents for complex lesions: latest angiographic data from the randomized rapamycin versus paclitaxel CORPAL study(abstr) J Am Coll Cardiol 2005;45(Suppl A):75A. 19. Kereiakes DJ, Kuntz RE, Mauri L, Krucoff MW. Surrogates, substudies, and real clinical end points in trials of drug-eluting stents J Am Coll Cardiol 2005;45:1206-1212.[Free Full Text] 20. Moliterno DJ. Healing Achilles—sirolimus versus paclitaxel N Engl J Med 2005;353:724-726.[Free Full Text] 21. Hayward JA, Chapman D. Biomembrane surfaces as models for polymer design: the potential for haemocompatibility Biomaterials 1984;5:135-142.[CrossRef][Web of Science][Medline] 22. Schwartz RS, Burke SE, Cromack K, et al. Marked neointimal inhibition from a drug eluting stent: effects of local ABT-578 in the porcine coronary model(abstr) Circulation 2006;106(Suppl II):II448. 23. Carter AJ, Brodeur A, Hasting W, et al. The effects of a diffusion barrier on the elution characteristics of ABT-578 via a phosphorylcholine matrix(abstr) J Am Coll Cardiol 2006;47(Suppl B):3B. 24. Ellis SG, Vandormael MG, Cowley MJ, et al. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease: implications for patient selection Circulation 1990;82:1193-1202. 25. van der Zwet PM, Reiber JH. A new approach for the quantification of complex lesion morphology: the gradient field transform: basic principles and validation results J Am Coll Cardiol 1994;24:216-224.[Abstract] 26. Sonoda S, Morino Y, Ako J, et al. SIRIUS Investigators Impact of final stent dimensions on long-term results after sirolimus-eluting stent implantation: serial intravascular ultrasound analysis from the SIRIUS trial J Am Coll Cardiol 2004;43:1959-1963.[Abstract/Free Full Text] 27. Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS)A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478-1492.[Free Full Text] 28. Ako J, Morino Y, Honda Y, et al. Late incomplete stent apposition after sirolimus eluting stent implantation: a serial intravascular ultrasound analysis J Am Coll Cardiol 2005;46:1002-1005.[Abstract/Free Full Text] 29. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome Circulation 1999;100;:1872-1878. 30. Meredith IT, Ormiston J, Whitbourn R, et al. First-in-human study of the Endeavor ABT-578-eluting phosphorylcholine-encapsulated stent system in de novo native coronary artery lesions: Endeavor I Trial EuroInterv 2005;2:157-164.
This article has been cited by other articles:
|
|
|
|
 
J-S Kim, I-K Jang, J-S Kim, T H Kim, M Takano, T Kume, N W Hur, Y-G Ko, D Choi, M-K Hong, et al.
Optical coherence tomography evaluation of zotarolimus-eluting stents at 9-month follow-up: comparison with sirolimus-eluting stents
Heart,
December 1, 2009;
95(23):
1907 - 1912.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Kirtane, R. Patel, C. O'Shaughnessy, P. Overlie, B. McLaurin, S. Solomon, L. Mauri, P. Fitzgerald, J. J. Popma, D. E. Kandzari, et al.
Clinical and Angiographic Outcomes in Diabetics From the ENDEAVOR IV Trial: Randomized Comparison of Zotarolimus- and Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease
J. Am. Coll. Cardiol. Intv.,
October 1, 2009;
2(10):
967 - 976.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. T. Meredith, S. Worthley, R. Whitbourn, D. L. Walters, D. McClean, M. Horrigan, J. J. Popma, D. E. Cutlip, A. DePaoli, M. Negoita, et al.
Clinical and Angiographic Results With the Next-Generation Resolute Stent System: A Prospective, Multicenter, First-in-Human Trial
J. Am. Coll. Cardiol. Intv.,
October 1, 2009;
2(10):
977 - 985.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Chevalier, S. Silber, S.-J. Park, E. Garcia, G. Schuler, H. Suryapranata, J. Koolen, K. E. Hauptmann, W. Wijns, M.-C. Morice, et al.
Randomized Comparison of the Nobori Biolimus A9-Eluting Coronary Stent With the Taxus Liberte Paclitaxel-Eluting Coronary Stent in Patients With Stenosis in Native Coronary Arteries: The NOBORI 1 Trial--Phase 2
Circ Cardiovasc Interv,
June 1, 2009;
2(3):
188 - 195.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Byrne, J. Mehilli, R. Iijima, S. Schulz, J. Pache, M. Seyfarth, A. Schomig, A. Kastrati, and for the Intracoronary Stenting and Angiographic Re
A polymer-free dual drug-eluting stent in patients with coronary artery disease: a randomized trial vs. polymer-based drug-eluting stents
Eur. Heart J.,
April 2, 2009;
30(8):
923 - 931.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Colombo and R. T. Gerber
Should dual antiplatelet therapy after drug-eluting stents be continued for more than 1 year?: Dual Antiplatelet Therapy After Drug-Eluting Stents Should Not Be Continued for More Than 1 Year and Preferably Indefinitely
Circ Cardiovasc Interv,
December 1, 2008;
1(3):
226 - 232.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Chevalier, C. Di Mario, F.-J. Neumann, F. Ribichini, P. Urban, J. J. Popma, P. J. Fitzgerald, D. E. Cutlip, D. O. Williams, J. Ormiston, et al.
A Randomized, Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of Zotarolimus- Versus Paclitaxel-Eluting Stents in De Novo Occlusive Lesions in Coronary Arteries: The ZoMaxx I Trial
J. Am. Coll. Cardiol. Intv.,
October 1, 2008;
1(5):
524 - 532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. van der Hoeven, S.-S. Liem, J. Dijkstra, S. C. Bergheanu, H. Putter, M. L. Antoni, D. E. Atsma, M. Bootsma, K. Zeppenfeld, J. W. Jukema, et al.
Stent Malapposition After Sirolimus-Eluting and Bare-Metal Stent Implantation in Patients with ST-Segment Elevation Myocardial Infarction: Acute and 9-Month Intravascular Ultrasound Results of the MISSION! Intervention Study
J. Am. Coll. Cardiol. Intv.,
April 1, 2008;
1(2):
192 - 201.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. E. Kip, K. Hollabaugh, O. C. Marroquin, and D. O. Williams
The Problem With Composite End Points in Cardiovascular Studies The Story of Major Adverse Cardiac Events and Percutaneous Coronary Intervention.
J. Am. Coll. Cardiol.,
February 19, 2008;
51(7):
701 - 707.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Pocock, A. J. Lansky, R. Mehran, J. J. Popma, M. P. Fahy, Y. Na, G. Dangas, J. W. Moses, T. Pucelikova, D. E. Kandzari, et al.
Angiographic surrogate end points in drug-eluting stent trials: a systematic evaluation based on individual patient data from 11 randomized, controlled trials.
J. Am. Coll. Cardiol.,
January 1, 2008;
51(1):
23 - 32.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Bode and M. Zehender
The use of antiplatelet agents following percutaneous coronary intervention: focus on late stent thrombosis
Eur. Heart J. Suppl.,
August 1, 2007;
9(suppl_D):
D10 - D19.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Dixon, C. L. Grines, and W. W. O'Neill
The Year in Interventional Cardiology
J. Am. Coll. Cardiol.,
July 17, 2007;
50(3):
270 - 285.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Daemen and P. W. Serruys
Drug-Eluting Stent Update 2007: Part I: A Survey of Current and Future Generation Drug-Eluting Stents: Meaningful Advances or More of the Same?
Circulation,
July 17, 2007;
116(3):
316 - 328.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, J. Narula, D. J. Sahn, et al.
Highlights of the Year in JACC 2006
J. Am. Coll. Cardiol.,
January 30, 2007;
49(4):
509 - 527.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods