Abstract
Background
Drug-eluting stents have shown promising clinical results in the treatment of acute coronary syndrome (ACS) patients. We aimed to evaluate the long-term outcome of Endeavor® zotarolimus-eluting stent (EZES) implantation in an ACS population and to compare these results with those obtained in patients treated with sirolimus-eluting (SES) and paclitaxel-eluting stents (PES).
Methods
This prospective study included 1481 consecutive ACS patients (72% myocardial infarction, age 65 ± 13 years, 62% male) treated with a drug-eluting stent: (SES, n = 925; PES, n = 417; EZES, n = 139). The primary end point was major adverse cardiac events (MACE) at 2 years, defined as the composite of death, myocardial infarction, and target vessel revascularization. Two-year follow-up was obtained in all patients.
Results
Baseline clinical and angiographic characteristics were mostly similar. Unadjusted 2-year MACE and death rates were lower in the EZES group than in the SES and PES groups (MACE: 18.7% vs. 25.3% vs. 30.2%, p = 0.02; death: 10.1% vs. 16.4% vs. 22.2%, p = 0.002, respectively). The rate of definite stent thrombosis at 2 years was lower in the EZES group without statistically significant difference (0.7% vs. 2.9% SES vs. 1.7% PES, p = 0.16). After adjusting for differences in baseline characteristics, EZES use was an independent correlate for 2-year MACE (vs. SES, hazard ratio 0.65, p = 0.049; vs. PES, hazard ratio 0.57, p = 0.01).
Conclusion
In an ACS patient population, a lower long-term MACE rate was observed in patients treated with an EZES when compared to treatment with first-generation drug-eluting stents. The use of EZES in contemporary practice has excellent long-term outcome in terms of low rates of revascularization and clinical events.
1
Introduction
First-generation drug-eluting stents, namely the CYPHER® (Cordis Corporation, Miami Lakes, FL) sirolimus-eluting stent (SES) and the TAXUS® (Boston Scientific, Natick, MA) paclitaxel-eluting stent (PES), have markedly reduced neointimal hyperplasia when compared to bare metal stents . Late and very late stent thromboses are concerning and have emerged as significant hazards necessitating prolonged dual antiplatelet therapy . These limitations led to the development of second-generation drug-eluting stents with superior designs that incorporate biocompatible polymers, thinner struts, and new stent alloys. Zotarolimus, a sirolimus analogue, is an immunosuppressive agent with a shorter half-life . The Endeavor® zotarolimus-eluting stent (EZES; Medtronic, Santa Rosa, CA) has been shown to reduce clinical and angiographic restenosis when compared to bare metal stents, and has comparable clinically-driven target lesion revascularization rates compared to first-generation drug-eluting stents . There are limited data comparing EZES with first-generation drug-eluting stents in “real-world” patients with acute coronary syndrome (ACS). This registry, Registry Experience at the Washington Hospital Center, drug-eluting stents — Endeavor for Myocardial Infarction (REWARDS-EMI), aimed to evaluate the long-term outcome of implanted EZES in a non-selective, real-world, ACS population and to compare the results with those obtained in patients treated with first-generation SES and PES.
2
Methods
The treatment group included consecutive patients who presented with ACS and received an EZES at our institution from 2008 to 2010. This patient group was then compared with consecutive ACS patients treated with first-generation SES and PES. All patients were treated with only 1 stent type. The primary objective was to assess clinical success and safety of ACS patients who received an EZES. All included patients provided written informed consent. The study complied with the Declaration of Helsinki for investigation in humans and was approved by the institutional ethics committee.
Interventional strategy was at the discretion of the operating interventional cardiologist. All patients received aspirin 325 mg before the procedure and were recommended to continue this regimen indefinitely. In addition, clopidogrel 75 mg/day was given after a 300- or 600-mg loading dose and was subsequently continued for 12 months. Cardiac history, baseline demographics, and angiographic data were prospectively collected; however, data analysis was performed retrospectively. Patients were followed via telephone or written survey for all major adverse cardiovascular events (MACE) during index hospitalization and at 30 days, 6 months, 1- and 2 years after stent implantation.
General inclusion criteria included: Patient age > 18 years and presentation with an ACS. Events were adjudicated by a Clinical Events Committee. The Clinical Events Committee was established prior to the initiation of this study to adjudicate MACE and other events throughout the study. The Clinical Events Committee consisted of two interventional cardiologists, independent from the clinical investigation, who reviewed unmonitored data that included, but were not limited to, case report form pages, hospital and clinical records, angiographic data, core lab data, and electrocardiogram reports. Baseline data included clinical and angiographic characteristics. Patients were followed at 30 days, 6 months, and annually for up to 2 years’ post-initial stent implantation. Follow up patient information was transcribed onto study case report forms. All data were analyzed and stored in a secure database within the Cardiovascular Research Institute Data Coordinating Center at our institution.
The primary end point was MACE at 2 years defined as the composite of death, myocardial infarction, and target vessel revascularization. ACS was defined as ST-segment deviation of > 1 mm or an elevation of the isoenzymes > 2 × the upper limit of normal (either CK-MB or troponin I). Myocardial infarction was defined as a total creatinine kinase increase ≥ 2×x the upper limit of normal and/or CK-MB ≥ 20 ng/ml, together with symptoms and/or ischemic electrocardiographic changes. Hypercholesterolemia was defined as fasting cholesterol > 250 mg/dl or the use of lipid-lowering therapy. Systemic hypertension was defined as blood pressure > 140/90 mmHg or the use of antihypertensive therapy. Renal impairment was defined as serum creatinine > 1.2 mg/dl. Congestive heart failure was defined as evidence of fluid retention from cardiac causes before admission. Target lesion revascularization was defined as ischemia-driven percutaneous or surgical repeat intervention in the stent or within 5 mm proximal or distal to the stent. Stent thrombosis was defined in accordance with the Academic Research Consortium definitions as definite or probable stent thrombosis.
Statistical analysis was performed using SAS version 8.2 (SAS Institute, Cary, NC). Continuous variables and categorical variables are expressed as mean ± SD and percentages, respectively. Analyses of differences among the 3 drug-eluting stents were performed using analysis of variance for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. After univariable analysis for baseline clinical and procedural characteristics, the following characteristics with p<0.1 were incorporated into the multivariable analysis to assess independent association with MACE: Stent type used, history of coronary artery disease, hypertension, left ventricular ejection fraction, diabetes mellitus, number of diseased vessels, left anterior descending artery disease, American College of Cardiology/American Heart Association (ACC/AHA) lesion type classification, number of treated lesions per patient, maximum stent length and diameter, number of implanted stents, acute myocardial infarction at presentation, and clopidogrel compliance. The results are presented as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Survival, survival free from MACE, and survival free from MACE and myocardial infarction were performed using the Kaplan–Meier method, and differences in parameters were assessed using the log-rank test. P values < 0.05 were considered statistically significant.
2
Methods
The treatment group included consecutive patients who presented with ACS and received an EZES at our institution from 2008 to 2010. This patient group was then compared with consecutive ACS patients treated with first-generation SES and PES. All patients were treated with only 1 stent type. The primary objective was to assess clinical success and safety of ACS patients who received an EZES. All included patients provided written informed consent. The study complied with the Declaration of Helsinki for investigation in humans and was approved by the institutional ethics committee.
Interventional strategy was at the discretion of the operating interventional cardiologist. All patients received aspirin 325 mg before the procedure and were recommended to continue this regimen indefinitely. In addition, clopidogrel 75 mg/day was given after a 300- or 600-mg loading dose and was subsequently continued for 12 months. Cardiac history, baseline demographics, and angiographic data were prospectively collected; however, data analysis was performed retrospectively. Patients were followed via telephone or written survey for all major adverse cardiovascular events (MACE) during index hospitalization and at 30 days, 6 months, 1- and 2 years after stent implantation.
General inclusion criteria included: Patient age > 18 years and presentation with an ACS. Events were adjudicated by a Clinical Events Committee. The Clinical Events Committee was established prior to the initiation of this study to adjudicate MACE and other events throughout the study. The Clinical Events Committee consisted of two interventional cardiologists, independent from the clinical investigation, who reviewed unmonitored data that included, but were not limited to, case report form pages, hospital and clinical records, angiographic data, core lab data, and electrocardiogram reports. Baseline data included clinical and angiographic characteristics. Patients were followed at 30 days, 6 months, and annually for up to 2 years’ post-initial stent implantation. Follow up patient information was transcribed onto study case report forms. All data were analyzed and stored in a secure database within the Cardiovascular Research Institute Data Coordinating Center at our institution.
The primary end point was MACE at 2 years defined as the composite of death, myocardial infarction, and target vessel revascularization. ACS was defined as ST-segment deviation of > 1 mm or an elevation of the isoenzymes > 2 × the upper limit of normal (either CK-MB or troponin I). Myocardial infarction was defined as a total creatinine kinase increase ≥ 2×x the upper limit of normal and/or CK-MB ≥ 20 ng/ml, together with symptoms and/or ischemic electrocardiographic changes. Hypercholesterolemia was defined as fasting cholesterol > 250 mg/dl or the use of lipid-lowering therapy. Systemic hypertension was defined as blood pressure > 140/90 mmHg or the use of antihypertensive therapy. Renal impairment was defined as serum creatinine > 1.2 mg/dl. Congestive heart failure was defined as evidence of fluid retention from cardiac causes before admission. Target lesion revascularization was defined as ischemia-driven percutaneous or surgical repeat intervention in the stent or within 5 mm proximal or distal to the stent. Stent thrombosis was defined in accordance with the Academic Research Consortium definitions as definite or probable stent thrombosis.
Statistical analysis was performed using SAS version 8.2 (SAS Institute, Cary, NC). Continuous variables and categorical variables are expressed as mean ± SD and percentages, respectively. Analyses of differences among the 3 drug-eluting stents were performed using analysis of variance for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. After univariable analysis for baseline clinical and procedural characteristics, the following characteristics with p<0.1 were incorporated into the multivariable analysis to assess independent association with MACE: Stent type used, history of coronary artery disease, hypertension, left ventricular ejection fraction, diabetes mellitus, number of diseased vessels, left anterior descending artery disease, American College of Cardiology/American Heart Association (ACC/AHA) lesion type classification, number of treated lesions per patient, maximum stent length and diameter, number of implanted stents, acute myocardial infarction at presentation, and clopidogrel compliance. The results are presented as adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Survival, survival free from MACE, and survival free from MACE and myocardial infarction were performed using the Kaplan–Meier method, and differences in parameters were assessed using the log-rank test. P values < 0.05 were considered statistically significant.
3
Results
Overall, 1481 patients were analyzed. Of them, 925 received SES, 417 received PES, and 139 received EZES. As presented in Table 1 , the average age of the population was 65 ± 13 years (62% male); 72% presented with an acute myocardial infarction. Baseline patient characteristics were generally comparable among the 3 groups ( Table 1 ). Patients who received an SES had a higher body mass index; while patients who received an EZES had a lower incidence of cardiogenic shock (2.9%).
| Variable | Overall (n = 1481) | CYPHER (n = 925) | TAXUS (n = 417) | ENDEAVOR (n = 139) | p Value a |
|---|---|---|---|---|---|
| Age (years ± SD) | 65 ± 13 | 64 ± 13 | 65 ± 13 | 67 ± 12 | 0.15 |
| Men | 911 (62%) | 559 (61%) | 263 (63%) | 89 (64%) | 0.55 |
| Body mass index (kg/m 2 ) | 29 ± 6 | 29 ± 7 | 28 ± 6 | 28 ± 7 | 0.038 |
| European American | 956 (65%) | 598 (65%) | 261 (63%) | 97 (70%) | 0.31 |
| African American | 365 (25%) | 217 (24%) | 114 (27%) | 34 (25%) | 0.31 |
| Diabetes mellitus | 525 (36%) | 324 (36%) | 158 (38%) | 43 (31%) | 0.36 |
| Chronic renal failure | 260 (18%) | 148 (16%) | 87 (21%) | 25 (18%) | 0.1 |
| Systemic hypertension b | 1202 (81%) | 752 (82%) | 335 (81%) | 115 (83%) | 0.8 |
| Hypercholesterolemia c | 1241 (85%) | 776 (86%) | 340 (82%) | 125 (90%) | 0.08 |
| Smoker at time of procedure | 384 (26%) | 235 (25%) | 115 (28%) | 34 (24%) | 0.65 |
| Family history of coronary artery disease | 696 (50%) | 449 (52%) | 185 (47%) | 62 (45%) | 0.09 |
| Prior myocardial infarction | 557 (19%) | 340 (18%) | 153 (19%) | 64 (20%) | 0.72 |
| Prior percutaneous coronary intervention | 323 (23%) | 198 (23%) | 91 (23%) | 34 (26%) | 0.76 |
| Prior coronary artery bypass graft surgery | 248 (17%) | 146 (16%) | 75 (18%) | 27 (19%) | 0.45 |
| Prior heart failure | 224 (16%) | 138 (16%) | 61 (15%) | 27 (20%) | 0.44 |
| Peripheral vascular disease | 238 (16%) | 135 (15%) | 72 (17%) | 31 (22%) | 0.06 |
| Clinical presentation | |||||
| Myocardial infarction this admission | 1060 (72%) | 664 (72%) | 307 (74%) | 89 (64%) | 0.07 |
| Cardiogenic shock | 123 (8.5%) | 83 (9.2%) | 36 (8.8%) | 4 (2.9%) | 0.042 |
| Baseline troponin I (ng/cc) | 14.6 ± 50.6 | 16.8 ± 56.1 | 11.8 ± 42.9 | 7.2 ± 21.6 | 0.06 |
| Baseline left ventricular ejection fraction (%) | 44 ± 14 | 44 ± 14 | 45 ± 13 | 46 ± 14 | 0.18 |
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