Zotarolimus-eluting stents (ZESs) demonstrated greater in-segment late luminal loss and in-segment binary restenosis rates compared to sirolimus-eluting stents (SESs) in several studies. However, no data are available in direct comparison between the clinical outcomes of the 2 stents in unselected patients with ST-segment elevation acute myocardial infarction (STEMI). The aim of the present study was to compare the clinical outcomes of ZESs and SESs in real-world patients with STEMI. A total of 873 patients with STEMI (306 patients in the ZES group and 567 patients in the SES group) were enrolled in a nationwide prospective Korea Acute Myocardial Infarction Registry (KAMIR) from January 2007 to January 2008. The primary end points were major adverse cardiac events, a composite of all causes of death, myocardial infarction, and target lesion revascularization during a 12-month clinical follow-up. During 1 year of follow-up, the primary end points occurred in 140 patients (16.0%). The use of glycoprotein IIb/IIIa inhibitors and the occurrence of multivessel disease were more common in the SES group. The SES group had a significantly lower incidence of major adverse cardiac events (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.07 to 2.16, p = 0.02), target lesion revascularization (HR 2.16, 95% CI 1.01 to 4.59, p = 0.046), and target vessel revascularization (HR 2.24, 95% CI 1.18 to 4.24, p = 0.013). However, no significant differences were found in death or myocardial infarction (HR 1.37, 95% CI 0.91 to 2.05, p = 0.129). In conclusion, SESs provided superior angiographic outcomes, translating into better clinical outcomes and negating any change in STEMI patient safety profiles compared to ZESs.
Zotarolimus-eluting stents (ZESs) are second-generation drug-eluting stent, composed of a new antiproliferative agent and a cobalt-based alloy stent platform integrated with biocompatible phosphorylcholine polymer. This was expected to be less prone to thrombosis and to have efficacy similar to that of the first-generation drug-eluting stents. Randomized trials were performed to assess the efficacy and safety of ZESs. In the ENDEAVOR II trial, ZESs markedly reduced angiographic restenosis and target lesion revascularization compared to bare metal stents. A randomized comparison with sirolimus-eluting stents (SESs) in the ENDEAVOR III trial showed similar clinical outcomes (a composite of all-cause death, myocardial infarction, and clinically driven target lesion revascularization). Despite significantly greater angiographic restenosis and late luminal loss in ZES group, stent thrombosis did not occur in either the SES or ZES group. Nonetheless, these trials excluded those with high-risk clinical characteristics (eg, acute myocardial infarction, renal insufficiency, left systolic dysfunction) and complex lesions (eg, unprotected left main, ostial lesion, long lesion, small lesion). No data are available on the direct comparison of the clinical outcomes between the 2 stents in unselected high-risk patients with ST-segment elevation acute myocardial infarction (STEMI). The aim of the present study was to compare the clinical outcomes of ZESs and SESs in unselected patients with STEMI.
Methods
The study population, enrolled in a nationwide prospective Korea Acute Myocardial Infarction Registry (KAMIR) from January 2007 to January 2008, consisted of 873 patients with STEMI (62.5 ± 12.7 years old, 73.9% men) who had undergone percutaneous coronary intervention (PCI) with ZES (Endeavor, Medtronic Vascular, Santa Rosa, California) or SES (Cypher, Cordis, Johnson & Johnson, Miami Lakes, Florida) placement in the infarct-related artery. When multivessel stenting was performed, the same class of stent was implanted. The entire study population completed 1 year of follow-up.
The KAMIR, launched in November 2005, is a Korean prospective multicenter data collection registry reflecting real-world treatment practices and outcomes in Asian patients diagnosed with acute myocardial infarction. The registry consists of 50 community and teaching hospitals with facilities for primary PCI and on-site cardiac surgery. Data were collected by a trained study coordinator using a standardized case report form and protocol. The ethics committee at each participating institution approved the study protocol.
The eligible patients were ≥18 years old at hospital admission, had a suggestive history with ST-segment elevation >2 mm in ≥2 precordial leads or >1 mm in ≥2 limb leads, or a new onset of left bundle branch block on the 12-lead electrocardiogram with a concomitant increase of at least one cardiac biomarker of necrosis (eg, creatine kinase-MB, troponin I and T). Patients with cardiogenic shock, severe left ventricular dysfunction, or left main disease and those receiving rescue PCI after failed thrombolysis were included in the present study. Patients were excluded if they had a zotarolimus or sirolimus allergy, had any general contraindication to the revascularization procedure and pharmacologic therapies, or had undergone previous PCI or coronary artery bypass grafting of the infarct-related artery. Those with a life expectancy <12 months also failed to meet the criteria.
All patients received ≥100 mg of aspirin and a 300- to 600-mg loading dose of clopidogrel and unfractionated heparin (50 to 70 U/kg) to maintain an activated clotting time at >250 to 300 seconds before, or at, the procedure. Loading doses of aspirin and clopidogrel were administered after patients agreed to undergo PCI. The maintenance dose was 100 mg/day for aspirin and 75 mg/day for clopidogrel. Cilostazol was started in 198 patients (22.7%) after PCI. The loading and maintenance dosage was 200 and 100 mg twice daily. Cilostazol was administered for ≥1 month after the procedure. Coronary artery stenting was performed using the standard technique. The decision for predilation, direct stenting, postadjunctive balloon inflation, and the administration of glycoprotein (GP) IIb/IIIa receptor blockers were all left to the discretion of the operator. A GP IIb/IIIa receptor blocker was usually administered to patients with clear angiographic evidence of thrombus during the intervention. Clinical follow-up was performed at 1, 6, and 12 months. Follow-up angiography was recommended at 6 months after PCI or at any time if the presence of ischemia was suggested by clinical symptoms or noninvasive methods such as stress testing or cardiac imaging.
The primary end points were major adverse cardiac events (a composite of all-cause death, myocardial infarction, and target lesion revascularization) during the 12 months of clinical follow-up. Recurrent myocardial infarction was defined as recurrent symptoms with new electrocardiographic changes compatible with myocardial infarction or cardiac markers at least twice the upper limit of normal. Target lesion revascularization was defined as any revascularization of the target lesion because of restenosis or reocclusion within the stent or adjacent 5-mm border. The secondary end points were all-cause death or myocardial infarction, target lesion revascularization, target vessel revascularization, and stent thrombosis. Target vessel revascularization was defined as any revascularization for stenosis at the target vessel. Stent thrombosis was defined as definite and probable stent thrombosis according to the Academic Research Consortium definition. Major bleeding was defined as any intracranial bleeding, bleeding events associated with causing death, the need for surgery, or transfusion, or any other clinically relevant bleeding, as judged by the investigator.
Continuous variables are presented as the mean ± SD and were compared using the Student t test. The chi-square test or Fisher’s exact test was used to determine the significance of differences in the categorical variables. The Breslow-Day test was performed to assess the homogeneity of the relative risk for major adverse cardiac events across participating centers.
A propensity score analysis was performed to adjust potential confounders using a logistic regression model. All available variables considered potentially relevant were included: age, gender, coronary risk factors (eg, history of hypertension, diabetes mellitus, hypercholesterolemia, current smoker, and family history of coronary artery disease), previous myocardial infarction, systolic blood pressure, heart rate, Killip class on presentation, left ventricular ejection fraction, symptom to balloon interval, primary PCI performed, serum creatinine level, location of culprit coronary lesion, number of diseased vessels, lesion complexity, pre- and postprocedural Thrombolysis In Myocardial Infarction flow, stent length, diameter, clopidogrel loading dose, use of GP IIb/IIIa inhibitors, and discharge medications. The predicted accuracy of the logistic model was assessed using the area under the receiver operating characteristic curve (c statistic), which was 0.764. The major adverse cardiac events rates between the 2 groups were compared using Cox proportional hazard models adjusted by propensity score and important risk co-variables that had significant effects (p <0.1) in the univariate analysis for clinical outcomes. All statistical tests were 2-tailed, and p <0.05 was considered significant. Analyses were performed using the Statistical Package for Social Sciences, version 15.0 (SPSS-PC, Chicago, Illinois).
Results
A total of 873 patients with STEMI were included in the present study. The groups were divided according to the drug-eluting stent type (ZES group, 306 patients and SES group, 567 patients). No significant differences in the baseline characteristics were found between the 2 groups ( Table 1 ).
| Variable | ZES Group (n = 306) | SES Group (n = 567) | p Value |
|---|---|---|---|
| Age (years) | 62.8 ± 13.6 | 62.3 ± 12.2 | 0.541 |
| Men | 224 (73.2%) | 421 (74.3%) | 0.737 |
| Diabetes mellitus | 80 (26.2%) | 159/565 (28.1%) | 0.547 |
| Hypertension | 127 (41.6%) | 263/565 (46.5%) | 0.165 |
| Hypercholesterolemia | 27 (8.9%) | 62/565 (11.0%) | 0.332 |
| Current smoker | 152 (50.0%) | 274/563 (48.7%) | 0.708 |
| Family history of coronary artery disease | 20 (6.6%) | 44/565 (7.8%) | 0.524 |
| Previous myocardial infarction | 4 (1.3%) | 8 (1.4%) | 0.984 |
| Previous percutaneous coronary intervention on nonculprit artery | 7 (2.3%) | 18 (3.2%) | 0.847 |
| Killip class ≥III on presentation | 44/293 (15.0%) | 88/534 (16.5%) | 0.583 |
| Cardiogenic shock on presentation | 24/293 (8.2%) | 54/536 (10.1%) | 0.375 |
| Systolic blood pressure at presentation (mm Hg) | 24.9 ± 31.3 (295) | 123.4 ± 29.7 (557) | 0.484 |
| Heart rate on presentation (beats/min) | 77.6 ± 20.8 (295) | 76.7 ± 19.3 (557) | 0.561 |
| Thrombolysis In Myocardial infarction risk index | 27.4 ± 16.1 (295) | 26.1 ± 14.0 (557) | 0.229 |
| Ejection fraction (%) | 50.8 ± 13.6 (278) | 51.3 ± 12.2 (514) | 0.720 |
| Ejection fraction <30% | 12/278 (4.3%) | 18/514 (3.5%) | 0.567 |
| Symptom to balloon time (min) | 317.1 ± 531.6 (280) | 352.3 ± 531.1 (535) | 0.369 |
| Primary percutaneous coronary intervention | 253 (82.7%) | 475 (83.8%) | 0.678 |
| Serum creatinine (mg/dl) | 1.1 ± 0.6 (304) | 1.2 ± 1.4 (564) | 0.663 |
The coronary angiographic and procedural characteristics are listed in Table 2 . The location, stent number, severity, complexity of the infarct-related artery, and postprocedural Thrombolysis In Myocardial Infarction flow were similar in the 2 groups. However, the SES group had a smaller stent diameter, longer stent length, and greater incidence of 3-vessel disease. The use of GP IIb/IIIa inhibitors was more common in the SES group (144 [82.2%] of 175 patients during PCI, and 133 [76.0%] of 175 received abciximab).
| Variable | ZES Group (n = 306) | SES Group (n = 567) | p Value |
|---|---|---|---|
| Location of culprit coronary lesion | |||
| Left anterior descending | 172 (56.2%) | 324 (57.1%) | 0.790 |
| Left circumflex | 17 (5.6%) | 50 (8.8%) | 0.084 |
| Right | 110 (35.9%) | 183 (32.3%) | 0.273 |
| Left main | 7 (2.3%) | 10 (1.8%) | 0.593 |
| No. of coronary arteries narrowed | |||
| 1 | 160 (52.3%) | 238 (42.0%) | 0.004 |
| 2 | 79 (25.8%) | 170 (29.9%) | 0.196 |
| 3 | 67 (21.9%) | 159 (28.0%) | 0.049 |
| ACC/AHA lesion score | |||
| B2 | 81/288 (28.1%) | 118/497 (23.7%) | 0.174 |
| C | 146/288 (50.7%) | 249/497 (50.0%) | 0.817 |
| Preprocedure TIMI flow 0 | 179 (58.5%) | 333 (58.7%) | 0.873 |
| Stent diameter (mm) | 3.2 ± 0.5 | 3.1 ± 0.4 | 0.002 |
| Stent length (mm) | 23.7 ± 5.1 | 25.8 ± 6.1 | <0.001 |
| Stent No. per lesion (n) | 1.18 ± 0.51 | 1.19 ± 0.49 | 0.821 |
| Postprocedure TIMI flow | |||
| 0 | 2 (0.7%) | 4 (0.7%) | 0.943 |
| I | 4 (1.3%) | 8 (1.4%) | 0.919 |
| II | 12 (3.9%) | 29 (5.1%) | 0.326 |
| III | 288 (94.1%) | 526 (92.8%) | 0.371 |
| Clopidogrel 600 mg loading dose | 110 (35.9%) | 217 (38.3%) | 0.498 |
| Glycoprotein IIb/IIIa inhibitor use | 50 (16.3%) | 125 (22.0%) | 0.045 |
The discharge medications are listed in Table 3 . Between the 2 groups, no significant differences were present in the type of medications that affect the clinical outcome such as antiplatelet agents, β blockers, and angiotensin-converting enzyme inhibitors.
| Variable | ZES Group (n = 274) | SES Group (n = 523) | p Value |
|---|---|---|---|
| Aspirin | 266 (98.9%) | 517 (99.2%) | 0.621 |
| Clopidogrel | 265 (98.5%) | 515 (98.8%) | 0.689 |
| Cilostazol | 69 (25.7%) | 110 (21.1%) | 0.149 |
| Statin | 220 (81.8%) | 431 (82.7%) | 0.742 |
| Angiotensin-converting enzyme inhibitor | 195 (72.5%) | 354 (67.9%) | 0.189 |
| Angiotensin II receptor blocker | 25 (9.3%) | 62 (11.9%) | 0.267 |
| β Blocker | 200 (74.3%) | 397 (76.2%) | 0.566 |
| Calcium channel blocker | 14 (5.2%) | 37 (7.1%) | 0.304 |
The in-hospital mortality rates, incidence of acute stent thrombosis, and incidence of major bleeding events were similar between the 2 groups. The rate of follow-up coronary angiography in the ZES and SES groups was 40.5% (111 of 274) and 38.4% (201 of 523), respectively (p = 0.521). The SES group had a significantly lower incidence of major adverse cardiac events at the 12-month clinical follow-up examination ( Table 4 ). The test results for assessing the homogeneity of the relative risk across the centers were not significant for major adverse cardiac events (Breslow-day test, p = 0.215), death or myocardial infarction (Breslow-day test, p = 0.448), or target lesion revascularization (Breslow-day test, p = 0.333). The adjusted clinical outcomes at 12 months showed that the SES group had a significantly lower incidence of major adverse cardiac events (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.07 to 2.16, p = 0.02), target lesion revascularization (HR 2.16, 95% CI 1.01 to 4.59, p = 0.046), and target vessel revascularization (HR 2.24, 95% CI 1.18 to 4.24, p = 0.013) but not death or myocardial infarction (HR 1.37, 95% CI 0.91 to 2.05, p = 0.129; Figures 1 to 3 and Table 5 ). Stent thrombosis (definite or probable) occurred less in the ZES group (1.0% vs 1.8%), but the difference was not statistically significant (p = 0.302).
