Comparison of 2 year Outcomes between Zotarolimus eluting and. Everolimus eluting New generation Cobalt Chromium Alloy Stents

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1 Comparison of 2 year Outcomes between Zotarolimus eluting and Everolimus eluting New generation Cobalt Chromium Alloy Stents in Real world Diabetic Patients Tadashi Miyazaki, MD, a,b,c Azeem Latib, MD, a,b Vasileios F. Panoulas, MD, PhD, MRCP, a,b,d Sakiko Miyazaki, MD, PhD, MPH, a,c Charis Costopoulos, MD, a,b Katsumasa Sato, MD, a,b Toru Naganuma, MD, a,b Hiroyoshi Kawamoto, MD, a,b Hiroyuki Daida, MD,PhD, c Antonio Colombo, MD a,b a Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy b Interventional Cardiology Unit, EMO GVM Centro Cuore Columbus, Milan, Italy c Cardiovascular medicine, Juntendo University, Tokyo, Japan d Imperial College London, National Heart and Lung Institute, London, UK Short title: R ZES vs EES in Real world Diabetic Patients Word count: 4929 words Key words: Diabetes mellitus, Drug eluting stents (DES), Percutaneous coronary intervention (PCI) Corresponding author: Antonio Colombo, MD EMO GVM Centro Cuore Columbus, Via M. Buonarroti, Milan, Italy Tel: , Fax: , E mail: info@emocolumbus.it

2 ABSTRACT Background: To date, it remains unknown whether different types of new generation drug eluting stents have a differential impact on long term outcomes in diabetic patients. Methods and Results: In this historical cohort study (2 Italian centers), we analyzed 400 diabetic patients with 553 coronary lesions treated with new generation CoCr zotarolimus eluting stents (R ZES: 136 patients, 196 lesions) or everolimus eluting stents (EES: 264 patients, 357 lesions) between October 2006 and August Primary endpoint was the occurrence of major adverse cardiac events (MACE) over a 2 year follow up period. MACE was defined as all cause mortality, any myocardial infarction (MI) and/or target lesion revascularization (TLR). Multi vessel revascularization, intervention for restenotic lesion and use of intravascular ultrasound were significantly higher in the R ZES group, whereas small stent ( 2.5 mm) deployment was significantly higher in the EES group. At 2 year follow up, there was no significant difference in occurrence of MACE (R ZES vs EES: 22.8% vs 18.9%, P = 0.39). Similarly, no significant differences were observed in the composite endpoint of all cause mortality/mi (10.0% vs 10.3%, P = 0.86) or TLR (12.4% vs 7.4%, P = 0.11). Adjustment for confounders and baseline propensity score matching did not alter the aforementioned associations. Conclusion: After 2 years of follow up similar outcomes (MACE, all cause mortality/mi, TLR) were observed in real world diabetic patients, including those with complex lesions and patient characteristics, treated with R ZES and EES.

3 Introduction Diabetic patients often have a constellation of cardiovascular risk factors which act synergistically in causing extensive, complex coronary artery disease [1]. The diffuse, complex pattern of coronary artery disease makes effective revascularization a challenging task, which is often associated with a worse prognosis compared to non diabetic patients [2]. With the advances in stent technology, newer generation ZES and EES have demonstrated significantly improved revascularization rates and excellent safety profiles compared to first generation ones [3]. Despite advances in percutaneous coronary intervention (PCI), the preferred revascularization modality for multivessel or left main disease amongst diabetic patients is coronary artery bypass surgery [4 7]. At present only one study comparing head to head ZES and EES in a diabetic cohort derived from a large registry showed no significant difference in major adverse cardiovascular events (MACE) at 1 year [8]. It remains unknown how these stents perform against each other, in the challenging population of diabetic patients in the long term despite the fact that the diabetic population is increasing at an accelerated rate. Thus, the aim of our study was to compare 2 year clinical outcomes of diabetic patients treated with the commonly used new generation CoCr ZES and EES, the safety and feasibility of which have individually been well investigated.

4 Methods Study design and patients All diabetic patients treated with new generation CoCr EES including Xience V or Prime (Abbott Vascular, Santa Clara, CA, USA), and PROMUS (Boston Scientific, Natick, MA, USA) or R ZES including Endeavor Resolute and Resolute Integrity (Medtronic, Santa Rosa, CA, USA) in San Raffaele Hospital (Milan, Italy) and Columbus Hospital (Milan, Italy) between October 2006 and August 2012 were included in this historical cohort study. Diabetes mellitus was defined either as per American Diabetes Association criteria; HbA1c 6.5%, fasting plasma glucose 126 mg/dl or random plasma glucose of 200 mg/dl, or under pharmacological or nonpharmacological treatments for diabetes. For data collection purposes, no restrictions other than hybrid stenting with other types of stents at the same setting or in staged PCI were applied. Concurrent use of the same type of drug eluting stent (e.g. Promus stent with Xience PRIME stent) was permitted. So as not to lose the advantage of using real world data, we did not exclude cases based on patient or lesion characteristics (e.g. end stage renal failure, acute coronary syndrome, chronic total occlusions and heavily calcified lesions requiring atherectomy). Staged procedures performed in 2 different occasions within 8 weeks were considered a single procedure for analysis purposes. Tandem lesions or a diffuse lesion in the same branch covered by 1 or more stents continuously without gap were considered as a single lesion. Definitions

5 For the current analysis we utilized stent length and stent diameter, as a surrogate marker of angiographic lesion length and reference vessel diameter, respectively. A stent was defined as small when its diameter was 2.5 mm or less, and long when its length was more than 27 mm [9]. In case a lesion was treated with multiple serial stents, we considered the smallest size stent to determine the treated vessel size. We also evaluated the complexity of the coronary lesion using the angiographic scoring system utilized in the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial [10]. Periprocedural MI was defined as increase in the cardiac troponin values (> 5 times 99th percentile upper reference limit (URL)) or rise in the MB fraction of creatine kinase (CK MB, > 3 times 99th percentile URL) within 12hrs of the procedures [11,12]. Stent thrombosis defined as definite, probable, or possible according to the Academic Research Consortium [12]. Regarding the clinical endpoints, the primary endpoint of MACE was defined as a composite of all cause mortality, any MI, including periprocedural MI, and any target lesion revascularization (TLR) which was also defined as per Academic Research Consortium criteria. Other end points of interest included the composite of death from all cause mortality/mi and TLR. Statistics Descriptive statistics of patient and lesion characteristics are presented. Categorical variables are reported as counts and percentages, and between group differences were assessed with the Chi square test or Fisher s exact test. Continuous variables are presented as means with standard deviation or medians with interquartile range (IQR) and were compared with the two sample Student s

6 t test or the Wilcoxon rank sum test for parametric and non parametric variables, respectively. The Kaplan Meier method was used to estimate 2 year outcome rates in each group, and the log rank test to compare between group differences. Covariates included in the multivariable Cox regression analysis for MACE and TLR consist of those identified at univariate analysis and those considered clinically relevant from previous literature [13,14], while stent type was forced into the final model as this was the variable of interest in this study. Propensity score was computed by a logistic regression model using the following variables; type of stent, age, male gender, diabetes treatment, chronic kidney disease, prior PCI, prior CABG, history of MI, left ventricular ejection fraction, angina type, number of diseased vessel, multi vessel PCI, more than 1 lesion treated per vessel, stent length per patient, at least 1 small stent use, at least 1 long stent use, at least 1 bifurcation lesion, at least 1 restenotic lesion, at least 1 occluded lesion, at least 1 complex lesion (lesion morphology B2 or C). One to one propensity score matching was applied to neutralize baseline confounders prior to comparing the primary endpoint. Hazard ratio (HR) and 95% confidence intervals were calculated, and statistical significance was defined as a two sided P value less than 0.05 throughout analysis. With a power of 80% and alpha 0.05, we estimated that a total sample size of 400 patients (with 1:2 ratio R ZES:EES) would be needed to detect > 5% difference in MACE at 2 years. We used SPSS 21.0 (SPSS, Chicago, IL, USA) for all statistical analyses.

7 Results In the present study we screened data on 733 diabetic patients who had 1139 lesions treated with PCI using EES (Xience V, Xience PRIME, PROMUS), and R ZES (Endeavor Resolute, Resolute Integrity) stents. Recurrent PCI during this interval and patients treated with more than one type of stent at the same time were excluded. The final number of eligible patients was 400 with 553 treated lesions. The median follow up period was 704 days (IQR ). There was no statistically significant difference in the median follow up period between the R ZES and the EES group (879.5 days vs days, P = 0.17). Mean age was 65.7 ± 8.6 years (65.6 ± 8.1 vs 65.7 ± 8.8, R ZES vs EES respectively, P = 0.94) (Table 1). Baseline patient characteristics including cardiovascular risk factors, with the exception of prior PCI, were similar amongst the two groups (Table 1). Most of the lesions (82.5% total; 87.2% R ZES vs 79.8% EES, P = 0.028) were complex (class B2 or C), prevalence of restenotic lesions was 19.2% (26.0% R ZES vs 15.4% EES, P = 0.002) (Table 2). Regarding the procedural results, multi vessel PCI (23.5% vs 14.0%, P = 0.017) and PCI for restenotic lesions (26.0% vs 15.4%, P = 0.002) were significantly higher in the R ZES group, whereas small stent deployment was significantly higher in the EES group (27.6% vs 37.8%, P = 0.015). IVUS was more frequently used in the R ZES group (30.1% vs 17.4%, P = 0.001) (Table 3). After 1:1 propensity score matching, as shown in Table 1 3, between R ZES group (128 patients, 181 lesions) and EES group (128 patients, 180 lesions), all variables including patient, lesion and procedure characteristics did not demonstrate any

8 statistically significant differences. In the overall study population, there were no significant differences in MACE (R ZES vs EES: 22.8% vs 18.9%; log rank P = 0.39), the composite endpoint of all cause mortality and any MI (10.0% vs 10.3%; P = 0.86) or TLR (12.4% vs 7.4%, P = 0.11) between R ZES and EES during the 2 year follow up period (Figure 1, Table 4). Even when adjusting for confounding variables, no differences also were observed in 2 year occurrence of MACE (R ZES vs EES: HR 1.11, 95% CI: , P = 0.68) or TLR (HR 1.53, 95% CI: , P = 0.19) (Table 5). Insulin use, chronic kidney disease, number of treated vessels and stent implantation in restenotic lesion were strong, independent predictive factors of MACE whereas stent length more than 27 mm and restenotic lesions were significantly and independently associated with TLR (Table 5). Concurring with the results before matching, each time to event curve and incidence of event calculated by Kaplan Meier method, showed no significant differences between the two stent groups (Figure 1, Table 4). Definite stent thrombosis occurred in 1 patient in each group during the 2 year follow up.

9 Discussion In this real world historical cohort study there was no significant difference in 2 year outcomes (MACE, death/mi, TLR) after second/third generation CoCr EES versus CoCr R ZES implantation in patients with diabetes. These findings are similar to those demonstrated in subanalyses of previous large cohort studies in all comer populations. The estimated event rates at 2 year follow up in the present study (Table 4) are slightly higher compared to the ones reported in the RESOLUTE ALL Comers (MACE: 12.5% vs 12.9%, TLR: 5.7% vs 5.1% for R ZES vs EES respectively) [9,15] and the TWENTE (The Real World Endeavor Resolute Versus Xience V Drug Eluting Stent Study in Twente) trial (MACE: 12.9% vs 11.8%, TLR: 4.9% vs 2.6% for R ZES vs EES respectively), both of which included patients with and without diabetes [16,17]. The latest, 4 year follow up result of the RESOLUTE ALL Comers trial, revealed similarly low rates of TLR (8.75% total ; 9.2% R ZES vs 8.0% EES, P = 0.33) between the two groups [18]. Our study included only diabetic patients, with more complex lesion characteristics than any of the afore mentioned studies and did not exclude high risk patients such as those with end stage renal failure requiring hemodialysis or those presenting with acute coronary syndromes. Furthermore, in the present study complex lesions, including restenotic and severely calcified ones were more prevalent compared to those in the studies mentioned above [9,15 17]. Half of study population belonged to low SYNTAX score (0 22) group whereas one fourth

10 had higher SYNTAX score ( 23) and the remaining had a history of CABG. In a pooled analysis of the international global RESOLUTE program [19], a composite event of cardiac mortality, any MI and ischemic driven TLR occurred in 11.3% of diabetic patients treated with R ZES at 2 years compared to 8.8% in non diabetic patients (P = 0.04). In another large pooled analysis comparing EES versus paclitaxel eluting stent (PES) [20], at 2 years, a composite event of cardiac mortality, any MI and ischemic driven TLR occurred in 10.2% among diabetic patients compared to 8.8% in non diabetic ones (P = 0.01). The MACE incidences of 6.9% at 1 year and 14.1% at 2 years in the low SYNTAX score group of the present study are comparable to those reported in the previously mentioned studies (Figure 2). The higher complexity of lesions and patient backgrounds is attributed to data collection from a real world population, rather than a strictly defined one by a prospective cohort protocol, and could explain the higher rates of MACE, MI/death and TLR seen in present study (Table 4). In another study from Korea, based on a subgroup analysis of a previous large all comers registry [21], a comparison of 1 year outcomes between patients treated with EES and Resolute stents in diabetic patients was performed [8]. That study demonstrated low occurrence of the primary endpoint (composite of cardiac death, target vessel MI and TLR at 1 year) in both groups; 3.5% in the Resolute group vs 3.7% EES group, relative risk 0.95, P = Although the diabetic patients were derived from an all comer population, the number of patients on insulin therapy (13.7%) was smaller compared to the one in the present study (28.0%). Similarly when compared to our study, the Korean registry had a much lower prevalence of

11 peripheral artery disease (2.1% vs 14.0%), chronic kidney disease (7.0% vs 20.8%), previous PCI (18.3% vs 59.8%), previous CABG (2.4% vs 25.8%), prior myocardial infarction (7.2% vs 45.0%) and complex lesions (restenotic: 6.5% vs 19.2%, severely calcified: 13.7% vs 30.9%, bifurcation: 13.2% vs 43.8%). Besides, as mentioned in the limitations of that study, post procedural cardiac enzyme tests are not performed routinely in Korea and may have influenced the event rate. Hence the population presented in the current study is more reflective of the real world diabetic population which is characterized by a high comorbidity burden, more complex lesion characteristics and worse outcomes than those presented in the study by Park et al. In the previous study [20], Stone et al. reported superior outcomes in 2 year mortality, MI, stent thrombosis, ischemia driven TLR and MACE in non diabetic patients with EES than that with PES, whereas no differences where seen amongst diabetics. Moreover, within the EES group, patients with insulin dependent diabetes exhibited the worst outcomes (MACE, MI, TLR), whereas this was not the case in the PES group, suggesting a differential performance of EES depending on diabetic state. These observations, led the authors to speculate a direct inhibitory effect of insulin on the vascular response to rapamycin, due to the interaction of rapamycin and glycosylation dependent enzymes in regulating cellular mitosis. Alternatively, a differential mode of action of rapamycin analogs between the intrinsic insulin deficient and resistant states was proposed. All of the drug eluting stents used in our study (Xience V, Xience PRIME, PROMUS, Endeavor Resolute and Resolute Integrity) are CoCr alloys eluting everolimus or zotarolimus,

12 both of which are rapamycin derivatives. Therefore, despite diversities in the platform design or carrier matrices, key elements for long term safety and outcomes, our data suggest no significant differences in patient outcomes between R ZES and EES. Study limitations This study carries limitations associated with the historical cohort design. Firstly it is subjection to selection bias as stent type choice was left to the operator s discretion. Given the relatively small sample size of the study, power may not have been adequate to detect small differences in clinical outcomes between the two groups. However differences of that kind of magnitude would have been of limited clinical value. Information on long term diabetes control, that could potentially affect the clinical prognosis were not available in the current study. Finally, in our institutions IVUS is not performed on a routine basis and IVUS measurement are not recorded in a systematic way. Lack of intravascular ultrasound or optical coherence tomography assessment in this study limited a more detailed description of stent expansion or neointimal formation in the two study groups.

13 Conclusion According to the current study there appear to be no significant differences in 2 year outcomes (MACE, composite of all cause mortality and any MI, and TLR) after R ZES versus EES stent implantation in patients with diabetes. Even though, our study cohort included more complex patients and lesions reflecting real world practice, our findings resemble the ones reported in previous studies in all comer populations.

14 References [1] Flaherty JD, Davidson CJ. Diabetes and coronary revascularization. Jama 2005;293(12): [2] Smith SC, Jr., Faxon D, Cascio W, Schaff H, Gardner T, Jacobs A, Nissen S, Stouffer R. Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group VI: revascularization in diabetic patients. Circulation 2002;105(18):e [3] Navarese EP, Tandjung K, Claessen B, Andreotti F, Kowalewski M, Kandzari DE, Kereiakes DJ, Waksman R, Mauri L, Meredith IT and others. Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta analysis. Bmj 2013;347:f6530. [4] Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Stahle E, Feldman TE, van den Brand M, Bass EJ and others. Percutaneous coronary intervention versus coronary artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360(10): [5] Banning AP, Westaby S, Morice MC, Kappetein AP, Mohr FW, Berti S, Glauber M, Kellett MA, Kramer RS, Leadley K and others. Diabetic and nondiabetic patients with left main and/or 3 vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel eluting stents. J Am Coll Cardiol 2010;55(11): [6] Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M, Cohen DJ, Rosenberg Y, Solomon SD and others. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367(25): [7] Mohr FW, Morice MC, Kappetein AP, Feldman TE, Stahle E, Colombo A, Mack MJ, Holmes DR, Jr., Morel MA, Van Dyck N and others. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three vessel disease and left main coronary disease: 5 year follow up of the randomised, clinical SYNTAX trial. Lancet 2013;381(9867):

15 [8] Park KW, Lee JM, Kang SH, Ahn HS, Kang HJ, Koo BK, Rhew JY, Hwang SH, Lee SY, Kang TS and others. Everolimus eluting Xience v/promus versus zotarolimus eluting resolute stents in patients with diabetes mellitus. JACC Cardiovasc Interv 2014;7(5): [9] Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE, Kelbaek H, van Boven AJ, Hofma SH, Linke A and others. Comparison of zotarolimus eluting and everolimus eluting coronary stents. N Engl J Med 2010;363(2): [10] Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, van den Brand M, Van Dyck N, Russell ME, Mohr FW and others. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005;1(2): [11] Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Thygesen K, Alpert JS, White HD, Jaffe AS and others. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012;60(16): [12] Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P and others. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115(17): [13] Elezi S, Dibra A, Mehilli J, Pache J, Wessely R, Schomig A, Kastrati A. Vessel size and outcome after coronary drug eluting stent placement: results from a large cohort of patients treated with sirolimus or paclitaxel eluting stents. J Am Coll Cardiol 2006;48(7): [14] Claessen BE, Smits PC, Kereiakes DJ, Parise H, Fahy M, Kedhi E, Serruys PW, Lansky AJ, Cristea E, Sudhir K and others. Impact of lesion length and vessel size on clinical outcomes after percutaneous coronary intervention with everolimus versus paclitaxel eluting stents pooled analysis from the SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) and COMPARE (Second generation everolimus eluting and paclitaxel eluting stents in real life practice) Randomized Trials. JACC Cardiovasc Interv 2011;4(11):

16 [15] Silber S, Windecker S, Vranckx P, Serruys PW. Unrestricted randomised use of two new generation drug eluting coronary stents: 2 year patient related versus stent related outcomes from the RESOLUTE All Comers trial. The Lancet 2011;377(9773): [16] von Birgelen C, Basalus MW, Tandjung K, van Houwelingen KG, Stoel MG, Louwerenburg JH, Linssen GC, Said SA, Kleijne MA, Sen H and others. A randomized controlled trial in second generation zotarolimus eluting Resolute stents versus everolimus eluting Xience V stents in real world patients: the TWENTE trial. J Am Coll Cardiol 2012;59(15): [17] Tandjung K, Sen H, Lam MK, Basalus MW, Louwerenburg JH, Stoel MG, van Houwelingen KG, de Man FH, Linssen GC, Said SA and others. Clinical Outcome Following Stringent Discontinuation of Dual Antiplatelet Therapy After 12 Months in Real World Patients Treated With Second Generation Zotarolimus Eluting Resolute and Everolimus Eluting Xience V Stents: 2 Year Follow Up of the Randomized TWENTE Trial. J Am Coll Cardiol 2013;61(24): [18] Taniwaki M, Stefanini GG, Silber S, Richardt G, Vranckx P, Serruys PW, Buszman PE, Kelbaek H, Windecker S. 4 year clinical outcomes and predictors of repeat revascularization in patients treated with new generation drug eluting stents: a report from the RESOLUTE All Comers trial (A Randomized Comparison of a Zotarolimus Eluting Stent With an Everolimus Eluting Stent for Percutaneous Coronary Intervention). J Am Coll Cardiol 2014;63(16): [19] Silber S, Serruys PW, Leon MB, Meredith IT, Windecker S, Neumann FJ, Belardi J, Widimsky P, Massaro J, Novack V and others. Clinical outcome of patients with and without diabetes mellitus after percutaneous coronary intervention with the resolute zotarolimus eluting stent: 2 year results from the prospectively pooled analysis of the international global RESOLUTE program. JACC Cardiovasc Interv 2013;6(4): [20] Stone GW, Kedhi E, Kereiakes DJ, Parise H, Fahy M, Serruys PW, Smits PC. Differential clinical responses to everolimus eluting and Paclitaxel eluting coronary stents in patients with and without diabetes mellitus. Circulation 2011;124(8):

17 [21] Park KW, Lee JM, Kang SH, Ahn HS, Yang HM, Lee HY, Kang HJ, Koo BK, Cho J, Gwon HC and others. Safety and efficacy of second generation everolimus eluting Xience V stents versus zotarolimus eluting resolute stents in real world practice: patient related and stent related outcomes from the multicenter prospective EXCELLENT and RESOLUTE Korea registries. J Am Coll Cardiol 2013;61(5):

18 Figure legend Figure 1 Kaplan Meier cumulative event curves for the primary endpoint and its individual components at 2 years Major adverse cardiac event is a composite of all cause mortality, any myocardial infarction and target lesion revascularization. Figure 2 Kaplan Meier cumulative event curves for the primary endpoint stratified by aseline SYNTAX score. The overall cohort was divided into 4 groups according to baseline SYNTAX score 0 22 low SYNTAX score group, intermediate SYNTAX score group and 33 high SYNTAX score group) and history of coronary artery bypass grafting. Estimated event rate at 1 year and 2 years were calculated by Kaplan Meier method, and differences between groups at 2 years were computed with log rank test. Major adverse cardiac event is a composite of all cause mortality, any myocardial infarction and target lesion revascularization.

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21 Table 1. Baseline characteristics of patients Overall cohort Propensity-score matched cohort R-ZES group EES group P value R-ZES group EES group P value n = 136 n = 264 n = 128 n = 128 Age (yrs) 65.6 ± ± ± ± Male 118 (86.8%) 217 (82.2%) (85.9%) 111 (86.7%) 0.86 Body-mass index (kg/m 2 ) 26.9 ( ) 27.2 ( ) ( ) 27.2 ( ) 0.78 Diabetes treatment Insulin therapy 31 (22.8%) 81 (30.7%) 29 (22.7%) 40 (31.3%) Oral hypoglycemics 91 (66.9%) 154 (58.3%) 86 (67.2%) 77 (60.2%) Exercise or diet alone 14 (10.3%) 29 (11.0%) 13 (10.2%) 11 (10.2%) Hypertension 117 (86.7%) 226 (85.6%) (87.4%) 105 (82.0%) 0.23 Dyslipidemia 107 (78.7%) 213 (81.0%) (78.9%) 99 (77.3%) 0.76 Chronic kidney disease* 28 (20.6%) 55 (21.5%) (19.5%) 32 (25.0%) 0.29 Previous PCI 72 (52.9%) 167 (63.3%) (53.1%) 75 (58.6%) 0.38 Previous CABG 33 (24.3%) 70 (26.5%) (24.2%) 34 (26.6%) 0.67 Previous myocardial infarction 53 (39.3%) 127 (48.3%) (39.1%) 63 (49.2%) 0.10 Peripheral artery disease 17 (12.5%) 39 (14.8%) (13.3%) 19 (14.8%) 0.72 Smoking history 84 (63.6%) 157 (60.6%) (62.9%) 79 (62.7%) 0.97 Family history of CAD 43 (32.1%) 101 (38.8%) (32.5%) 51 (40.2%) 0.21 LVEF (%) 55.0 ( ) 55.0 ( ) ( ) 55.0 ( ) 0.85 Clinical presentation Silent myocardial ischemia 46 (33.8%) 90 (34.1%) (33.6%) 37 (28.9%) Stable angina pectoris 70 (51.5%) 124 (47.0%) (51.6%) 64 (50.0%) Unstable angina pectoris 19 (14.0%) 43 (16.3%) (14.1%) 22 (17.2%) Myocardial infarction 1 (0.7%) 7 (2.7%) (0.8%) 5 (3.9%) Number of diseased vessels vessel disease 19 (14.0%) 34 (12.9%) 18 (14.1%) 13 (10.2%) 2 vessel disease 36 (26.5%) 85 (32.2%) 36 (28.1%) 47 (36.7%) 3 vessel disease 81 (59.6%) 145 (54.9%) 74 (57.8%) 68 (53.1%) SYNTAX score 18.0 ( ) 17.0 ( ) ( ) 18.0 ( ) 0.62 Results are mean ± SD, n (%) or median (IQR). *Chronic kidney disease was defined as estimated glomerular filtration rate (Modification of Diet in Renal Disease Study Group) less than 60mL/min/1.73m 2. CAD, coronary artery disease

22 Table 2. Baseline characteristics of target lesions Overall cohort Propensity-score matched cohort R-ZES group EES group P value R-ZES group EES group P value n = 196 n = 357 n = 181 n = 180 Site of lesion LMS 13 (6.6%) 22 (6.2%) 12 (6.6%) 17 (9.4%) LAD 73 (37.2%) 126 (35.3%) 69 (38.1%) 65 (36.1%) LCx 45 (23.0%) 97 (27.2%) 39 (21.5%) 47 (26.1%) RCA 59 (30.1%) 94 (26.3%) 55 (30.4%) 41 (22.8%) Bypass graft 6 (3.1%) 18 (5.0%) 6 (3.3%) 10 (5.6%) Lesion morphology B2/C 171 (87.2%) 285 (79.8%) (86.2%) 150 (83.3%) 0.45 Small diameter ( 2.5 mm)* 54 (27.6%) 135 (37.8%) (28.7%) 55 (30.6%) 0.70 Long lesion (> 27 mm) 99 (50.5%) 169 (47.3%) (50.8%) 90 (50.0%) 0.88 Bifurcation lesion 89 (45.4%) 153 (42.9%) (46.4%) 79 (43.9%) 0.63 Restenotic lesion 51 (26.0%) 55 (15.4%) (24.3%) 37 (20.6%) 0.39 Severely calcified lesion 58 (29.6%) 113 (31.7%) (29.8%) 59 (32.8%) 0.55 Chronic total occlusion 26 (13.3%) 31 (8.7%) (9.9%) 21 (11.7%) 0.60 Thrombus present 5 (2.6%) 6 (1.7%) (2.2%) 4 (2.2%) 0.64 *Number of lesions in which a small stent of 2.5 mm or smaller diameter was implanted. Substituted stent length per lesion for lesion length. LAD, left anterior descending artery; LCx, left circumflex artery; LMS, left main stem; RCA, right coronary artery

23 Table 3. Characteristics of revascularization procedure Overall cohort Propensity-score matched cohort R-ZES group EES group P value R-ZES group EES group P value Per patient n=136 n=264 n=128 n=128 Number of vessels treated 1.27 ± ± ± ± Multivessel treatment 32 (23.5%) 37 (14.0%) (21.1%) 24 (18.8%) 0.64 Number of lesions treated 1.46 ± ± ± ± Number of stents per patient 1.96 ± ± ± ± Stent length per patient (mm) 38.0 ( ) 33.0 ( ) ( ) 38.0 ( ) 0.97 Per lesion n=196 n=357 n=181 n=180 Number of stents per lesion 1.35 ± ± ± ± Stent length per lesion (mm) 30.0 ( ) 23.0 ( ) ( ) 26.5 ( ) 0.42 Long stenting (> 27 mm) 99 (50.5%) 169 (47.3%) (50.8%) 99 (50.0%) 0.88 Use of small stent* 54 (27.6%) 135 (37.8%) (28.7%) 55 (30.6%) 0.70 Direct stenting 13 (6.6%) 39 (10.9%) (6.3%) 19 (11.2%) 0.10 Post-stent balloon 148 (76.3%) 257 (73.2%) (76.5%) 139 (77.7%) 0.80 Rotablator use 4 (2.0%) 5 (1.4%) (1.7%) 3 (1.7%) 0.66 IVUS done 59 (30.1%) 62 (17.4%) (28.7%) 44 (24.4%) 0.36 Results are n (%), mean ± SD or median (IQR). *Defined as a stent of 2.5 mm or smaller diameter. IVUS, intravascular ultrasound

24 Table 4. 2-year event rate estimated by Kaplan-Meier method Over all cohort prior to propensity-score matching Outcomes R-ZES + EES R-ZES EES P value* Major adverse cardiac event 20.3% 22.8% 18.9% 0.39 All-cause mortality & any MI 10.0% 10.0% 10.3% 0.86 Target lesion revascularization 9.4% 12.4% 7.4% 0.11 Propensity-score matched cohort Outcomes R-ZES + EES R-ZES EES P value* Major adverse cardiac event 22.9% 20.9% 25.3% 0.47 All-cause mortality & any MI 10.6% 9.1% 13.2% 0.52 Target lesion revascularization 10.8% 11.2% 10.0% 0.84 *Calculated by log-rank test applied to compare the R-ZES group and the EES group. A composite of all-cause mortality, any myocardial infarction and target lesion revascularization. Incidence of target lesion revascularization was calculated based on lesion number.

25 Table 5. Independent predictors of major adverse cardiac event (MACE) and target lesion revascularization (TLR) in the overall cohort. Independent predictors of MACE* Independent predictors of TLR Covariates HR 95% CI P value Covariates HR 95%CI P value Type of stent, R-ZES 1.01 ( ) 0.97 Type of stent, R-ZES 1.53 ( ) 0.19 Age 1.07 ( ) 0.38 Insulin therapy 1.71 ( ) Insulin treatment 1.84 ( ) Chronic kidney disease 1.86 ( ) Chronic kidney disease 1.87 ( ) Long stenting per lesion 2.02 ( ) LVEF less than 40% 1.92 ( ) Use of small stent 1.49 ( ) 0.21 Number of vessels treated 1.75 ( ) Restenotic lesion 2.53 ( ) Stent length per patient 1.03 ( ) At least 1 restenotic lesion 2.04 ( ) Computed with multivariable Cox proportional-hazards model. *MACE is a composite of all-cause mortality, any myocardial infarction and target lesion revascularization. Per 5-year increase. Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 ml/min/1.73m 2. Per 5 mm increase. Long stenting was defined as more than 27 mm in total stent length. Defined as a stent of 2.5 mm or smaller diameter.