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Comparison of Outcomes Between Zotarolimus- and Sirolimus-Eluting Stents in Patients With ST-Segment Elevation Acute Myocardial Infarction
Comparison of Outcomes Between Zotarolimus- and Sirolimus-Eluting Stents in Patients With ST-Segment Elevation Acute Myocardial Infarction Hyun Kuk Kim, MDa, Myung Ho Jeong, MDa,*, Young Keun Ahn, MDa, Jong Hyun Kim, MDb, Shung Chull Chae, MDc, Young Jo Kim, MDd, Seung Ho Hur, MDe, In Whan Seong, MDf, Taek Jong Hong, MDg, Dong Hoon Choi, MDh, Myeong Chan Cho, MDi, Chong Jin Kim, MDj, Ki Bae Seung, MDk, Wook Sung Chung, MDk, Yang Soo Jang, MDl, Seung Woon Rha, MDm, Jang Ho Bae, MDn, Jeong Gwan Cho, MDa, and Seung Jung Park, MDo; Korea Acute Myocardial Infarction Registry Investigators 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 ⴝ 0.02), target lesion revascularization (HR 2.16, 95% CI 1.01 to 4.59, p ⴝ 0.046), and target vessel revascularization (HR 2.24, 95% CI 1.18 to 4.24, p ⴝ 0.013). However, no significant differences were found in death or myocardial infarction (HR 1.37, 95% CI 0.91 to 2.05, p ⴝ 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. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:813– 818) 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.1 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 a Chonnam National University Hospital, Gwangju, South Korea; bBusan Hanseo Hospital, Busan, South Korea; cKyungpook National University Hospital, Daegu, South Korea; dYeungnam University Hospital, Gyeongsan, South Korea; eKeimyung University Hospital, Daegu, South Korea; f Chungnam National University Hospital, Daejeon, South Korea; gBusan National University Hospital, Busan, South Korea; hYonsei University Severans Hospital, Seodaemun-gu, South Korea; iChungbuk National University Hospital, Cheongju-si, South Korea; jKyung Hee University Hospital, Seoul, South Korea; kCatholic University Hospital, Seoul, South Korea; lYonsei University Hospital, Seoul, South Korea; mKorea University Hospital, Seoul, South Korea; nKonyang University Hospital, Daejon, South Korea; and oUlsan University Hospital, Ulsan, South Korea. *Corresponding author: Tel: (82) 62-220-6243; fax: (82) 62-228-7174. E-mail address: [email protected] (J. Myung Ho).
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.11.009
revascularization compared to bare metal stents.2 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.3 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 highrisk 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 www.AJConline.org
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Table 1 Baseline clinical characteristics Variable Age (years) Men Diabetes mellitus Hypertension Hypercholesterolemia Current smoker Family history of coronary artery disease Previous myocardial infarction Previous percutaneous coronary intervention on nonculprit artery Killip class ⱖIII on presentation Cardiogenic shock on presentation Systolic blood pressure at presentation (mm Hg) Heart rate on presentation (beats/min) Thrombolysis In Myocardial infarction risk index Ejection fraction (%) Ejection fraction ⬍30% Symptom to balloon time (min) Primary percutaneous coronary intervention Serum creatinine (mg/dl)
ZES Group (n ⫽ 306)
SES Group (n ⫽ 567)
p Value
62.8 ⫾ 13.6 224 (73.2%) 80 (26.2%) 127 (41.6%) 27 (8.9%) 152 (50.0%) 20 (6.6%) 4 (1.3%) 7 (2.3%) 44/293 (15.0%) 24/293 (8.2%) 24.9 ⫾ 31.3 (295) 77.6 ⫾ 20.8 (295) 27.4 ⫾ 16.1 (295) 50.8 ⫾ 13.6 (278) 12/278 (4.3%) 317.1 ⫾ 531.6 (280) 253 (82.7%) 1.1 ⫾ 0.6 (304)
62.3 ⫾ 12.2 421 (74.3%) 159/565 (28.1%) 263/565 (46.5%) 62/565 (11.0%) 274/563 (48.7%) 44/565 (7.8%) 8 (1.4%) 18 (3.2%) 88/534 (16.5%) 54/536 (10.1%) 123.4 ⫾ 29.7 (557) 76.7 ⫾ 19.3 (557) 26.1 ⫾ 14.0 (557) 51.3 ⫾ 12.2 (514) 18/514 (3.5%) 352.3 ⫾ 531.1 (535) 475 (83.8%) 1.2 ⫾ 1.4 (564)
0.541 0.737 0.547 0.165 0.332 0.708 0.524 0.984 0.847 0.583 0.375 0.484 0.561 0.229 0.720 0.567 0.369 0.678 0.663
Table 3 Medications at discharge
Table 2 Angiographic and procedural characteristics 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 110 (35.9%) 217 (38.3%) 0.498 dose Glycoprotein IIb/IIIa 50 (16.3%) 125 (22.0%) 0.045 inhibitor use ACC/AHA ⫽ American College of Cardiology/American Heart Association; TIMI ⫽ Thrombolysis In Myocardial infarction.
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
Variable
ZES Group (n ⫽ 274)
SES Group (n ⫽ 523)
p Value
Aspirin Clopidogrel Cilostazol Statin Angiotensin-converting enzyme inhibitor Angiotensin II receptor blocker  Blocker Calcium channel blocker
266 (98.9%) 265 (98.5%) 69 (25.7%) 220 (81.8%) 195 (72.5%)
517 (99.2%) 515 (98.8%) 110 (21.1%) 431 (82.7%) 354 (67.9%)
0.621 0.689 0.149 0.742 0.189
25 (9.3%) 200 (74.3%) 14 (5.2%)
62 (11.9%) 397 (76.2%) 37 (7.1%)
0.267 0.566 0.304
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 ⱖ18 years old at hospital admission, had a suggestive history with ST-segment elevation ⬎2 mm in ⱖ2 precordial leads or ⬎1 mm in ⱖ2 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 kinaseMB, 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
Coronary Artery Disease/ZES and SES in STEMI
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Table 4 Clinical outcome according to stent type Variable In-hospital outcomes Death Acute stent thrombosis Major bleeding events 12-Month outcomes (cumulative) Death Myocardial infarction Repeated percutaneous coronary intervention Target lesion revascularization Target vessel revascularization Coronary artery bypass grafting Major adverse cardiac events* Stent thrombosis (definite/probable)
ZES Group (n ⫽ 306)
SES Group (n ⫽ 567)
p Value
32 (10.5%) 1 (0.3%) 3 (1.0%)
44 (7.8%) 2 (0.4%) 6 (1.1%)
0.177 0.950 0.914
48 (15.7%) 1 (0.3%)
60 (10.6%) 4 (0.7%)
0.029 0.479
14 (4.6%) 20 (6.5%) 3 (1.0%) 63 (20.5%) 3 (1.0%)
13 (2.3%) 19 (3.4%) 0 (0.0%) 77 (13.6%) 11 (1.8%)
0.063 0.030 0.018 0.004 0.302
* Composite of death, myocardial infarction, and target lesion revascularization.
Figure 1. Twelve-month major adverse cardiac events (composite of allcause death, myocardial infarction, and target lesion revascularization)-free survival in ZES and SES groups.
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 ⱖ100 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 ⱖ1 month after the procedure. Coronary artery stenting was performed using the standard technique. The decision for predilation, direct stenting, postadjunctive balloon inflation, and the
Figure 2. Twelve-month target lesion revascularization-free survival in ZES and SES groups.
Figure 3. Twelve-month death/myocardial infarction-free survival in ZES and SES groups.
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 infarction4 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 myocar-
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Table 5 Adjusted clinical outcomes at 12 months for zotarolimus-eluting stents (ZESs) compared to sirolimus-eluting stents (SESs) 12-Month Outcomes (Cumulative) Death or myocardial infarction Repeated percutaneous coronary intervention Target lesion revascularization Target vessel revascularization Major adverse cardiac events*
Unadjusted OR (95% CI)
p Value
Adjusted OR (95% CI)
p Value
1.46 (1.01–2.12)
0.045
1.37 (0.91–2.05)
0.129
2.16 (1.01–4.58) 2.10 (1.12–3.94) 1.61 (1.16–2.23)
0.046 0.020 0.005
2.16 (1.01–4.59) 2.24 (1.18–4.24) 1.52 (1.07–2.16)
0.046 0.013 0.020
* Composite of death, myocardial infarction, and target lesion revascularization. OR ⫽ odds ratio. Table 6 Clinical characteristics and outcomes according to glycoprotein (GP) IIb/IIIa inhibitor use Variable Age (years) Men Diabetes mellitus Hypertension Current smoker Cardiogenic shock at presentation Cardiogenic shock periprocedure In-hospital outcomes Death Acute stent thrombosis Major bleeding events 12-Month outcomes (cumulative) Death Myocardial infarction Target lesion revascularization Target vessel revascularization Major adverse cardiac events* Stent thrombosis (definite/probable)
GP Group (n ⫽ 175)
Non-GP Group (n ⫽ 698)
p Value
61.9 ⫾ 11.5 129 (73.7%) 43 (24.6%) 72 (41.1%) 80/174 (46.0%) 18/170 (10.6%) 22 (12.6%)
62.6 ⫾ 12.9 516 (73.9%) 196/695 (28.2%) 318/695 (45.8%) 346/693 (49.9%) 60/659 (9.1%) 55 (7.9%)
0.451 0.955 0.336 0.273 0.351 0.555 0.050
19 (10.9%) 0 (0.0%) 2 (1.1%)
57 (8.2%) 3 (0.4%) 7 (1.0%)
0.259 0.385 0.870
26 (14.9%) 1 (0.6%) 8 (4.6%) 10 (5.7%) 35 (20.0%) 4 (2.3%)
82 (11.7%) 4 (0.6%) 19 (2.7%) 29 (4.2%) 105 (15.0%) 10 (1.4%)
0.264 0.998 0.206 0.372 0.148 0.344
* Composite of death, myocardial infarction, and target lesion revascularization.
dial 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.5 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.6 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 coro-
nary 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). The coronary angiographic and procedural characteristics are listed in Table 2. The location, stent number, severity, complexity of the infarct-related artery, and postproce-
Coronary Artery Disease/ZES and SES in STEMI
dural 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). 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,  blockers, and angiotensin-converting enzyme inhibitors. 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). Discussion Comparing the clinical efficacy and safety among patients treated with ZES and SES for acute STEMI, ZES implantation was associated with an increased incidence of major adverse cardiac events, mainly by an increased incidence of restenosis in the target lesion. The Thrombolysis In Myocardial Infarction risk index, Killip class, and serum creatinine level were used as parameters for a risk stratification tool in the present study. These parameters have been shown to predict both short- and long-term clinical outcomes in patients with STEMI.7–9 These parameters, indicating clinical status that affects the prognosis, were similar between the 2 groups. In the ENDEAVOR III study, increased neointimal hyperplasia and greater angiographic late lumen loss using ZESs compared to SESs were observed, but the clinical outcomes were not different between the 2 drug-eluting stents.3 Differences in the clinical outcomes were observed in our study. The following were considered in the results. The ENDEAVOR III study included only 113 patients in the SES group and 323 in the ZES group. It was deemed insufficient for detecting differences in clinical events such as target lesion revascularization. The relation between in-
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stent late lumen loss and the probability of target lesion revascularization in the ZES group was affected by lesion complexity.10 Comparing our study to the ENDEAVOR III study, the prevalence of type B2/C lesions (64.6% vs 75.7%) and multivessel disease (38.8% vs 54.4%) was much greater and incorporated more clinically high-risk patients. Thus, the possibility of an upward drift in late lumen loss and in-stent restenosis was present; hence, greater differences could be observed between the 2 stents. In a meta-analysis of trials, adjunctive use of abciximab was associated with short- and long-term mortality reduction in patients with acute STEMI who underwent primary angioplasty.11 In our study, however, a GP IIb/IIIa inhibitor was administered mostly according to the provision of the national medical insurance owing to cost concerns. Thrombotic acute occlusion, the no reflow phenomenon, or a suspicious highly thrombotic lesion during or after the procedure were the only accepted indications. Therefore, increased use of GP IIb/IIIa inhibitors suggested a greater thrombotic burden in the culprit lesion. In our study, 175 patients received a GP IIb/IIIa inhibitor (GP group). No significant differences were found between the GP and non-GP groups in age or the prevalence of coronary risk factors such as diabetes mellitus, hypertension, and current smoker. No significant differences were identified in our study for in-hospital and 12-month death, myocardial infarction, and stent thrombosis. The only difference between the 2 groups was the periprocedural occurrence of cardiogenic shock (12.6% in the GP group vs 7.9% in the non-GP group, p ⫽ 0.05), with a similar rate of cardiogenic shock at presentation (Table 6). Although the ZES group was expected to have lower rates of stent thrombosis compared to first-generation drugeluting stents such as SESs and paclitaxel-eluting stents, stent thrombosis occurred at a similar rate in our study and in a randomized trial.12 An additional unpublished randomized trial in Korea (the ZEST trial: “Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent versus Sirolimus-Eluting Stent and PacliTaxel-Eluting Stent for Coronary Lesions”) proved otherwise (0% in SES, 0.7% in ZES). The incidence of stent thrombosis in our data were greater than in the ZEST trial. STEMI and left ventricular ejection fraction are known to be independent predictors of stent thrombosis.13 Patients with STEMI or severe left ventricular dysfunction were excluded from the ZEST trial, which might be a reason for any disparity. The present study had several limitations. First, the nonrandomized nature of the registry data could have resulted in a selection bias. The number of patients who had undergone ZES and SES implantation was unequal. As demonstrated in the angiographic characteristics, SESs were used more often in lesions with a long length and small diameter and in the presence of 3-vessel disease. These findings resulted in a serious negative bias against SES use. Although most confounders were included in the multivariate analysis using the propensity score, it is possible that some potential confounders were included. Second, our study lacked systemic angiographic follow-up and quantitative coronary analysis that might have affected the rate of revascularization. As stated, the rates of follow-up angiography between the 2 stent groups were not significantly dif-
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ferent (p ⫽ 0.521). However, we could not exclude that the routine angiographic follow-up findings resulted in additional revascularization procedures, magnifying the difference in clinical outcomes between ZESs and SESs. Finally, the clinical data encompassed a 1-year period in our study. The long-term safety of drug-eluting stent could not be fully evaluated. It warrants large-scale prospective randomized trials of a longer duration to assess the safety of ZESs across the entire range of coronary artery diseases, including STEMI.
4. 5.
6. 7.
Appendix The Korea Acute Myocardial Infarction Registry (KAMIR) Study Group of the Korean Circulation Society was as follows: Myung Ho Jeong, Young Jo Kim, Chong Jin Kim, Myeong Chan Cho, Young Keun Ahn, Jong Hyun Kim, Shung Chull Chae, Seung Ho Hur, In Whan Seong, Taek Jong Hong, Dong Hoon Choi, Jei Keon Chae, Jae Young Rhew, Doo Il Kim, In Ho Chae, Jung Han Yoon, Bon Kwon Koo, Byung Ok Kim, Myoung Yong Lee, Kee Sik Kim, Jin Yong Hwang, Seok Kyu Oh, Nae Hee Lee, Kyoung Tae Jeong, Seung Jea Tahk, Jang Ho Bae, Seung Woon Rha, Keum Soo Park, Kyoo Rok Han, Tae Hoon Ahn, Moo Hyun Kim, Joo Young Yang, Chong Yun Rhim, Hyeon Cheol Gwon, Seong Wook Park, Young Youp Koh, Seung Jae Joo, Soo Joong Kim, Dong Kyu Jin, Jin Man Cho, Wook Sung Chung, Yang Soo Jang, Jeong Gwan Cho, Ki Bae Seung, and Seung Jung Park. 1. Kandzari DE, Leon MB. Overview of pharmacology and clinical trials program with the zotarolimus-eluting endeavor stent. J Interv Cardiol 2006;19:405– 413. 2. Fajadet J, Wijns W, Laarman GJ, Kuck KH, Ormiston J, Münzel T, Popma JJ, Fitzgerald PJ, Bonan R, Kuntz RE; ENDEAVOR II Investigators. Randomized, double-blind, multicenter study of the endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114:798 – 806. 3. Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O’Shaughnessy C, Ball MW, Turco M, Applegate RJ, Gurbel PA, Midei MG, Badre SS, Mauri L, Thompson KP, LeNarz LA, Kuntz RE; ENDEAVOR III Investigators. Comparison of zotarolimus-eluting and sirolimus-elut-
8.
9.
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11.
12.
13.
ing stents in patients with native coronary artery disease: a randomized controlled trial. J Am Coll Cardiol 2006;48:2440 –2447. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525–2538. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –2351. D’Agostino RB Jr. Propensity scores in cardiovascular research. Circulation 2007;115:2340 –2343. Truong QA, Cannon CP, Zakai NA, Rogers IS, Giugliano RP, Wiviott SD, McCabe CH, Morrow DA, Braunwald E. Thrombolysis In Myocardial Infarction (TIMI) risk index predicts long-term mortality and heart failure in patients with ST-elevation myocardial infarction in the TIMI 2 clinical trial. Am Heart J 2009;157:673– 679. De Luca G, van’t Hof AW, de Boer MJ, Hoorntje JC, Gosselink AT, Dambrink JH, Ottervanger JP, Zijlstra F, Suryapranata H. Impaired myocardial perfusion is a major explanation of the poor outcome observed in patients undergoing primary angioplasty for ST-segmentelevation myocardial infarction and signs of heart failure. Circulation 2004;109:958 –961. Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 2002;137:555–562. Mehta RH, Leon MB, Sketch MH Jr; ENDEAVOR II Continued Access Registry. The relation between clinical features, angiographic findings, and the target lesion revascularization rate in patients receiving the endeavor zotarolimus-eluting stent for treatment of native coronary artery disease: an analysis of ENDEAVOR I, ENDEAVOR II, ENDEAVOR II Continued Access Registry, and ENDEAVOR III. Am J Cardiol 2007;100:62M–70M. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE, Neumann FJ, Van de Werf F, Antman EM, Topol EJ. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005; 293:1759 –1765. Chevalier B, Di Mario C, Neumann FJ, Ribichini F, Urban P, Popma JJ, Fitzgerald PJ, Cutlip DE, Williams DO, Ormiston J, Grube E, Whitbourn R, Schwartz LB; ZoMaxx I investigators. A randomized, controlled, multicenter trial to evaluate the safety and efficacy of zotarolimus-versus paclitaxel-eluting stents in de novo occlusive lesions in coronary arteries the ZoMaxx I trial. JACC Cardiovasc Interv 2008;1:524 –532. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–2317.
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.11.009
revascularization compared to bare metal stents.2 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.3 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 highrisk 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 www.AJConline.org
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Table 1 Baseline clinical characteristics Variable Age (years) Men Diabetes mellitus Hypertension Hypercholesterolemia Current smoker Family history of coronary artery disease Previous myocardial infarction Previous percutaneous coronary intervention on nonculprit artery Killip class ⱖIII on presentation Cardiogenic shock on presentation Systolic blood pressure at presentation (mm Hg) Heart rate on presentation (beats/min) Thrombolysis In Myocardial infarction risk index Ejection fraction (%) Ejection fraction ⬍30% Symptom to balloon time (min) Primary percutaneous coronary intervention Serum creatinine (mg/dl)
ZES Group (n ⫽ 306)
SES Group (n ⫽ 567)
p Value
62.8 ⫾ 13.6 224 (73.2%) 80 (26.2%) 127 (41.6%) 27 (8.9%) 152 (50.0%) 20 (6.6%) 4 (1.3%) 7 (2.3%) 44/293 (15.0%) 24/293 (8.2%) 24.9 ⫾ 31.3 (295) 77.6 ⫾ 20.8 (295) 27.4 ⫾ 16.1 (295) 50.8 ⫾ 13.6 (278) 12/278 (4.3%) 317.1 ⫾ 531.6 (280) 253 (82.7%) 1.1 ⫾ 0.6 (304)
62.3 ⫾ 12.2 421 (74.3%) 159/565 (28.1%) 263/565 (46.5%) 62/565 (11.0%) 274/563 (48.7%) 44/565 (7.8%) 8 (1.4%) 18 (3.2%) 88/534 (16.5%) 54/536 (10.1%) 123.4 ⫾ 29.7 (557) 76.7 ⫾ 19.3 (557) 26.1 ⫾ 14.0 (557) 51.3 ⫾ 12.2 (514) 18/514 (3.5%) 352.3 ⫾ 531.1 (535) 475 (83.8%) 1.2 ⫾ 1.4 (564)
0.541 0.737 0.547 0.165 0.332 0.708 0.524 0.984 0.847 0.583 0.375 0.484 0.561 0.229 0.720 0.567 0.369 0.678 0.663
Table 3 Medications at discharge
Table 2 Angiographic and procedural characteristics 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 110 (35.9%) 217 (38.3%) 0.498 dose Glycoprotein IIb/IIIa 50 (16.3%) 125 (22.0%) 0.045 inhibitor use ACC/AHA ⫽ American College of Cardiology/American Heart Association; TIMI ⫽ Thrombolysis In Myocardial infarction.
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
Variable
ZES Group (n ⫽ 274)
SES Group (n ⫽ 523)
p Value
Aspirin Clopidogrel Cilostazol Statin Angiotensin-converting enzyme inhibitor Angiotensin II receptor blocker  Blocker Calcium channel blocker
266 (98.9%) 265 (98.5%) 69 (25.7%) 220 (81.8%) 195 (72.5%)
517 (99.2%) 515 (98.8%) 110 (21.1%) 431 (82.7%) 354 (67.9%)
0.621 0.689 0.149 0.742 0.189
25 (9.3%) 200 (74.3%) 14 (5.2%)
62 (11.9%) 397 (76.2%) 37 (7.1%)
0.267 0.566 0.304
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 ⱖ18 years old at hospital admission, had a suggestive history with ST-segment elevation ⬎2 mm in ⱖ2 precordial leads or ⬎1 mm in ⱖ2 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 kinaseMB, 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
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Table 4 Clinical outcome according to stent type Variable In-hospital outcomes Death Acute stent thrombosis Major bleeding events 12-Month outcomes (cumulative) Death Myocardial infarction Repeated percutaneous coronary intervention Target lesion revascularization Target vessel revascularization Coronary artery bypass grafting Major adverse cardiac events* Stent thrombosis (definite/probable)
ZES Group (n ⫽ 306)
SES Group (n ⫽ 567)
p Value
32 (10.5%) 1 (0.3%) 3 (1.0%)
44 (7.8%) 2 (0.4%) 6 (1.1%)
0.177 0.950 0.914
48 (15.7%) 1 (0.3%)
60 (10.6%) 4 (0.7%)
0.029 0.479
14 (4.6%) 20 (6.5%) 3 (1.0%) 63 (20.5%) 3 (1.0%)
13 (2.3%) 19 (3.4%) 0 (0.0%) 77 (13.6%) 11 (1.8%)
0.063 0.030 0.018 0.004 0.302
* Composite of death, myocardial infarction, and target lesion revascularization.
Figure 1. Twelve-month major adverse cardiac events (composite of allcause death, myocardial infarction, and target lesion revascularization)-free survival in ZES and SES groups.
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 ⱖ100 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 ⱖ1 month after the procedure. Coronary artery stenting was performed using the standard technique. The decision for predilation, direct stenting, postadjunctive balloon inflation, and the
Figure 2. Twelve-month target lesion revascularization-free survival in ZES and SES groups.
Figure 3. Twelve-month death/myocardial infarction-free survival in ZES and SES groups.
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 infarction4 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 myocar-
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Table 5 Adjusted clinical outcomes at 12 months for zotarolimus-eluting stents (ZESs) compared to sirolimus-eluting stents (SESs) 12-Month Outcomes (Cumulative) Death or myocardial infarction Repeated percutaneous coronary intervention Target lesion revascularization Target vessel revascularization Major adverse cardiac events*
Unadjusted OR (95% CI)
p Value
Adjusted OR (95% CI)
p Value
1.46 (1.01–2.12)
0.045
1.37 (0.91–2.05)
0.129
2.16 (1.01–4.58) 2.10 (1.12–3.94) 1.61 (1.16–2.23)
0.046 0.020 0.005
2.16 (1.01–4.59) 2.24 (1.18–4.24) 1.52 (1.07–2.16)
0.046 0.013 0.020
* Composite of death, myocardial infarction, and target lesion revascularization. OR ⫽ odds ratio. Table 6 Clinical characteristics and outcomes according to glycoprotein (GP) IIb/IIIa inhibitor use Variable Age (years) Men Diabetes mellitus Hypertension Current smoker Cardiogenic shock at presentation Cardiogenic shock periprocedure In-hospital outcomes Death Acute stent thrombosis Major bleeding events 12-Month outcomes (cumulative) Death Myocardial infarction Target lesion revascularization Target vessel revascularization Major adverse cardiac events* Stent thrombosis (definite/probable)
GP Group (n ⫽ 175)
Non-GP Group (n ⫽ 698)
p Value
61.9 ⫾ 11.5 129 (73.7%) 43 (24.6%) 72 (41.1%) 80/174 (46.0%) 18/170 (10.6%) 22 (12.6%)
62.6 ⫾ 12.9 516 (73.9%) 196/695 (28.2%) 318/695 (45.8%) 346/693 (49.9%) 60/659 (9.1%) 55 (7.9%)
0.451 0.955 0.336 0.273 0.351 0.555 0.050
19 (10.9%) 0 (0.0%) 2 (1.1%)
57 (8.2%) 3 (0.4%) 7 (1.0%)
0.259 0.385 0.870
26 (14.9%) 1 (0.6%) 8 (4.6%) 10 (5.7%) 35 (20.0%) 4 (2.3%)
82 (11.7%) 4 (0.6%) 19 (2.7%) 29 (4.2%) 105 (15.0%) 10 (1.4%)
0.264 0.998 0.206 0.372 0.148 0.344
* Composite of death, myocardial infarction, and target lesion revascularization.
dial 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.5 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.6 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 coro-
nary 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). The coronary angiographic and procedural characteristics are listed in Table 2. The location, stent number, severity, complexity of the infarct-related artery, and postproce-
Coronary Artery Disease/ZES and SES in STEMI
dural 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). 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,  blockers, and angiotensin-converting enzyme inhibitors. 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). Discussion Comparing the clinical efficacy and safety among patients treated with ZES and SES for acute STEMI, ZES implantation was associated with an increased incidence of major adverse cardiac events, mainly by an increased incidence of restenosis in the target lesion. The Thrombolysis In Myocardial Infarction risk index, Killip class, and serum creatinine level were used as parameters for a risk stratification tool in the present study. These parameters have been shown to predict both short- and long-term clinical outcomes in patients with STEMI.7–9 These parameters, indicating clinical status that affects the prognosis, were similar between the 2 groups. In the ENDEAVOR III study, increased neointimal hyperplasia and greater angiographic late lumen loss using ZESs compared to SESs were observed, but the clinical outcomes were not different between the 2 drug-eluting stents.3 Differences in the clinical outcomes were observed in our study. The following were considered in the results. The ENDEAVOR III study included only 113 patients in the SES group and 323 in the ZES group. It was deemed insufficient for detecting differences in clinical events such as target lesion revascularization. The relation between in-
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stent late lumen loss and the probability of target lesion revascularization in the ZES group was affected by lesion complexity.10 Comparing our study to the ENDEAVOR III study, the prevalence of type B2/C lesions (64.6% vs 75.7%) and multivessel disease (38.8% vs 54.4%) was much greater and incorporated more clinically high-risk patients. Thus, the possibility of an upward drift in late lumen loss and in-stent restenosis was present; hence, greater differences could be observed between the 2 stents. In a meta-analysis of trials, adjunctive use of abciximab was associated with short- and long-term mortality reduction in patients with acute STEMI who underwent primary angioplasty.11 In our study, however, a GP IIb/IIIa inhibitor was administered mostly according to the provision of the national medical insurance owing to cost concerns. Thrombotic acute occlusion, the no reflow phenomenon, or a suspicious highly thrombotic lesion during or after the procedure were the only accepted indications. Therefore, increased use of GP IIb/IIIa inhibitors suggested a greater thrombotic burden in the culprit lesion. In our study, 175 patients received a GP IIb/IIIa inhibitor (GP group). No significant differences were found between the GP and non-GP groups in age or the prevalence of coronary risk factors such as diabetes mellitus, hypertension, and current smoker. No significant differences were identified in our study for in-hospital and 12-month death, myocardial infarction, and stent thrombosis. The only difference between the 2 groups was the periprocedural occurrence of cardiogenic shock (12.6% in the GP group vs 7.9% in the non-GP group, p ⫽ 0.05), with a similar rate of cardiogenic shock at presentation (Table 6). Although the ZES group was expected to have lower rates of stent thrombosis compared to first-generation drugeluting stents such as SESs and paclitaxel-eluting stents, stent thrombosis occurred at a similar rate in our study and in a randomized trial.12 An additional unpublished randomized trial in Korea (the ZEST trial: “Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent versus Sirolimus-Eluting Stent and PacliTaxel-Eluting Stent for Coronary Lesions”) proved otherwise (0% in SES, 0.7% in ZES). The incidence of stent thrombosis in our data were greater than in the ZEST trial. STEMI and left ventricular ejection fraction are known to be independent predictors of stent thrombosis.13 Patients with STEMI or severe left ventricular dysfunction were excluded from the ZEST trial, which might be a reason for any disparity. The present study had several limitations. First, the nonrandomized nature of the registry data could have resulted in a selection bias. The number of patients who had undergone ZES and SES implantation was unequal. As demonstrated in the angiographic characteristics, SESs were used more often in lesions with a long length and small diameter and in the presence of 3-vessel disease. These findings resulted in a serious negative bias against SES use. Although most confounders were included in the multivariate analysis using the propensity score, it is possible that some potential confounders were included. Second, our study lacked systemic angiographic follow-up and quantitative coronary analysis that might have affected the rate of revascularization. As stated, the rates of follow-up angiography between the 2 stent groups were not significantly dif-
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ferent (p ⫽ 0.521). However, we could not exclude that the routine angiographic follow-up findings resulted in additional revascularization procedures, magnifying the difference in clinical outcomes between ZESs and SESs. Finally, the clinical data encompassed a 1-year period in our study. The long-term safety of drug-eluting stent could not be fully evaluated. It warrants large-scale prospective randomized trials of a longer duration to assess the safety of ZESs across the entire range of coronary artery diseases, including STEMI.
4. 5.
6. 7.
Appendix The Korea Acute Myocardial Infarction Registry (KAMIR) Study Group of the Korean Circulation Society was as follows: Myung Ho Jeong, Young Jo Kim, Chong Jin Kim, Myeong Chan Cho, Young Keun Ahn, Jong Hyun Kim, Shung Chull Chae, Seung Ho Hur, In Whan Seong, Taek Jong Hong, Dong Hoon Choi, Jei Keon Chae, Jae Young Rhew, Doo Il Kim, In Ho Chae, Jung Han Yoon, Bon Kwon Koo, Byung Ok Kim, Myoung Yong Lee, Kee Sik Kim, Jin Yong Hwang, Seok Kyu Oh, Nae Hee Lee, Kyoung Tae Jeong, Seung Jea Tahk, Jang Ho Bae, Seung Woon Rha, Keum Soo Park, Kyoo Rok Han, Tae Hoon Ahn, Moo Hyun Kim, Joo Young Yang, Chong Yun Rhim, Hyeon Cheol Gwon, Seong Wook Park, Young Youp Koh, Seung Jae Joo, Soo Joong Kim, Dong Kyu Jin, Jin Man Cho, Wook Sung Chung, Yang Soo Jang, Jeong Gwan Cho, Ki Bae Seung, and Seung Jung Park. 1. Kandzari DE, Leon MB. Overview of pharmacology and clinical trials program with the zotarolimus-eluting endeavor stent. J Interv Cardiol 2006;19:405– 413. 2. Fajadet J, Wijns W, Laarman GJ, Kuck KH, Ormiston J, Münzel T, Popma JJ, Fitzgerald PJ, Bonan R, Kuntz RE; ENDEAVOR II Investigators. Randomized, double-blind, multicenter study of the endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation 2006;114:798 – 806. 3. Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O’Shaughnessy C, Ball MW, Turco M, Applegate RJ, Gurbel PA, Midei MG, Badre SS, Mauri L, Thompson KP, LeNarz LA, Kuntz RE; ENDEAVOR III Investigators. Comparison of zotarolimus-eluting and sirolimus-elut-
8.
9.
10.
11.
12.
13.
ing stents in patients with native coronary artery disease: a randomized controlled trial. J Am Coll Cardiol 2006;48:2440 –2447. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525–2538. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –2351. D’Agostino RB Jr. Propensity scores in cardiovascular research. Circulation 2007;115:2340 –2343. Truong QA, Cannon CP, Zakai NA, Rogers IS, Giugliano RP, Wiviott SD, McCabe CH, Morrow DA, Braunwald E. Thrombolysis In Myocardial Infarction (TIMI) risk index predicts long-term mortality and heart failure in patients with ST-elevation myocardial infarction in the TIMI 2 clinical trial. Am Heart J 2009;157:673– 679. De Luca G, van’t Hof AW, de Boer MJ, Hoorntje JC, Gosselink AT, Dambrink JH, Ottervanger JP, Zijlstra F, Suryapranata H. Impaired myocardial perfusion is a major explanation of the poor outcome observed in patients undergoing primary angioplasty for ST-segmentelevation myocardial infarction and signs of heart failure. Circulation 2004;109:958 –961. Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 2002;137:555–562. Mehta RH, Leon MB, Sketch MH Jr; ENDEAVOR II Continued Access Registry. The relation between clinical features, angiographic findings, and the target lesion revascularization rate in patients receiving the endeavor zotarolimus-eluting stent for treatment of native coronary artery disease: an analysis of ENDEAVOR I, ENDEAVOR II, ENDEAVOR II Continued Access Registry, and ENDEAVOR III. Am J Cardiol 2007;100:62M–70M. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE, Neumann FJ, Van de Werf F, Antman EM, Topol EJ. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005; 293:1759 –1765. Chevalier B, Di Mario C, Neumann FJ, Ribichini F, Urban P, Popma JJ, Fitzgerald PJ, Cutlip DE, Williams DO, Ormiston J, Grube E, Whitbourn R, Schwartz LB; ZoMaxx I investigators. A randomized, controlled, multicenter trial to evaluate the safety and efficacy of zotarolimus-versus paclitaxel-eluting stents in de novo occlusive lesions in coronary arteries the ZoMaxx I trial. JACC Cardiovasc Interv 2008;1:524 –532. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–2317.