Drug-eluting stents (DES) have been shown to significantly reduce rates of restenosis and target lesion revascularization (TLR) in patients with coronary artery disease when compared with bare-metal stents (BMS).1-4 The polymers in the first generation DES were considered to be associated with allergic reactions and inflammation, which in combination with incomplete strut endothelialization have led to early and late stent thrombosis.5,6
The Endeavor zotarolimus-eluting stent (ZES, Medtronic, Inc., Santa Rosa, California, USA) received Conformité Européenne Marking in August 2005 and United States Food and Drug Administration approval in February 2008. The safety and efficacy of the Endeavor ZES has been evaluated in a number of clinical trials, and the results consistently show low rates of angiographic restenosis and repeat revascularization as well as a favorable safety profile, with a low rate of late stent thrombosis beyond 12 months of follow-up.7,8
Although randomized controlled studies are the preferred trial methodology to evaluate new DES, clinical registries are able to provide insight into the performance of DES in broader patient populations as well as special patient subsets. The purpose of China Endeavor Registry study (E-China) was to evaluate real world clinical performance of the Endeavor ZES coronary system in Chinese patients.
Study design and patients
The E-China is a prospective, nonrandomized, multicenter registry conducted at 46 centers in China. The registry includes 2210 adult patients who underwent single-vessel or multi-vessel percutaneous coronary intervention (PCI) from November 2007 to September 2008. All patients with single and multiple coronary artery lesions suitable for stenting were eligible for recruitment in the registry. Consecutive patients for whom implantation with an Endeavor ZES was intended were enrolled at the time of stent implantation. Inclusion criteria were: >18 years of age, signed “Patient Informed Consent Form”, one or more native artery target lesions suitable for implantation of one or more Endeavor ZES, lesion length and vessel diameter of the target lesion(s) are according to the ‘Indications for Use’, and the patient is willing and able to cooperate with registry procedures and required follow up visits. Exclusion criteria were: women with known pregnancy or who are lactating; patients with hypersensitivity or allergies to aspirin, heparin, clopidogrel, drugs such as zotarolimus, rapamycin, tacrolimus, sirolimus or similar drugs, or any other analogue or derivative, cobalt, chromium, nickel, molybdenum or contrast media; contradiction to antiplatelet and/or anticoagulation therapy; a lesion that prevents complete inflation of an angioplasty balloon; current medical condition with a life expectancy of less than 12 months; the subject is participating in another device or drug study, and patients with medical conditions that preclude the follow-up as defined in the protocol or that otherwise limits participation in this registry. This study was conducted according to the Declaration of Helsinki. The medical ethics committees approved the study protocol at sites at which such approval was required. Written informed consent was obtained from all patients.
Before stent implantation, all patients received daily aspirin per their physician's usual practice and either clopidogrel 75 mg/d for 3 days before the procedure or a preprocedural loading dose of clopidogrel (at least 300 mg). The recommended maintenance regimen was clopidogrel 75 mg/d for at least 12 weeks and aspirin at least 100 mg/d indefinitely. Use of platelet glycoprotein IIb/IIIa inhibitor was allowed at physician discretion. Clinical follow-up was scheduled at 30 days, 6 months, and 12 months and consisted of telephone or in-office assessments. Patients were followed for 12 months to determine the mid-term clinical outcome of the index procedure.
Data collection and management
Data were recorded on case report forms. For quality control purposes, clinical sites were randomly monitored, and 50% of the data were monitored.
Study end points
The primary end point of this registry was the rate of major adverse cardiac events (MACE) at 12 months. For this study, we defined MACE as the composite end point of death, myocardial infarction (MI; Q wave and non-Q wave), emergent cardiac bypass surgery, or TLR (repeat percutaneous transluminal coronary angioplasty or coronary artery bypass graft). Non-Q wave MI was defined as elevated creatine kinase (CK) ≥2×the upper limit of normal with the presence of elevated CK-MB in the absence of new pathologic Q waves. Secondary end points were the rates of MACE at 30 days and 6 months; the per protocol stent thrombosis rate (early defined as 0 to 30 days; late defined as 31 to 360 days); and the procedural, device, and lesion success rates. Stent thrombosis (early and late) rates according to Academic Research Consortium (ARC) definitions were also analyzed.
We also evaluated event rates in patient subgroups known to have a higher risk of MACE, such as those with diabetes mellitus, acute myocardial infarction (AMI), and multi-vessel disease.
With an estimated event rate for MACE at 12 months of approximately 11% and with an assumed loss to follow-up rate of 10%, a sample size of 2200 patients was needed so that the 95% confidence interval of MACE at 12 months would not exceed 12.4%. Categorical variables were reported with percentages and counts, and continuous variables were reported with the means and standard deviations. The P values were calculated with a 2-sample t test for continuous variables or Fisher's exact test for categorical variables. P values <0.05 were considered statistically significant. Statistical analyses were performed with the SPSS 12.0 Software (SPSS, Inc., USA).
Patient demographic data and characteristics
In total, 2210 patients were enrolled. The mean age was (60.9±11.0) years, and 74.9% of patients were men (Table 1). The incidence of diabetes was 22.4%, acute coronary syndrome was 90.3%, and moderate-to-severe renal impairment was 1.2% (Table 1). Notably 35.2% (778/2210) patients presented with an AMI within 3 days.
Lesion and procedural characteristics
Lesion and procedural characteristics are reported in Table 2. The population included patients with single-vessel disease (80.9%) and multiple-vessel disease (19.1%). The average lesion length was (24.08±13.59) mm. In total, 47.62% of lesions were located in LAD and 4.84% were ostial lesions. The average stent length was (27.95±14.70) mm. The Endeavor ZES was the only stent implanted in 95.38% of lesions. Other lesions received a BMS (0.30%) or another DES (4.32%) in addition to the Endeavor ZES. The overall lesion success rate was 99.85%, and the overall procedure success rate was 99.32%.
At baseline and periprocedure, 99.04% of patients were taking aspirin plus clopidogrel, 11.9% of patients were taking a GP IIb/IIIa inhibitor. The percentage of patients taking dual antiplatelet therapy was 99.3% at 30 days, 98.9% at 6 months, and 86.6% at 12 months.
One-year clinical follow-up rate was 95.5% (2111/2210). The 12-month rate of MACE for all patients in the registry was 3.03% (Table 3). Cardiac death or MI rate was 1.28% and target lesion revascularization rate was 1.66%, non-target lesion target vessel revascularization (TVR) was 0.52%, TVR was 2.18%, and target vessel failure was 3.22%. There was only one case of emergent cardiac bypass surgery. The 12-month overall incidence of all ARC-defined stent thrombosis was 0.43%. At 12 months, the ARC definite and probable stent thrombosis rate was 0.33%. The ARC definite and probable late stent thrombosis rate was 0.14%.
The rates of MACE, TLR, and ARC definite and probable stent thrombosis at 12 months are reported for key subgroups in Table 4. There was no significant difference in rate of MACE between overall patients cohort (3.03%) and patients with diabetes (3.80%, P >0.05), patients with AMI (3.23%, P >0.05), female patients (3.21%, P >0.05), or patients with multi-vessel disease (4.67%, P >0.05). However rate of TLR was higher in patients with multi-vessel disease compared with overall patient cohort (4.67% vs. 1.66%, P <0.05).
This study reports 12-month clinical outcomes from a large Chinese registry of patients treated with the Endeavor ZES. These results, obtained from 46 heart centers, provide sufficient evidence for the safe and effective use of the Endeavor ZES in real world practice in Chinese patients. The results are consistent with previous clinical trials from western countries, and this study also included patients with high-risk characteristics and complex lesions that are usually excluded from randomized trials. Those patients included patients with diabetes, AMI and multi-vessel disease. Our data show risk of MACE was comparable between those patients and overall patient cohort, but patients with multi-vessel disease had more TLR.
One-year follow-up was completed in 95.5%, which represents good patient participation and compares favorably with 88% to 95% from other published studies.9-11 The overall 12-month MACE rate was 3.03%. It is important to note that in the E-China Registry the definition of MACE included emergent cardiac bypass surgery, as was the cases with other Endeavor trials, but not so for all DES registries.12 Comprehensive outcomes reported for the sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) in recent registry reports suggest that the Endeavor ZES performs similarly to other DES. A MACE rate of 5.8% at 12 months was reported for the SES in the e-Cypher registry. 13 The proportion of patients with SES-related thrombosis who were being treated with dual antiplatelet therapy was 84.1% in e-Cypher, and 71.5% of patients in ARRIVE with PES thrombosis were receiving dual antiplatelet therapy at 12 months.11,12 Patients receiving the Endeavor ZES experienced a low rate of stent thrombosis (0.43%), which could be due to the comparatively high use of dual antiplatelet therapy.14 The importance of adequate antiplatelet therapy during and after stent placement has been highlighted in a number of recent publications and is an element that can be highly variable in real-world patient populations. Premature discontinuation of antiplatelet agents has been shown to increase the incidence of stent thrombosis.15,16 In this registry, 86.6 % of patients at 12 months were taking dual antiplatelet therapy. It is unclear how long dual antiplatelet therapy should be continued, because late stent thrombosis is reported well beyond 12 months.17,18 We believe another important factor contributing to lower stent thrombosis rate may be related to the new polymer in this stent platform. The design characteristics of the Endeavor ZES were intended to optimize patient safety. Experimental results in animal models have indicated that the Endeavor ZES has improved healing responses and restored endothelial function compared with earlier DES, more closely resembling a BMS. Surrogate safety end points in patients, with optical coherence tomography have also shown beneficial responses with the Endeavor ZES compared with earlier DES.19
Prospective registry studies of Endeavor ZES from western countries have been reported prior to our study, but present trial is the first large registry study in Chinese patients. Compared with previous study, “better” performance of Endeavor ZES in the E-China could be due to the anthropological nature of the patients, different study enrollment period and study design, and we could not compare the actual data among those studies directly. A significant limitation of this study is the potential for underreporting of adverse events. Several measures, including random monitoring of 50% of patients enrolled and adjudication of events by review of electrocardiogram and laboratory values for MI and angiography for stent thrombosis and revascularization, were employed to minimize the occurrence of underreporting of adverse events. Longer follow-up of patients receiving the Endeavor ZES will be necessary to confirm the extended long-term safety of this DES.
In conclusion, mid-term results from the E-China Registry suggest that real-world outcomes among over 2200 Chinese patients with both simple and complex characteristics and coronary lesions are safe and effective. These 12-month results clearly provide evidence for the safety and effectiveness of the Endeavor ZES in real-world Chinese patients and are consistent with those reported in the previous ENDEAVOR trials.
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