Long-term outcomes are imperative to confirm safety of drug-eluting stents. There have been 2 randomized controlled trials comparing everolimus-eluting stents (EESs) and Resolute zotarolimus-eluting stents (ZES-Rs). To date, long-term clinical outcomes of these stents were limited to only 1 report, which has recently reported 4-year comparisons of these stents. Therefore, more evidence is needed regarding long-term clinical outcomes of the second-generation stents. This study compared the long-term clinical outcomes of EES with ZES-R in “all-comer” cohorts up to 3-year follow-up. The EXCELLENT and RESOLUTE-Korea registries prospectively enrolled 3,056 patients treated with EES and 1,998 with ZES-R, respectively, without exclusions. Stent-related composite outcomes (target lesion failure) and patient-related composite events up to 3-year follow-up were compared in crude and propensity score–matched analyses. Of 5,054 patients, 3,830 patients (75.8%) had off-label indication (2,217 treated with EES and 1,613 treated with ZES-R). The stent-related outcome (189 [6.2%] vs 127 [6.4%], p = 0.812) and the patient-related outcome (420 [13.7%] vs 250 [12.5%], p = 0.581) did not differ between EES and ZES-R, respectively, at 3 years, which was corroborated by similar results from the propensity score–matched cohort (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.70 to 1.20, p = 0.523 and 0.85, 95% CI 0.70 to 1.02, p = 0.081, for stent- and patient-related outcomes, respectively). The rate of definite or probable stent thrombosis up to 3 years (22 [0.7%] vs 10 [0.5%], p = 0.370) was also similar. The rate of very late definite or probable stent thrombosis was very low and comparable between the 2 stents (3 [0.1%] vs 1 [0.1%], p = 0.657). In multivariate analysis, chronic renal failure (adjusted HR 3.615, 95% CI 2.440 to 5.354, p <0.001) and off-label indication (adjusted HR 1.782, 95% CI 1.169 to 2.718, p = 0.007) were the strongest predictors of target lesion failure at 3 years. In conclusion, both stents showed comparable safety and efficacy at 3-year follow-up in this robust real-world registry with unrestricted use of EES and ZES-R. Overall incidences of target lesion failure and definite stent thrombosis, including very late stent thrombosis, were low, even in the patients with off-label indications, suggesting excellent long-term safety and sustained efficacy of both types of second-generation drug-eluting stents.
Highlights
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Long-term outcomes are imperative to confirm safety of drug-eluting stents. Despite its wide use in routine clinical practice, only a few long-term data, comparing second-generation everolimus-eluting stents (EESs) versus Resolute zotarolimus-eluting stents (ZES-R), have been reported.
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To date, long-term clinical outcomes of these stents were limited to only 1 report, which has recently reported 4-year comparisons of EES and ZES-R. Therefore, more evidence is needed regarding long-term clinical outcomes of the second-generation stents.
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The study evaluated the long-term safety and efficacy of the Xience V/Promus EES and Resolute ZES up to 3-year follow-up in everyday real-world use from large prospective registries of these DESs.
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Our study showed that the occurrence of stent- and patient-related outcomes was comparable between the 2 stents up to 3 years of follow-up after unrestricted use of EES and ZES-R. The low rates of individual outcomes and definite stent thrombosis, including very late stent thrombosis, even in patients with off-label indications, suggest the long-term durability of the efficacy and safety of both second-generation DESs.
Second-generation drug-eluting stents (DESs), developed with the purpose of improving long-term safety, have almost completely replaced the first-generation DESs in the treatment of coronary artery disease. This has mostly been due to the representative second-generation DES, Xience V/Promus everolimus-eluting stent (EES; Abbott Vascular, Santa Clara, California), which showed sustained safety and efficacy up to 3 years in comparisons with first-generation DESs. Another second-generation DES, the Resolute zotarolimus-eluting stent (ZES-R; Medtronic Cardiovascular, Minneapolis, Minnesota) showed comparable clinical outcomes up to 2-year follow-up, compared with EES, and is also used often in daily routine practice. Although 4-year comparison of these stents was recently published, long-term clinical outcomes of these stents were limited only to this report despite its wide use in routine clinical practice, especially regarding the ZES-R. Thus, more data about their everyday use are needed. Previously, we published the 1-year comparison of EES versus ZES-R in 5,054 patients from 2 multicenter all-comers registries (the EXCELLENT and RESOLUTE-Korea registries). The purpose of this study was to evaluate the long-term safety and efficacy of the Xience V/Promus EES and Resolute ZES up to 3-year follow-up in everyday real-world use from large prospective registries of these DESs.
Methods
Extended description of study methods including statistical analysis is presented in Supplementary Data . This study evaluated 3-year clinical outcomes of Xience V/Promus EES and Resolute ZES from 2 prospective multicenter registries: the EXCELLENT and RESOLUTE-Korea, which enrolled all-comers treated with ≥1 EESs or ZES-R (3,056/29 and 1,998/25 patients/participating centers, respectively) without exclusions ( Supplementary Figure 1 ). The study protocol was approved by the ethics committee at each participating center and was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent.
During the enrollment period of each registry, the EES was available in diameters of 2.25, 2.50, 2.75, 3.00, 3.50, and 4.00 mm, with each available in lengths of 8, 12, 15, 18, 23, and 28 mm. In contrast, the ZES was available in diameters of 2.25, 2.50, 2.75, 3.00, 3.50, and 4.00 mm and in lengths of 8 and 14 mm for stents with a diameter of ≤2.5 mm; 9, 15, and 38 mm for stents with a diameter of ≥3.00 mm; and 12, 14, 18, 24, and 30 mm for all available stent diameters. Coronary interventions were performed according to current standard techniques. The choice of the stent, predilatation, poststenting adjunctive balloon inflation, and the use of intravascular ultrasound or glycoprotein IIb/IIIa inhibitors were left to the operators’ discretion. All patients received a loading dose of aspirin or were on long-term therapy before the procedure. A loading dose of 300 to 600 mg of clopidogrel was administered to all patients who were not taking clopidogrel before the procedure. After procedure, all patients were given aspirin (at least 100 mg/day) indefinitely and clopidogrel (75 mg/day) for at least 6 months after the index procedure. The decision to obtain cardiac biomarkers and electrocardiograms after procedure, as well as maintenance of dual antiplatelet therapy (DAPT) beyond 6 months, was left to the treating physician.
After the index PCI, follow-ups were performed at 1, 3, 9, 12 months and annually thereafter; angiography was optional at 9 months. Clinical follow-up data were obtained at outpatients visits or if not feasible, by telephone and/or medical questionnaire. At each follow-up session, regardless of outpatient visits, telephone, and/or medical questionnaire, detailed medication data including aspirin, clopidogrel, or other angina medications were collected. All relevant medical records were reviewed for any clinical event and adjudicated by an external clinical event committee. Using the Korean health system’s unique identification numbers, the vital status of all patients was crosschecked. Therefore, even in patients who were lost to follow-up, the occurrence of mortality was confirmed. All the medical records, follow-up, and events data were collected through electronic case report forms with strict security measures (T&W software, Seoul, Korea).
The primary outcome (stent related) was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (MI, not clearly attributed to a non–target vessel), or a clinically indicated target lesion revascularization (TLR) at 3 years. The major secondary outcome, the patient-oriented composite events (POCE), included all-cause mortality, any MI (including non–target vessel territory), and any revascularization. Other secondary outcomes included individual components of TLF and POCE, and stent thrombosis (ST) defined as definite, probable, or possible. All clinical outcomes, including ST, were defined according to the Academic Research Consortium, including the addendum to the definition of MI. The indication of PCI was considered “off label” if any of the following features were present: serum creatinine concentration ≥140 μmol/L (1.6 mg/dl); left ventricular ejection fraction <30%; an acute MI within the previous 72 hours; >1 lesion per vessel; ≥2 vessels treated with a stent; a lesion length ≥28 mm; or a bifurcated lesion, bypass graft, in-stent restenosis, unprotected left main coronary artery, presence of thrombus, or total occlusion, as with the previous randomized controlled trials.
The statistical analysis was performed in 2 parts. First, analysis of primary and secondary clinical outcomes was performed in the crude population. Second, a propensity score–matched population was selected to adjust for uneven distribution of baseline characteristics. Kaplan-Meier analysis was used to calculate cumulative incidence of primary and secondary clinical outcomes, and the log-rank test was used to compare between-group differences. A logistic regression model was conducted to generate propensity score, which was the probability that a patient received a ZES-R. The adjusted covariates that were used to calculate the propensity score are listed in the Supplementary Methods . For matching, nearest neighbor matching with a caliper width of 0.6 SD was used because this value has been shown to eliminate >90% of the bias in the observed confounders. The discrimination and calibration abilities of propensity score model were assessed by C statistics (0.637) and the Hosmer-Lemeshow statistics (p = 0.515). To reduce possible confounding factors from the differences in baseline characteristics, multivariate-adjusted stratified Cox proportional hazard regression to find independent predictors of TLF and exploratory subgroup analysis was performed in propensity score–matched cohorts. All probability values were 2-sided, and p values <0.05 were considered statistically significant.
Results
A total of 5,054 patients (7,084 lesions) were enrolled (EES group: 3,056 patients/4,248 lesions and ZES-R group: 1,998 patients/2,836 lesions). The flow of the study patients is shown in Supplementary Figure 1 . Through 3 years, 110 (3.5%) and 120 patients (6.0%) were lost to follow-up in the EES and ZES-R groups, respectively. However, all were confirmed to be alive. The distribution of cardiac risk factors was similar, except for dyslipidemia, lesion complexity, and left main disease ( Tables 1 and 2 ). High-risk patients and lesions were frequent, implying that our registries were an enriched PCI population, reflecting real-world practice in Korea. The device, lesion, and procedure success rates were excellent and similar for both stents ( Table 2 ).
| Variable | Total (N = 5054) | EES (N = 3056) | ZES-R (N = 1998) | p Value |
|---|---|---|---|---|
| Age (years) | 63.9 ± 10.8 (5054) | 63.9 ± 10.8 (3056) | 63.9 ± 10.9 (1998) | 0.897 |
| Male | 3419/5054 (67.6%) | 2053/3056 (67.2%) | 1366/1998 (68.4%) | 0.389 |
| BMI (kg/m 2 ) | 24.9 ± 9.32 (4892) | 25.0 ± 11.8 (2935) | 24.8 ± 3.1 (1957) | 0.333 |
| Diabetes mellitus | 1855/5029 (36.9%) | 1149/3031 (37.9%) | 706/1998 (35.3%) | 0.068 |
| Hypertension | 3251/5025 (64.7%) | 1980/3027 (65.4%) | 1271/1998 (63.6%) | 0.195 |
| Dyslipidemia | 3268/5017 (65.1%) | 1850/3019 (61.3%) | 1418/1998 (71.0%) | <0.001 |
| Peripheral artery disease | 80/4989 (1.6%) | 47/2991 (1.6%) | 33/1998 (1.7%) | 0.909 |
| Chronic renal failure † | 186/5017 (3.7%) | 105/3019 (3.5%) | 81/1998 (4.1%) | 0.321 |
| Current smoker | 1506/4971 (30.3%) | 893/2998 (29.8%) | 613/1973 (31.1%) | 0.344 |
| Previous percutaneous coronary intervention | 757/5035 (15.0%) | 440/3041 (14.5%) | 317/1998 (15.9%) | 0.184 |
| Previous coronary bypass | 87/5039 (1.7%) | 56/3041 (1.8%) | 31/1998 (1.6%) | 0.507 |
| Previous MI | 326/5034 (6.5%) | 212/3036 (7.0%) | 114/1998 (5.7%) | 0.079 |
| Previous heart failure | 102/4992 (2.0%) | 62/2994 (2.1%) | 40/1998 (2.0%) | 0.919 |
| Previous stroke | 395/4996 (7.9%) | 250/2998 (8.3%) | 145/1998 (7.3%) | 0.181 |
| Family history of CAD | 263/4898 (5.4%) | 171/2900 (5.9%) | 92/1998 (4.6%) | 0.053 |
| LV ejection fraction | 58.8 ± 11.4 (4453) | 59.3 ± 11.4 (2714) | 58.0 ± 11.4 (1739) | <0.001 |
| LVEF <30% | 75/4453 (1.7%) | 41/2714 (1.5%) | 34/1739 (2.0%) | 0.283 |
| Clinical indication for PCI | <0.001 | |||
| Stable angina pectoris | 1696/5036 (33.7%) | 1095/3038 (36.0%) | 601/1998 (30.1%) | <0.001 |
| Unstable angina pectoris | 1856/5036 (36.9%) | 1117/3038 (36.8%) | 739/1998 (37.0%) | 0.881 |
| Acute myocardial infarction | 1330/5036 (26.4%) | 729/3038 (24.0%) | 601/1998 (30.1%) | <0.001 |
| NSTEMI | 624/5036 (12.4%) | 344/3038 (11.3%) | 280/1998 (14.0%) | 0.005 |
| STEMI | 706/5036 (14.0%) | 385/3038 (12.7%) | 321/1998 (16.1%) | 0.001 |
| Silent ischemia | 154/5036 (3.1%) | 97/3038 (3.2%) | 57/1998 (2.9%) | 0.505 |
| No. of coronaries involved | <0.001 | |||
| 1 | 2207/5037 (43.8%) | 1424/3046 (46.7%) | 783/1991 (39.3%) | |
| 2 | 1597/5037 (31.7%) | 923/3046 (30.3%) | 674/1991 (33.9%) | |
| 3 | 1233/5037 (24.5%) | 699/3046 (22.9%) | 534/1991 (26.8%) | |
| No. of treated lesions/patient | 1.49 ± 0.77 (5024) | 1.47 ± 0.74 (3038) | 1.53 ± 0.80 (1986) | 0.009 |
| At least 1 ISR | 373/5054 (7.4%) | 231/3056 (7.6%) | 142/1998 (7.1%) | 0.548 |
| At least 1 bifurcation | 832/5054 (16.5%) | 388/3056 (12.7%) | 444/1998 (22.2%) | <0.001 |
| At least 1 thrombotic total ‡ | 561/5054 (11.1%) | 293/3056 (9.6%) | 268/1998 (13.4%) | <0.001 |
| At least 1 small vessel § | 1033/5054 (20.4%) | 612/3056 (20.0%) | 421/1998 (21.1%) | 0.368 |
| At least 1 long lesion ¶ | 2215/5054 (43.8%) | 1240/3056 (40.6%) | 975/1998 (48.8%) | <0.001 |
| Multivessel PCI | 1569/5054 (31.0%) | 930/3056 (30.4%) | 639/1998 (32.0%) | 0.250 |
| GP IIb/IIIa antagonist use | 133/4759 (2.8%) | 61/2763 (2.2%) | 72/1996 (3.6%) | 0.004 |
| At least one off-label indication ‖ | 3830/5054 (75.8%) | 2217/3056 (72.5%) | 1613/1998 (80.7%) | <0.001 |
| Medication at discharge | ||||
| Aspirin | 4929/5018 (98.2%) | 2969/3030 (98.0%) | 1960/1988 (98.6%) | 0.126 |
| Clopidogrel | 4937/5017 (98.4%) | 2974/3027 (98.2%) | 1963/1990 (98.6%) | 0.301 |
| Statin | 4335/4998 (86.7%) | 2613/3023 (86.4%) | 1722/1975 (87.2%) | 0.468 |
| ACE inhibitor | 1843/4966 (37.1%) | 1113/3011 (37.0%) | 730/1955 (37.3%) | 0.810 |
| Angiotensin-II receptor blocker | 1562/4939 (31.6%) | 939/3016 (31.1%) | 623/1923 (32.4%) | 0.363 |
| Beta-blocker | 3159/4970 (63.6%) | 1853/3009 (61.6%) | 1306/1961 (66.6%) | <0.001 |
| Calcium-channel blocker | 1343/4931 (27.2%) | 830/3016 (27.5%) | 513/1915 (26.8%) | 0.577 |
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