Methods

A pooled analysis from 2 prospective, multicenter, randomized trials of triple versus dual antiplatelet therapy was performed. The 2 studies involved 5 cardiac centers in Korea from August 2004 to March 2006. The design, exclusion and inclusion criteria, and data collection of the DECLARE-DIABETES and DECLARE-LONG trials have been previously described. In brief, 2 randomized studies included 900 patients ≥18 years of age with angina pectoris and/or positive stress test result and a native coronary lesion. Patients were considered eligible if they had diabetes mellitus (DECLARE-DIABETES trial) or long lesions (DECLARE-LONG trial, length ≥25 mm and planned total stent length ≥32 mm), had angina pectoris and/or positive stress test result, and had clinically significant angiographic stenosis in a native coronary vessel with 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% (a contraindication to cilostazol); recent history of hematologic disease or leukocyte count <3,000/mm ³ and/or platelet count <100,000/mm ³ ; hepatic dysfunction with aspartate or alanine aminotransferase level ≥3 times the upper normal reference limit; history of renal dysfunction or serum creatinine level ≥2.0 mg/dl; serious noncardiac co-morbid disease with a life expectancy <1 year; planned bifurcation stenting in the side branch; primary angioplasty for acute myocardial infarction (MI) within 24 hours; or inability to follow the protocol. In patients with multiple lesions that fulfilled the inclusion and exclusion criteria, the operator determined the hierarchy of lesions and declared the target lesion for each patient before the procedure (DECLARE-LONG trial) or the first stented lesion was considered the target lesion (DECLARE-DIABETES trial). 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 were randomly assigned in a 1:1 ratio to sirolimus-eluting stent or paclitaxel-eluting stent implantation. After DES randomization, patients were randomly allocated in a 1:1 ratio to the triple (aspirin, clopidogrel, and cilostazol; triple group, n = 450) or dual (aspirin and clopidogrel; standard group, n = 450) antiplatelet group by a 2-by-2 factorial design using a computer-generated randomization sequence. All patients received aspirin (200 mg/day ≥24 hours before procedure and thereafter) and clopidogrel (loading dose 300 mg, followed by 75 mg/day for ≥6 months). Patients in the triple group received a loading dose of cilostazol 200 mg immediately after the procedure and 100 mg 2 times/day for 6 months.

Coronary stenting was performed with the standard technique. The decision of predilation or direct stenting was made by the operator. Use of intravenous glycoprotein IIb/IIIa inhibitors was at the operators’ discretion. A 12-lead electrocardiogram was obtained after the procedure and before discharge. Serum levels of creatine kinase-MB isoenzyme was assessed 8, 12, and 24 hours after the procedure and thereafter if considered necessary.

The primary end point consisted of long-term clinical outcomes including major adverse cardiac events (MACEs; death, MI, and target lesion revascularization [TLR]). The secondary end point included stent thrombosis, target vessel revascularization (TVR), and adverse drug reactions. Adverse drug reactions included major bleeding (need for transfusion, decrease in hemoglobin >5 g/dl, need for surgical intervention, or resulting in hypotension requiring inotropic support), minor bleeding, any adverse reactions (neutropenia <1.5 × 109/L, thrombocytopenia <100 × 109/L, skin rash, liver dysfunction, and gastrointestinal trouble), and incidence of drug discontinuation during the treatment period.

Q-wave MI was defined by the postprocedural presence of new Q waves >0.04 second in 2 contiguous leads. Non–Q-wave MI was defined as a creatine kinase-MB fraction >3 times the upper limit of normal. TLR was defined as a repeat intervention (surgical or percutaneous) within the stent or in the 5-mm proximal or distal segments adjacent to the stent. TVR was defined as a reintervention of a lesion in the same epicardial vessel. TLR or TVR was considered clinically driven if prompted by symptoms consistent with myocardial ischemia, preceded by an abnormal stress test result consistent with myocardial ischemia, if there were other electrocardiographic changes consistent with myocardial ischemia, or if lesion diameter stenosis was >70% at follow-up. 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, and MI not clearly attributable to another coronary lesion.

Clinical follow-up visits were scheduled at 30, 90, 180, 270 days and every 3 months thereafter. At every visit, physical examination, electrocardiogram, cardiac events, and angina recurrence were monitored. All adverse clinical events were adjudicated by an independent events committee blinded to treatment groups. Preprocedure and postprocedure angiograms obtained after intracoronary nitroglycerin administration were submitted to the 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). Quantitative coronary angiographic measurements were obtained in the stent and in the segment (stented segment and margins 5 mm proximal and distal to stent).

Analyses of 2 groups were performed according to the intention-to-treat principle. Continuous variables are presented as mean ± SD or median (interquartile range) and compared using Student’s 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. Rate of survival free from TLR and MACEs during the 2-year follow-up period was analyzed using Kaplan-Meier analyses, and the difference between rates was assessed by log-rank test. Univariate and multivariable Cox proportional hazards models were used to examine the association of antiplatelet regimen with risks of clinical events. Multivariate analyses involved a backward elimination technique, and variables with a p value <0.20 and clinically relevant predictors were used in the final model, together with stent type used. Stratified Cox analyses and likelihood-ratio test were performed to assess the homogeneity of the hazard ratio (HR) across uses of cilostazol in subgroup analysis including diabetics, patients with small vessel disease, long lesions, and left anterior descending coronary artery lesions. The proportional hazards assumption was confirmed by testing of partial (Schoenfeld) residuals, and no relevant violations were found. All p values were 2-sided and a probability value of p <0.05 was considered statistically significant. Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, North Carolina).

Results

Table 1 lists baseline clinical characteristics of the study groups. There were no significant differences between the 2 groups in baseline clinical characteristics and risk factors. Table 2 presents angiographic characteristics and procedural results. The 2 groups had similar anatomic and procedural characteristics except a higher prevalence of multivessel stenting in the triple group. Quantitative coronary measurements are listed in Table 3 . There were also no differences between the 2 groups. Mean durations of clopidogrel use were 529 ± 386 days in the triple group and 528 ± 388 days in the standard group (p = 0.982).

Nine-month clinical outcomes are presented in Table 4 . TLR (2.7% vs 6.9%, p = 0.003) and TVR (3.6% vs 7.6%, p = 0.009) were significantly decreased in the triple group versus the standard group, with no difference in death, MI, or stent thrombosis. MACEs (2.9% vs 7.3%, p = 0.002) and the composite outcomes of death, MI, and TVR (3.8% vs 8.0%, p = 0.007) were also significantly decreased in the triple group versus the standard group, mainly driven by decreased repeat revascularization.

Table 4

Clinical outcomes at 24 months

Variable	Triple	Standard	p Value
	(n = 450)	(n = 450)
9-month outcomes
Death	1 (0.2%)	2 (0.4%)	0.999
Cardiac	1 (0.2%)	1 (0.2%)
Noncardiac	0	1 (0.2%)
Myocardial infarction	2 (0.4%)	2 (0.4%)	0.999
Q wave	1 (0.2%)	1 (0.2%)
Non–Q wave	1 (0.2%)	1 (0.2%)
Target lesion revascularization	12 (2.7%)	31 (6.9%)	0.003
Stent thrombosis	1 (0.2%)	2 (0.4%)	0.999
Acute (<1 day)	0	1 (0.2%)
Subacute (1 day–1 month)	1 (0.2%)	0
Late (1–9 months)	0	1 (0.2%)
Target vessel revascularization	16 (3.6%)	34 (7.6%)	0.009
Death/myocardial infarction/target vessel revascularization	17 (3.8%)	36 (8.0%)	0.007
Major adverse cardiac events (death/myocardial infarction/target lesion revascularization)	13 (2.9%)	33 (7.3%)	0.002
2-year outcomes
Death	5 (1.1%)	6 (1.3%)	0.762
Cardiac	4 (0.9%)	2 (0.4%)
Noncardiac	1 (0.2%)	4 (0.9%)
Myocardial infarction	4 (0.9%)	2 (0.4%)	0.686
Q wave	2 (0.4%)	1 (0.2%)
Non–Q wave	2 (0.4%)	1 (0.2%)
Target lesion revascularization	19 (4.2%)	41 (9.1%)	0.003
Stent thrombosis	1 (0.2%)	4 (0.9%)	0.374
Acute (<1 day)	0	1 (0.2%)
Subacute (1 day–1 month)	1 (0.2%)	0
Late (1–12 months)	0	1 (0.2%)
Very late (>12 months)	0	2 (0.4%)
Target vessel revascularization	28 (6.2%)	45 (10.0%)	0.038
Death/myocardial infarction/target vessel revascularization	34 (7.6%)	51 (11.3%)	0.053
Major adverse cardiac events (death/myocardial infarction/target lesion revascularization)	25 (5.6%)	47 (10.4%)	0.007

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