Abstract
Background
Angiographic and clinical outcomes associated with coronary stents eluting the new molecular entity zotarolimus have been well characterized in a variety of geographies and patient subsets. The Endeavor Japan study is the first prospective clinical trial to evaluate the safety and efficacy of the Endeavor zotarolimus-eluting stent (ZES) in the treatment of Japanese patients with single de novo lesions in native coronary arteries.
Methods and materials
This nonrandomized, prospective, multicenter, single-arm trial of 99 subjects with inclusion criteria (elective percutaneous revascularization of single native de novo coronary artery lesions with length ≥14 and ≤27 mm with reference vessel diameters between 2.25 and 3.5 mm) selected to enhance statistical comparability to the ENDEAVOR II randomized study as historical control. The primary end point was target vessel failure (TVF) at 9 months.
Results
At 9 months, the TVF rate was 5.2%, compared with 7.9% in the ZES arm of ENDEAVOR II ( P =.412). Notable baseline differences between the Endeavor Japan and ENDEAVOR II populations were mean age (68.2 vs. 61.6 years; P <.001), diabetes (38.4% vs. 18.2%; P <.001), and unstable angina (4.6% vs. 30.3%; P <.001). Despite cohort differences, acute, 9-month, and 3-year clinical outcomes were similar in the two groups, as were 8-month angiographic indices. Finally, out to 3 years, no stent thrombosis was observed in Japanese subjects.
Conclusions
These findings demonstrate that, in a Japanese population, the Endeavor ZES has similar safety and efficacy compared with other geographies, with sustained clinical benefit and safety to 3 years.
1
Introduction
Compared with bare metal stents, a number of polymer-coated drug-eluting stents (DES) have been shown to significantly reduce angiographic and clinical restenosis and therefore repeat revascularization procedures , although late safety concerns have been raised with sirolimus- and paclitaxel-eluting DES platforms and their durable polymers . The Endeavor stent (Medtronic CardioVascular, Santa Rosa, CA, USA) combines a biocompatible phosphorylcholine polymer with a new molecular entity, zotarolimus, and has shown consistent safety and efficacy benefits across a broad range of lesion subsets and patient populations .
While reported results have been consistent, the novelty of the polymer and the drug eluted by the Endeavor platform raise important questions. In particular, whether or not genetic or racial variations might affect safety or effectiveness in Japanese patients has never been reported. This question was prospectively explored in order to support the regulatory approval processes and clinical practice guidelines in Japan.
The Endeavor Japan Study was a single-arm, multicenter, confirmatory, clinical trial using data from the ENDEAVOR II trial as a historical control . Endeavor Japan was prospectively designed to mimic the inclusion/exclusion criteria, procedures, event definitions, and angiographic analyses, including the use of identical core laboratories from ENDEAVOR II . These design features were selected specifically to enhance the poolability, statistical comparisons, and interpretability of the Endeavor stent performance in a Japanese population.
2
Methods
2.1
Study design and patient population
Endeavor Japan was a prospective, multicenter, single-arm, open-label study, enrolling 99 patients at 11 centers in Japan. The primary objective of the study was to evaluate the safety and efficacy of the Endeavor stent for the treatment of single de novo lesions in native coronary arteries.
Eligible subjects were aged 20 years or greater and had symptomatic ischemic heart disease due to stenotic lesions of native coronary arteries amenable to percutaneous treatment with stenting. Angiographic inclusion criteria included a single de novo lesion that had not been previously treated with any interventional procedure, ≥14 and ≤27 mm in length, with a reference vessel diameter ≥2.25 and ≤3.5 mm. Multivessel percutaneous coronary intervention (PCI) was not allowed in this trial.
Major clinical exclusion criteria were left ventricular ejection fraction <30%; myocardial infarction (MI) within the preceding 72 h; contraindications or allergy to aspirin, heparin, ticlopidine, cobalt, nickel, chromium, molybdenum, or sensitivity to contrast media; serum creatinine >2.0 mg/dl; platelet count <100,000 cells/mm 3 or >700,000 cells/mm 3 ; leukocyte count <3000 cells/mm 3 ; history of stroke or transient ischemic attack within the preceding 6 months; and any coronary interventional procedure within 30 days before or after the implantation of the study stent.
Principal angiographic exclusion criteria were a target lesion with any of the following characteristics: located in a native vessel distal to a bypass graft anastomosis; left main or aorto-ostial target location; severe calcification; evidence of thrombus; proximal to a >45° bend in vessel; or a target lesion involving a bifurcation. The target vessel was required to have at least TIMI Grade 2 flow.
Clinical follow-up was scheduled at 30 days and 9 months postprocedure; telephone and/or clinic visit assessments were scheduled at 6, 12, 24, 36, 48, and 60 months postprocedure. All patients were scheduled for angiographic follow-up at 8 months. Patients were asked to return for a full clinical follow-up if they had any repeat intervention, any diagnostic testing/imaging, or experienced any ischemic symptoms during follow-up. Intravascular ultrasound (IVUS) was performed at the investigators’ discretion.
The study was conducted in accordance with the Declaration of Helsinki and Japanese Good Clinical Practice Guidelines based on the International Conference on Harmonization–Good Clinical Practice Guidelines. The medical ethics committees of all sites approved the study protocol, and written informed consent was obtained from all patients.
2.2
Stent system
The Endeavor DES consists of a cobalt-based alloy stent with a phosphorylcholine coating that releases the drug zotarolimus. The synthetic phosphorylcholine drug carrier has an outer phospholipid portion that mimics the outer membrane of red blood cells and has been demonstrated to reduce thrombogenicity in vitro and in vivo . Zotarolimus is an analogue of sirolimus and was developed to prevent restenosis . The phosphorylcholine–zotarolimus formulation results in substantially all of the zotarolimus being eluted within 14 days of stent implantation.
2.3
Stent implantation and adjunctive drug therapies
The only thienopyridine available in Japan at the time of the Endeavor Japan study was ticlopidine. Subjects were required to have either a history of tolerating ticlopidine or tolerate a preprocedural 14-day trial period of ticlopidine 200 mg bid and be expected to be able to continue ticlopidine for at least 12 weeks following the index procedure. Prior to stent implantation, patients received a minimum of 200 mg aspirin and a 200-mg dose of ticlopidine. During the procedure, heparin was administered to maintain an activated clotting time ≥250 s. No glycoprotein IIb/IIIa inhibitors were available in Japan during the course of this study.
The target lesion was predilated with standard percutaneous transluminal balloon angioplasty. The investigational plan did not allow direct stenting of the target lesion or use of other procedures (e.g., cutting balloon or atherectomy). The predilatation balloon diameter had to be at least 0.5 mm smaller than the diameter of the planned stent, and balloon length had to be shorter than the lesion length.
Implantation of the Endeavor stent was performed according to the Instructions for Use, and the selected stent size was required to be 3 mm longer than the lesion length and predilated area.
Following the procedure, patients received 100 mg bid of aspirin and 200 mg bid of ticlopidine for a minimum of 12 weeks and then 100 mg qd of aspirin indefinitely.
2.4
Data management
The study was monitored by sponsor clinical research associates. Data was managed and analyzed by the Duke Clinical Research Institute (Durham, NC, USA). Suspected clinical events were identified by investigators and included all death, MI, revascularization procedures, stent thrombosis, bleeding, vascular complications, and cerebrovascular accident. All such events were adjudicated by an independent clinical events committee using prespecified criteria. An independent data and safety monitoring board periodically reviewed the progress of the study and safety data.
2.5
End points and definitions
The primary composite end point was target vessel failure (TVF; composite of target vessel revascularization, Q-wave or non–Q-wave MI, or cardiac death that could not be clearly attributed to a nontarget vessel) at 9 months postprocedure.
Secondary end points included major adverse cardiac events (MACE); clinically driven target lesion or vessel revascularization; in-stent and in-segment late loss; in-stent and in-segment binary angiographic restenosis (≥50% stenosis) and in-stent and in-segment minimal lumen diameter.
2.6
Long-term follow-up
Characterization of rarer safety events may be augmented by longer follow-up time periods. Thus, beyond the 9-month primary effectiveness end point, clinical follow-up for stent thrombosis, MI, cardiovascular death, and all death was completed annually. Of the planned 5-year follow-up, for this analysis the 3-year follow-up was completed for both the historical and study cohort in Japan.
2.7
Angiographic analysis
All images and findings from angiograms obtained at baseline, during the index procedure, and during the follow-up period, including unscheduled imaging, were evaluated by an independent angiographic core laboratory (Brigham and Women’s Angiographic Core Laboratory, Boston, MA, USA). Standard image acquisition was performed with two or more angiographic projections of the stenosis before and after stent placement. Qualitative analysis included the modified American College of Cardiology (ACC)/American Heart Association (AHA) classification of lesion morphology . Quantitative angiographic analysis was performed with a validated automated edge detection algorithm (Medis CMS, Leiden, The Netherlands) .
2.8
Statistical analysis
The main objective of this study was to evaluate the safety and efficacy of the Endeavor Coronary Stent System in a Japanese population. Estimates of the TVF rate at 9 months post-implant were based on a meta-analysis of previous clinical studies, at 13.6% for the bare metal stent. With a target sample size of 100 patients, the upper 95% confidence bound for the TVF rate could therefore be below 13.6% to demonstrate noninferiority compared to the uncoated metal stent.
All analyses were based on the intention-to-treat principle. Clinically relevant baseline and follow-up variables were tabulated. Mean, standard deviation, number of evaluable patients, and range were reported for continuous variables, and numbers and percentages were listed for categorical variables.
A secondary analysis, comparing data to the Endeavor DES arm of the ENDEAVOR II Trial, was also performed.
Statistical comparisons were performed using two-sided significance tests, unless otherwise specified. Where appropriate, a P value of .05 or less was considered statistically significant. All statistical analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC, USA).
2
Methods
2.1
Study design and patient population
Endeavor Japan was a prospective, multicenter, single-arm, open-label study, enrolling 99 patients at 11 centers in Japan. The primary objective of the study was to evaluate the safety and efficacy of the Endeavor stent for the treatment of single de novo lesions in native coronary arteries.
Eligible subjects were aged 20 years or greater and had symptomatic ischemic heart disease due to stenotic lesions of native coronary arteries amenable to percutaneous treatment with stenting. Angiographic inclusion criteria included a single de novo lesion that had not been previously treated with any interventional procedure, ≥14 and ≤27 mm in length, with a reference vessel diameter ≥2.25 and ≤3.5 mm. Multivessel percutaneous coronary intervention (PCI) was not allowed in this trial.
Major clinical exclusion criteria were left ventricular ejection fraction <30%; myocardial infarction (MI) within the preceding 72 h; contraindications or allergy to aspirin, heparin, ticlopidine, cobalt, nickel, chromium, molybdenum, or sensitivity to contrast media; serum creatinine >2.0 mg/dl; platelet count <100,000 cells/mm 3 or >700,000 cells/mm 3 ; leukocyte count <3000 cells/mm 3 ; history of stroke or transient ischemic attack within the preceding 6 months; and any coronary interventional procedure within 30 days before or after the implantation of the study stent.
Principal angiographic exclusion criteria were a target lesion with any of the following characteristics: located in a native vessel distal to a bypass graft anastomosis; left main or aorto-ostial target location; severe calcification; evidence of thrombus; proximal to a >45° bend in vessel; or a target lesion involving a bifurcation. The target vessel was required to have at least TIMI Grade 2 flow.
Clinical follow-up was scheduled at 30 days and 9 months postprocedure; telephone and/or clinic visit assessments were scheduled at 6, 12, 24, 36, 48, and 60 months postprocedure. All patients were scheduled for angiographic follow-up at 8 months. Patients were asked to return for a full clinical follow-up if they had any repeat intervention, any diagnostic testing/imaging, or experienced any ischemic symptoms during follow-up. Intravascular ultrasound (IVUS) was performed at the investigators’ discretion.
The study was conducted in accordance with the Declaration of Helsinki and Japanese Good Clinical Practice Guidelines based on the International Conference on Harmonization–Good Clinical Practice Guidelines. The medical ethics committees of all sites approved the study protocol, and written informed consent was obtained from all patients.
2.2
Stent system
The Endeavor DES consists of a cobalt-based alloy stent with a phosphorylcholine coating that releases the drug zotarolimus. The synthetic phosphorylcholine drug carrier has an outer phospholipid portion that mimics the outer membrane of red blood cells and has been demonstrated to reduce thrombogenicity in vitro and in vivo . Zotarolimus is an analogue of sirolimus and was developed to prevent restenosis . The phosphorylcholine–zotarolimus formulation results in substantially all of the zotarolimus being eluted within 14 days of stent implantation.
2.3
Stent implantation and adjunctive drug therapies
The only thienopyridine available in Japan at the time of the Endeavor Japan study was ticlopidine. Subjects were required to have either a history of tolerating ticlopidine or tolerate a preprocedural 14-day trial period of ticlopidine 200 mg bid and be expected to be able to continue ticlopidine for at least 12 weeks following the index procedure. Prior to stent implantation, patients received a minimum of 200 mg aspirin and a 200-mg dose of ticlopidine. During the procedure, heparin was administered to maintain an activated clotting time ≥250 s. No glycoprotein IIb/IIIa inhibitors were available in Japan during the course of this study.
The target lesion was predilated with standard percutaneous transluminal balloon angioplasty. The investigational plan did not allow direct stenting of the target lesion or use of other procedures (e.g., cutting balloon or atherectomy). The predilatation balloon diameter had to be at least 0.5 mm smaller than the diameter of the planned stent, and balloon length had to be shorter than the lesion length.
Implantation of the Endeavor stent was performed according to the Instructions for Use, and the selected stent size was required to be 3 mm longer than the lesion length and predilated area.
Following the procedure, patients received 100 mg bid of aspirin and 200 mg bid of ticlopidine for a minimum of 12 weeks and then 100 mg qd of aspirin indefinitely.
2.4
Data management
The study was monitored by sponsor clinical research associates. Data was managed and analyzed by the Duke Clinical Research Institute (Durham, NC, USA). Suspected clinical events were identified by investigators and included all death, MI, revascularization procedures, stent thrombosis, bleeding, vascular complications, and cerebrovascular accident. All such events were adjudicated by an independent clinical events committee using prespecified criteria. An independent data and safety monitoring board periodically reviewed the progress of the study and safety data.
2.5
End points and definitions
The primary composite end point was target vessel failure (TVF; composite of target vessel revascularization, Q-wave or non–Q-wave MI, or cardiac death that could not be clearly attributed to a nontarget vessel) at 9 months postprocedure.
Secondary end points included major adverse cardiac events (MACE); clinically driven target lesion or vessel revascularization; in-stent and in-segment late loss; in-stent and in-segment binary angiographic restenosis (≥50% stenosis) and in-stent and in-segment minimal lumen diameter.
2.6
Long-term follow-up
Characterization of rarer safety events may be augmented by longer follow-up time periods. Thus, beyond the 9-month primary effectiveness end point, clinical follow-up for stent thrombosis, MI, cardiovascular death, and all death was completed annually. Of the planned 5-year follow-up, for this analysis the 3-year follow-up was completed for both the historical and study cohort in Japan.
2.7
Angiographic analysis
All images and findings from angiograms obtained at baseline, during the index procedure, and during the follow-up period, including unscheduled imaging, were evaluated by an independent angiographic core laboratory (Brigham and Women’s Angiographic Core Laboratory, Boston, MA, USA). Standard image acquisition was performed with two or more angiographic projections of the stenosis before and after stent placement. Qualitative analysis included the modified American College of Cardiology (ACC)/American Heart Association (AHA) classification of lesion morphology . Quantitative angiographic analysis was performed with a validated automated edge detection algorithm (Medis CMS, Leiden, The Netherlands) .
2.8
Statistical analysis
The main objective of this study was to evaluate the safety and efficacy of the Endeavor Coronary Stent System in a Japanese population. Estimates of the TVF rate at 9 months post-implant were based on a meta-analysis of previous clinical studies, at 13.6% for the bare metal stent. With a target sample size of 100 patients, the upper 95% confidence bound for the TVF rate could therefore be below 13.6% to demonstrate noninferiority compared to the uncoated metal stent.
All analyses were based on the intention-to-treat principle. Clinically relevant baseline and follow-up variables were tabulated. Mean, standard deviation, number of evaluable patients, and range were reported for continuous variables, and numbers and percentages were listed for categorical variables.
A secondary analysis, comparing data to the Endeavor DES arm of the ENDEAVOR II Trial, was also performed.
Statistical comparisons were performed using two-sided significance tests, unless otherwise specified. Where appropriate, a P value of .05 or less was considered statistically significant. All statistical analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC, USA).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
