Author + information
- Received July 5, 2010
- Revision received October 4, 2010
- Accepted October 5, 2010
- Published online March 15, 2011.
- Seung-Whan Lee, MD⁎,
- Seong-Wook Park, MD⁎,⁎ (, )
- Young-Hak Kim, MD⁎,
- Sung-Cheol Yun, PhD⁎,
- Duk-Woo Park, MD⁎,
- Cheol Whan Lee, MD⁎,
- Soo-Jin Kang, MD⁎,
- Seung-Jung Park, MD⁎,
- Jae-Hwan Lee, MD†,
- Si Wan Choi, MD†,
- In-Whan Seong, MD†,
- Nae-Hee Lee, MD‡,
- Yoon Haeng Cho, MD‡,
- Won-Yong Shin, MD§,
- Seung-Jin Lee, MD§,
- Se-Whan Lee, MD§,
- Min-Su Hyon, MD∥,
- Duk-Won Bang, MD∥,
- Young-Jin Choi, MD¶,
- Hyun-Sook Kim, MD¶,
- Bong-Ki Lee, MD#,
- Keun Lee, MD⁎⁎,
- Hoon-Ki Park, MD⁎⁎,
- Chang-Bum Park, MD⁎⁎,
- Sang-Gon Lee, MD††,
- Min-Kyu Kim, MD‡‡,
- Kyoung-Ha Park, MD‡‡,
- Woo-Jung Park, MD‡‡,
- DECLARE-LONG II Study Investigators
- ↵⁎Reprints requests and correspondence:
Dr. Seong-Wook Park, Department of Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, Korea
Objectives The purpose of this study was to determine whether cilostazol reduces intimal hyperplasia in patients undergoing long zotarolimus-eluting stent implantation (stent length: ≥30 mm) for native long coronary lesions (length: ≥25 mm).
Background Restenosis after drug-eluting stent implantation remains a significant clinical problem in long coronary lesions.
Methods Patients (n = 499) were assigned randomly to triple (aspirin, clopidogrel, and cilostazol, triple group: n = 250) or dual antiplatelet therapy (aspirin and clopidogrel and placebo, dual group: n = 249) for 8 months after long zotarolimus-eluting stent implantation. The primary end point was in-stent late loss at the 8-month angiography according to the intention-to-treat principle.
Results The 2 groups had similar baseline characteristics. The in-stent (0.56 ± 0.55 mm vs. 0.68 ± 0.59 mm, p = 0.045) and in-segment (0.32 ± 0.54 mm vs. 0.47 ± 0.54 mm, p = 0.006) late loss were significantly lower in the triple versus dual group, as were 8-month in-stent restenosis (10.8% vs. 19.1%, p = 0.016), in-segment restenosis (12.2% vs. 20.0%, p = 0.028), and 12-month ischemic-driven target lesion revascularization (5.2% vs. 10.0%, p = 0.042) rates. At 12 months, major adverse cardiac events including death, myocardial infarction, and ischemic-driven target lesion revascularization tended to be lower in the triple group than the dual group (7.2% vs. 12.0%, p = 0.07). Percent intimal hyperplasia volume by volumetric intravascular ultrasound analysis was reduced from 27.1 ± 13.2% for the dual group to 22.1 ± 9.9% for the triple group (p = 0.017).
Conclusions Patients receiving triple antiplatelet therapy after long zotarolimus-eluting stent implantation had decreased extent of late luminal loss, percent intimal hyperplasia volume, and angiographic restenosis, resulting in a reduced risk of 12-month target lesion revascularization compared with patients receiving dual antiplatelet therapy. (Triple Versus Dual Antiplatelet Therapy after ABT578-Eluting Stent; NCT00589927)
Cilostazol, a phosphodiesterase III inhibitor, has antiproliferative effects, as shown by its reduction of intimal hyperplasia and restenosis rates after balloon angioplasty and bare-metal stent (BMS) implantation (1,2). We previously reported that cilostazol significantly reduced 6-month restenosis and 9-month target lesion revascularization (TLR) after drug-eluting stent (DES) implantation in patients or lesions at high risk for restenosis (3,4). However, our previous studies had an unblinded design with relatively short-term (6-month) follow-up angiography and a 2 × 2 factorial design using 2 different DESs. Therefore, to determine whether cilostazol reduces neointimal hyperplasia, primarily contributing to restenosis, after DES implantation, we undertook a randomized, double-blind, placebo-controlled study comparing triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) and dual antiplatelet therapy (aspirin, clopidogrel, and placebo) for 8 months in long coronary lesions treated with zotarolimus-eluting stent (ZES) (Endeavor stent, Medtronic Vascular, Santa Rosa, California) implantation.
This prospective, double-blind, randomized study (DECLARE-LONG II [Drug-Eluting Stenting Followed by Cilostazol Treatment Reduces Late Restenosis in Patients with Long Coronary Lesions] trial) involved 499 patients 18 years of age or older with stable angina or acute coronary syndrome and a native long coronary lesion (length ≥25 mm, a diameter stenosis ≥50%, and visual reference diameter ≥2.5 mm). The study involved 10 cardiac centers in Korea between December 2007 and December 2008. Patients were excluded if they had contraindication to aspirin, clopidogrel, or cilostazol; left main disease; graft vessel disease; left ventricular ejection fraction <30%; recent history of hematologic disease or leukocyte count <3,000/mm3, platelet count <100,000/mm3, or both; hepatic dysfunction with aspartate aminotransferase or alanine aminotransferase 3 times or more of the upper normal limit; history of renal dysfunction or serum creatinine level ≥2.0 mg/dl; serious noncardiac disease with a life expectancy <1 year; planned bifurcation stenting in side branch; ST-segment elevation myocardial infarction; or inability to follow the protocol. In patients with multiple lesions, the first long stented lesion was considered to be the target lesion. The institutional review board at each participating center approved the protocol. All patients provided written informed consent.
Randomization and procedures
After successful ZES implantation (stent length ≥30 mm), patients were allocated randomly in a 1:1 ratio to triple antiplatelet group (aspirin, clopidogrel, and cilostazol, triple group: n = 250) or dual antiplatelet therapy (aspirin, clopidogrel, and placebo, dual group: n = 249) using an interactive web response system. Stratified and block randomization was performed according to participation sites. A matching box of 100 mg cilostazol and placebo (tablet identical to cilostazol) were prepared with a patient allocation number.
From at least 24 h before the procedure and thereafter, all patients received aspirin (loading dose of 200 mg, followed by 200 mg daily indefinitely) and clopidogrel (loading dose of 300 mg, followed by 75 mg daily for at least 12 months). Patients also received a loading dose of 2 study tablets (cilostazol 200 mg or matching placebo, 2 tablets) within 1 h after the procedure, followed by cilostazol 100 mg twice daily or placebo 1 tablet twice daily for 8 months.
Coronary stenting was performed according to a standard technique. The decision of predilation or direct stenting was made by the operator, as was use of intravascular ultrasound (IVUS) or intravenous glycoprotein IIb/IIIa inhibitors. Creatine kinase and creatine kinase-myocardial band isoenzymes were assessed at 8, 12, and 24 h after procedure, and thereafter if necessary.
Study end point and definitions
The primary end point was in-stent late loss at the 8-month follow-up angiography. The secondary end points included angiographic outcomes such as in-segment late loss and binary restenosis (diameter stenosis: >50%) and percent intimal hyperplasia volume by quantitative volumetric IVUS analysis. Twelve-month definite or probable stent thrombosis; ischemic-driven target vessel revascularization (TVR); ischemic-driven TLR; and major adverse cardiac events, including death, myocardial infarction (MI), and ischemic-driven TLR also were assessed. Safety assessments included incidence of Thrombolysis In Myocardial Infarction major, minor, and minimal bleeding (5); any study drug adverse reactions; and incidence of drug discontinuation.
Angiographic success was defined as in-segment diameter stenosis <30% by quantitative coronary angiography (QCA). MI was defined as creatine kinase-myocardial band elevation >3 times or creatine kinase elevation >2 times the upper normal limit with at least one of the following: ischemic symptoms, development of pathological Q waves, and ischemic electrocardiographic changes. Revascularization was defined as ischemia driven if there was stenosis of at least 50% of the diameter, as documented by positive functional study results, ischemic changes on an electrocardiogram, or ischemic symptoms, or in the absence of documented ischemia, if there was stenosis of at least 70% as assessed by quantitative coronary analysis. Stent thrombosis was assessed according to the Academic Research Consortium definitions (6) and was classified by the timing of the event (acute [0 to 24 h], subacute [0 to 30 days], late [>31 days]).
Repeat coronary angiography was performed at 8 months after stenting. Clinical follow-up visits were scheduled at 30, 120, and 240 days and at 1 year. At every visit, physical examination, electrocardiogram, drug compliance, cardiac events, and angina recurrence were monitored. Drug compliance was assessed using a compliance questionnaire. Laboratory and clinical assessment of adverse drug side effects were performed at every visit. Figure 1 shows flow of patients during follow-up. All adverse clinical events were assessed by an independent events committee blinded to treatment groups.
Pre-procedure, post-procedure, and follow-up angiograms obtained after intracoronary nitroglycerin administration were submitted to a 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). QCA measurements were obtained for both in-stent and in-segment (stented segment and margins 5 mm proximal and distal to stent). Patterns of restenosis were assessed using the Mehran classification (7).
IVUS imaging and analysis
IVUS imaging was performed after intracoronary administration of 0.2 mg nitroglycerin using motorized transducer pullback (0.5 mm/s) and a commercial scanner consisting of a 30-MHz transducer within 3.2-F imaging sheath (SCIMED, Boston Scientific Scimed Inc., Freemont, California). Quantitative volumetric IVUS analysis was performed by a core laboratory (Asan Medical Center, Seoul, Korea). Using computerized planimetry, stent, lumen, and intimal hyperplasia (stent minus lumen) areas were measured every 1 mm within the stented segment; volumes were calculated using Simpson's rule. Percent intimal hyperplasia volume was calculated as intimal hyperplasia volume divided by stent volume. To adjust for different stent lengths, the volume index was calculated as volume data divided by stent length.
Based on the ENDEAVOR II (Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions) (8), we assumed a mean in-stent late loss of 0.61 ± 0.46 mm in the dual group. Calculation of the sample size was based on a 25% reduction of the triple group for an assumed mean in-stent late loss (3,4), a 2-sided alpha level of 0.05, and 90% power. To demonstrate superiority of triple versus dual antiplatelet therapy group, 194 patients per group were needed. The total sample size was estimated to be 486 patients (243 patients per group) on the expectation of a 20% loss for angiographic follow-up. Analyses of 2 groups were performed according to the intention-to-treat principle or a per-protocol basis (patients analyzed as part of their assigned treatment group only if they follow the assigned antiplatelet regimen for 8 months). Continuous variables are presented as mean ± SD or median (interquartile range) and were compared using the Student unpaired t test or the Mann–Whitney U test. Categorical variables are presented as numbers or percentages and were compared using the chi-square test or Fisher exact test. A p value <0.05 was considered to indicate a significant difference. Statistical analysis was performed using commercially available software (SPSS software version 11 for Windows, SPSS, Inc., Chicago, Illinois).
Table 1 shows the baseline clinical characteristics of the 2 groups of patients. There were no significant differences between groups in baseline clinical characteristics or risk factors.
Procedural results and in-hospital outcomes
The 2 groups had similar anatomic and procedural characteristics (Table 2). Procedure-related enzyme elevation occurred in 8.4% in the triple group and in 11.6% in the dual group (p = 0.08). Acute stent thrombosis developed only in 1 patient in the triple group. In-hospital events, including Q-wave MI (defined as documentation of a new abnormal Q-wave after the index revascularization), emergency bypass surgery, and death, did not occur in either group.
Baseline and post-procedural QCA outcomes are shown in Table 3. The 2 groups had similar baseline and post-procedural QCA characteristics.
The 8-month follow-up angiography was performed in 85.8% (85.2% of triple group and 86.3% of dual group, p = 0.714). QCA measurements at follow-up are shown in Table 3. The in-stent (0.56 ± 0.55 mm vs. 0.68 ± 0.59 mm, p = 0.045, absolute reduction: 0.12, 95% CI: 0.02 to 0.22) and in-segment (0.32 ± 0.54 mm vs. 0.47 ± 0.54 mm, p = 0.006, absolute reduction: 0.15, 95% CI: 0.04 to 0.42) late loss were significantly lower in the triple group than in the dual group. In-stent and in-segment minimum lumen diameter was larger in the triple group than in the dual group. Consequently, in-stent restenosis (10.8% vs. 19.1%, relative risk: 0.57, 95% CI: 0.35 to 0.91, p = 0.016) and in-segment restenosis (12.2% vs. 20.0%, relative risk: 0.61, 95% CI: 0.39 to 0.96, p = 0.028) was significantly lower in the triple group than in the dual group. Patterns of in-stent restenosis are shown in Table 4. Focal restenosis (30.8% vs. 11.6%, p = 0.049) was more prevalent in the triple versus the dual group.
When outcomes were analyzed on a per-protocol basis (185 of 203 patients in the triple group and 205 of 221 patients in the dual group), triple therapy had a significantly smaller in-stent late loss (0.56 ± 0.52 mm vs. 0.69 ± 0.60 mm, p = 0.024) and in-segment late loss (0.31 ± 0.50 mm vs. 0.47 ± 0.54 mm, p = 0.003). In-stent restenosis (9.7% vs. 19.5%, p = 0.007) and in-segment restenosis (10.8% vs. 20.5%, p = 0.009) also was significantly lower in the triple group versus the dual group.
IVUS images (n = 122, 65 in the triple group and 57 in the dual group) at the post-procedure and follow-up study were enrolled in an IVUS substudy. In this population, baseline clinical and procedural characteristics were similar in both groups (data not shown). The triple group had similar lumen volume index at follow-up, but the intimal hyperplasia volume index was reduced from 2.09 ± 1.17 mm3/m for the dual group to 1.60 ± 0.87 mm3/m for the triple group (p = 0.010) (Table 5). Percent intimal hyperplasia volume also was reduced from 27.1 ± 13.2% for the dual group stent to 22.1 ± 9.9% for the triple group (p = 0.017).
A 12-month clinical follow-up was performed in all living patients (Table 6). Death, MI, or stent thrombosis was not statistically different between the 2 groups. However, ischemic-driven TLR (5.2% vs. 10.0%, relative risk: 0.52, 95% CI: 0.27 to 0.99, p = 0.042) and ischemic-driven TVR (5.2% vs. 10.4%, relative risk: 0.50, 95% CI: 0.26 to 0.95, p = 0.029) were significantly lower in the triple versus the dual group. Composite outcomes of death, MI, and ischemic-driven TVR (7.2% vs. 12.4%, p = 0.049) and major adverse cardiac event, including death, MI, and ischemic-driven TLR, tended to be lower in the triple versus the dual group (7.2% vs. 12.0%, p = 0.07).
Adverse drug side effects and compliance
Thrombolysis In Myocardial Infarction major, minor, and minimal bleedings were not statistically different between 2 groups (Table 7). Headache was more common in the triple group than in the dual group. Study drug discontinuation for adverse events and other reasons was more common in the triple versus the dual group (18.8% vs. 12.2%, p = 0.02), and most study drug discontinuations occurred within 3 months after randomization. The most common reasons for discontinuation of cilostazol in the triple group were headache, skin rash, and gastrointestinal disturbance.
The major finding of this study is that triple antiplatelet therapy for 8 months, compared with dual therapy, is associated with reduction of late loss and angiographic restenosis after long ZES implantation without an increased risk of serious adverse drug effects. This translates into a reduced risk of 12-month TLR.
Although the effectiveness of DES has been demonstrated in many patient subgroups, as shown by reductions in neointimal hyperplasia, angiographic restenosis, and repeat revascularization rates, restenosis remains a significant clinical problem in patients with complex lesions, such as those with long coronary lesions. Our randomized, double-blind, multicenter trial showed that addition of cilostazol for 8 months significantly reduced 8-month late loss after long ZES implantation. In-stent late loss was reduced from 0.68 ± 0.59 mm to 0.56 ± 0.55 mm (p < 0.05), and in-segment late loss was reduced from 0.47 ± 0.54 mm to 0.32 ± 0.54 mm (p < 0.05). Absolute reduction of in-stent and in-segment late loss was 0.12 and 0.15 mm, respectively. These findings were similar to those of trials using BMS and DES treated with cilostazol ranging from 0.11 to 0.15 mm (2–4). Volumetric IVUS analysis supported effectiveness of cilostazol by showing a reduction in the percent intimal hyperplasia volume and intimal hyperplasia volume index in the triple group.
Recent trials showed that a cilostazol-based regimen for 6 months after DES implantation reduced 6-month restenosis by 49% in diabetic patients (4) or by 40% in patients with long lesions (3). In the BMS era, a previous trial showed a 36% reduction of 6-month restenosis (2). In the present study, decreased late loss in cilostazol-treated patients culminated in a reduced rate of in-stent restenosis by 43% and of in-segment restenosis by 39%, which also were similar to those of previous studies (2–4). Therefore, consistent reduction of intimal hyperplasia and restenosis across BMS or DES implantation suggests that cilostazol would be a valuable option in patients or lesions at high risk for restenosis after coronary stenting.
In addition, we found that 1-year ischemic-driven TLRs were decreased by 48% in the triple group. The magnitude of risk reduction of TLR by triple therapy was comparable with those of previous trials using DES (3,4). In the meanwhile, although the incidence of death or MI was not different in either group, major adverse cardiac events and composite outcomes of death, MI, and ischemic-driven TVR were reduced in triple therapy, mainly driven by reduced repeat revascularization. Furthermore, owing to the antiplatelet property of cilostazol, previous studies demonstrated that triple antiplatelet therapy significantly reduced death, stent thrombosis, and MI after stent implantation in a broad range of persons (9), especially in acute coronary syndrome patients (10,11). Thus, triple antiplatelet therapy may improve the efficacy of DES in terms of angiographic and clinical outcomes in patients or lesions at high risk for restenosis and cardiac events.
The triple group had a higher rate of drug discontinuation than the dual group, but there were similar episodes of bleeding complications. This finding was demonstrated clinically in previous reports (9,10). Moreover, significant adverse drug events were not detected in the triple group, suggesting that patients undergoing coronary stenting can be treated safely with the triple antiplatelet regimen.
First, this study showed efficacy of cilostazol after long ZES implantation. The usefulness of such an approach may be relevant to ZES. Thus, the change in late loss (approximately 20%) and restenosis (approximately 40%) should be clarified in other second-generation DESs with much lower rates of late loss. However, considering previous studies (3,4) showing the effectiveness of cilostazol after sirolimus- or paclitaxel-eluting stent implantation, cilostazol may be effective in other DES. Second, these findings have not been observed in other populations, such as white persons, in the DES era. Therefore, the effectiveness of cilostazol should be determined in other populations.
We have shown that triple antiplatelet therapy after long ZES implantation resulted in a significantly smaller late loss and a reduced risk of angiographic restenosis and TLR compared with dual antiplatelet therapy. Our findings suggested that adding cilostazol on standard care improved the efficacy of DES in patients or lesions at high risk for restenosis in routine practice.
Dr. Seong-Wook Park has received consulting fees from Cordis; lecture fees from Cordis, Medtronic, and Boston Scientific; and research grant support from Cordis and Medtronic. Drs. Sang-Gon Lee and Keun Lee has received lecture fees from Cordis, Abbott Vascular, and Medtronic. Drs. Bong-Li Lee, Duk-Won Bang, Min-Su Hyon, Se-Whan Lee, Won-Yong Shin, Yoon-Haeng Cho, Woo-Jung Park, and Si-Wan Choi has received lecture fees from Cordis and Boston Scientific. Dr. Young-Kin Choi has received lecture fees from Cordis. Dr. Seung-Jin Lee has received research grant support from Cordis. Dr. Nae-Hee Lee has received lecture fees from Cordis, Medtronic, and Boston Scientific. Dr. In-Whan Seong has received research grant support from Boston Scientific. Drs. Jae-Hwan Lee, Duk-Woo Park, and Young-Hak Kim has received lecture fees from Cordis and Medtronic. Dr. Seung-Whan Lee has received lecture fees from Otsuka and Cordis. Dr. Cheol-Whan Lee has received lecture fees from Pfizer and Medtronic. Dr. Seong-Park has received lecture fees from Sanofi-Aventis, Otsuka, Cordis, and Medtronic. All other authors have reported that they have no relationships to disclose.
DECLARE-LONG II was supported by Korea Otsuka Pharmaceutical Co., Ltd (funding source), and the Cardiovascular Research Foundation, Seoul, Korea. Korea Otsuka Pharmaceutical Co., Ltd., had no role in the study design, data collection, data analysis, or data interpretation; had no access to the clinical trial database; and did not have the opportunity to review or comment on the report.
For full author disclosures, please see the end of this paper.
- Abbreviations and Acronyms
- bare-metal stent(s)
- confidence interval
- drug-eluting stent(s)
- external elastic membrane
- intravascular ultrasound
- myocardial infarction
- quantitative coronary angiography
- target lesion revascularization
- target vessel revascularization
- zotarolimus-eluting stent(s)
- Received July 5, 2010.
- Revision received October 4, 2010.
- Accepted October 5, 2010.
- American College of Cardiology Foundation
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