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Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention
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Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention Khurshid Ahmed (MD) a,b , Myung Ho Jeong (MD, PhD, FACC, FAHA, FESC, FSCAI, FAPSIC) a,∗ , Rabin Chakraborty (MD) b , Sumera Ahmed (MHM) b , Young Joon Hong (MD) a , Doo Sun Sim (MD) a , Keun Ho Park (MD) a , Ju Han Kim (MD) a , Youngkeun Ahn (MD) a , Jung Chaee Kang (MD) a , Myeong Chan Cho (MD) c , Chong Jin Kim (MD) d , Young Jo Kim (MD) e , other Korea Acute Myocardial Infarction Registry Investigators a The Heart Center of Chonnam National University Hospital, Chonnam National University Research Institute of Medical Sciences, Gwangju, Republic of Korea b Apollo Gleneagles Hospital, Kolkata, India c Chungbuk National University Hospital, Chungju, Republic of Korea d East West Neo Medical Center, Seoul, Republic of Korea e Yeungnam University Hospital, Daegu, Republic of Korea
a r t i c l e
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Article history: Received 22 September 2012 Received in revised form 11 December 2013 Accepted 3 February 2014 Available online xxx Keywords: ST-segment elevation myocardial infarction Drug-eluting stent Coronary angioplasty Chronic kidney failure
a b s t r a c t Background: Chronic kidney disease (CKD) is associated with poor outcomes after percutaneous coronary intervention (PCI). The aim of the study was to compare zotarolimus- and everolimus-eluting stents used during primary PCI in patients with acute myocardial infarction (AMI) and CKD. Methods: We selected 854 consecutive ST-elevation MI patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 ) undergoing primary PCI who were followed up for 12 months. They were divided into two groups based on type of stents implanted: (1) zotarolimus-eluting stent (ZES) and (2) everolimus-eluting stent (EES). The study end point was the 12-month major adverse cardiac events (MACE) which included all-cause death, non-fatal MI, target lesion revascularization (TLR), and target vessel revascularization (TVR). Results: The average number of stents used per vessel was 1.4 ± 0.7. A total of 433 patients received ZES and 421 patients received EES. There was no significant difference in the incidence of 12-month MI, TLR, or TVR. All-cause death was found to be borderline significant between two groups (2.8% in ZES vs 0.9% in EES, p = 0.05). The incidence of 12-month MACE in ZES and EES was 5.7% and 2.6% respectively, p = 0.022. Stent thrombosis did not differ between groups (p = 0.677). Kaplan–Meier analysis did not show significant difference for 12-month MACE-free survival between groups (log-rank p = 0.158). It remained the same even after propensity adjustment for multiple confounders in Cox model (p = 0.326). Conclusions: Implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12month MACE and death in STEMI patients with CKD undergoing primary PCI. © 2014 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Introduction
∗ Corresponding author at: Professor, Principal Investigator of Korea Acute Myocardial Infarction Registry, Chonnam National University Hospital, 671 Jaebongro, Dong-gu, Gwangju 501-757, Republic of Korea. Tel.: +82 62 220 6243; fax: +82 62 228 7174. E-mail addresses: [email protected], [email protected] (M.H. Jeong).
Patients with chronic kidney disease (CKD) present with accelerated atherosclerosis and higher cardiovascular morbidity and mortality [1–3]. Furthermore, CKD is associated with adverse outcome following percutaneous coronary intervention (PCI) [4,5], likely related to endothelial dysfunction, inflammation, and platelet activation. After PCI with bare metal stents (BMS), the need for repeat revascularization remains high [6], although the
http://dx.doi.org/10.1016/j.jjcc.2014.02.002 0914-5087/© 2014 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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restenosis rate in mild to moderate CKD is not increased at 9 months [7]. Retrospective analyses have demonstrated that, in the intermediate term, despite a higher overall mortality and morbidity after PCI, patients with end-stage renal disease [8] as well as those with milder degrees of CKD [9] benefit from lower rates of target vessel revascularization (TVR) with drug-eluting stent (DES) versus BMS placement. Despite the high prevalence of coronary artery disease among CKD patients, this patient population has been consistently excluded from the major clinical trials in cardiovascular medicine [10]. We sought to investigate which of the most commonly used stents best suit patients with moderate to severe CKD undergoing primary PCI. We compared 12-month the clinical outcomes in two types of stents. Methods This is a retrospective study that was carried out in the Heart Center of Chonnam National University Hospital, Gwangju, Korea. The permission to carry out the study was obtained from the hospital authorities (Institutional Review Board number 05-49, I2008-01-009) and written informed consent was taken from all patients. Korea Acute Myocardial Infarction Registry The Korea Acute Myocardial Infarction Registry is a prospective, multicenter, observational registry designed to examine current epidemiology in hospital management and the outcome of patients with acute myocardial infarction (AMI) in Korea for the commemoration of the 50th anniversary of the Korean Circulation Society. The registry included 52 community and university hospitals for primary PCI with 1-year clinical follow-up. Data were collected at each site by a well-trained study coordinator based on a standardized protocol [11]. Study population Patients were enrolled in the registry after admission to participating hospitals with a suspected diagnosis of AMI. Patients’ medical documents were used to note the demographic data, clinical characteristics, and relevant laboratory results. A total of 854 consecutive patients with ST-segment elevation MI with CKD undergoing primary PCI from April 2006 through September 2010 were selected in this study. We studied their 12-month clinical outcomes (follow-up rate was 100%). CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated using the Modification of Diet in Renal Disease (MDRD) method [12]. Patients on hemodialysis or continuous ambulatory peritoneal dialysis, with cardiogenic shock and evidence of heart failure were excluded from this study. They were divided into two groups based on the type of stents implanted – zotarolimus-eluting stents (ZES, n = 433, endeavor = 369 and resolute = 64; Medtronic CardioVascular, Santa Rosa, CA, USA), and everolimus-eluting stents (EES, n = 421). Definitions and clinical endpoints A final diagnosis of AMI was made according to the European Society of Cardiology/American College of Cardiology (ACC) diagnostic criteria of AMI [13]. Hypertension was defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg at rest, at repeated measurements or treatment
with anti-hypertensive medications. Diabetes was defined as having an established diagnosis of diabetes mellitus or use of oral hypoglycemic agent or insulin to lower blood glucose levels. Hyperlipidemia was defined as a total cholesterol level >200 mg/dL or treatment with a lipid-lowering agent. Coronary artery disease was defined as history of MI, revascularization procedure, or obstructive coronary artery disease. Peripheral blood samples were obtained using direct venipuncture. Blood samples were centrifuged and serum was removed and stored at a temperature of −70 ◦ C until the assay could be performed for proteins and sugar. Absolute creatine kinaseMB levels were determined by radioimmunoassay (Dade Behring, Inc., Miami, FL, USA). Cardiac specific troponin I levels were measured by a paramagnetic particle, chemiluminescent immunoenzymatic assay (Beckham, Coulter, Inc., Fullerton, CA, USA). Twelve-hour fasting serum levels of total cholesterol, triglyceride, and low- and high-density lipoprotein cholesterol were measured by standard enzymatic methods. Blood samples for high-sensitivity C-reactive protein (CRP) were obtained on admission and analyzed turbidimetrically with sheep antibodies against human CRP; this has been validated against the Dade Behring method. Two-dimensional echocardiography was performed in all patients and left ventricular ejection fraction was assessed using modified Simpson’s biplanar method. The morphology in coronary angiography was classified according to the criteria of ACC/American Heart Association (AHA) [14]. Degree of coronary flow was classified by Thrombolysis In Myocardial Infarction (TIMI) score [15]. Renal function was assessed by eGFR, which was calculated using the MDRD method [12]. teh presence of left main coronary artery stenosis was defined as a luminal stenosis ≥50%. Multivessel disease was defined as the presence of a lesion with >50% diameter stenosis in a non-infarct related coronary artery. Successful PCI was defined as TIMI flow three with residual stenosis ≤50% in the infarct-related artery. Inhospital complications included any of atrio-ventricular block, bradycardia, ventricular tachycardia/ventricular fibrillation, atrial fibrillation, cardiogenic shock, no re-flow, dissection, acute renal failure, metabolic acidosis/lactic acidosis, cerebrovascular event, or infection/sepsis. All patients were administered loading doses of aspirin 325 mg and clopidogrel 300–600 mg before PCI. Anticoagulation during PCI was performed according to the routine practices of each hospital. After the procedure, aspirin 100–300 mg (once per day) was prescribed indefinitely. Clopidogrel was prescribed continuously for 1 year to patients who underwent DES implantation. The clinical endpoint of this study was the major adverse cardiac events (MACE) which included all-cause death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR) and TVR during the 12-month follow-up. Non-fatal MI was defined as the presence of clinical symptoms, electrocardiographic change, or abnormal imaging findings of MI combined with an increase in creatine kinase-MB fraction or troponin T/I more than the 99th percentile of the upper normal limit that was not related to an interventional procedure. TVR defined as clinically driven repeat revascularization of a lesion in the same epicardial vessel treated in the index procedure at 12-month follow-up. TLR was defined as any revascularization of the target lesion due to restenosis or re-occlusion within 5 mm proximal/distal to the stent. All data were recorded on a standardized, electronic, web-based registry at http://www.kamir.or.kr. Statistical analysis SPSS 17.0 for windows (SPSS, Inc., Chicago, IL, USA) was used for all analysis. Continuous variables were presented as
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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mean ± standard deviation; comparisons were conducted by Student’s t-test. Discrete variables were presented as percentages and frequencies; comparisons were conducted by chi-square statistics. A p-value <0.05 was considered statistically significant. Kaplan–Meier curves were constructed to examine the incidence of clinical endpoints. Cox proportional hazard analysis was performed to identify a model with independent predictive factors with determination of a hazard ratio and its 95% confidence interval for each variable in the model. Covariates included in the model were age, stent length, pre-procedure TIMI flow grade 0, creatinine kinaseMB, and the use of thrombus aspiration device. As the number of 12-month MACE was relatively small in our study population, we limited the variables into the model. The results are presented as adjusted hazard ratios with 95% confidence intervals and p-values. We performed propensity score matching to enable an even more rigorous adjustment for selection biases and confounding factors.
Results A total of 854 consecutive patients with AMI and CKD undergoing PCI were included in the present study. The average age of the total population was 64.1 ± 12.7 years and 81.6% were men. The mean stent length was 23.0 ± 6.5 mm and the mean stent diameter was 3.2 ± 0.5 mm. The average number of stents used per vessel was 1.4 ± 0.7.
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Baseline clinical and laboratory characteristics and concomitant medications Baseline clinical and laboratory characteristics and concomitant medications of the two groups are presented in Table 1. Patients in the ZES group were older with lower heart rate, higher prevalence of family history of coronary artery disease, and higher serum level of creatinine kinase-MB. Use of calcium-channel blockers and fibrates was less frequently observed in the ZES group compared to that in the EES group. Coronary angiographic and procedural characteristics Coronary angiographic characteristics and procedural results of the two groups are presented in Table 2. Patients in the ZES group had higher pre-PCI TIMI grade 0 flow, larger stent length, and higher use of thrombus aspiration device compared to the EES group. Other coronary angiographic characteristics did not show statistically meaningful differences between the two groups. Twelve-month clinical outcomes The 12-month clinical outcomes are presented in Table 3. The incidence of 12-month MACE was higher in the ZES group compared to that in the EES group (5.7% vs 2.6%) and the incidence
Table 1 Baseline clinical and laboratory characteristics, and concomitant medications. Variable Age (years) Male gender Systolic blood pressure (mmHg) Heart rate (beats/min) Left ventricular ejection fraction (%) Killip class >1 Hypertension Diabetes mellitus Previous history of coronary artery disease Family history of coronary artery disease Smoking history Hyperlipidemia Laboratory characteristics Glucose (mg/dL) Creatinine (mg/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) hsCRP (mg/dL) NT-pro-BNP (pg/mL) HbA1C (%) Max.CK-MB (U/L) Troponin-I (ng/mL) Discharge medication Aspirin Clopidogrel Cliostazol Calcium channel blocker Beta blocker ACE inhibitor Angiotensin receptor blocker Nitrate Diuretics Spiranolactone Fibrate Statin
ZES n = 433 66.3 ± 13.4 346 (79.9) 123.8 ± 29.9 72.5 ± 18.8 52.3 ± 17.2 138 (31.9) 227 (52.4) 111 (25.6) 42 (9.7) 45 (10.4) 268 (61.9) 53 (12.2) 175.9 ± 75.3 1.5 ± 1.4 180.0 ± 40.8 125.0 ± 79.9 43.2 ± 16.1 112.5 ± 35.6 4.2 ± 13.8 3784.1 ± 7772.3 6.5 ± 1.4 211.8 ± 357.3 64.9 ± 111.9 410 (94.7) 411 (94.9) 110 (25.4) 10 (2.3) 341 (78.7) 253 (58.4) 93 (21.4) 202 (46.6) 75 (17.3) 37 (8.5) 0 (0) 324 (74.8)
EES n = 421
p value
63.5 ± 11.8 351 (83.3) 127.7 ± 31.8 75.7 ± 21.7 51.9 ± 23.4 134 (31.8) 230 (54.6) 125 (29.7) 38 (0.09) 25 (5.9) 271 (64.4) 67 (1.6)
0.001 0.191 0.066 0.027 0.813 0.979 0.531 0.182 0.771 0.013 0.440 0.149
185.7 ± 85.9 1.4 ± 1.6 181.7 ± 43.2 132.7 ± 112.4 42.7 ± 11.0 114.7 ± 36.4 5.8 ± 15.1 4226.1 ± 7900.1 6.6 ± 1.4 163.3 ± 157.9 57.9 ± 174.5
0.076 0.586 0.558 0.263 0.587 0.387 0.132 0.564 0.374 0.011 0.535
409 (97.1) 410 (97.4) 113 (26.8) 26 (6.2) 359 (85.3) 272 (64.6) 87 (20.7) 185 (43.9) 77 (18.3) 30 (7.1) 4 (0.9) 309 (73.4)
0. 997 0.998 0.696 0.005 0.062 0.059 0.652 0.490 0.738 0.485 0.042 0.290
Data are expressed as mean ± standard deviation, or number (percentage). ACE inhibitor, angiotensin-converting enzyme inhibitor; EES, everolimus-eluting stent; HbA1C, hemoglobin A1C; HDL-C, high-density lipoprotein cholesterol; hsCRP, highsensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Max.CK-MB, maximum creatine kinase-MB; NT-pro-BNP, N-terminal pro-brain natriuretic peptide; ZES, zotarolimus-eluting stent.
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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Table 2 Coronary angiographic characteristics and procedural results. Variable
Discussion
ZES n = 433
EES n = 421
p value
Intervened coronary artery Left main Left anterior descending Left circumflex Right coronary Multi-vessel involvement
7 (1.6) 182 (42.0) 41 (9.5) 201 (46.2) 233 (53.8)
5 (1.2) 200 (47.5) 44 (10.5) 171 (40.6) 241 (57.3)
0.592 0.114 0.639 0.082 0.311
ACC/AHA lesion type C Pre-TIMI grade 0 flow Post-TIMI grade 3 flow Total number of stents Stent length (mm) Stent diameter (mm) Pre-PCI diameter stenosis (%) Post-PCI diameter stenosis (%) Intravascular ultrasound use Glycoprotein IIb/IIIa inhibitor Thrombus aspiration PCI success rate In-hospital complications
188 (43.4) 260 (60.0) 1 (0.23) 1.4 ± 0.7 23.7 ± 7.2 3.2 ± 0.5 91.4 ± 13.8 10.3 ± 7.9 105 (24.3) 67 (15.5) 179 (41.3) 423 (97.7) 49 (11.3)
180 (42.7) 217 (51.5) 2 (0.5) 1.5 ± 0.7 22.3 ± 5.7 3.2 ± 0.4 90.6 ± 15.3 11.9 ± 14.3 129 (30.6) 65 (15.4) 129 (30.6) 407 (96.7) 40 (9.5)
0.877 0.020 0.557 0.112 0.003 0.333 0.581 0.146 0.061 0.989 0.001 0.943 0.361
Data are expressed as mean ± standard deviation or number (percentage). ACC/AHA, American College of Cardiology/American Heart Association; EES, everolimus-eluting stent; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; ZES, zotarolimus-eluting stent.
of all-cause death was higher in ZES with borderline significance compared to EES (2.8% vs 0.9%). It is however noteworthy that non-fatal MI, TVR, TLR, and stent thrombosis were not statistically significantly different between groups. A total of five cases of stent thromboses developed of which two were sub-acute (one in ZES, one in EES) and three were late stent thromboses (two in ZES, one in EES). The average rate of PCI success was 98.3%. Kaplan–Meier survival analysis demonstrated insignificant differences in freedom from MACE and death between two groups (Fig. 1). Cox proportional hazard analysis revealed no statistical differences in the incidence of MACE and death when adjusted for multiple confounders. MACE and all-cause death at 12 months did not differ significantly between the two groups despite propensity score adjustment using Cox model, p = 0.326 for MACE, p = 0.569 for death (Fig. 2). Subgroup analysis stratified by eGFR below 30 mL/min/1.73 m2 or above 30 mL/min/1.73 m2 was performed. This was analyzed by using Cox regression model adjusted by propensity score. The results are presented in the forest plot as shown in Fig. 3. This did not show any significant differences in 12-month MACE between ZES and EES either in eGFR >30 mL/min/1.73 m2 or <30 mL/min/1.73 m2 subgroups.
The present study demonstrates that implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12month MACE and death in STEMI patients with CKD undergoing primary PCI. Most studies of cardiovascular outcomes have found that a breakpoint for the development of contrast-induced nephropathy, acute or subacute stent thrombosis, later restenosis, recurrent myocardial infarction, diastolic/systolic congestive heart failure, and cardiovascular death occurs below an eGFR of 60 mL/min/1.73 m2 , which roughly corresponds to a serum creatinine level higher than 1.5 mg/dL in the general population [16–18]. A study by Bonello et al. [19] showed a graded increase in serious in-hospital complications (death, vascular complications, need for transfusion, acute renal failure, MACE), 1-month events (death, repeat MI, TLR, MACE), and 1-year outcomes (death, MI, TLR, MACE) as renal function declined. In spite of these poor outcomes, use of PCI is associated with superior long-term survival when compared with medical therapy alone in the management of acute coronary syndrome in CKD patients [20]. The frequency of clinical adverse events was also higher according to the stages of CKD. Hachinohe et al. [21] demonstrated when patients with non-ST segment elevation MI have severe CKD, the conservative or deferred invasive strategy with prescription of cardio-protective medication and prevention of further deterioration in renal function should be considered. They demonstrated that early invasive strategy was superior to deferred invasive strategy in mild CKD patients. However, this tendency decreased as renal function decreased and deferred strategy was superior to early invasive strategy in severe CKD patients. Although the use of new interventional devices, including stents, improved immediate procedural success rates, CKD patients also had higher long-term mortality rates (27.7% versus 6.1%, p < 0.0001) than patients with normal renal function [22]. There are several leading explanations for CKD being such a potent risk factor for adverse outcomes: (a) excess co-morbidities in CKD patients, including older age and diabetes; (b) underused end-organ protective strategies in CKD patients, or therapeutic nihilism; (c) excess toxicities from conventional therapies used including radiocontrast material and antithrombotic agents; and (d) the unique pathobiology of the CKD state, which includes intrarenal vasoconstriction when exposed to iodinated contrast agents [23]. Coronary stents have substantially improved the efficacy of percutaneous revascularization. Use of DES has further reduced the rates of in-stent restenosis and repeat revascularization compared to BMS [24]. Despite the widespread use of DES in treating coronary
Table 3 Clinical outcomes at 1 month and 12 months. Outcome variable
Major adverse cardiac event All-cause death Cardiac death Non-cardiac death Non-fatal myocardial infarction Repeat revascularization Target vessel Target lesion Non-target vessel Coronary artery bypass grafting Stent thrombosis
At 1 month
At 12 months
ZES n = 432
EES n = 419
p value
ZES n = 433
EES n = 421
p value
9 (2.1) 7 (1.6) 5 (1.2) 2 (0.5) 1 (0.2) 1 (0.2) 0 (0) 0 (0) 1 (0.2) 0 (0)
5 (1.2) 2 (0.5) 0 (0) 2 (0.5) 1 (0.2) 2 (0.5) 0 (0) 0 (0) 2 (0.5) 0 (0)
0.305 0.102 0.027 0.978 0.984 0.547 0.999 0.999 0.547 0.999
25 (5.7) 12 (2.8) 6 (1.4) 6 (1.4) 1 (0.2) 11 (2.5) 4 (0.9) 5 (1.2) 2 (0.5) 1 (0.2) 3 (0.7)
11 (2.6) 4 (0.9) 1 (0.2) 3 (0.7) 1 (0.2) 7 (1.7) 1 (0.2) 1 (0.2) 5 (1.2) 1 (0.2) 2 (0.5)
0.022 0.050 0.063 0.336 0.984 0.372 0.189 0.109 0.240 0.984 0.677
Data are expressed as number (percentage). EES, everolimus-eluting stent; ZES, zotarolimus-eluting stent.
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Fig. 1. Kaplan–Meier curves for 12-month MACE and death-free survival between the two commonly used stent types in patients with acute myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. EES, everolimus-eluting stent; MACE, major adverse cardiac event; ZES, zotarolimus-eluting stent.
Fig. 2. Propensity adjusted 12-month MACE and death-free survival between the two commonly used stent types in patients with acute myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. MACE, major adverse cardiac event.
Fig. 3. Estimates of hazard ratio (forest plot) for the primary end point (12-month major adverse cardiac event) in subgroups eGFR >30 mL/min/1.732 m2 and eGFR <30 mL/min/1.732 m2 . CI, confidence interval; EES, everolimus-eluting stent; eGFR, estimated glomerular filtration rate; ZES, zotarolimus-eluting stent.
artery disease which is prevalent among end-stage renal disease patients, the safety and efficacy of DES in this population have not been well defined. The overall results of a meta-analysis including 869 patients by Abdel-Latif et al. [25] indicate that DES use in these patients is safe and results in a modest yet statistically significant reduction in adverse clinical events. Importantly, the procedural success with DES was similar to that encountered with BMS. DES use significantly reduced the risk of TLR/TVR and MACE, but did not significantly influence the risk of all-cause mortality or MI. A study by Serruys et al. [26] demonstrated that at 13 months, the new-generation ZES was found to be non-inferior to the EES in the general population. Our study showed that either of the two commonly used stents can be used to treat AMI patients with CKD (eGFR <60 mL/min/1.73 m2 ) undergoing primary PCI, with similar risk of 12-month MACE. DESs have significantly reduced rates of restenosis compared to BMS, but an increased risk of late stent thrombosis has emerged as a major concern [27]. However, we observed no significant between-group difference in overall rates of stent thrombosis. Our observations may be influenced by selection bias and residual confounding or may represent a true finding; it is at least hypothesis-generating that needs to be further evaluated using a long-term randomized controlled study.
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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Study limitations The present study is limited due to its retrospective nature. We did not study outcomes stratified by every stage of CKD and for patients on dialysis. Patients did not undergo follow-up stress test or coronary angiography; silent ischemia and restenosis could have been under diagnosed. Information regarding renal function after PCI and details of scheduled angiographic follow-up were not collected in the KAMIR. Follow-up renal function test after PCI to rule out acute kidney injury was not checked. Conclusions Implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12-month MACE and death in STEMI patients with CKD undergoing primary PCI. Conflict of interest There are no potential conflicts to declare. Acknowledgments This study was performed with the support of Korea Ministry of Health & Welfare (A084869), and The Korean Health Technology R&D Project (HI13C1527), Ministry of Health & Welfare. The authors are highly thankful to Dr. Sumera Ahmed for her help in statistical analysis and formulation of this manuscript. References [1] Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697–701. [2] Dumaine R, Collet JP, Tanguy ML, Mansencal N, Dubois-Rande JL, Henry P, Steg PG, Michel PL, Allouch P, Cohen A, Colin P, Durand E, Montalescot G, SYCOMORE Investigators. Prognostic significance of renal insufficiency in patients presenting with acute coronary syndrome (the Prospective Multicenter SYCOMORE study). Am J Cardiol 2004;94:1543–7. [3] Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47–55. [4] Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, Berger PB. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002;39:1113–9. [5] Naidu SS, Selzer F, Jacobs A, Faxon D, Marks DS, Johnston J, Detre K, Wilensky RL. Renal insufficiency is an independent predictor of mortality after percutaneous coronary intervention. Am J Cardiol 2003;92:1160–4. [6] Azar RR, Prpic R, Ho KK, Kiernan FJ, Shubrooks Jr SJ, Baim DS, Popma JJ, Kuntz RE, Cohen DJ. Impact of end-stage renal disease on clinical and angiographic outcomes after coronary stenting. Am J Cardiol 2000;86: 485–9. [7] Best PJ, Berger PB, Davis BR, Grines CL, Sadeghi HM, Williams BA, Willerson JT, Granett JR, Holmes Jr DR, PRESTO Investigators. Impact of mild or moderate chronic kidney disease on the frequency of restenosis: results from the PRESTO trial. J Am Coll Cardiol 2004;44:1786–91. [8] Das P, Moliterno DJ, Charnigo R, Mukherjee D, Steinhubl SR, Sneed JD, Booth DC, Ziada KM. Impact of drug-eluting stents on outcomes of patients with end-stage renal disease undergoing percutaneous coronary revascularization. J Invasive Cardiol 2006;18:405–8.
[9] Lemos PA, Arampatzis CA, Hoye A, Daemen J, Ong AT, Saia F, van der Giessen WJ, McFadden EP, Sianos G, Smits PC, de Feyter P, Hofma SH, van Domburg RT, Serruys PW. Impact of baseline renal function on mortality after percutaneous coronary intervention with sirolimus-eluting stents or bare metal stents. Am J Cardiol 2005;95:167–72. [10] Charytan D, Kuntz RE. The exclusion of patients with chronic kidney disease from clinical trials in coronary artery disease. Kidney Int 2006;70: 2021–30. [11] Hachinohe D, Jeong MH, Saito S, Kim MC, Cho KH, Ahmed K, Hwang SH, Lee MG, Sim DS, Park KH, Kim JH, Hong YJ, Ahn Y, Kang JC, Kim JH, et al. Clinical impact of thrombus aspiration during primary percutaneous coronary intervention: results from Korea Acute Myocardial Infarction Registry. J Cardiol 2012;59:249–57. [12] National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–266. [13] Apple FS, Wu AH, Jaffe AS. European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials. Am Heart J 2002;144:981–6. [14] Kini AS. Coronary angiography, lesion classification and severity assessment. Cardiol Clin 2006;24:153–62, v. [15] Manginas A, Gatzov P, Chasikidis C, Voudris V, Pavlides G, Cokkinos DV. Estimation of coronary flow reserve using the Thrombolysis In Myocardial Infarction (TIMI) frame count method. Am J Cardiol 1999;83:1562–5. A7. [16] McCullough PA, Soman SS, Shah SS, Smith ST, Marks KR, Yee J, Borzak S. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol 2000;36:679–84. [17] Beattie JN, Soman SS, Sandberg KR, Yee J, Borzak S, Garg M, McCullough PA. Determinants of mortality after myocardial infarction in patients with advanced renal dysfunction. Am J Kidney Dis 2001;37:1191–200. [18] Szczech LA, Best PJ, Crowley E, Brooks MM, Berger PB, Bittner V, Gersh BJ, Jones R, Califf RM, Ting HH, Whitlow PJ, Detre KM, Holmes D, Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Outcomes of patients with chronic renal insufficiency in the bypass angioplasty revascularization investigation. Circulation 2002;105:2253–8. [19] Bonello L, De Labriolle A, Roy P, Steinberg DH, Okabe T, Pinto Slottow TL, Xue Z, Torguson R, Suddath WO, Satler LF, Kent KM, Pichard AD, Lindsay J, Waksman R. Impact of optimal medical therapy and revascularization on outcome of patients with chronic kidney disease and on dialysis who presented with acute coronary syndrome. Am J Cardiol 2008;102:535–40. [20] Keeley EC, Kadakia R, Soman S, Borzak S, McCullough PA. Analysis of long-term survival after revascularization in patients with chronic kidney disease presenting with acute coronary syndromes. Am J Cardiol 2003;92: 509–14. [21] Hachinohe D, Jeong MH, Saito S, Ahmed K, Hwang SH, Lee MG, Sim DS, Park KH, Kim JH, Hong YJ, Ahn Y, Kang JC, Kim JH, Chae SC, Kim YJ, et al. Management of non-ST-segment elevation acute myocardial infarction in patients with chronic kidney disease (from the Korea Acute Myocardial Infarction Registry). Am J Cardiol 2011;108:206–13. [22] Rubenstein MH, Harrell LC, Sheynberg BV, Schunkert H, Bazari H, Palacios IF. Are patients with renal failure good candidates for percutaneous coronary revascularization in the new device era. Circulation 2000;102:2966–72. [23] McCullough PA. Cardiorenal risk: an important clinical intersection. Rev Cardiovasc Med 2002;3:71–6. [24] Kirtane AJ, Gupta A, Iyengar S, Moses JW, Leon MB, Applegate R, Brodie B, Hannan E, Harjai K, Jensen LO, Park SJ, Perry R, Racz M, Saia F, Tu JV, et al. Safety and efficacy of drug-eluting and bare metal stents: comprehensive meta-analysis of randomized trials and observational studies. Circulation 2009;119:3198–206. [25] Abdel-Latif A, Mukherjee D, Mesgarzadeh P, Ziada KM. Drug-eluting stents in patients with end-stage renal disease: meta-analysis and systematic review of the literature. Catheter Cardiovasc Interv 2010;76:942–8. [26] Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE, Kelbaek H, van Boven AJ, Hofma SH, Linke A, Klauss V, Wijns W, Macaya C, Garot P, DiMario C, et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med 2010;363:136–46. [27] Nakazawa G. Stent thrombosis of drug eluting stent: pathological perspective. J Cardiol 2011;58:84–91.
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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Original article
Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention Khurshid Ahmed (MD) a,b , Myung Ho Jeong (MD, PhD, FACC, FAHA, FESC, FSCAI, FAPSIC) a,∗ , Rabin Chakraborty (MD) b , Sumera Ahmed (MHM) b , Young Joon Hong (MD) a , Doo Sun Sim (MD) a , Keun Ho Park (MD) a , Ju Han Kim (MD) a , Youngkeun Ahn (MD) a , Jung Chaee Kang (MD) a , Myeong Chan Cho (MD) c , Chong Jin Kim (MD) d , Young Jo Kim (MD) e , other Korea Acute Myocardial Infarction Registry Investigators a The Heart Center of Chonnam National University Hospital, Chonnam National University Research Institute of Medical Sciences, Gwangju, Republic of Korea b Apollo Gleneagles Hospital, Kolkata, India c Chungbuk National University Hospital, Chungju, Republic of Korea d East West Neo Medical Center, Seoul, Republic of Korea e Yeungnam University Hospital, Daegu, Republic of Korea
a r t i c l e
i n f o
Article history: Received 22 September 2012 Received in revised form 11 December 2013 Accepted 3 February 2014 Available online xxx Keywords: ST-segment elevation myocardial infarction Drug-eluting stent Coronary angioplasty Chronic kidney failure
a b s t r a c t Background: Chronic kidney disease (CKD) is associated with poor outcomes after percutaneous coronary intervention (PCI). The aim of the study was to compare zotarolimus- and everolimus-eluting stents used during primary PCI in patients with acute myocardial infarction (AMI) and CKD. Methods: We selected 854 consecutive ST-elevation MI patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 ) undergoing primary PCI who were followed up for 12 months. They were divided into two groups based on type of stents implanted: (1) zotarolimus-eluting stent (ZES) and (2) everolimus-eluting stent (EES). The study end point was the 12-month major adverse cardiac events (MACE) which included all-cause death, non-fatal MI, target lesion revascularization (TLR), and target vessel revascularization (TVR). Results: The average number of stents used per vessel was 1.4 ± 0.7. A total of 433 patients received ZES and 421 patients received EES. There was no significant difference in the incidence of 12-month MI, TLR, or TVR. All-cause death was found to be borderline significant between two groups (2.8% in ZES vs 0.9% in EES, p = 0.05). The incidence of 12-month MACE in ZES and EES was 5.7% and 2.6% respectively, p = 0.022. Stent thrombosis did not differ between groups (p = 0.677). Kaplan–Meier analysis did not show significant difference for 12-month MACE-free survival between groups (log-rank p = 0.158). It remained the same even after propensity adjustment for multiple confounders in Cox model (p = 0.326). Conclusions: Implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12month MACE and death in STEMI patients with CKD undergoing primary PCI. © 2014 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Introduction
∗ Corresponding author at: Professor, Principal Investigator of Korea Acute Myocardial Infarction Registry, Chonnam National University Hospital, 671 Jaebongro, Dong-gu, Gwangju 501-757, Republic of Korea. Tel.: +82 62 220 6243; fax: +82 62 228 7174. E-mail addresses: [email protected], [email protected] (M.H. Jeong).
Patients with chronic kidney disease (CKD) present with accelerated atherosclerosis and higher cardiovascular morbidity and mortality [1–3]. Furthermore, CKD is associated with adverse outcome following percutaneous coronary intervention (PCI) [4,5], likely related to endothelial dysfunction, inflammation, and platelet activation. After PCI with bare metal stents (BMS), the need for repeat revascularization remains high [6], although the
http://dx.doi.org/10.1016/j.jjcc.2014.02.002 0914-5087/© 2014 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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restenosis rate in mild to moderate CKD is not increased at 9 months [7]. Retrospective analyses have demonstrated that, in the intermediate term, despite a higher overall mortality and morbidity after PCI, patients with end-stage renal disease [8] as well as those with milder degrees of CKD [9] benefit from lower rates of target vessel revascularization (TVR) with drug-eluting stent (DES) versus BMS placement. Despite the high prevalence of coronary artery disease among CKD patients, this patient population has been consistently excluded from the major clinical trials in cardiovascular medicine [10]. We sought to investigate which of the most commonly used stents best suit patients with moderate to severe CKD undergoing primary PCI. We compared 12-month the clinical outcomes in two types of stents. Methods This is a retrospective study that was carried out in the Heart Center of Chonnam National University Hospital, Gwangju, Korea. The permission to carry out the study was obtained from the hospital authorities (Institutional Review Board number 05-49, I2008-01-009) and written informed consent was taken from all patients. Korea Acute Myocardial Infarction Registry The Korea Acute Myocardial Infarction Registry is a prospective, multicenter, observational registry designed to examine current epidemiology in hospital management and the outcome of patients with acute myocardial infarction (AMI) in Korea for the commemoration of the 50th anniversary of the Korean Circulation Society. The registry included 52 community and university hospitals for primary PCI with 1-year clinical follow-up. Data were collected at each site by a well-trained study coordinator based on a standardized protocol [11]. Study population Patients were enrolled in the registry after admission to participating hospitals with a suspected diagnosis of AMI. Patients’ medical documents were used to note the demographic data, clinical characteristics, and relevant laboratory results. A total of 854 consecutive patients with ST-segment elevation MI with CKD undergoing primary PCI from April 2006 through September 2010 were selected in this study. We studied their 12-month clinical outcomes (follow-up rate was 100%). CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated using the Modification of Diet in Renal Disease (MDRD) method [12]. Patients on hemodialysis or continuous ambulatory peritoneal dialysis, with cardiogenic shock and evidence of heart failure were excluded from this study. They were divided into two groups based on the type of stents implanted – zotarolimus-eluting stents (ZES, n = 433, endeavor = 369 and resolute = 64; Medtronic CardioVascular, Santa Rosa, CA, USA), and everolimus-eluting stents (EES, n = 421). Definitions and clinical endpoints A final diagnosis of AMI was made according to the European Society of Cardiology/American College of Cardiology (ACC) diagnostic criteria of AMI [13]. Hypertension was defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg at rest, at repeated measurements or treatment
with anti-hypertensive medications. Diabetes was defined as having an established diagnosis of diabetes mellitus or use of oral hypoglycemic agent or insulin to lower blood glucose levels. Hyperlipidemia was defined as a total cholesterol level >200 mg/dL or treatment with a lipid-lowering agent. Coronary artery disease was defined as history of MI, revascularization procedure, or obstructive coronary artery disease. Peripheral blood samples were obtained using direct venipuncture. Blood samples were centrifuged and serum was removed and stored at a temperature of −70 ◦ C until the assay could be performed for proteins and sugar. Absolute creatine kinaseMB levels were determined by radioimmunoassay (Dade Behring, Inc., Miami, FL, USA). Cardiac specific troponin I levels were measured by a paramagnetic particle, chemiluminescent immunoenzymatic assay (Beckham, Coulter, Inc., Fullerton, CA, USA). Twelve-hour fasting serum levels of total cholesterol, triglyceride, and low- and high-density lipoprotein cholesterol were measured by standard enzymatic methods. Blood samples for high-sensitivity C-reactive protein (CRP) were obtained on admission and analyzed turbidimetrically with sheep antibodies against human CRP; this has been validated against the Dade Behring method. Two-dimensional echocardiography was performed in all patients and left ventricular ejection fraction was assessed using modified Simpson’s biplanar method. The morphology in coronary angiography was classified according to the criteria of ACC/American Heart Association (AHA) [14]. Degree of coronary flow was classified by Thrombolysis In Myocardial Infarction (TIMI) score [15]. Renal function was assessed by eGFR, which was calculated using the MDRD method [12]. teh presence of left main coronary artery stenosis was defined as a luminal stenosis ≥50%. Multivessel disease was defined as the presence of a lesion with >50% diameter stenosis in a non-infarct related coronary artery. Successful PCI was defined as TIMI flow three with residual stenosis ≤50% in the infarct-related artery. Inhospital complications included any of atrio-ventricular block, bradycardia, ventricular tachycardia/ventricular fibrillation, atrial fibrillation, cardiogenic shock, no re-flow, dissection, acute renal failure, metabolic acidosis/lactic acidosis, cerebrovascular event, or infection/sepsis. All patients were administered loading doses of aspirin 325 mg and clopidogrel 300–600 mg before PCI. Anticoagulation during PCI was performed according to the routine practices of each hospital. After the procedure, aspirin 100–300 mg (once per day) was prescribed indefinitely. Clopidogrel was prescribed continuously for 1 year to patients who underwent DES implantation. The clinical endpoint of this study was the major adverse cardiac events (MACE) which included all-cause death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR) and TVR during the 12-month follow-up. Non-fatal MI was defined as the presence of clinical symptoms, electrocardiographic change, or abnormal imaging findings of MI combined with an increase in creatine kinase-MB fraction or troponin T/I more than the 99th percentile of the upper normal limit that was not related to an interventional procedure. TVR defined as clinically driven repeat revascularization of a lesion in the same epicardial vessel treated in the index procedure at 12-month follow-up. TLR was defined as any revascularization of the target lesion due to restenosis or re-occlusion within 5 mm proximal/distal to the stent. All data were recorded on a standardized, electronic, web-based registry at http://www.kamir.or.kr. Statistical analysis SPSS 17.0 for windows (SPSS, Inc., Chicago, IL, USA) was used for all analysis. Continuous variables were presented as
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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mean ± standard deviation; comparisons were conducted by Student’s t-test. Discrete variables were presented as percentages and frequencies; comparisons were conducted by chi-square statistics. A p-value <0.05 was considered statistically significant. Kaplan–Meier curves were constructed to examine the incidence of clinical endpoints. Cox proportional hazard analysis was performed to identify a model with independent predictive factors with determination of a hazard ratio and its 95% confidence interval for each variable in the model. Covariates included in the model were age, stent length, pre-procedure TIMI flow grade 0, creatinine kinaseMB, and the use of thrombus aspiration device. As the number of 12-month MACE was relatively small in our study population, we limited the variables into the model. The results are presented as adjusted hazard ratios with 95% confidence intervals and p-values. We performed propensity score matching to enable an even more rigorous adjustment for selection biases and confounding factors.
Results A total of 854 consecutive patients with AMI and CKD undergoing PCI were included in the present study. The average age of the total population was 64.1 ± 12.7 years and 81.6% were men. The mean stent length was 23.0 ± 6.5 mm and the mean stent diameter was 3.2 ± 0.5 mm. The average number of stents used per vessel was 1.4 ± 0.7.
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Baseline clinical and laboratory characteristics and concomitant medications Baseline clinical and laboratory characteristics and concomitant medications of the two groups are presented in Table 1. Patients in the ZES group were older with lower heart rate, higher prevalence of family history of coronary artery disease, and higher serum level of creatinine kinase-MB. Use of calcium-channel blockers and fibrates was less frequently observed in the ZES group compared to that in the EES group. Coronary angiographic and procedural characteristics Coronary angiographic characteristics and procedural results of the two groups are presented in Table 2. Patients in the ZES group had higher pre-PCI TIMI grade 0 flow, larger stent length, and higher use of thrombus aspiration device compared to the EES group. Other coronary angiographic characteristics did not show statistically meaningful differences between the two groups. Twelve-month clinical outcomes The 12-month clinical outcomes are presented in Table 3. The incidence of 12-month MACE was higher in the ZES group compared to that in the EES group (5.7% vs 2.6%) and the incidence
Table 1 Baseline clinical and laboratory characteristics, and concomitant medications. Variable Age (years) Male gender Systolic blood pressure (mmHg) Heart rate (beats/min) Left ventricular ejection fraction (%) Killip class >1 Hypertension Diabetes mellitus Previous history of coronary artery disease Family history of coronary artery disease Smoking history Hyperlipidemia Laboratory characteristics Glucose (mg/dL) Creatinine (mg/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) hsCRP (mg/dL) NT-pro-BNP (pg/mL) HbA1C (%) Max.CK-MB (U/L) Troponin-I (ng/mL) Discharge medication Aspirin Clopidogrel Cliostazol Calcium channel blocker Beta blocker ACE inhibitor Angiotensin receptor blocker Nitrate Diuretics Spiranolactone Fibrate Statin
ZES n = 433 66.3 ± 13.4 346 (79.9) 123.8 ± 29.9 72.5 ± 18.8 52.3 ± 17.2 138 (31.9) 227 (52.4) 111 (25.6) 42 (9.7) 45 (10.4) 268 (61.9) 53 (12.2) 175.9 ± 75.3 1.5 ± 1.4 180.0 ± 40.8 125.0 ± 79.9 43.2 ± 16.1 112.5 ± 35.6 4.2 ± 13.8 3784.1 ± 7772.3 6.5 ± 1.4 211.8 ± 357.3 64.9 ± 111.9 410 (94.7) 411 (94.9) 110 (25.4) 10 (2.3) 341 (78.7) 253 (58.4) 93 (21.4) 202 (46.6) 75 (17.3) 37 (8.5) 0 (0) 324 (74.8)
EES n = 421
p value
63.5 ± 11.8 351 (83.3) 127.7 ± 31.8 75.7 ± 21.7 51.9 ± 23.4 134 (31.8) 230 (54.6) 125 (29.7) 38 (0.09) 25 (5.9) 271 (64.4) 67 (1.6)
0.001 0.191 0.066 0.027 0.813 0.979 0.531 0.182 0.771 0.013 0.440 0.149
185.7 ± 85.9 1.4 ± 1.6 181.7 ± 43.2 132.7 ± 112.4 42.7 ± 11.0 114.7 ± 36.4 5.8 ± 15.1 4226.1 ± 7900.1 6.6 ± 1.4 163.3 ± 157.9 57.9 ± 174.5
0.076 0.586 0.558 0.263 0.587 0.387 0.132 0.564 0.374 0.011 0.535
409 (97.1) 410 (97.4) 113 (26.8) 26 (6.2) 359 (85.3) 272 (64.6) 87 (20.7) 185 (43.9) 77 (18.3) 30 (7.1) 4 (0.9) 309 (73.4)
0. 997 0.998 0.696 0.005 0.062 0.059 0.652 0.490 0.738 0.485 0.042 0.290
Data are expressed as mean ± standard deviation, or number (percentage). ACE inhibitor, angiotensin-converting enzyme inhibitor; EES, everolimus-eluting stent; HbA1C, hemoglobin A1C; HDL-C, high-density lipoprotein cholesterol; hsCRP, highsensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Max.CK-MB, maximum creatine kinase-MB; NT-pro-BNP, N-terminal pro-brain natriuretic peptide; ZES, zotarolimus-eluting stent.
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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Table 2 Coronary angiographic characteristics and procedural results. Variable
Discussion
ZES n = 433
EES n = 421
p value
Intervened coronary artery Left main Left anterior descending Left circumflex Right coronary Multi-vessel involvement
7 (1.6) 182 (42.0) 41 (9.5) 201 (46.2) 233 (53.8)
5 (1.2) 200 (47.5) 44 (10.5) 171 (40.6) 241 (57.3)
0.592 0.114 0.639 0.082 0.311
ACC/AHA lesion type C Pre-TIMI grade 0 flow Post-TIMI grade 3 flow Total number of stents Stent length (mm) Stent diameter (mm) Pre-PCI diameter stenosis (%) Post-PCI diameter stenosis (%) Intravascular ultrasound use Glycoprotein IIb/IIIa inhibitor Thrombus aspiration PCI success rate In-hospital complications
188 (43.4) 260 (60.0) 1 (0.23) 1.4 ± 0.7 23.7 ± 7.2 3.2 ± 0.5 91.4 ± 13.8 10.3 ± 7.9 105 (24.3) 67 (15.5) 179 (41.3) 423 (97.7) 49 (11.3)
180 (42.7) 217 (51.5) 2 (0.5) 1.5 ± 0.7 22.3 ± 5.7 3.2 ± 0.4 90.6 ± 15.3 11.9 ± 14.3 129 (30.6) 65 (15.4) 129 (30.6) 407 (96.7) 40 (9.5)
0.877 0.020 0.557 0.112 0.003 0.333 0.581 0.146 0.061 0.989 0.001 0.943 0.361
Data are expressed as mean ± standard deviation or number (percentage). ACC/AHA, American College of Cardiology/American Heart Association; EES, everolimus-eluting stent; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; ZES, zotarolimus-eluting stent.
of all-cause death was higher in ZES with borderline significance compared to EES (2.8% vs 0.9%). It is however noteworthy that non-fatal MI, TVR, TLR, and stent thrombosis were not statistically significantly different between groups. A total of five cases of stent thromboses developed of which two were sub-acute (one in ZES, one in EES) and three were late stent thromboses (two in ZES, one in EES). The average rate of PCI success was 98.3%. Kaplan–Meier survival analysis demonstrated insignificant differences in freedom from MACE and death between two groups (Fig. 1). Cox proportional hazard analysis revealed no statistical differences in the incidence of MACE and death when adjusted for multiple confounders. MACE and all-cause death at 12 months did not differ significantly between the two groups despite propensity score adjustment using Cox model, p = 0.326 for MACE, p = 0.569 for death (Fig. 2). Subgroup analysis stratified by eGFR below 30 mL/min/1.73 m2 or above 30 mL/min/1.73 m2 was performed. This was analyzed by using Cox regression model adjusted by propensity score. The results are presented in the forest plot as shown in Fig. 3. This did not show any significant differences in 12-month MACE between ZES and EES either in eGFR >30 mL/min/1.73 m2 or <30 mL/min/1.73 m2 subgroups.
The present study demonstrates that implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12month MACE and death in STEMI patients with CKD undergoing primary PCI. Most studies of cardiovascular outcomes have found that a breakpoint for the development of contrast-induced nephropathy, acute or subacute stent thrombosis, later restenosis, recurrent myocardial infarction, diastolic/systolic congestive heart failure, and cardiovascular death occurs below an eGFR of 60 mL/min/1.73 m2 , which roughly corresponds to a serum creatinine level higher than 1.5 mg/dL in the general population [16–18]. A study by Bonello et al. [19] showed a graded increase in serious in-hospital complications (death, vascular complications, need for transfusion, acute renal failure, MACE), 1-month events (death, repeat MI, TLR, MACE), and 1-year outcomes (death, MI, TLR, MACE) as renal function declined. In spite of these poor outcomes, use of PCI is associated with superior long-term survival when compared with medical therapy alone in the management of acute coronary syndrome in CKD patients [20]. The frequency of clinical adverse events was also higher according to the stages of CKD. Hachinohe et al. [21] demonstrated when patients with non-ST segment elevation MI have severe CKD, the conservative or deferred invasive strategy with prescription of cardio-protective medication and prevention of further deterioration in renal function should be considered. They demonstrated that early invasive strategy was superior to deferred invasive strategy in mild CKD patients. However, this tendency decreased as renal function decreased and deferred strategy was superior to early invasive strategy in severe CKD patients. Although the use of new interventional devices, including stents, improved immediate procedural success rates, CKD patients also had higher long-term mortality rates (27.7% versus 6.1%, p < 0.0001) than patients with normal renal function [22]. There are several leading explanations for CKD being such a potent risk factor for adverse outcomes: (a) excess co-morbidities in CKD patients, including older age and diabetes; (b) underused end-organ protective strategies in CKD patients, or therapeutic nihilism; (c) excess toxicities from conventional therapies used including radiocontrast material and antithrombotic agents; and (d) the unique pathobiology of the CKD state, which includes intrarenal vasoconstriction when exposed to iodinated contrast agents [23]. Coronary stents have substantially improved the efficacy of percutaneous revascularization. Use of DES has further reduced the rates of in-stent restenosis and repeat revascularization compared to BMS [24]. Despite the widespread use of DES in treating coronary
Table 3 Clinical outcomes at 1 month and 12 months. Outcome variable
Major adverse cardiac event All-cause death Cardiac death Non-cardiac death Non-fatal myocardial infarction Repeat revascularization Target vessel Target lesion Non-target vessel Coronary artery bypass grafting Stent thrombosis
At 1 month
At 12 months
ZES n = 432
EES n = 419
p value
ZES n = 433
EES n = 421
p value
9 (2.1) 7 (1.6) 5 (1.2) 2 (0.5) 1 (0.2) 1 (0.2) 0 (0) 0 (0) 1 (0.2) 0 (0)
5 (1.2) 2 (0.5) 0 (0) 2 (0.5) 1 (0.2) 2 (0.5) 0 (0) 0 (0) 2 (0.5) 0 (0)
0.305 0.102 0.027 0.978 0.984 0.547 0.999 0.999 0.547 0.999
25 (5.7) 12 (2.8) 6 (1.4) 6 (1.4) 1 (0.2) 11 (2.5) 4 (0.9) 5 (1.2) 2 (0.5) 1 (0.2) 3 (0.7)
11 (2.6) 4 (0.9) 1 (0.2) 3 (0.7) 1 (0.2) 7 (1.7) 1 (0.2) 1 (0.2) 5 (1.2) 1 (0.2) 2 (0.5)
0.022 0.050 0.063 0.336 0.984 0.372 0.189 0.109 0.240 0.984 0.677
Data are expressed as number (percentage). EES, everolimus-eluting stent; ZES, zotarolimus-eluting stent.
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Fig. 1. Kaplan–Meier curves for 12-month MACE and death-free survival between the two commonly used stent types in patients with acute myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. EES, everolimus-eluting stent; MACE, major adverse cardiac event; ZES, zotarolimus-eluting stent.
Fig. 2. Propensity adjusted 12-month MACE and death-free survival between the two commonly used stent types in patients with acute myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. MACE, major adverse cardiac event.
Fig. 3. Estimates of hazard ratio (forest plot) for the primary end point (12-month major adverse cardiac event) in subgroups eGFR >30 mL/min/1.732 m2 and eGFR <30 mL/min/1.732 m2 . CI, confidence interval; EES, everolimus-eluting stent; eGFR, estimated glomerular filtration rate; ZES, zotarolimus-eluting stent.
artery disease which is prevalent among end-stage renal disease patients, the safety and efficacy of DES in this population have not been well defined. The overall results of a meta-analysis including 869 patients by Abdel-Latif et al. [25] indicate that DES use in these patients is safe and results in a modest yet statistically significant reduction in adverse clinical events. Importantly, the procedural success with DES was similar to that encountered with BMS. DES use significantly reduced the risk of TLR/TVR and MACE, but did not significantly influence the risk of all-cause mortality or MI. A study by Serruys et al. [26] demonstrated that at 13 months, the new-generation ZES was found to be non-inferior to the EES in the general population. Our study showed that either of the two commonly used stents can be used to treat AMI patients with CKD (eGFR <60 mL/min/1.73 m2 ) undergoing primary PCI, with similar risk of 12-month MACE. DESs have significantly reduced rates of restenosis compared to BMS, but an increased risk of late stent thrombosis has emerged as a major concern [27]. However, we observed no significant between-group difference in overall rates of stent thrombosis. Our observations may be influenced by selection bias and residual confounding or may represent a true finding; it is at least hypothesis-generating that needs to be further evaluated using a long-term randomized controlled study.
Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002
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Study limitations The present study is limited due to its retrospective nature. We did not study outcomes stratified by every stage of CKD and for patients on dialysis. Patients did not undergo follow-up stress test or coronary angiography; silent ischemia and restenosis could have been under diagnosed. Information regarding renal function after PCI and details of scheduled angiographic follow-up were not collected in the KAMIR. Follow-up renal function test after PCI to rule out acute kidney injury was not checked. Conclusions Implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12-month MACE and death in STEMI patients with CKD undergoing primary PCI. Conflict of interest There are no potential conflicts to declare. Acknowledgments This study was performed with the support of Korea Ministry of Health & Welfare (A084869), and The Korean Health Technology R&D Project (HI13C1527), Ministry of Health & Welfare. The authors are highly thankful to Dr. Sumera Ahmed for her help in statistical analysis and formulation of this manuscript. References [1] Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697–701. [2] Dumaine R, Collet JP, Tanguy ML, Mansencal N, Dubois-Rande JL, Henry P, Steg PG, Michel PL, Allouch P, Cohen A, Colin P, Durand E, Montalescot G, SYCOMORE Investigators. Prognostic significance of renal insufficiency in patients presenting with acute coronary syndrome (the Prospective Multicenter SYCOMORE study). Am J Cardiol 2004;94:1543–7. [3] Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47–55. [4] Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, Berger PB. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002;39:1113–9. [5] Naidu SS, Selzer F, Jacobs A, Faxon D, Marks DS, Johnston J, Detre K, Wilensky RL. Renal insufficiency is an independent predictor of mortality after percutaneous coronary intervention. Am J Cardiol 2003;92:1160–4. [6] Azar RR, Prpic R, Ho KK, Kiernan FJ, Shubrooks Jr SJ, Baim DS, Popma JJ, Kuntz RE, Cohen DJ. Impact of end-stage renal disease on clinical and angiographic outcomes after coronary stenting. Am J Cardiol 2000;86: 485–9. [7] Best PJ, Berger PB, Davis BR, Grines CL, Sadeghi HM, Williams BA, Willerson JT, Granett JR, Holmes Jr DR, PRESTO Investigators. Impact of mild or moderate chronic kidney disease on the frequency of restenosis: results from the PRESTO trial. J Am Coll Cardiol 2004;44:1786–91. [8] Das P, Moliterno DJ, Charnigo R, Mukherjee D, Steinhubl SR, Sneed JD, Booth DC, Ziada KM. Impact of drug-eluting stents on outcomes of patients with end-stage renal disease undergoing percutaneous coronary revascularization. J Invasive Cardiol 2006;18:405–8.
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Please cite this article in press as: Ahmed K, et al. Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol (2014), http://dx.doi.org/10.1016/j.jjcc.2014.02.002