A Randomized Comparison of Sirolimus- Versus Paclitaxel-Eluting Stent Implantation in Patients With Diabetes Mellitus

Patient selection

This prospective randomized study included 400 patients ≥18 years of age with angina pectoris and/or a positive stress test and a native coronary lesion. The study involved 5 cardiac centers in Korea between May 2005 and March 2006. Patients were considered eligible if they had DM, presented with angina pectoris, or had a positive stress test and had clinically significant angiographic stenosis in a native coronary vessel with a diameter stenosis ≥50% and visual reference diameter ≥2.5 mm. Patients were excluded if they had a contraindication to aspirin, clopidogrel, or cilostazol; 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/mm³and/or platelet count <100,000/mm³; hepatic dysfunction with asparatate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 times the upper normal reference limit; history of renal dysfunction or serum creatinine level ≥2.0 mg/dl; serious noncardiac comorbid disease with a life expectancy <1 year; planned bifurcation stenting in the side branch; primary angioplasty for acute myocardial infarction (AMI) within 24 h; or inability to follow the protocol. In patients with multiple lesions fulfilling the inclusion and exclusion criteria, the first stented lesion was considered as target lesion. The institutional review board at each participating center approved the protocol. All patients provided written informed consent.

Randomization and procedures

Once the guidewire had crossed the target lesion, patients were randomly assigned in a 1:1 ratio to SES or PES implantation. After DES randomization, patients were randomly allocated in a 1:1 ratio to the triple antiplatelet group (aspirin, clopidogrel, and cilostazol; triple group; n = 200) or the dual antiplatelet therapy group (aspirin and clopidogrel; standard group; n = 200) (antiplatelet arm) on the basis of a 2 × 2 factorial design with a computer-generated randomization sequence. Random assignments were stratified according to participation sites and blocked with block size of 4 or 6 and were distributed in sealed envelopes to each participating center. The block size was concealed. From at least 24 h before the procedure and thereafter, all patients received aspirin (200 mg daily) and clopidogrel (loading dose of 300 mg, followed by 75 mg daily for at least 6 months). Patients in the triple group received a loading dose of 200 mg cilostazol immediately after the procedure and 100 mg twice/day for 6 months.

Coronary stenting was performed with the standard technique. The decision of pre-dilation or direct stenting was made by the operator. The use of intravenous glycoprotein IIb/IIIa inhibitors was at the operator's discretion. A 12-lead electrocardiogram was obtained after the procedure and before discharge. Serum levels of creatine kinase-myocardial band isoenzyme were assessed 8, 12, and 24 h after the procedure and thereafter if considered necessary.

Study end point and definitions

The primary end point of this trial was in-segment restenosis on 6-month follow-up study (defined as in-segment stenosis of at least 50%). The secondary end points included 6-month angiographic outcomes such as in-segment late loss and the rate of in-stent restenosis at 6 months (defined as in-stent stenosis of at least 50%), stent thrombosis, target vessel revascularization (TVR), and major adverse cardiac events (MACE) including death, myocardial infarction (MI), and target lesion revascularization (TLR).

The diagnosis of DM was considered confirmed in all patients receiving active treatment with an oral hypoglycemic agent or insulin; for patients with a diagnosis of diabetes who were on a dietary therapy alone, enrollment in the trial required the documentation of an abnormal blood glucose level after an overnight fast. Angiographic success was defined as in-segment final diameter stenosis <30% by quantitative coronary angiography (QCA). A Q-wave MI was defined by the post-procedural presence of new Q waves of >0.04 s in 2 contiguous leads. Non–Q-wave MI was defined as a creatine kinase-myocardial band fraction >3 times the upper limit of normal. Target lesion revascularization was considered clinically driven if prompted by symptoms consistent with myocardial ischemia, if preceded by an abnormal stress test result consistent with myocardial ischemia, if there were other electrocardiographic changes consistent with myocardial ischemia, or if the lesion diameter stenosis was more than 70% at follow-up (11). Stent thrombosis was defined as any of the following after the procedure: angiographic documentation of stent occlusion with or without the presence of thrombus associated with an acute ischemic event, unexplained sudden death, or MI not clearly attributable to another coronary lesion (12,13).

Follow-up

Repeat coronary angiography was mandatory at 6 months after stenting or earlier if indicated by clinical symptoms or evidence of myocardial ischemia. Clinical follow-up visits were scheduled at 30, 90, 180, and 270 days. At every visit, physical examination, electrocardiogram, cardiac events, and angina recurrence were monitored. 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.

QCA analysis

Coronary angiograms were obtained after intracoronary nitroglycerin administration. Procedure (baseline), post-procedure, and follow-up angiograms were submitted to the angiographic core analysis center (Asan Medical Center, Seoul, Korea), in which intraobserver and interobserver correlation coefficients were 0.92 and 0.93, respectively. Digital angiograms were analyzed with an automated edge detection system (CASS II, Pie Medical, Maastricht, the Netherlands). The core laboratory was blinded to the treatment assignment. Angiographic variables included absolute lesion length, stent length, reference vessel diameter, minimal lumen diameter (MLD), percent diameter stenosis, binary restenosis rate, acute gain, late loss, and the patterns of recurrent restenosis. The QCA measurements of target lesions were obtained for both the stented segment only (in-stent) and the region including the stented segment as well as the margins 5 mm proximal and distal to the stent (in-segment). In-segment late loss was calculated with maximal regional late loss method (14). Patterns of angiographic restenosis were quantitatively assessed with the Mehran classification (15).

Statistical analysis

On the basis of results from a previous study (10), we assumed an in-segment angiographic restenosis rate of 7% in the SES group and 19% in the PES group. With a 2-sided 5% significance level, we estimated that 163 patients/group were needed to detect this difference with a statistical power of 90%. Expecting that approximately 20% of the patients would not return for angiographic follow-up, total sample size was estimated to 400 patients (200 patients/group). Analyses of 2 groups were performed according to the intention-to-treat principle. Continuous variables are presented as mean ± SD or median (interquartile range [IQR]) and compared with Student unpaired tor Mann-Whitney Utests. Categorical variables are presented as numbers or percentages and were compared with chi-square or Fisher exact tests. The relative risk (RR) and its 95% confidence interval (CI) were computed for outcome measures. The Breslow-Day test was performed to assess the homogeneity of the RR across participating centers and use of cilostazol (16). The adjusted RR and CI after controlling the center and use of cilostazol were computed by the Mantel-Haenszel method. For the primary outcome, we also calculated the absolute difference between SES and PES patients with and without cilostazol. A p value <0.05 was considered to indicate a significant difference. All statistical analyses were performed with SAS version 9.1 (SAS Institute, Cary, North Carolina).

Baseline characteristics of the patients

Table 1shows the baseline clinical characteristics of the study groups. There were no significant differences between the 2 groups in baseline clinical characteristics and risk factors.

Procedural results and in-hospital outcomes

Table 2shows angiographic characteristics and procedural results. The 2 groups have similar anatomical and procedural characteristics. All stents were successfully implanted, and the angiographic success rate was 99.5% in all groups. The 2 groups were treated with similar stented lengths and number of implanted stents/target lesion. Procedure-related non–Q-wave MI occurred similarly in both arms. Acute stent thrombosis developed in 1 patient (0.5%) treated with SES during hospital stay. In-hospital events, including Q-wave MI, emergency bypass surgery, or death, did not occur in either group.

Angiographic outcomes

Baseline and post-procedural QCA outcomes for study groups are shown in Table 3.The 2 groups had similar baseline and post-procedural QCA characteristics, except for higher maximal inflation pressure in the SES group versus the PES group.

Follow-up angiography was performed in 330 patients (82.5%)—176 (88%) SES and 154 (77%) PES patients. The median duration of angiographic follow-up was similar in the 2 groups (187 [IQR: 178 to 201] and 188 [IQR: 178 to 203] days for the SES and PES groups, respectively, p = 0.762). Results of QCA measurements at follow-up are shown in Table 3. The in-stent and -segment late loss were significantly lower in the SES versus in the PES group. Follow-up in-stent and -segment MLD also were significantly larger in SES versus in PES. In-segment restenosis, the pre-specified primary end point, was identified in 7 (4.0%) SES and 32 (20.8%) PES patients (RR: 0.19; 95% CI: 0.09 to 0.42; p < 0.001). In-stent restenosis rate was also lower in the SES than in the PES group (3.4% vs. 18.2%; RR: 0.19; 95% CI: 0.08 to 0.44; p < 0.001). The test for assessing the homogeneity of the RR across the center and use of cilostazol were not significant for in-segment (Breslow-Day test, p = 0.317) and in-stent restenosis (Breslow-Day test, p = 0.246). Although there was interaction between types of DES and use of cilostazol in relative measure (p < 0.001 for in-segment restenosis), absolute measure was not statistically significant (p = 0.861). This phenomenon was due to 0% in-segment restenosis of the SES + cilostazol group. With regard to in-segment restenosis, the pre-specified primary end point, absolute difference was 8% in SES patients and 6.8% in PES patients, according to use of the cilostazol (p = 0.861) (Fig. 1).

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Figure 1

The In-Segment Restenosis Rate According to Drug-Eluting Stent and Use of Cilostazol

There is interaction between the type of drug-eluting stent and use of cilostazol for in-segment restenosis (p < 0.001). Although there was significant difference in relative measure of in-segment restenosis rate due to 0% in-segment restenosis rate of the sirolimus-eluting stent + cilostazol group, the absolute measure was not statistically different (p = 0.861).

In patients with restenoses, a pattern of focal restenosis (type I) was more common in the SES than in the PES group (Table 4).

Clinical outcomes

A minimum 9-month clinical follow-up was performed in all patients. One cardiac death occurred in PES patients due to nontarget vessel MI. Myocardial infarction occurred in 1 patient/group. During 9 months, only 1 stent thrombosis occurred in the SES patients, which was angiographically documented at 6 h after index procedure. The patient was successfully treated with repeat intervention (Table 5).

The rates of TLR (2.0% vs. 7.5%; RR: 0.27; 95% CI: 0.09 to 0.79; p = 0.017) and TVR (3.5% vs. 8.0%, p = 0.053) were lower in the SES than in the PES group. Clinically driven TLR (1.5% vs. 6.0%, p = 0.032) and TVR (2.0% vs. 7.5%, p = 0.017) rates were also lower in the SES than in the PES group. At 9 months, MACE was lower in the SES than in the PES group (2.0% vs. 8.0%; RR: 0.25; 95% CI: 0.09 to 0.73; p = 0.010). The composite of death, MI, or TVR was also significantly lower in the SES than in the PES patients (3.5% vs. 8.5%, p = 0.035).

Study limitations

The present study has several limitations. First, our use of routine 6-month angiography might have resulted in an underestimation of the rates of restenosis and TLR compared with a study with a longer angiographic follow-up period. Second, there might be possible bias associated with clinical decisions related to TLR by operators, but this limitation has mostly been compensated for by ischemic-driven TLR. Third, the rate of angiographic follow-up was nonuniform in both groups.