The RESOLUTE China Registry is a prospective, multicenter, all-comers, observational study of patients in China implanted with the Resolute zotarolimus-eluting stent (R-ZES). R-ZES was commercially available before the enrollment began. All patients suitable for R-ZES implantation according to applicable guidelines were candidates for enrollment at 30 centers and were treated per standard hospital practice. Dual antiplatelet therapy (DAPT) was prescribed for a minimum of 6 months per current European Society of Cardiology guidelines and the device instructions for use. There were 1,800 patients enrolled with a mean age of 61.3 ± 10.9 years, 76% of patients were men, and 61% had complex disease. DAPT use was 94% at 1 year. Target lesion failure (cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization) at 1 year was 3.5% (95% confidence interval 2.7% to 4.5%). The rate of cardiac death was 0.6%, target vessel myocardial infarction 2.3%, and clinically driven target lesion revascularization 0.9%. The 1-year rate of definite or probable stent thrombosis was 0.5% (8 of 1,750); 0.4% (7 of 1,750) occurred early (0 to 30 days) and 1 event occurred late (1 to 12 months). One stent thrombosis occurred in a patient who had an interruption of DAPT within the first month; all other stent thromboses occurred while on DAPT. Outcomes did not differ significantly between monitored and unmonitored patients (difference in target lesion failure, p = 0.264). In conclusion, the RESOLUTE China Registry confirms the safety and effectiveness of R-ZES in a large real-world Chinese population.
From 1990 to 2010, coronary heart disease moved from the seventh to second leading cause of death in China. The emerging challenge of treating cardiovascular disease in China has led to an increased interest in the assessment of outcomes in the Chinese population after drug-eluting stent (DES) implantation in this population. The Resolute zotarolimus-eluting stent (R-ZES; Medtronic Inc., Santa Rosa, California) has been shown to be safe and effective among all-comers populations in a European randomized study and an international registry that did not include sites in China. The RESOLUTE China Registry, the largest R-ZES study in the Chinese population, was designed to characterize real-world clinical outcomes of R-ZES in an all-comers population of Chinese patients requiring stent implantation. The 1-year outcomes of the RESOLUTE China Registry are described in this report.
Methods
The RESOLUTE China Registry was a closed-cohort observational study that prospectively enrolled patients from 30 sites. Patients were enrolled from December 2010 to March 2012. Patient follow-up was planned at 30 days, 6 months, and annually through 5 years. The study conformed to the Declaration of Helsinki, the protocol was approved by independent ethics committees for all sites, and all patients provided written informed consent before enrollment. The RESOLUTE China Registry was registered in ClinicalTrials.gov ( NCT01243749 ). The study design and oversight was directed by a steering committee of study investigators and a representative from the sponsor.
All patients who were aged ≥18 years and eligible for elective implantation of an R-ZES in ≥1 target lesions were candidates for enrollment. Patients were excluded if they had a known intolerance to materials or drugs used in the study, were pregnant or lactating, were highly unlikely to adhere to follow-up requirements, had a planned surgery within 6 months of the index procedure that required interruption of dual antiplatelet therapy (DAPT), or had previously enrolled in the RESOLUTE China Registry.
Stent implantation was done according to routine hospital practice, applicable guidelines, and the R-ZES instructions for use. Investigators were advised to attempt treatment of all lesions with R-ZES, but implantation of other stents was permitted. If delivery failure occurred or there were insufficient R-ZES available, any DES or bare-metal stent could be implanted. The protocol recommended DAPT using aspirin and clopidogrel 75 mg each for 3 days before procedure or a periprocedural loading dose of aspirin 250 to 500 mg and clopidogrel 300 to 600 mg. The protocol further recommended aspirin 75 mg indefinitely and clopidogrel for at least 6 months (R-ZES instructions for use and European guidelines) and up to 12 months (American guidelines). DAPT use could be continued beyond 12 months by the physician’s decision.
Site monitoring (R&G PharmaStudies Co Ltd, Shanghai, China) was prespecified to be conducted at all sites to verify 100% of informed consent forms and source data from 50% of patients. Additional monitoring was conducted based on clinical events committee–adjudicated events. Data management and statistical analysis were undertaken by the sponsor.
Clinical outcomes studied in this registry included target lesion failure (TLF; defined as cardiac death, target vessel myocardial infarction [Q wave and non–Q wave], or clinically driven target lesion revascularization) and Academic Research Consortium definite or probable stent thrombosis. Other outcomes analyzed included target vessel failure (cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization), major adverse cardiac events (MACEs; death, myocardial infarction, emergent coronary artery bypass graft, or clinically driven target lesion revascularization), a composite outcome (death, myocardial infarction, or any revascularization), significant bleeding complications, and the components of composite outcomes. Deaths were considered cardiac unless an unequivocal noncardiac cause could be established. Revascularization could have been by percutaneous or surgical methods. Target vessel myocardial infarction and myocardial infarction were adjudicated according to the extended historical definition.
A bleeding complication was defined as a procedure-related hemorrhagic event that required a transfusion or surgical repair (including hematoma requiring treatment of retroperitoneal bleeding). A significant bleeding complication was defined as intracranial bleeding or bleeding that led to DAPT interruption, required transfusion, or resulted in substantial hemodynamic compromise requiring treatment.
Effectiveness was measured as attainment of <50% residual stenosis at the target lesion using any percutaneous method (lesion success), using only the assigned device (device success), or resulting in no in-hospital MACE (procedure success).
Complex patient status was defined as having ≥1 of the following characteristics: serum creatinine level ≥140 μmol/L, left ventricular ejection fraction <30%, acute myocardial infarction (within 72 hours), >1 lesion per vessel, ≥2 vessels stented, lesions of >27 mm, bifurcation, bypass graft, in-stent restenosis, unprotected left main, thrombus, or total occlusion.
Outcomes were adjudicated by an independent clinical events committee comprised of cardiologists who were not participants in the study. Clinical event adjudication definitions were the same as those used in other studies comprising the RESOLUTE Global Clinical Program. Safety oversight was provided by a data safety monitoring board composed of 2 cardiologists and a statistician not participating in the study. Safety data were reviewed on a regular basis, and the board could recommend early study closure to the sponsor and steering committee. The Cardiovascular Research Foundation (New York, New York) coordinated the clinical events committee and data safety monitoring board.
All analyses were conducted according to the intention-to-treat principle, and no data imputation for missing values was performed. Descriptive statistics and 95% confidence intervals were calculated for clinically relevant variables.
The sample size was calculated assuming a 1-year TLF rate of 6.8%, which was derived from the E-Five registry. The E-Five registry used a similar all-comers registry design to the RESOLUTE China Registry, used the first-generation ZES approved in China at the time of sample size calculation (Endeavor, Medtronic Inc, Santa Rosa, California), and included sites in China. A sample size of 1,800 patients would provide a 95% confidence interval with a 1.2% margin of error and would allow for a maximum of 5% rate of loss to follow-up.
Baseline characteristics and outcomes through 1 year of follow-up were compared between monitored and unmonitored patients, and descriptive statistics were done for key subgroups: men, women, bifurcation, diabetes, multivessel treatment, chronic total occlusion, acute coronary syndromes, long lesion (>27 mm), small vessel (<2.5 mm), ST-segment elevation myocardial infarction, and non–ST-segment elevation myocardial infarction or unstable angina. To adjust for differences in baseline patient characteristics between groups, propensity scores were calculated using logistic regression with treatment group as the dependent variable and the covariates as the predictors. The baseline characteristics included in the propensity score models were age, sex, diabetes, current smoker, hyperlipidemia, hypertension, previous myocardial infarction, previous coronary artery bypass graft, unstable angina or myocardial infarction, lesion in left ascending artery, B2/C lesion, moderate-to-severe calcification, tortuosity ≥45°, Thrombolysis In Myocardial Infarction flow 3, reference vessel diameter, lesion length, and percent diameter stenosis.
The effect of DAPT adherence on definite or probable stent thrombosis events through 1 year of follow-up was analyzed. Patients were grouped according to the time of first interruption of either aspirin or thienopyridine therapy after procedure. Patients were included in this analysis if they started on DAPT within 1 day after stent implantation, had no previous stent thrombosis events observed during the study, and had follow-up data available regarding the DAPT use. The association between DAPT adherence and stent thrombosis events was analyzed in 3 main groups: patients with no interruption, interruption during the first month after procedure, and interruption during 1 to 12 months after procedure.
Statistical analyses were performed using SAS software, version 9.1 or later (SAS Institute, Cary, North Carolina). p Values <0.5 were considered statistically significant.
Results
There were 1,800 patients with 2,320 lesions enrolled, and follow-up at 1 year was 97% (n = 1,750). Baseline patient demographic and clinical characteristics are listed in Table 1 , and lesion characteristics are listed in Table 2 . The mean age of the patients was 61.3 ± 10.9 years, 76% were men, and 61% were complex. Most patients were treated in de novo lesions (98%, n = 2,281). Lesion success was 100% (2,319 of 2,320), device success was 97% (2,244 of 2,320), and procedure success was 98% (1,763 of 1,799). Predilatation was used in 83% (1,919 of 2,320) and direct stenting in 17% (401 of 2,320) of lesions. Overlapping stents were used in 20% (n = 368) of patients (507 lesions). Glycoprotein IIb/IIIa inhibitors were used in 16% (n = 317 of 1,937) of procedures. DAPT use was 96% (n = 1,712 of 1,780) at 6 months and 94% (n = 1,633 of 1,730) at 1 year.
| Characteristic | All Patients (n = 1,800) | Monitored (n = 898) | Unmonitored (n = 902) | p Value ∗ |
|---|---|---|---|---|
| Age (yrs) | 61.3 ± 10.9 | 61.1 ± 10.9 | 61.5 ± 10.8 | 0.458 |
| Men | 1,361 (76) | 672 (75) | 689 (76) | 0.476 |
| Current smoker | 644 (36) | 318 (35) | 326 (36) | 0.768 |
| Diabetes mellitus | 528 (29) | 265 (30) | 263 (29) | 0.877 |
| Insulin dependent | 19 (1) | 4 (<1) | 15 (2) | 0.019 |
| Hyperlipidemia | 735 (41) | 377 (42) | 358 (40) | 0.338 |
| Hypertension | 1,148 (64) | 579 (64) | 569 (63) | 0.556 |
| Previous myocardial infarction | 642/1,788 (36) | 323/891 (36) | 319/897 (36) | 0.768 |
| Revascularization for angina or myocardial infarction | 0.607 | |||
| Silent angina | 45/1,783 (3) | 24/886 (3) | 21/897 (2) | |
| Stable angina | 133/1,783 (8) | 59/886 (7) | 74/897 (8) | |
| Unstable angina | 1,045/1,783 (58) | 524/886 (59) | 521/897 (58) | |
| Acute myocardial infarction | 560/1,783 (31) | 279/886 (32) | 281/897 (31) | |
| Serum creatinine (μmol/L) | 80.43 ± 31.80 | 78.74 ± 27.60 | 82.10 ± 35.41 | 0.029 |
| Complex patients † | 1,102 (61) | 537 (60) | 565 (63) | 0.227 |
∗ Comparing monitored and unmonitored.
† Complex patients had 1,550 lesions (67%). Refer to the Methods section for the definition of complex patient status.
| Characteristic | All Patients (n = 1,800 Patients; n = 2,320 Lesions) | Monitored (n = 898 Patients; n = 1,129 Lesions) | Unmonitored (n = 902 Patients; n = 1,191 Lesions) | p Value ∗ |
|---|---|---|---|---|
| Vessel location (patients) | ||||
| Left anterior descending | 1,120 (62) | 552 (62) | 568 (63) | 0.528 |
| Left circumflex | 416 (23) | 195 (22) | 221 (24) | 0.163 |
| Right | 577 (32) | 282 (31) | 295 (33) | 0.579 |
| Left main | 40 (2) | 19 (2) | 21 (2) | 0.873 |
| Saphenous vein graft | 13 (1) | 5 (1) | 8 (1) | 0.580 |
| Left/right internal mammary artery | 2 (<1) | 2 (<1) | 0 | 0.249 |
| Chronic total occlusion (lesions) | 167 (7) | 89 (8) | 78 (7) | 0.228 |
| Class B2/C (lesions) | 1,570 (68) | 756 (67) | 814 (68) | 0.478 |
| Bifurcation (lesions) | 345 (15) | 164 (15) | 181 (15) | 0.683 |
| Lesion length (mm) | 24.91 ± 13.73 | 24.93 ± 14.54 | 24.89 ± 12.93 | 0.945 |
| Preprocedural reference vessel diameter (mm) | 3.03 ± 0.50 | 3.02 ± 0.50 | 3.03 ± 0.51 | 0.846 |
| Preprocedural minimal lumen diameter (mm) | 0.49 ± 0.56 | 0.48 ± 0.53 | 0.50 ± 0.59 | 0.278 |
| Preprocedural diameter stenosis (%) | 84.06 ± 17.77 | 84.42 ± 17.00 | 83.71 ± 18.46 | 0.334 |
| Number of lesions treated per patient | 1.4 ± 0.7 | 1.4 ± 0.7 | 1.4 ± 0.7 | 0.836 |
| Total stent length per patient (mm) | 42.2 ± 28.3 | 42.14 ± 29.29 | 42.34 ± 27.31 | 0.878 |
| Total stent length per lesion (mm) | 29.5 ± 15.5 | 29.48 ± 16.16 | 29.51 ± 14.77 | 0.960 |
| Number of stents per patient | 1.8 ± 1.1 | 1.79 ± 1.07 | 1.79 ± 1.03 | 0.997 |
| Number of stents per lesion | 1.3 ± 0.5 | 1.26 ± 0.55 | 1.26 ± 0.52 | 0.784 |
The primary outcome of 1-year TLF was 3.5% (n = 61 of 1,750, 95% confidence interval 2.7% to 4.5%; Table 3 and Figure 1 ) and was primarily driven by target vessel myocardial infarction. There were 8 total events of definite or probable stent thrombosis: 7 early (≤30 days) and 1 late (31 to 360 days; Table 3 and Figure 1 ). The rate of significant bleeding complications was 1.4% (n = 25 of 1,750) at 1 year, and 5 of these 25 patients received glycoprotein IIb/IIIa inhibitors at stent implantation.
| Clinical Event | All Patients (n = 1,750) | Monitored (n = 873) | Unmonitored (n = 877) | Adjusted p Value ∗ |
|---|---|---|---|---|
| TLF | 61 (3.5) | 34 (3.9) | 27 (3.1) | 0.264 |
| Target vessel failure | 68 (3.9) | 37 (4.2) | 31 (3.5) | 0.331 |
| MACE | 70 (4.0) | 40 (4.6) | 30 (3.4) | 0.142 |
| Composite outcome | 109 (6.2) | 62 (7.1) | 47 (5.4) | 0.083 |
| Cardiac death or target vessel myocardial infarction | 52 (3.0) | 30 (3.4) | 22 (2.5) | 0.197 |
| Death or target vessel myocardial infarction | 60 (3.4) | 36 (4.1) | 24 (2.7) | 0.078 |
| Death | 20 (1.1) | 10 (1.1) | 10 (1.1) | 0.900 |
| Cardiac death | 11 (0.6) | 4 (0.5) | 7 (0.8) | 0.413 |
| Noncardiac death | 9 (0.5) | 6 (0.7) | 3 (0.3) | 0.283 |
| Target vessel myocardial infarction | 41 (2.3) | 26 (3.0) | 15 (1.7) | 0.062 |
| Clinically driven target lesion revascularization | 16 (0.9) | 6 (0.7) | 10 (1.1) | 0.396 |
| Clinically driven target vessel revascularization | 25 (1.4) | 10 (1.1) | 15 (1.7) | 0.412 |
| Definite/probable stent thrombosis | 8 (0.5) | 1 (0.1) | 7 (0.8) | 0.089 |
| Early (≤30 days) | 7 (0.4) | 1 (0.1) | 6 (0.7) | 0.126 |
| Late (31–360 days) | 1 (0.1) | 0 | 1 (0.1) | 0.902 |
| Significant bleeding | 25 (1.4) | 14 (1.6) | 11 (1.3) | 0.462 |
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