Methods

This prospective randomized study included 256 patients aged 18 years and older with coronary artery disease. The study involved 8 cardiac centers in Korea from September 2008 to January 2012. Patients were considered eligible if they had DM with either stable angina or an acute coronary syndrome and who had at least 1 coronary lesion (defined as stenosis of >50% and visual reference diameter of ≥2.5 mm) suitable for stent implantation. The diagnosis of DM was confirmed in all patients receiving active treatment with an oral hypoglycemic agent or insulin. For patients with a diagnosis of DM who were on a dietary therapy alone, documentation of an abnormal blood glucose level after an overnight fast was required. Patients were excluded if they had contraindication to aspirin and clopidogrel, unprotected left main disease (diameter stenosis ≥50% by visual estimate), graft vessel disease, left ventricular ejection fraction <30%, recent history of hematologic disease or leukocyte count <3,000/mm ³ and/or platelet count <100,000/mm ³ , hepatic dysfunction with aspartate aminotransferase or alanine aminotransferase ≥3× the upper normal reference limit, history of renal dysfunction or serum creatinine level of ≥2.0 mg/dl, serious noncardiac co-morbid disease with a life expectancy <1 year, primary angioplasty for acute myocardial infarction (MI) within 24 hours, or inability to follow the protocol. In patients with multiple lesions fulfilling the inclusion and exclusion criteria, the first stented lesion was considered as the target lesion. The institutional review board at each participating center approved the protocol. All patients provided written informed consent.

Once the guidewire had crossed the target lesion, patients who met the inclusion and exclusion criteria were randomly assigned in a 1:1 ratio to R-ZES (Endeavor Resolute, Medtronic Cardiovascular, Santa Rosa, California) or SES (Cypher Select Plus, Cordis, Johnson & Johnson, Warren, New Jersey) implantation using interactive Web response system. The allocation sequence was computer generated, stratified according to participating, center and blocked with block sizes of 4 and 6 varying randomly. Random assignments were stratified according to participation sites. The procedure was performed according to standard techniques. Administration of glycoprotein IIb/IIIa inhibitors was at the discretion of the operator. After the procedure, all patients received 100 mg/day of aspirin indefinitely and 75 mg/day of clopidogrel for at least 12 months. A 12-lead electrocardiogram was obtained after the procedure and before discharge. Serum levels of creatine kinase, its MB isoenzyme, were assessed 8, 12, and 24 hours after the procedure, and thereafter if considered necessary.

The primary end point of this trial was in-segment late loss at 9-month angiographic follow-up. The secondary end points included 9-month angiographic outcomes of in-stent late loss, in-stent and in-segment binary restenoses at 9 months (diameter stenosis of ≥50%). At 12 months, stent thrombosis, ischemia-driven target lesion revascularization, ischemia-driven target vessel revascularization, and major adverse cardiac events including death from any cause, MI, or ischemia-driven target lesion revascularization were also assessed.

Angiographic success was defined as in-segment diameter stenosis of <30% by quantitative coronary angiographic analysis. MI was defined as creatine kinase-MB elevation of >3× or creatine kinase elevation of >2× the upper normal limit with at least 1 of the following: ischemic symptoms, development of pathologic Q waves, and ischemic electrocardiographic changes. Revascularization was defined as ischemia driven if there was stenosis of ≥50% of the diameter, as documented by a positive functional study, ischemic changes on an electrocardiogram, or ischemic symptoms, or in the absence of documented ischemia, if there was stenosis of ≥70% as assessed by quantitative coronary analysis. Stent thrombosis was assessed according to the Academic Research Consortium definitions and was classified by the timing of the event (acute, 0 to 24 hours; subacute, 1 to 30 days; and late, >31 days).

Repeat coronary angiography was mandatory at 9 months after stenting, or earlier if indicated by clinical symptoms or evidence of myocardial ischemia. Clinical follow-up visits were scheduled at 30, 120, and 240 days and 1 year. At each participating center, patient data were recorded prospectively on standard case report forms and gathered in the central data management center (Asan Medical Center, Seoul, Korea). All adverse clinical events were adjudicated by an independent events committee blinded to the treatment groups.

Coronary angiograms were obtained after intracoronary nitroglycerin administration. Procedural (baseline), postprocedural, and follow-up angiograms were submitted to the angiographic core analysis center (Asan Medical Center, Seoul, Korea). Digital angiograms were analyzed using an automated edge detection system (CASS II; Pie Medical, Maastricht, The Netherlands). Angiographic variables included absolute lesion length, stent length, reference vessel diameter, minimum lumen diameter, percent diameter stenosis, binary restenosis rate, acute gain, late loss, and the patterns of restenosis. Quantitative coronary angiographic measurements of target lesions were obtained for the stented segment (in stent) and the margins 5 mm proximal and distal to the stent (in segment). In-segment late loss was calculated within the analysis segment itself, but separately considering stented segment, proximal and distal edges and taking the maximum change in minimum lumen diameter within those 3 segments and applying it to this segment as a whole (maximal regional late loss method). Patterns of angiographic restenosis were assessed using the Mehran classification.

On the basis of results from previous trial, we assumed an in-segment angiographic late loss of 0.43 ± 0.45 mm in both arms. Calculation of the sample size was based on a margin of noninferiority for in-segment late loss of 0.129 mm, which is equal to 30% of an assumed mean late loss after the implantation of SES. Using a 1-sided 5% significance level, we estimated that 152 patients per group were needed to demonstrate noninferiority of R-ZES with a statistical power of 80%. Expecting that approximately 20% of the patients would not return for follow-up angiography, total sample size was estimated to be 380 patients. Analyses of the 2 groups were performed according to the intention-to-treat principle. Continuous variables are presented as mean ± SD or median (interquartile range) and were compared using Student unpaired t or Mann-Whitney U test. Categorical variables are presented as numbers or percentages and were compared using chi-square or Fisher’s exact test. The noninferiority hypothesis was assessed statistically using a Z-test, by which 1-sided p values for noninferiority were calculated to compare differences between groups with margins of noninferiority, according the method of Chow and Liu. All p values are 2-sided, except those from noninferiority testing of the primary end point. A p value <0.05 was considered to indicate a significant difference. All statistical analyses were performed using SAS, version 9.1 (SAS Institute, Cary, North Carolina).

Results

Patient recruitment was prematurely halted on January 2012, owing to discontinuing production of SES. From September 2009 to January 2012, 256 patients were enrolled (127 in R-ZES group and 129 in SES). Table 1 lists similar baseline clinical characteristics between 2 groups, except more men in the SES group (p = 0.031). The similar angiographic and procedural characteristics are also listed in Table 2 , except the more maximal inflation pressure in the SES group (p <0.001). The angiographic success rate was 100% in both groups.

The 2 groups had similar baseline and postprocedural quantitative coronary angiographic characteristics ( Table 3 ). Follow-up angiography was performed in 175 patients (68.4%), with 85 (66.9%) of R-ZES and 90 (69.8%) of SES patients. The median duration of angiographic follow-up was similar in 2 groups (290 days [interquartile range 263 to 310] and 293 days [interquartile range 259 to 339] for the R-ZES and SES groups, respectively, p = 0.931). Patients undergoing angiographic follow-up were more likely to have stable angina (p = 0.033) than those who did not return for angiographic follow-up. Those with angiographic follow-up have similar anatomical and procedural characteristics, except the more maximal inflation pressure (p = 0.037). Quantitative coronary angiographic measurements at follow-up are listed in Table 3 . In-segment late loss of R-ZES using maximal regional late loss method, the prespecified primary end point, was noninferior to that of SES group (0.34 ± 0.30 vs 0.39 ± 0.43 mm; difference, −0.048; 95% confidence interval, −0.157 to 0.061; upper 1-sided 95% confidence interval, 0.044; p <0.001 for noninferiority; Figure 1 ). In-segment late loss using analysis segment late loss method was similar between the R-ZES and SES groups (0.11 ± 0.30 vs 0.17 ± 0.37 mm; difference, −0.052; 95% confidence interval, −0.153 to 0.050; p = 0.317). In-stent late loss and the rates of in-segment and in-stent binary restenosis were not statistically different between the 2 groups. There was no significant difference for the patterns of restenosis between the 2 groups. In the R-ZES group, 1 was focal (class IC). In the SES group, 4 were focal (3 in class 1B and 1 in class 1C) and 2 were diffuse (1 in class II and 1 in class IV).

Table 3

Quantitative angiographic measurements

Variable	R-ZES (n = 127)	SES (n = 129)	p
Reference diameter (mm)	3.06 ± 0.50	3.02 ± 0.45	0.436
Lesion length (mm)	21.1 ± 12.2	21.8 ± 11.3	0.673
Stented length at the target lesion (mm)	27.2 ± 11.6	26.7 ± 11.0	0.724
Minimum lumen diameter (mm)
In segment
Before procedure	1.06 ± 0.41	1.08 ± 0.43	0.742
After procedure	2.31 ± 0.56	2.29 ± 0.44	0.843
At follow-up	2.25 ± 0.56	2.14 ± 0.57	0.192
In stent
After procedure	2.71 ± 0.48	2.67 ± 0.42	0.502
At follow-up	2.54 ± 0.57	2.45 ± 0.58	0.302
Diameter stenosis (%)
In segment
Before procedure	65.5 ± 12.2	64.4 ± 12.5	0.506
After procedure	18.4 ± 11.2	17.0 ± 9.9	0.305
At follow-up	21.9 ± 12.0	25.0 ± 21.0	0.232
In stent
After procedure	7.5 ± 9.0	7.5 ± 7.2	0.966
At follow-up	15.2 ± 11.0	16.7 ± 15.5	0.474
Acute gain (mm)
In segment	1.25 ± 0.59	1.21 ± 0.47	0.613
In stent	1.65 ± 0.52	1.59 ± 0.45	0.359
Late loss (mm)
In segment	0.34 ± 0.30	0.39 ± 0.43	0.391
In stent	0.22 ± 0.29	0.21 ± 0.40	0.849
Binary angiographic restenosis
In segment	1/85 (1.2)	6/90 (6.7)	0.119
In stent	1/85 (1.2)	3/90 (3.3)	0.621

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