This article has Open Peer Review reports available.
Study design and rationale of 'Influence of Cilostazol-based triple anti-platelet therapy on ischemic complication after drug-eluting stent implantation (CILON-T)' study: A multicenter randomized trial evaluating the efficacy of Cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease
- Seung-Pyo Lee†1,
- Jung-Won Suh†1, 2,
- Kyung Woo Park1,
- Hae-Young Lee1,
- Hyun-Jae Kang1,
- Bon-Kwon Koo1,
- In-Ho Chae2,
- Dong-Ju Choi2,
- Seung-Woon Rha3,
- Jang-Whan Bae4,
- Myeong-Chan Cho4,
- Taek-Geun Kwon5,
- Jang-Ho Bae5Email author,
- Hyo-Soo Kim1Email author and
- CILON-T investigators1, 2, 3, 4, 5
© Lee et al; licensee BioMed Central Ltd. 2010
Received: 15 April 2010
Accepted: 24 August 2010
Published: 24 August 2010
Current guidelines recommend dual anti-platelet therapy, aspirin and clopidogrel, for patients treated with drug-eluting stent for coronary heart disease. In a few small trials, addition of cilostazol on dual anti-platelet therapy (triple anti-platelet therapy) showed better late luminal loss. In the real-world unselected patients with coronary heart disease, however, the effect of cilostazol on platelet reactivity and ischemic vascular events after drug-eluting stent implantation has not been tested. It is also controversial whether there is a significant interaction between lipophilic statin and clopidogrel.
CILON-T trial was a prospective, randomized, open-label, multi-center, near-all-comer trial to demonstrate the superiority of triple anti-platelet therapy to dual anti-platelet therapy in reducing 6 months' major adverse cardiovascular/cerebrovascular events, composite of cardiac death, nonfatal myocardial infarction, target lesion revascularization and ischemic stroke. It also tested whether triple anti-platelet therapy is superior to dual anti-platelet therapy in inhibiting platelet reactivity in patients receiving percutaneous coronary intervention with drug-eluting stent. Total 960 patients were randomized to receive either dual anti-platelet therapy or triple anti-platelet therapy for 6 months and also, randomly stratified to either lipophilic statin (atorvastatin) or non-lipophilic statin (rosuvastatin) indefinitely. Secondary endpoints included all components of major adverse cardiovascular/cerebrovascular events, platelet reactivity as assessed by VerifyNow P2Y12 assay, effect of statin on major adverse cardiovascular/cerebrovascular events, bleeding complications, and albumin-to-creatinine ratio to test the nephroprotective effect of cilostazol. Major adverse cardiovascular/cerebrovascular events will also be checked at 1, 2, and 3 years to test the 'legacy' effect of triple anti-platelet therapy that was prescribed for only 6 months after percutaneous coronary intervention.
CILON-T trial will give powerful insight into whether triple anti-platelet therapy is superior to dual anti-platelet therapy in reducing ischemic events and platelet reactivity in the real-world unselected patients treated with drug-eluting stent for coronary heart disease. Also, it will verify the laboratory and clinical significance of drug interaction between lipophilic statin and clopidogrel.
National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier# NCT00776828).
Current guidelines recommend at least 6 months of dual anti-platelet agents, consisting of aspirin and a thienopyridine, after percutaneous coronary intervention (PCI) and ideally, 1 year of both drugs . However, some patients experience acute thrombotic events, the incidence of which has been diverse from less than 1% to 3% [2, 3] even with good adherence to this dual anti-platelet therapy (DAT), and also, late restenotic complication after PCI. In addition, as interventional cardiologists face more and more complex lesions, the risk of ischemic events, including cardiac events, may tend to rise. These problems raise the issue to whether there are effective additional methods or drugs to prevent ischemic complications.
Cilostazol is a selective phosphodiesterase-3 (PDE-3) inhibitor, which has various effects including vasodilatory, anti-platelet and partially, anti-inflammatory effect. Several investigators have focused on cilostazol as one of the candidate drugs that can reduce ischemic events after PCI. Inspite of the fact that cilostazol is metabolized by CYP 3A  and to a lesser degree 2C19 , the same pathway as that of clopidogrel, cilostazol was suggested to be effective in reducing platelet reactivity in vitro  and also, efficacious and safe in reducing thrombotic complications in the real world . Also, several studies have suggested that cilostazol successfully and safely reduces restenosis rate after PCI [8–11]. In a meta-analysis, cilostazol has shown to be consistently helpful in reducing binary angiographic restenosis and repeat revascularization. But these data were derived mainly from the BMS era . Data from a few randomized trials have suggested that cilostazol reduces late luminal loss also in drug-eluting stents (DES) [10, 13]. But, these trials were underpowered to see whether cilostazol reduces the ultimate core endpoint of clinical trials, major adverse cardiac events (MACE) or major adverse cardiovascular/cerebrovascular events (MACCE). And the restricted inclusion criteria of the previous randomized trial cannot answer to the question whether cilostazol would be effective also in a routine clinical practice. These previous reports call for a large, randomized, controlled study to investigate whether cilostazol can really reduce MACE/MACCE after PCI in a real-world practice and also, for an extensive follow-up of these patients to see whether the effects persists in the long-term, as in a recent pooled analysis .
Additionally, there have been numerous questions as to whether there are significant interaction between clopidogrel and lipophilic statin and whether such interaction can be overcome by the addition of cilostazol. Although data on this matter is controversial but somewhat been in favor of being no significant in vivo interaction between clopidogrel and lipophilic statin , the interpretation and application of these data have been restricted by the unrandomized/unstratified manner of the studies [16–18] and non-prospective collection of the data . Also, although the pleiotrophic effect of cilostazol in renal function has been demonstrated in some animal experiments [20, 21], whether this holds true for humans have never been investigated.
In order to provide a definite answer to the above questions, we planned the 'Influence of CIL ostazol-based triple anti-platelet therapy ON Ischemic Complication after drug-eluting stenT implantation (CILON-T)' study. In this study, we compared the efficacy and safety of triple anti-platelet therapy (TAT), composed of aspirin, clopidogrel and cilostazol, with the conventional DAT by evaluating MACCE and platelet reactivity in an unselected population of patients receiving PCI with DES for coronary heart disease (CHD) in real-world practice. In addition, we would like to get answers for the issues whether lipophilic statin-clopidogrel interaction would influence the patient outcome and whether cilostazol can overcome such interaction, using atorvastatin (Lipitor®, Pfizer) dependent on cytochrome P450-3A4 (CYP3A4) for metabolism versus rosuvastatin (Crestor®, AstraZeneca) independent from CYP3A4.
Study objectives, hypothesis and design
Patients at least 18 years of age who had typical ischemic symptoms or positive stress test and a native coronary lesion (≥50% diameter stenosis by visual estimation on coronary angiogram and reference diameter≥2.5 mm)) were included in this study. Five high-volume centers in Korea participated and enrolled the patients in this multicenter, open-label, prospective, randomized trial. There were nearly no angiographic limitations about the number of lesions, vessels, location of lesions or their length, to investigate the effect of cilostazol in the real-world setting. The following patients were excluded from the study; cardiogenic shock; explicit side effect or contraindications to anti-platelet agents including cilostazol; concomitant treatment with any other anti-platelet agent or anticoagulant other than the study drugs; current user of cilostazol before the entry of study. The detailed inclusion and exclusion criteria are summarized in Appendix 2.
Randomization and interventions
All patients received 300 mg aspirin and 300~600 mg clopidogrel loading before the procedure unless the patient had been taking these medications for at least 1 week before the procedure. Patients were randomized to receive either conventional DAT or TAT and also, randomly stratified to take equipotent doses of either atorvastatin 20 mg or rosuvastatin 10 mg per day before the interventional procedure. The patients were also stratified according to the enrolling medical centers/hospitals. A loading dose of cilostazol (Otsuka Korea) 200 mg was given immediately before the procedure. Random allocation of the patients was done via a Web-based computerized program separately managed at medical research collaboration center, Seoul National University Hospital. PCI was done according to the standard technique and the decision of the pre-dilatation and use of glycoprotein IIb/IIIa inhibitors were up to the operator's discretion. The target lesion/vessel was designated as the first lesion/vessel that was intervened. Platelet reactivity was measured by using the Ultegra Rapid Platelet Function Assay (VerifyNow® Aspirin and VerifyNow® P2Y12 assay, Accumetrics Inc., San Diego, California, USA) immediately before discharge.
After enrollment and index PCI procedure, clinical follow-up was planned at 1, 3, 6 months and all patients were recommended follow-up coronary angiography at 6 months according to local clinical practice. Platelet reactivity was also measured at 6 months after index procedure. The investigators were urged to follow the patients, either by office visits or by telephone contacts as necessary. Patient adherence to the study drug was checked at every outpatient visit and the decision of the drug discontinuation was always discussed and checked under the physician's recommendation.
P2Y12 reaction unit (PRU) as assessed by VerifyNow® P2Y12 assay
Cardiac death, nonfatal MI, TLR, target vessel revascularization (TVR), stent thrombosis and ischemic stroke
MACCE according to the type of statin and its interaction with clopidogrel
Bleeding, as defined according to the TIMI bleeding classifications , major bleeding defined by the presence of at least 1 of the following: intracranial bleeding (documented with magnetic resonance imaging, computed tomography, any other examination or autopsy), or clinically overt bleeding resulting in a 5 g/dL decrease in hemoglobin value (or, when hemoglobin values were not available, a 15% decrease in hematocrit).
Angiographic outcome, such as late luminal loss, binary restenosis at 6 months' follow-up angiography
Sample size calculation
To test the hypothesis that TAT is superior to DAT in reducing MACCE at 6 months after PCI, based on the previous outcome data [10, 13, 23], we assumed that MACCE rate in DAT and TAT group would be 10% and 5% respectively. Using a superiority design, an estimated total of 960 patients was needed to ensure a power of at least 80% to detect a 5% difference in the composite of ischemic vascular events between the two anti-platelet therapy groups using a two-sided t-test, with a sampling ratio of DAT:TAT at 1:1, bilateral risk set at 5% and drop-out rate estimated to be 10%.
All analysis will be done by intention-to-treat method (all patients analyzed as part of their assigned treatment group). However, per protocol (patients analyzed as part of their assigned group only if they actually received their assigned treatment) and as-treated analysis will also be performed solely for descriptive comparison.
The primary endpoint of 6 months' MACCE will be analyzed using χ2-test on an intention-to-treat analysis. The hypothesis will be evaluated based on a superiority testing. The clinical secondary endpoints will also be tested based on χ2-test, similarly as primary endpoint testing. The endpoints will be analyzed in pre-specified subgroups, which includes the presence of diabetes mellitus, long lesions (lesion length≥28 mm), small vessel lesions (lesion diameter < 2.75 mm), age and sex. Also, most importantly, post-hoc analysis of MACCE according to the type of statin given (atorvastatin vs. rosuvastatin) will be done. Analysis of platelet function will be tested using repeated ANOVA method with the Bonferroni's correction.
Continuous variables will be presented as mean ± SD and compared with the use of unpaired Student's t-test or in the case of non-normal distribution, Mann-Whitney U test. Categorical variables will be summarized as number or percentages and compared with χ2 or Fisher's exact test, as appropriate. Survival curves using all available follow-up data will also be constructed for time-to-event variables using Kaplan-Meier estimates and compared by log-rank test. A p-value < 0.05 will be considered statistically significant.
The Executive Committee, constituted of the study chairperson and the principal investigators of the investigating centers, approved the final trial design and protocol issued to the Data and Safety Monitoring Board (DSMB) and the clinical sites. In addition, it was also responsible for reviewing the results, determining the adjudication of the publication, and selection of secondary projects by members of the Steering Committee.
Data Safety Monitoring Board (DSMB)
An independent DSMB, composed of general and interventional cardiologists, and a biostatistician abided by the applicable regulatory guidelines and did not participate in the trial. The DSMB committee reviewed the safety data from this study and made recommendations, based on safety analyses of unanticipated device effects (UADEs), serious adverse events (SAEs), protocol deviation, device failures, and follow-up reports. In addition to the scheduled DSMB meetings, that were determined prior to the initiation of the study, the board convened a meeting at any time if safety problems became an issue. The DSMB were responsible for recommending the Executive Committee to modify or stop the study if there were any safety or compliance issue. However, the final decisions regarding study modifications rested with the Executive Committee. Cumulative safety data were reported to the DSMB and reviewed on an ongoing basis throughout enrollment and follow-up to ensure safety of the patients. Every effort was made to allow the DSMB to conduct an unbiased review of the patients' safety information. All DSMB reports were made available to the appropriate agencies upon request but were otherwise remained strictly confidential. Prior to the DSMB's first review of the data, the DSMB charter was drafted. The plan defined the stopping rules for stopping the trial for safety. The first meeting of the DSMB was requested for discussion of the protocol and an understanding of all the protocol elements. The DSMB developed a consensus understanding of all trial endpoints and definitions used in the event adjudication process.
Clinical Event Adjudication Committee (CEAC)
The Clinical Events Adjudication Committee (CEAC) was comprised of interventional and non-interventional cardiologists who were not participants in the study. The CEAC was responsible for the development of specific criteria used for categorization of clinical events and clinical endpoints in the study, which were based on protocol. At the onset of the trial, the CEAC established clear rules stating the minimum amount of data required, and the algorithm followed in order to classify a clinical event. All members of the CEAC were blinded to the primary results of the trial and met regularly to review and adjudicate all clinical events in which the required minimum data was available. The Committee also reviewed and ruled on all deaths that occurred throughout the trial.
Data Coordination and Site Management
Data coordination and site management services were performed by the Clinical Trials Center at Seoul National University Hospital.
This study was approved by institutional review board of Seoul National University Hospital.
With the advent of various coronary balloons, stents and wires, PCI is widely used and accepted not only to improve angina symptoms but also to reduce cardiovascular mortality, albeit in the setting of acute coronary syndrome. Although the development of DES has been a major leap in the field of interventional cardiology in reducing recurrent ischemic events, it has been mandatory to use DAT for at least 6 months and preferably, 1 year to prevent stent thrombosis (ST). Even under the protection of DAT, some subsets of patients suffer from cardiovascular ischemic events including ST, necessitating search for new methods to prevent future ischemic cardiovascular events.
Rationale of cilostazol use to prevent ischemic cardiovascular events
Cilostazol is a selective PDE3 inhibitor that prevents degradation of intracellular cAMP into 5'-AMP. It has various action mechanisms on various cells. For example, cilostazol has been shown to inhibit the expression of platelet activation markers, such as p-selectin  and glycoprotein IIb/IIIa receptors, thus inhibiting platelet aggregation and adhesion . It has also been proved that cilostazol enhances endothelial function by nitric oxide production  and reduces various inflammatory responses in endothelial cells . Furthermore, cilostazol is pro-apoptotic to vascular smooth muscle cells and ultimately reduces neointimal formation . Taken together, cilostazol is a drug that may prevent ST, restenosis and improve endothelial function theoretically.
Previous reports of cilostazol use in PCI and the rationale of the CILON-T trial
With the potential benefit of cilostazol on vascular function in vitro, there have been several previous efforts to prove the efficacy of cilostazol in patients undergoing PCI. For example, the efficacy of cilostazol has been tested in patients who received percutaneous transluminal coronary angioplasty (PTCA) , bare-metal stenting [7, 9, 30] and also in those at high risk of events after DES implantation [10, 13]. A recent systematic review of the above mentioned trials utilizing adjunctive cilostazol has reported an appraisal of cilostazol for inhibiting neointimal hyperplasia . However, very few trials have effectively nor properly addressed the issue of whether cilostazol can reduce MAC(C)E, the ultimate concern of all trials. Especially, this issue has never been addressed in the DES era nor in the situation of real-world practice, urging a need for a randomized clinical trial to answer this question.
Issues sought in the CILON-T trial
In addition to the primary endpoint of whether TAT would be superior to DAT in reducing the ischemic vascular events after PCI, CILON-T trial is planned to assess several issues that remains to be answered. The issue of whether laboratory benefits are directly connected with clinical outcomes will be sought. Specifically, there have been papers demonstrating that PRU levels predicted adverse cardiovascular events in high risk patients [31–33] and that cilostazol reduced the average level of platelet activation in patients with coronary heart disease  and also, PRU level . However, racial difference is one factor that can influence the platelet reactivity  and there remains a paradox between the higher level of PRU and lower rate of thrombotic events after DES implantation in Asians. Simply compared, the rate of stent thrombosis involving more than 3,000 patients around 1.5 years after DES implantation is 1.9% in Europeans  while 0.77% in Japanese . In this CILON-T trial, we can get valuable information whether cilostazol-induced reduction of PRU levels would lead to beneficial clinical outcomes.
It is also expected to shed light on whether non-CYP3A4-metabolized statin is superior to CYP3A4-metabolized statin in terms of MAC(C)E and if so, whether cilostazol would be effective in reducing this difference. In vitro studies have persistently suggested that the effect of clopidogrel would be reduced by concomitant use of lipophilic statin [37, 38] but large in vivo studies do not show trend toward detrimental effect of these types of statin [16–18, 39]. However, these in vivo results come from observational registry data or post-hoc analysis of randomized clinical trials. Therefore, our data would add additional information to clopidogrel-statin interaction issue and also, if any, a new finding on the effect of cilostazol in this drug interaction.
In conclusion, we still do not know whether TAT is superior to DAT in reducing MACCE after DES implantation for coronary heart disease in the unselected real-world patients. Furthermore, whether cilostazol-induced PRU level reduction will turn out to improve clinical outcomes has never been elucidated. We hope to address these issues in the CILON-T trial where we enrolled a large unselected population of patients treated with DES for significant coronary heart disease.
Appendix 1. Endpoints of CILON-T trial
MACCE (composite of cardiac death, nonfatal MI, TLR and ischemic stroke)
Individual composites of MACCE
Platelet reactivity unit as assessed by Ultegra Rapid Platelet Function Assay (VerifyNow®)
MACCE according to the type of statin and its interaction with clopidogrel
Bleeding complications, as defined by TIMI classification
Angiographical outcome at 6 months' angiographical follow-up (late luminal loss, binary restenosis)
Appendix 2. Enrollment criteria for CILON-T trial
General inclusion criteria
At least 18 years of age
Able to confirm and understand the risk, benefits and treatment alternatives of receiving cilostazol and
also to provide written informed consent
Significant coronary artery stenosis (≥50% by visual estimate)
Evidence of myocardial ischemia (stable angina, acute coronary syndrome with evidence of myocardial
ischemia by symptomatic assessment or by stress test)
Adequate candidate for percutaneous coronary intervention (PCI)
General exclusion criteria
Known hypersensitivity or contraindications to heparin, aspirin, clopidogrel, contrast media, cilostazol or statin
Previous anti-platelet user (excluding aspirin or clopidogrel) or warfarin user
Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plans to become pregnant in the near future
History of bleeding diasthesis or coagulopathy or baseline thrombocytopenia (PLT count < 120,000/μL)
Chronic kidney disease (defined as Cr≥2.0 mg/dL or on dialysis)
Poor left ventricular systolic function (LVEF < 30%)
Significant liver disease (defined as AST/ALT > 3×UNL or liver cirrhosis Child B/C)
Significant dyslipidemia (total cholesterol≥350 mg/dL or triglyceride≥840 mg/dL)
Age > 80
Chronic alcohol use or drug abuser
Angiographic inclusion criteria
Target lesion(s) located in a native coronary artery with visually estimated diameter≥2.5 mm
Target lesion(s) amenable to PCI (left main, bifurcation and chronic total occlusion lesion included)
Angiographic exclusion criteria
Target lesion(s) with ISR
This study was supported by a grant from the Clinical Research Center for Ischemic Heart Disease, Seoul, Republic of Korea (A040152), a grant from the Innovative Research Institute for Cell Therapy, Seoul National University Hospital (A062260), sponsored by the Ministry of Health, Welfare & Family, Republic of Korea.
- King SB, Smith SC, Hirshfeld JW, Jacobs AK, Morrison DA, Williams DO, Feldman TE, Kern MJ, O'Neill WW, Schaff HV, Whitlow PL, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW: 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation. 2008, 117: 261-295. 10.1161/CIRCULATIONAHA.107.188208.View ArticlePubMedGoogle Scholar
- Kimura T, Morimoto T, Nakagawa Y, Tamura T, Kadota K, Yasumoto H, Nishikawa H, Hiasa Y, Muramatsu T, Meguro T, Inoue N, Honda H, Hayashi Y, Miyazaki S, Oshima S, Honda T, Shiode N, Namura M, Sone T, Nobuyoshi M, Kita T, Mitsudo K, j-Cypher Registry Investigators: Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation. Circulation. 2009, 119: 987-995. 10.1161/CIRCULATIONAHA.108.808311.View ArticlePubMedGoogle Scholar
- Brar SS, Leon MB, Stone GW, Mehran R, Moses JW, Brar SK, Dangas G: Use of drug-eluting stents in acute myocardial infarction: a systematic review and meta-analysis. J Am Coll Cardiol. 2009, 53: 1677-1689. 10.1016/j.jacc.2009.03.013.View ArticlePubMedGoogle Scholar
- Suri A, Forbes WP, Bramer SL: Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999, 37 (Suppl 2): 61-68. 10.2165/00003088-199937002-00007.View ArticlePubMedGoogle Scholar
- Suri A, Bramer SL: Effect of omeprazole on the metabolism of cilostazol. Clin Pharmacokinet. 1999, 37 (Suppl 2): 53-59. 10.2165/00003088-199937002-00006.View ArticlePubMedGoogle Scholar
- Jeong YH, Lee SW, Choi BR, Kim IS, Seo MK, Kwak CH, Hwang JY, Park SW: Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol. 2009, 53: 1101-1109. 10.1016/j.jacc.2008.12.025.View ArticlePubMedGoogle Scholar
- Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, Han KH, Lee CW, Kang DH, Song JK, Kim JJ, Park SJ: Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol. 2005, 46: 1833-1837. 10.1016/j.jacc.2005.07.048.View ArticlePubMedGoogle Scholar
- Park SW, Lee CW, Kim HS, Lee NH, Nah DY, Hong MK, Kim JJ, Park SJ: Effects of cilostazol on angiographic restenosis after coronary stent placement. Am J Cardiol. 2000, 86: 499-503. 10.1016/S0002-9149(00)01001-8.View ArticlePubMedGoogle Scholar
- Douglas JS, Holmes DR, Kereiakes DJ, Grines CL, Block E, Ghazzal ZM, Morris DC, Liberman H, Parker K, Jurkovitz C, Murrah N, Foster J, Hyde P, Mancini GB, Weintraub WS, Cilostazol for Restenosis Trial (CREST) Investigators: Coronary stent restenosis in patients treated with cilostazol. Circulation. 2005, 112: 2826-2832. 10.1161/CIRCULATIONAHA.104.530097.View ArticlePubMedGoogle Scholar
- Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Kim HS, Ko JK, Park JH, Lee JH, Choi SW, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Park SJ: Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients). J Am Coll Cardiol. 2008, 51: 1181-1187. 10.1016/j.jacc.2007.11.049.View ArticlePubMedGoogle Scholar
- Chen KY, Rha SW, Li YJ, Poddar KL, Jin Z, Minami Y, Wang L, Kim EJ, Park CG, Seo HS, Oh DJ, Jeong MH, Ahn YK, Hong TJ, Kim YJ, Hur SH, Seong IW, Chae JK, Cho MC, Bae JH, Choi DH, Jang YS, Chae IH, Kim CJ, Yoon JH, Chung WS, Seung KB, Park SJ, Korea Acute Myocardial Infarction Registry Investigators: Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 2009, 119: 3207-3214. 10.1161/CIRCULATIONAHA.108.822791.View ArticlePubMedGoogle Scholar
- Biondi-Zoccai GG, Lotrionte M, Anselmino M, Moretti C, Agostoni P, Testa L, Abbate A, Cosgrave J, Laudito A, Trevi GP, Sheiban I: Systematic review and meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary intervention. Am Heart J. 2008, 155: 1081-1089. 10.1016/j.ahj.2007.12.024.View ArticlePubMedGoogle Scholar
- Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Kim HS, Ko JK, Park JH, Lee JH, Choi SW, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Park SJ, DECLARE-Long Study Investigators: Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial). Am J Cardiol. 2007, 100: 1103-1108. 10.1016/j.amjcard.2007.05.032.View ArticlePubMedGoogle Scholar
- Lee SW, Chun KJ, Park SW, Kim HS, Kim YH, Yun SC, Kim WJ, Lee JY, Park DW, Lee CW, Hong MK, Rhee KS, Chae JK, Ko JK, Park JH, Lee JH, Choi SW, Jeong JO, Seong IW, Jon S, Cho YH, Lee NH, Kim JH, Park SJ: Comparison of Triple antiplatelet therapy and dual antiplatelet therapy in patients at high risk of restenosis after drug-eluting stent implantation (from the DECLARE-DIABETES and -LONG Trials). Am J Cardiol. 2010, 105: 168-173. 10.1016/j.amjcard.2009.08.667.View ArticlePubMedGoogle Scholar
- Angiolillo DJ, Alfonso F: Clopidogrel-statin interaction: myth or reality?. J Am Coll Cardiol. 2007, 50: 296-298. 10.1016/j.jacc.2007.04.041.View ArticlePubMedGoogle Scholar
- Saw J, Brennan DM, Steinhubl SR, Bhatt DL, Mak KH, Fox K, Topol EJ: Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial. J Am Coll Cardiol. 2007, 50: 291-295. 10.1016/j.jacc.2007.01.097.View ArticlePubMedGoogle Scholar
- Wienbergen H, Gitt AK, Schiele R, Juenger C, Heer T, Meisenzahl C, Limbourg P, Bossaller C, Senges J: Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies. Am J Cardiol. 2003, 92: 285-288. 10.1016/S0002-9149(03)00626-X.View ArticlePubMedGoogle Scholar
- Mukherjee D, Kline-Rogers E, Fang J, Munir K, Eagle KA: Lack of clopidogrel-CYP3A4 statin interaction in patients with acute coronary syndrome. Heart. 2005, 91: 23-26. 10.1136/hrt.2004.035014.View ArticlePubMedPubMed CentralGoogle Scholar
- Brophy JM, Babapulle MN, Costa V, Rinfret S: A pharmacoepidemiology study of the interaction between atorvastatin and clopidogrel after percutaneous coronary intervention. Am Heart J. 2006, 152: 263-269. 10.1016/j.ahj.2005.08.023.View ArticlePubMedGoogle Scholar
- Matousovic K, Grande JP, Chini CC, Chini EN, Dousa TP: Inhibitors of cyclic nucleotide phosphodiesterase isozymes type-III and type-IV suppress mitogenesis of rat mesangial cells. J Clin Invest. 1995, 96: 401-410. 10.1172/JCI118049.View ArticlePubMedPubMed CentralGoogle Scholar
- Tohma T, Shimabukuro M, Oshiro Y, Yamakawa M, Shimajiri Y, Takasu N: Cilostazol, a phosphodiesterase inhibitor, reduces microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty rat. Metabolism. 2004, 53: 1405-1410. 10.1016/j.metabol.2004.06.005.View ArticlePubMedGoogle Scholar
- Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P: Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987, 76: 142-154.View ArticlePubMedGoogle Scholar
- Han Y, Li Y, Wang S, Jing Q, Wang Z, Wang D, Shu Q, Tang X: Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: a randomized, controlled study. Am Heart J. 2009, 157: 733-739. 10.1016/j.ahj.2009.01.006.View ArticlePubMedGoogle Scholar
- Inoue T, Sohma R, Morooka S: Cilostazol inhibits the expression of activation-dependent membrane surface glycoprotein on the surface of platelets stimulated in vitro. Thromb Res. 1999, 93: 137-143. 10.1016/S0049-3848(98)00172-8.View ArticlePubMedGoogle Scholar
- Minami N, Suzuki Y, Yamamoto M, Kihira H, Imai E, Wada H, Kimura Y, Ikeda Y, Shiku H, Nishikawa M: Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Life Sci. 1997, 61: 383-389. 10.1016/S0024-3205(97)00986-7.View ArticleGoogle Scholar
- Nakamura T, Houchi H, Minami A, Sakamoto S, Tsuchiya K, Niwa Y, Minakuchi K, Nakaya Y: Endothelium-dependent relaxation by cilostazol, a phosphodiesteras III inhibitor, on rat thoracic aorta. Life Sci. 2001, 69: 1709-1715. 10.1016/S0024-3205(01)01258-9.View ArticlePubMedGoogle Scholar
- Otsuki M, Saito H, Xu X, Sumitani S, Kouhara H, Kurabayashi M, Kasayama S: Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-kappaB binding to its recognition sequence. Atherosclerosis. 2001, 158: 121-128. 10.1016/S0021-9150(01)00431-2.View ArticlePubMedGoogle Scholar
- Kim MJ, Park KG, Lee KM, Kim HS, Kim SY, Kim CS, Lee SL, Chang YC, Park JY, Lee KU, Lee IK: Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F. Hypertension. 2005, 45: 552-556. 10.1161/01.HYP.0000158263.64320.eb.View ArticlePubMedGoogle Scholar
- Tsuchikane E, Fukuhara A, Kobayashi T, Kirino M, Yamasaki K, Izumi M, Otsuji S, Tateyama H, Sakurai M, Awata N: Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty. Circulation. 1999, 100: 21-26.View ArticlePubMedGoogle Scholar
- Ge J, Han Y, Jiang H, Sun B, Chen J, Zhang S, Du Z: RACTS: a prospective randomized antiplatelet trial of cilostazol versus ticlopidine in patients undergoing coronary stenting: long-term clinical and angiographic outcome. J Cardiovasc Pharmacol. 2005, 46: 162-166. 10.1097/01.fjc.0000167012.82930.8f.View ArticlePubMedGoogle Scholar
- Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, Buonamici P, Antoniucci D, Abbate R, Gensini GF: Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation. 2009, 119: 237-242. 10.1161/CIRCULATIONAHA.108.812636.View ArticlePubMedGoogle Scholar
- Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS: Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J. 2008, 29: 992-1000. 10.1093/eurheartj/ehn046.View ArticlePubMedGoogle Scholar
- Patti G, Nusca A, Mangiacapra F, Gatto L, D'Ambrosio A, Di Sciascio G: Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol. 2008, 52: 1128-1133. 10.1016/j.jacc.2008.06.038.View ArticlePubMedGoogle Scholar
- Kim JY, Lee K, Shin M, Ahn M, Choe H, Yoo BS, Yoon J, Choe KH, Lee SH: Cilostazol could ameliorate platelet responsiveness to clopidogrel in patients undergoing primary percutaneous coronary intervention. Circ J. 2007, 71: 1867-1872. 10.1253/circj.71.1867.View ArticlePubMedGoogle Scholar
- Price MJ, Nayak KR, Barker CM, Kandzari DE, Teirstein PS: Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2009, 103: 1339-1343. 10.1016/j.amjcard.2009.01.341.View ArticlePubMedGoogle Scholar
- Airoldi F, Colombo A, Morici N, Latib A, Cosgrave J, Buellesfeld L, Bonizzoni E, Carlino M, Gerckens U, Godino C, Melzi G, Michev I, Montorfano M, Sangiorgi GM, Qasim A, Chieffo A, Briguori C, Grube E: Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation. 2007, 116: 745-754. 10.1161/CIRCULATIONAHA.106.686048.View ArticlePubMedGoogle Scholar
- Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER: Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003, 107: 32-37. 10.1161/01.CIR.0000047060.60595.CC.View ArticlePubMedGoogle Scholar
- Neubauer H, Gunesdogan B, Hanefeld C, Spiecker M, Mugge A: Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function--a flow cytometry study. Eur Heart J. 2003, 24: 1744-1749. 10.1016/S0195-668X(03)00442-1.View ArticlePubMedGoogle Scholar
- Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, Topol EJ: Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation. 2003, 108: 921-924. 10.1161/01.CIR.0000088780.57432.43.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.