This study was designed to prospectively evaluate the safety and efficacy of the 38-mm Resolute zotarolimus-eluting stent (R-ZES). Drug-eluting stents with long lengths are needed to ensure coverage of long lesions in some patients. Patients recruited from the RESOLUTE US and RESOLUTE Asia studies were implanted with at least one 38-mm R-ZES. Up to 2 lesions (in separate vessels) could be implanted with length ≤35 mm and a reference vessel diameter of 3.0 to 4.2 mm. The primary end point was 1-year target lesion failure, defined as cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. The 1-year target lesion failure rate using 1 vessel per patient was compared with a performance goal (19%) derived from historical data. There were 223 patients enrolled (n = 269 lesions). The mean age was 60.9 ± 10.9 years, 79% were men, and 38% had diabetes. Target lesion failure rate using a single-vessel analysis was 4.5%, and the upper limit of the 1-sided 95% confidence interval (7.5%) was less than the performance goal of 19%. A secondary analysis using all lesions resulted in a target lesion failure rate of 5.4% (upper limit of 1-sided 95% confidence interval, 8.6%). Baseline characteristics and clinical outcomes were similar between patients with and without diabetes. The rate of probable or definite stent thrombosis was 0.9%. In conclusion, the 38-mm length of the R-ZES was found to be safe and effective with a low rate of target lesion failure and stent thrombosis and no differences in outcomes between patients with and without diabetes.
Drug-eluting stents have been found to be efficacious and cost-effective in complex disease subgroups such as long lesions. Use of multiple, overlapping, first-generation drug-eluting stents has led to greater periprocedural myocardial ischemia, stent fracture, and late stent thrombosis related to impaired vascular healing compared with using a single longer stent. Although studies of overlapping stents using new-generation drug-eluting stents have shown more promising results, the advantages of stenting long lesions with fewer long stents remain. Drug-eluting stents with a length of 38 mm can cover lesions of ≤35 mm using a single stent. Studies of new-generation 38-mm drug-eluting stents have demonstrated safety and efficacy at 1-year follow-up. To date, however, no study has reported data regarding the use of the Resolute zotarolimus-eluting stent (R-ZES; Medtronic Inc, Santa Rosa, California) in the 38-mm size. The safety and efficacy of the 38-mm R-ZES at 1 year after implantation were investigated in a prospective substudy of the RESOLUTE US (R-US; ClinicalTrials.gov , NCT00726453 ) and RESOLUTE Asia (R-Asia; ClinicalTrials.gov , NCT01132456 ) studies, both of which were part of the RESOLUTE Global Clinical Program.
Methods
In the RESOLUTE 38-mm substudy, patients were enrolled from the R-US and R-Asia prospective, observational, nonrandomized, multicenter trials. The RESOLUTE 38-mm substudy was prospectively designed to include patients requiring treatment of de novo lesions in native coronary arteries from the R-Asia and R-US trials. The study methods for R-US have been described previously. The study methods for the RESOLUTE 38-mm substudy are briefly described here.
Included patients were enrolled at 46 clinical sites in the United States, Bangladesh, India, Hong Kong, Malaysia, Singapore, and Thailand. Patients were enrolled in the R-US from January 2010 through March 2011 and R-Asia from June 2010 through March 2011. R-US and R-Asia trials were performed in accordance with the International Conference on Harmonisation Good Clinical Practices guidelines. Institutional review boards approved clinical activities at all sites, and all patients provided written informed consent before enrollment.
Patients were ≥18 years old and considered to be candidates for revascularization with a single target lesion or 2 target lesions in separate vessels—at least 1 of which required implantation with a 38-mm stent. Patients were excluded for pregnancy, contraindications to drug-eluting stents or drugs used in the study, and serious cardiovascular or circulatory co-morbidities. Lesion length in enrolled patients was ≤35 mm and reference vessel diameter was 3.0 to 4.2 mm.
Study stents were 38 mm in length and 3.0, 3.5, or 4.0 mm in diameter. Patients were prescribed dual antiplatelet therapy (aspirin and clopidogrel, ticlopidine, or prasugrel) for a minimum of 6 months. Aspirin was continued indefinitely thereafter. Patient follow-up occurred at 30 days, 6, 9, and 12 months, with planned follow-up at 18 months and annually through 5 years.
Clinical monitoring was conducted on case report forms and other documentation from 100% of patients enrolled in the study. The Harvard Clinical Research Institute (Boston, Massachusetts) conducted data management for R-US. Medtronic, Inc. (the sponsor of both studies) conducted data management for R-Asia. Data safety monitoring boards were used for patient safety surveillance and clinical events committees were used for event adjudication. These committees were coordinated by the Harvard Clinical Research Institute for the R-US and the Cardiovascular Research Foundation for the R-Asia. The Harvard Clinical Research Institute Safety Group prepared reports of pooled data between the studies for review by the data safety monitoring boards.
The primary end point was target lesion failure at 1 year after procedure, a composite of cardiac death, target vessel myocardial infarction (MI; Q wave and non–Q wave), or clinically driven target lesion revascularization by percutaneous or surgical methods.
All deaths were considered cardiac unless an unequivocal noncardiac cause could be established. Major adverse cardiac event was a composite of death, target vessel MI (Q wave and non–Q wave), emergent coronary artery bypass graft, or clinically driven repeat target lesion revascularization by percutaneous or surgical methods. Target vessel failure was a composite of cardiac death, target vessel MI, or clinically driven target vessel revascularization by percutaneous or surgical methods. Target vessel MI events presented in this study were adjudicated according to extended historical criteria. Stent thrombosis was adjudicated using Academic Research Consortium criteria.
Lesion success was defined as <50% residual stenosis of the target lesion using any percutaneous method. Device success was defined as <50% residual stenosis of the target lesion using only the assigned device. Procedure success was defined as <50% residual stenosis of the target lesion and no in-hospital major adverse cardiac events.
The primary analysis of the pooled 38-mm substudy was the 1-year target lesion failure rate compared with a prespecified performance goal that met the Food and Drug Administration requirements. The performance goal was derived from a logistic regression model based on all patients implanted with the Endeavor zotarolimus-eluting stent or Driver bare-metal stent (both of Medtronic Inc, Santa Rosa, California) in the ENDEAVOR stent clinical program. The predicted rates of target lesion failure were calculated for patients with Endeavor zotarolimus-eluting stent and bare-metal stent with a lesion length of 31 mm (average of 27 and 35 mm), and the performance goal was set at 19%, which is >48% the expected target lesion failure rate for patients with Endeavor zotarolimus-eluting stent and preserves 51% of the benefit compared with bare-metal stent. Therefore, the study hypothesis was that the study population would have a 1-year target lesion failure rate of <19%. A 1-sided upper 95% confidence interval of the 38-mm R-ZES 1-year target lesion failure rate was calculated. If this upper limit was <19%, the clinical objective would be considered to have been met.
The ENDEAVOR studies used to derive the performance goal only from enrolled patients with single-vessel treatment, but the RESOLUTE 38-mm substudy enrolled patients with dual vessels treated. To ensure continuity with the historical data, therefore, the primary analysis of the target lesion failure end point was based on a single vessel for all dual-vessel treated patients. For dual-vessel treated patients with 38-mm R-ZES implanted in both vessels, 1 vessel or lesion was randomly selected as the target vessel or lesion and the other was considered to be the nontarget vessel or lesion. For dual-vessel treated patients with 1 vessel implanted with a 38-mm R-ZES and the other vessel without a 38-mm R-ZES, the vessel or lesion implanted with the R-ZES 38-mm was considered to be the target vessel or lesion. A clinical event that was clearly not attributed to the target vessel was not included in the target vessel analysis. The target lesion failure rate counting all lesions was also calculated as a secondary analysis.
Data were not imputed for primary or secondary end point analyses. Secondary end point analyses were conducted using similar statistical techniques as in the primary end point analysis.
At a 1-sided 0.05 level of significance, a sample size of 199 evaluable patients yields 80% power to test the hypothesis, assuming that the true 38-mm R-ZES 1-year target lesion failure rate is 12.8%. Accounting for 10% loss to follow-up rate, a total sample size of 221 patients was needed.
Comparability between the cohorts of patients with 38-mm drug-eluting stents in R-US and R-Asia was assessed using a 2-stage prespecified analysis. The first stage assessed the homogeneity of the covariates between the 2 cohorts. Some of the baseline covariates were significantly different between the cohorts; those covariates were adjusted using propensity scores to account for any covariate imbalances. The second stage was to categorize patients into quintiles based on this propensity score. The 85% confidence interval of propensity score quintile–adjusted difference between the cohorts in target lesion failure at 1 year was calculated. Because the 85% confidence interval crossed zero, the 2 cohorts were considered poolable.
SAS, version 9.1, or higher (SAS Institute, Cary, North Carolina) was used for all statistical analyses. p Values <0.05 were considered statistically significant.
Results
There were 223 patients included in the analysis, 114 from R-US (29 sites) and 109 from R-Asia (17 sites), with a total of 269 lesions. A total of 222 (>99%) had follow-up data through 1 year. Patients had a mean age of 60.9 ± 10.6 years; most were men and a substantial portion had diabetes mellitus ( Table 1 ). Overall mean lesion length (n = 261) was 25.22 ± 8.83 mm ( Table 2 ).
| Characteristic | Value |
|---|---|
| Age (yrs) | 60.9 ± 10.6 |
| Men | 176 (79) |
| Diabetes mellitus | 84 (38) |
| Insulin-dependent diabetes mellitus | 23 (10) |
| Hypertension (history) ∗ | 167 (75) |
| Hyperlipidemia (history) † | 131 (59) |
| Current smoker | 42 (19) |
| Family history of coronary artery disease | 71 (37) |
| Previous MI | 70 (32) |
| Previous percutaneous coronary intervention | 61 (27) |
| Previous coronary artery bypass grafting | 16 (7) |
| Cardiac status | |
| Stable angina pectoris | 76 (39) |
| Unstable angina pectoris | 92 (47) |
| MI | 26 (13) |
∗ Defined as a history of systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mg Hg, or requiring medication.
† Defined as a history of cholesterol ≥200 mg/dl, low-density lipoprotein >100 mg/dl, or requiring medication.
| Characteristic | Value |
|---|---|
| Vessel disease status (patients) | |
| Single | 103/223 (46) |
| Double | 81/223 (36) |
| Triple | 39/223 (18) |
| Coronary artery location (patients) | |
| Left anterior descending | 116/223 (52) |
| Left circumflex | 45/223 (20) |
| Right | 99/223 (44) |
| Lesion location | |
| Proximal | 99/263 (38) |
| Mid | 115/263 (44) |
| Distal | 45/263 (17) |
| Ostial | 4/263 (2) |
| Lesion length (mm) | |
| <10 | 12/261 (5) |
| 10–19.9 | 64/261 (25) |
| ≥20 | 185/261 (71) |
| Branch vessel disease (lesions) | 126/263 (48) |
| B2/C lesions | 240/263 (91) |
| Lesion length (mm) | 25.22 ± 8.83 |
| Reference vessel diameter (mm) | 2.78 ± 0.42 |
| Minimum lumen diameter (mm) | 0.80 ± 0.36 |
| Preprocedural stenosis (% of diameter) | 71 ± 12 |
The rate of lesion success was 100% (n = 263 of 263), and device success was achieved in 97% (n = 257 of 265) of the lesions. The rate of procedure success was 96% (n = 210 of 218).
Dual antiplatelet therapy adherence was 92% (n = 205 of 222) at 1 month, 91% (n = 203) at 6 months, 90% (n = 199) at 9 months, and 90% (n = 196) at 1 year.
The primary end point was met with a rate of target lesion failure at 1 year of 4.5% (upper limit of 95% confidence interval 7.5%) using the prespecified single-vessel analysis, which was significantly lower than the performance goal of 19%. The 1-year rate of target lesion failure was 5.4% (upper limit of 95% confidence interval 8.6%) when all lesions in all vessels were included ( Figure 1 ). Most events (n = 10 of 12) occurred in the first 30 days. The rate of definite or probable stent thrombosis was 0.9% (n = 2), and both events occurred in the first 30 days ( Table 3 and Figure 2 ). There were no late definite or probable stent thrombosis events. Both patients who experienced definite or probable stent thrombosis events received dual antiplatelet therapy without interruption after stent placement. There were 12 patients who experienced a side branch occlusion (5%), 5 of whom experienced a target vessel MI.
| Outcome | Months | |||
|---|---|---|---|---|
| 1 (n = 223) | 6 (n = 223) | 9 (n = 223) | 12 (n = 222) | |
| Target lesion failure | 10 (4.5) | 10 (4.5) | 11 (4.9) | 12 (5.4) |
| Target vessel failure | 10 (4.5) | 11 (4.9) | 14 (6.3) | 15 (6.8) |
| Major adverse cardiac event | 10 (4.5) | 11 (4.9) | 12 (5.4) | 14 (6.3) |
| Cardiac death or target vessel MI | 9 (4.0) | 9 (4.0) | 10 (4.5) | 10 (4.5) |
| Death (all) | 1 (0.4) | 1 (0.4) | 2 (0.9) | 2 (0.9) |
| Cardiac only | 1 (0.4) | 1 (0.4) | 2 (0.9) | 2 (0.9) |
| Target vessel MI | 8 (3.6) | 8 (3.6) | 8 (3.6) | 8 (3.6) |
| Clinically driven target lesion revascularization | 2 (0.9) | 2 (0.9) | 2 (0.9) | 3 (1.4) |
| Target vessel revascularization | 2 (0.9) | 3 (1.3) | 5 (2.2) | 6 (2.7) |
| Early definite or probable stent thrombosis (0–30 days) | 2 (0.9) | NA | NA | NA |
| Late definite or probable stent thrombosis (1–12 mo) | NA | 0 | 0 | 0 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
