Even in the drug-eluting stent era, restenosis has remained an unresolved issue, particularly in the treatment of complex coronary lesions. In this study, patient-level data from 3 randomized trials (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients With Diabetes Mellitus [DECLARE-DIABETES] and Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients With Long Native Coronary Lesions [DECLARE-LONG] I and II) were pooled to estimate the differential antirestenotic efficacy of add-on cilostazol according to the implanted drug-eluting stent in patients at high risk for restenosis. A total of 1,399 patients underwent sirolimus-eluting stent (SES; n = 450), paclitaxel-eluting stent (n = 450), and zotarolimus-eluting stent (n = 499) implantation and received triple-antiplatelet therapy (TAT; aspirin, clopidogrel, and cilostazol, n = 700) and dual-antiplatelet therapy (aspirin and clopidogrel, n = 699). Randomization of antiplatelet regimen was stratified by stent type. In-stent late loss after TAT was significantly lower than that after dual-antiplatelet therapy, regardless of implanted stent type. However, the incidence of in-segment restenosis after TAT was significantly lower with SES (0.5% vs 6.7%, p = 0.014) and zotarolimus-eluting stent (12.2% vs 20.0%, p = 0.028) implantation but not paclitaxel-eluting stent implantation (14.4% vs 20.0%, p = 0.244). A significant interaction was present between stent type and antiplatelet regimen for the risk for in-segment restenosis (p = 0.004). Post hoc analysis using bootstrap resampling methods showed that the relative risk reduction for in-segment restenosis after TAT was most prominent with SES implantation. In conclusion, add-on cilostazol effectively reduced restenosis in patients at high risk for restenosis, particularly in those receiving SES, suggesting the sustainable utility of add-on cilostazol therapy in newer generation drug-eluting stents with comparable efficacy with that of SES.
Cilostazol administration is known to be an effective pharmacologic intervention to inhibit neointimal proliferation after bare-metal stent and drug-eluting stent (DES) implantation through the inhibition of the phosphodiesterase III pathway. Previously, we demonstrated that the addition of cilostazol to standard dual-antiplatelet therapy (DAT) for 6 or 8 months in a complex lesion subset reduced angiographic restenosis. However, whether cilostazol differentially affects relative angiographic outcomes with different stent types is unknown. Therefore, we pooled patient-level data from 3 randomized trials (Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients With Diabetes Mellitus [DECLARE-DIABETES] and Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients With Long Native Coronary Lesions [DECLARE-LONG] I and II) to estimate the differential efficacy of add-on cilostazol to prevent angiographic in-segment restenosis according to implanted stent type.
Methods
The overall features of DECLARE-DIABETES, DECLARE-LONG I, and DECLARE-LONG II are listed in Table 1 . As previously described, the 3 studies were prospective, randomized controlled trials to compare the efficacy and safety of received triple-antiplatelet therapy (TAT; aspirin, clopidogrel, and cilostazol) and DAT (aspirin and clopidogrel) in patients with diabetes (DECLARE-DIABETES) and in those with long coronary lesions (≥25 mm; DECLARE-LONG I and II). Inclusion and exclusion criteria of each study are provided in the online supplement . The institutional review board at each participating center approved the protocol. All patients provided written informed consent.
| Variable | DECLARE-DIABETES | DECLARE-LONG I | DECLARE-LONG II |
|---|---|---|---|
| No. of sites | 5 | 5 | 10 |
| No. of patients | 400 | 500 | 499 |
| Stent type | SES (n = 200)/PES (n = 200) | SES (n = 250)/PES (n = 250) | ZES |
| Age (yrs) | 60.9 ± 8.8 | 61.1 ± 9.0 | 61.5 ± 9.0 |
| Men | 232 (58.0%) | 321 (64.2%) | 353 (70.7%) |
| Hypertension ‡ | 238 (59.5%) | 275 (55.0%) | 307 (61.5%) |
| Diabetes mellitus | 400 (100.0%) | 116 (33.2%) | 176 (35.3%) |
| Acute coronary syndromes | 232 (58.0%) | 273 (54.6%) | 263 (52.7%) |
| Primary end point | In-stent LL at 6 mo | In-stent LL at 6 mo | In-stent LL at 8 mo |
| Angiographic follow-up timing (mo) | 6 | 6 | 8 |
| Recruitment period | May 2005 to March 2006 | August 2004 to August 2005 | December 2007 to December 2008 |
| Reference vessel diameter (mm) | ≥2.5 | ≥2.5 | ≥2.5 |
| Lesion length (mm) | No limit | ≥25 | ≥25 |
| Major patient and lesion inclusion criteria | Patients with diabetes, de novo lesions | De novo long lesions | De novo long lesions |
| Major patient and lesion exclusion criteria ∗ | Complex and high risk † | Complex and high risk † | Complex and high risk † |
∗ Patients in all trials were excluded if unable to take aspirin, clopidogrel, or cilostazol.
† Including left main coronary artery disease, graft vessel disease, planned bifurcation stenting in the side branch, primary angioplasty for acute myocardial infarction within 24 hours, patients with left ventricular ejection fractions <30%, history of hematologic disease, hepatic dysfunction, renal dysfunction, or serious noncardiac co-morbid disease with a life expectancy <1 year.
‡ Systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg or receiving antihypertensive medication.
In DECLARE-DIABETES and DECLARE-LONG I, after the guidewire crossed the target lesion, implanted stent type was randomized in a 1:1 ratio to sirolimus-eluting stent (SES) or paclitaxel-eluting stent (PES) implantation, and thereafter, randomization of antiplatelet regimen in a 1:1 ratio to TAT or DAT was stratified by stent type. In DECLARE-LONG II, after successful zotarolimus-eluting stent (ZES) implantation, antiplatelet regimen was randomly assigned in a 1:1 ratio to TAT or DAT. From ≥24 hours before the procedure and thereafter, all patients received aspirin (200 mg/day) and clopidogrel (loading dose of 300 mg, followed by 75 mg/day) for all patients. Patients in the TAT group received a loading dose of cilostazol 200 mg immediately after the procedure and 100 mg twice daily for ≥6 months.
Repeat coronary angiography was mandatory at 6 months in DECLARE-DIABETES and DECLARE-LONG I or at 8 months in DECLARE-LONG II after stenting, or earlier if indicated by clinical symptoms or evidence of myocardial ischemia.
The primary end point was the incidence of in-segment angiographic restenosis at follow-up angiography. The secondary end points included other angiographic outcomes, such as the incidence of in-stent restenosis, in-segment late loss, and in-stent late loss. Angiographic restenosis was defined as diameter stenosis >50% at follow-up angiography.
The clinical outcomes included death, myocardial infarction, target lesion revascularization, target vessel revascularization, stent thrombosis, and bleeding events. Q-wave myocardial infarction was defined by the postprocedural presence of new Q waves >0.04 seconds in 2 contiguous leads. Non-Q-wave myocardial infarction was defined as a creatine kinase-MB fraction >3 times the upper limit of normal. Target lesion revascularization 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. Target vessel revascularization was defined as a reintervention of a lesion in the same epicardial vessel. Revascularization was defined as ischemia driven if there was stenosis of ≥50% of the diameter, as documented by positive functional study results, ischemic changes on electrocardiography, 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. Major bleeding was defined as the need for transfusion, decrease in hemoglobin >5 g/dl, need for surgical intervention, or resulting in hypotension requiring inotropic support. Major adverse cardiac events were the composite of death, myocardial infarction, and ischemia-driven target lesion revascularization.
Clinical follow-up visits were scheduled at 30, 120, and 240 days and at 1 year. At every visit, physical examination and electrocardiography were performed, and drug compliance, cardiac events, and angina recurrence were monitored.
Coronary angiograms were obtained after intracoronary nitroglycerin administration. Preprocedural (baseline), postprocedural, and follow-up angiograms were submitted to the angiographic core analysis center (Asan Medical Center, Seoul, Korea) for analysis by independent angiographers. Digital angiograms were analyzed using an automated edge detection system (CAAS II; Pie Medical, Maastricht, The Netherlands). Quantitative coronary angiographic analysis measurements of target lesions were obtained for the stented segment only (in stent) and the region that included the stented segment and the margins 5 mm proximal and distal to the stent (in segment).
Subgroup classifications according to implanted stent type were prespecified. All data are presented on the basis of the intent-to-treat principle. Baseline characteristics and 1-year clinical outcomes were compared between antiplatelet regimen and various stent type strata, and adjustments were not made for multiple comparisons. Continuous variables were compared using Student’s unpaired t tests or Mann-Whitney U tests and are presented as mean ± SD. Categorical variables were compared using chi-square or Fisher’s exact tests and are presented as numbers or percentages. Because we combined the 3 randomized trials, we performed a test of homogeneity (using the Q statistic) across the trials. On the basis of the homogeneity test, the 3 trials could be combined (p = 0.787 for in-stent restenosis and p = 0.903 for in-segment angiographic restenosis). To determine the relative risk reduction of TAT compared with DAT according to the implanted stent, we used the bootstrap resampling method. Then, we compared the obtained p values with the Bonferroni correction cutoff value of 0.025 (0.05/2). A p value <0.05 was considered to indicate a significant difference. All p values were 2 sided. Statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina) and R version 2.10.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Of the 1,399 patients enrolled in the DECLARE-DIABETES, DECLARE LONG I, and DECLARE-LONG II trials, 700 patients received TAT and 699 received DAT. Supplementary Table 1 lists baseline clinical, angiographic, and procedural characteristics between patients receiving the 2 antiplatelet regimens. There were no statistical differences between groups except in the left ventricular ejection fraction.
Table 2 shows angiographic outcomes. Follow-up angiography was performed in 83.8% of patients (83.6% in the TAT group and 84.0% in the DAT group, p = 0.83). In-segment and in-stent late loss was significantly lower in the TAT group. The rate of binary angiographic restenosis was also significantly lower in the TAT group. Accordingly, as listed in Supplementary Table 2 , the 1-year rates of ischemia-driven target lesion revascularization, ischemia-driven target vessel revascularization, and major adverse cardiac events were significantly lower in the TAT group than the DAT group. Major bleeding events were not significantly different between groups.
| Variable | TAT (n = 700) | DAT (n = 699) | p Value |
|---|---|---|---|
| Reference diameter (mm) | 2.91 ± 0.43 | 2.89 ± 0.45 | 0.526 |
| Lesion length (mm) | 31.9 ± 13.4 | 32.2 ± 13.4 | 0.691 |
| Minimum luminal diameter (mm) | |||
| In segment | |||
| Before procedure | 0.82 ± 0.49 | 0.79 ± 0.48 | 0.246 |
| After procedure | 2.25 ± 0.47 | 2.25 ± 0.49 | 0.820 |
| At follow-up | 2.01 ± 0.55 | 1.95 ± 0.59 | <0.001 |
| In stent | |||
| After procedure | 2.58 ± 0.41 | 2.58 ± 0.43 | 0.938 |
| At follow-up | 2.22 ± 0.61 | 2.11 ± 0.65 | 0.003 |
| Diameter stenosis (%) | |||
| In segment | |||
| Before procedure | 70.5 ± 15.6 | 70.6 ± 15.5 | 0.921 |
| After procedure | 17.4 ± 11.2 | 17.0 ± 10.6 | 0.531 |
| At follow-up | 26.3 ± 17.7 | 29.7 ± 18.6 | 0·001 |
| In stent | |||
| After procedure | 8.1 ± 13.1 | 7.5 ± 12.1 | 0.429 |
| At follow-up | 21.9 ± 20.4 | 25.1 ± 21.6 | 0.010 |
| Acute gain (mm) | |||
| In segment | 1.76 ± 0.57 | 1.79 ± 0.60 | 0.384 |
| In stent | 1.44 ± 0.61 | 1.46 ± 0.65 | 0.554 |
| Late loss (mm) | |||
| In segment | 0.17 ± 0.51 | 0.31 ± 0.54 | <0.001 |
| In stent | 0.35 ± 0.55 | 0.47 ± 0.57 | <0.001 |
| Binary angiographic restenosis | |||
| In segment | 53 (9.0%) | 92 (15.7%) | 0.003 |
| In stent | 48 (8.2%) | 80 (13.6%) | 0.01 |
Baseline clinical, angiographic, and procedural characteristics stratified by type of implanted stent and randomly assigned antiplatelet regimen are listed in Table 3 . There were no statistical differences between the TAT and DAT groups except in gender in patients receiving SES and the left ventricular ejection fraction in those receiving PES.
| Variable | SES (n = 450) | ZES (n = 499) | PES (n = 450) | |||
|---|---|---|---|---|---|---|
| TAT (n = 225) | DAT (n = 225) | TAT (n = 250) | DAT (n = 249) | TAT (n = 225) | DAT (n = 225) | |
| Age (yrs) | 60.9 ± 9.3 | 61.6 ± 8.6 | 60.9 ± 9.1 | 62.1 ± 9.0 | 61.0 ± 8.1 | 60.4 ± 9.6 |
| Men | 157 (69.8%) | 133 (59.1%) ∗ | 175 (70.0%) | 178 (71.5%) | 123 (54.7%) | 140 (62.2%) |
| Hypertension | 119 (52.9%) | 133 (59.1%) | 146 (58.4%) | 161 (64.7%) | 137 (60.0%) | 124 (55.1%) |
| Diabetes mellitus | 144 (64.0%) | 138 (61.3%) | 92 (36.8%) | 84 (33.7%) | 141 (62.7%) | 143 (63.6%) |
| Total cholesterol ≥200 mg/dl | 60 (26.7%) | 68 (30.2%) | 106 (42.4%) | 112 (45.0%) | 76 (33.8%) | 60 (26.8%) |
| Current smokers | 68 (30.2%) | 78 (34.7%) | 76 (30.4%) | 75 (30.1%) | 74 (32.9%) | 78 (34.7%) |
| Previous percutaneous coronary intervention | 22 (9.8%) | 24 (10.7%) | 18 (7.2%) | 16 (6.4%) | 28 (12.4%) | 26 (11.6%) |
| Clinical diagnosis | ||||||
| Stable angina pectoris | 102 (45.3%) | 95 (42.2%) | 110 (44.0%) | 126 (50.6%) | 99 (44.0%) | 99 (44.0%) |
| Unstable angina pectoris | 88 (39.1%) | 85 (37.8%) | 112 (44.8%) | 100 (40.2%) | 73 (32.4%) | 77 (34.2%) |
| Acute myocardial infarction | 35 (15.6%) | 45 (20.0%) | 28 (11.2%) | 23 (9.2%) | 53 (23.6%) | 49 (21.8%) |
| Left ventricular ejection fraction (%) | 59.1 ± 10.4 | 58.4 ± 9.5 | 60.7 ± 6.7 | 59.8 ± 8.0 | 59.5 ± 9.5 | 57.6 ± 10.2 ∗ |
| Multivessel disease | 142 (63.1%) | 126 (56.0%) | 87 (34.8%) | 93 (37.3%) | 156 (69.3%) | 148 (65.8%) |
| Target vessel | ||||||
| Left anterior descending coronary artery | 141 (62.7%) | 136 (60.4%) | 149 (59.6%) | 155 (62.2%) | 139 (61.8%) | 131 (58.2%) |
| Left circumflex coronary artery | 23 (10.2%) | 31 (13.8%) | 40 (16.0%) | 29 (11.6%) | 27 (12.0%) | 24 (10.7%) |
| Right coronary artery | 61 (27.1%) | 58 (25.8%) | 61 (24.4%) | 65 (26.1%) | 59 (26.2%) | 70 (31.1%) |
| Maximal inflation pressure (atm) | 16.1 ± 3.6 | 15.6 ± 3.4 | 16.6 ± 3.8 | 16.5 ± 3.8 | 15.0 ± 3.7 | 14.5 ± 3.3 |
| Use of intravascular ultrasound | 90 (40.0%) | 82 (36.4%) | 194 (77.6%) | 195 (78.3%) | 81 (36.0%) | 82 (36.4%) |
| Total stent length at the target lesion (mm) | 37.0 ± 13.8 | 37.2 ± 14.4 | 37.3 ± 12.5 | 39.1 ± 12.9 | 38.8 ± 15.8 | 36.2 ± 13.5 |
| Number of used stents at the target lesion | 1.4 ± 0.5 | 1.4 ± 0.6 | 1.5 ± 0.6 | 1.6 ± 0.6 | 1.4 ± 0.6 | 1.4 ± 0.6 |
| Procedure-related non-Q-wave myocardial infarction | 20 (8.9%) | 15 (6.7%) | 21 (8.4%) | 29 (11.6%) | 19 (8.4%) | 27 (12.0%) |
Follow-up angiography was performed in 85.8% of SES patients, 79.6% of PES patients, and 85.8% of ZES patients (p = 0.013). Table 4 lists angiographic outcomes. For each DES type, the TAT group showed consistent reductions of in-segment late loss (absolute reduction with SES 0.13 mm, with PES 0.15 mm, and with ZES 0.15 mm) and in-stent late loss (absolute reduction with SES 0.13 mm, with PES 0.11 mm, and with ZES 0.11 mm). Therefore, the relative reduction of late loss was greater in patients receiving SES. The incidence of in-segment restenosis after TAT was significantly lower in the SES group (0.5% vs 6.7%, p = 0.014) and the ZES group (12.2% vs 20.0%, p = 0.028) but not the PES group (14.4% vs 20.2%, p = 0.244). Similarly, the incidence of in-stent restenosis after TAT was significantly lower in the SES group (0.5% vs 5.7%, p = 0.023) and the ZES group (10.8% vs 19.1%, p = 0.016) but not the PES group (13.3% vs 15.7%, p = 0.602). Logistic regression analysis demonstrated a significant interaction between antiplatelet regimen and implanted stent type for in-segment restenosis (p = 0.004) and in-stent restenosis (p = 0.004) ( Figure 1 ). Post hoc analysis using bootstrap resampling methods showed that the relative risk reduction of in-segment restenosis after TAT was significantly greater in the SES group compared with the ZES (p = 0.001) and PES (p <0.001) groups.
