Journal of the American College of Cardiology Vol. 57, No. 3, by the American College of Cardiology Foundation ISSN /$36.

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1 Journal of the American College of Cardiology Vol. 57, No. 3, by the American College of Cardiology Foundation ISSN /$36.00 Published by Elsevier Inc. doi: /j.jacc Cardiovascular Disease Multicenter Randomized Trial Evaluating the Efficacy of Cilostazol on Ischemic Vascular Complications After Drug-Eluting Stent Implantation for Coronary Heart Disease Results of the CILON-T (Influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stent implantation) Trial Jung-Won Suh, MD,* Seung-Pyo Lee, MD,* Kyung-Woo Park, MD,* Hae-Young Lee, MD,* Hyun-Jae Kang, MD,* Bon-Kwon Koo, MD,* Young-Seok Cho, MD, Tae-Jin Youn, MD, In-Ho Chae, MD, Dong-Ju Choi, MD, Seung-Woon Rha, MD, Jang-Ho Bae, MD, Taek-Geun Kwon, MD, Jang-Whan Bae, MD, Myeong-Chan Cho, MD, Hyo-Soo Kim, MD* Seoul, Seongnam, Daejon, and Cheongju, Korea Objectives Background Methods Results Conclusions We aimed to test whether cilostazol has beneficial effects in the real-world patients treated with intracoronary drug-eluting stents (DES). The addition of cilostazol on the conventional dual antiplatelet therapy has been reported to reduce platelet reactivity and to improve clinical outcomes after percutaneous coronary intervention in previous studies. In a randomized multicenter trial, we enrolled 960 patients who received DES. They were randomized to receive either dual antiplatelet therapy (DAT) (aspirin and clopidogrel) or triple antiplatelet therapy (TAT) (aspirin, clopidogrel, and cilostazol) for 6 months. Primary end point was the composite of cardiac death, nonfatal myocardial infarction, ischemic stroke, or target lesion revascularization (TLR). Secondary end points were P2Y 12 reaction unit (PRU) measured with the VerifyNow P2Y12 assay (Accumetrics, San Diego, California) at discharge and at 6 months after the index procedure. All-cause death, stent thrombosis, and each component of the primary end point at 6 months were other secondary end points. Analysis was done on an intention-to-treat basis. At 6 months follow-up, there was no difference in the primary end point between the 2 groups (8.5% in TAT vs. 9.2% in DAT, p 0.74). In secondary end point analysis, the TAT group achieved lower PRU levels than the DAT group both at discharge ( PRU vs PRU, p 0.001) and at 6 months ( PRU vs PRU, p 0.001). In the Cox proportional hazards analysis, lesion length ( 28 mm, hazard ratio [HR]: 2.10, 95% confidence interval [CI]: 1.25 to 3.52), and PRU level at discharge (every increase in tertile, HR: 1.61, 95% CI: 1.16 to 2.25) were predictors of the primary end point, but not the use of cilostazol (HR: 0.90, 95% CI: 0.54 to 1.52). Despite the greater reduction of platelet reactivity by addition of cilostazol to conventional DAT, TAT did not show superiority in reducing the composite of adverse cardiovascular outcomes after DES implantation. (The Efficacy of CILostazol ON Ischemic Complications After DES Implantation [CILON-T]; NCT ) (J Am Coll Cardiol 2011;57:280 9) 2011 by the American College of Cardiology Foundation *From the Cardiovascular Center, Seoul National University Hospital, Seoul, Korea; Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea; Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea; Heart Center, Konyang University Hospital, Daejon, Korea; and the Chungbuk National University Hospital, Cheongju, Korea. This study was supported by a grant from the Clinical Research Center for Ischemic Heart Disease (A040152) and a grant from the Innovative Research Institute for Cell Therapy, Seoul National University Hospital (A062260), both sponsored by the Ministry of Health, Welfare & Family, Republic of Korea. Dr. Hyo-Soo Kim is also a professor of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, sponsored by the World Class University program of the Ministry of Education and Science, Korea. All other authors have reported that they have no relationships to disclose. The first two authors contributed equally to this work. Manuscript received June 8, 2010; revised manuscript received August 13, 2010, accepted August 18, 2010.

2 JACC Vol. 57, No. 3, 2011 January 18, 2011:280 9 Suh et al. Cilostazol and Ischemic Events After PCI 281 Drug-eluting stents (DES) reduce the rate of restenosis and have expanded the application of percutaneous coronary interventions (PCI). However, restenosis still exists (1,2), and there are concerns about long-term thrombotic complications after DES (3 5). See page 290 DES implantation is typically followed by aspirin plus clopidogrel therapy (DAT). However, a substantial number of patients, 15% to 30%, have high residual platelet reactivity on DAT, and there have been reports describing an association between high post-treatment platelet reactivity (PPR) and atherothrombotic cardiovascular complications after PCI (6 8). Among various assays assessing PPR, the results of VerifyNow P2Y12 (Accumetrics, San Diego, California) have shown good predictability of atherothrombotic outcomes (8 10). However, these studies are based on data for Caucasians. There are few reports about the efficacy of the VerifyNow P2Y12 system in predicting clinical outcomes in Asians. Cilostazol is a selective phosphodiesterase-3 inhibitor that is commonly used as a vasodilator with antiplatelet activity in patients with peripheral arterial disease (11). In addition, it has been reported to have anti-inflammatory and antiapoptotic effects (12,13), and has reduced restenosis in studies with coronary stents (14 17). Adjunctive cilostazol treatment on top of the standard DAT (triple antiplatelet therapy [TAT]), in patients with type 2 diabetes mellitus, enhances inhibition of platelet P2Y12 signaling, and cilostazol intensifies platelet inhibition in patients who showed high PPR despite conventional DAT (18,19). Registry data have shown that TAT reduced stent thrombosis, nonfatal myocardial infarction (MI), and cardiac death compared with DAT (20,21). Following these favorable results, cilostazol has been suggested as a powerful candidate of adjunctive therapy that can overcome limitations of DES, with respect to both thrombosis and restenosis. However, there have been no large-scale randomized trials to verify superiority of TAT to DAT in the inhibition of platelet reactivity and in reducing adverse clinical outcomes in patients who underwent DES implantation. The aim of the present clinical trial (CILON-T [The Efficacy of CILostazol ON Ischemic Complications After DES Implantation]) was to assess the safety and the efficacy of TAT versus DAT in reducing adverse cardiovascular outcomes including thrombosis and restenosis in the realworld all-comer patients with DES implantation. Another aim is to verify the superiority of TAT to DAT in the inhibition of platelet reactivity. Methods Patients. The CILON-T trial (22) was a prospective, open-label randomized trial at 5 centers in South Korea: the Seoul National University Hospital, Seoul National University Bundang Hospital, Korea Guro Hospital, Konyang University Hospital, and Chungbuk National University Hospital. Patients were enrolled between September 2006 and June Men and women were eligible if they were 18 to 80 years of age, had angina pectoris or a positive stress test, and had native coronary artery lesions for which DES implantation was feasible. Reasons for exclusion were: hepatic dysfunction; renal dysfunction (serum creatinine 2.0 mg/dl or on dialysis); left ventricular ejection fraction 30% or New York Heart Association functional class III or IV; uncorrected hematological disease; contraindication to or history of allergy to aspirin, clopidogrel, or cilostazol; or expected survival 2 years because of other medical conditions. Patients already Abbreviations and Acronyms CI confidence interval DAT dual antiplatelet therapy DES drug-eluting stent(s) HR hazard ratio MI myocardial infarction NPV negative predictive value PCI percutaneous coronary intervention PPR post-treatment platelet reactivity PPV positive predictive value PRU P2Y 12 reaction unit ROC receiver-operating characteristic TAT triple antiplatelet therapy TIMI Thombolysis In Myocardial Infarction TLR target lesion revascularization taking warfarin or antiplatelet agents except aspirin or clopidogrel were also excluded. All patients gave written informed consent, and the institutional review boards at 5 centers approved this study. Procedures. All patients were given aspirin and clopidogrel before coronary intervention. Loading doses of aspirin (300 mg) and clopidogrel (300 to 600 mg) were given to patients who had not taken aspirin or clopidogrel before. Aspirin (100 mg daily) and clopidogrel (75 mg daily) were given for at least 6 months. Patients were randomly assigned to DAT or TAT. Stratification was performed according to the participating center and the type of statin (CYP3A4 metabolized vs. non-cyp3a4 metabolized) in order to rule out any potential statin clopidogrel drug interaction. This was an open-label study with blinded evaluation, and a placebo was not used. The TAT group received a loading dose of cilostazol 200 mg, and then 100 mg twice daily for 6 months on top of conventional DAT. Coronary stenting was performed according to standard PCI technique. The decision of pre-dilation or direct stenting was made by the operator, as was the use of glycoprotein IIb/IIIa inhibitor. Platelet function test. The VerifyNow assay is a pointof-care assay using whole blood and was utilized according to the instructions of the manufacturer (18,23). The VerifyNow P2Y12 assay reports the results as P2Y 12 reaction units (PRU). This assay mimics turbidometric aggregation and utilizes disposable cartridges containing 20 M ADP and 22 nm PGE 1. Aggregation testing using ADP as a sole agonist activates P2Y 1 and P2Y 12

3 282 Suh et al. JACC Vol. 57, No. 3, 2011 Cilostazol and Ischemic Events After PCI January 18, 2011:280 9 purinergic signaling; adding PGE 1 increases the specificity of the test for P2Y 12 signaling (18,24). In a separate channel of the cartridge in which iso-trap is used as an agonist, a baseline value for platelet function is obtained, enabling assessment of platelet inhibition (% inhibition) without having to wean the patient off antiplatelet treatment. We performed the VerifyNow P2Y12 assay at discharge and at 6 months after the index procedure. Study end points and clinical follow-up. The primary end point of the CILON-T trial was the composite of major adverse cardiovascular events, cardiac death, nonfatal MI, clinically driven target lesion revascularization (TLR), and ischemic stroke at 6 months. Secondary end points were PRU levels measured at discharge and at 6 months after DES implantation. Other secondary end points were all-cause death, stent thrombosis, and each component of the primary end point at 6 months. Safety assessments included bleeding complications according to Thombolysis In Myocardial Infarction (TIMI) criteria (25), heart rate, and the incidence of drug discontinuation during the treatment period. The cause of death was regarded as cardiovascular unless there was documented evidence of a clear noncardiovascular cause. MI was defined as a creatinine kinase myocardial band 3 times upper limit of normal. Ischemic stroke was defined as a new focal neurologic deficit of vascular origin lasting at least 24 h that was proven to be nonhemorrhagic by either computed tomography or magnetic resonance imaging scanning. TLR was considered clinically driven when it was associated with typical symptoms on clinical assessment, typical signs on stress test, or 70% diameter stenosis on angiographic follow-up. Stent thrombosis was defined as any of the following: angiographic documentation of occlusion of the target lesion associated with an acute ischemic event, irrespective of the presence of angiographically visible thrombi, unexplained sudden death, and MI not clearly relevant to another coronary lesion. Clinical follow-up was done at 1, 3, and 6 months and 1 year, and all patients were recommended to have follow-up coronary angiography at 6 months. The investigators followed the patients, either by office visits or by telephone contacts as necessary. The compliance of the drugs and adverse events were assessed at every visit for clinical follow-up. Statistical analysis. To test the hypothesis that TAT is superior to DAT in reducing the primary end point at 6 months after the index procedure, the event rate was assumed to be 10% in the DAT group and 5% in the TAT group, respectively, based on previously published reports (15,16,26,27). Using a superiority design, it was estimated that a total of 960 patients would be needed to ensure a power of 80% to detect a 5% difference in the primary end point between the 2 groups using a 2-tailed test, with a sampling ratio of DAT:TAT at 1:1, bilateral risk set at 5%, and the estimated dropout rate of 10%. Analyses of the 2 groups were performed according to the intention-to-treat principle. The Kolmogorov-Smirnov test was used for normality test. Comparison of continuous variables was performed using Student t test or, in the case of non-normal distribution, Mann-Whitney U test as appropriate. Categorical variables were presented as numbers or percentages and were compared using chi-square or Fischer exact tests. Analysis of platelet function test was performed with repeated measures analysis of variance method with the Bonferroni correction. Pre-specified subgroup analysis according to diabetes mellitus, age, sex, and angiographic variables (lesion length, reference vessel diameter) was performed. Cox proportional hazards analysis was used to assess clinical and angiographic predictors of adverse clinical outcomes. A receiver-operating characteristic (ROC) curve analysis was used to determine the ability of the post-treatment platelet reactivity to distinguish between patients with and without atherothrombotic events after PCI. The best cutoff value was defined as the point with the highest sum of sensitivity and specificity. SPSS version 17.0 (SPSS Inc., Chicago, Illinois) was used for all statistical analyses, and p 0.05 was considered statistically significant. Role of funding source. Neither the Innovative Research Institute for Cell Therapy nor Clinical Research Center for Ischemic Heart Disease, Ministry of Health & Welfare had involvement in study design, in collection, analysis, or interpretation of data, or in writing of the report. The corresponding author had full access to all the data in the study and had the final responsibility for the decision to submit for publication. Results The clinical trial algorithm is shown in Figure 1. Among the initially randomized patients, 5 patients withdrew consent, 7 patients failed to implant DES for the target lesion, and 33 patients withdrew from the study by the duty physician s judgment for several reasons, which included high risk of significant bleeding in the near future, and planned operation that needed antiplatelet agent modification or discontinuation. The total dropout rate was about 5% in each group (i.e., within the expected range) and did not differ significantly between the groups. Baseline clinical, angiographic, and procedural characteristics of the 915 patients who entered the study are shown in Tables 1 and 2. No significant differences existed between the 2 groups. Profiles of medication at discharge were not different between the 2 groups except angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB), which were more frequently prescribed in the DAT than in the TAT group (45.2% vs. 37.0%, p 0.012) (Table 3). PPR in 2 groups. The VerifyNow P2Y12 assay was performed at 2 different time points: at discharge (n 716, TAT: n 355, DAT: n 361) and 6 months (n 608, TAT: n 299, DAT: n 309) after the index procedure. The duration of hospital stay after the procedure was not different between the 2 groups (TAT: days vs. DAT: days, p 0.33). The TAT

4 JACC Vol. 57, No. 3, 2011 January 18, 2011:280 9 Suh et al. Cilostazol and Ischemic Events After PCI 283 Figure 1 Flow of Patients Through the Study DAT dual antiplatelet therapy; MI myocardial infarction; PCI percutaneous coronary intervention; PRU P2Y 12 reaction unit; TAT triple antiplatelet therapy; TLR target lesion revascularization. Baseline Table 1Clinical Baseline Characteristics Clinical Characteristics TAT (n 457) DAT (n 458) p Value Age, yrs 64.8 (13) 64.0 (13) 0.79 Men 321 (68.6%) 326 (68.3%) 0.94 Hypertension 291 (64.5%) 305 (66.9%) 0.45 Diabetes mellitus 160 (35.5%) 147 (32.2%) 0.30 Dietary therapy alone 24 (5.3%) 17 (3.7%) Oral hypoglycemic agent 103 (22.8%) 116 (25.4%) Insulin 33 (7.3%) 14 (3.1%) Current smoker 107 (23.7%) 122 (26.8%) 0.47 Previous percutaneous coronary intervention 29 (6.4%) 39 (8.6%) 0.23 Previous coronary artery bypass surgery 8 (1.8%) 13 (2.7%) 0.28 Clinical diagnosis 0.75 Stable angina 168 (41.3%) 153 (37.1%) Unstable angina 174 (42.8%) 196 (47.6%) Acute myocardial infarction 42 (10.3%) 42 (10.2%) Silent ischemia 8 (1.9%) 5 (1.2%) Systolic BP (mm Hg) 130 ( ) 126 ( ) 0.30 Diastolic BP (mm Hg) 79.5 (70 87) 78 (70 84) 0.27 Heart rate, min 1 68 ( ) 68 (61 76) 0.76 Total cholesterol, mg/dl ( ) ( ) 0.98 LDL cholesterol, mg/dl ( ) ( ) 0.60 Hematocrit, % 39.9 ( ) 40.1 ( ) 0.31 Creatinine, mg/dl 1.0 ( ) 1.0 ( ) 0.44 Data are n (%) or median (interquartile range). BP blood pressure; DAT dual antiplatelet therapy; LDL low-density lipoprotein; TAT triple antiplatelet therapy.

5 284 Suh et al. JACC Vol. 57, No. 3, 2011 Cilostazol and Ischemic Events After PCI January 18, 2011:280 9 Angiographic Table 2 Angiographic Characteristics Characteristics and Procedural andresults Procedural Results TAT (n 457) DAT (n 458) p Value Lesion locations 0.17 Left anterior descending coronary artery 220 (48.4%) 222 (49.3%) Left circumflex artery 91 (20.2%) 107 (23.5%) Right coronary artery 105 (23.1%) 124 (27.6%) Left main coronary artery 23 (5.1%) 13 (2.9%) ACC/AHA lesion classification 0.63 A 12 (2.8%) 10 (2.3%) B1 126 (29.7%) 126 (29.1%) B2 55 (13.0%) 46 (10.6%) C 231 (54.5%) 251 (58.0%) Ostial lesions 112 (24.5%) 109 (23.8%) 0.80 Calcified lesions 105 (24.1%) 128 (29.3%) Bifurcation lesion 145 (31.7%) 132 (28.8%) 0.56 Thrombus on angiography 34 (7.8%) 38 (8.7%) 0.64 Lesion length, mm 21.1 (13.4) 22.2 (13.9) 0.24 Reference vessel diameter, mm 2.88 ( ) 2.91 ( ) 0.57 Baseline minimum lumen diameter, mm 0.66 ( ) 0.70 ( ) 0.35 Post-procedural minimum lumen diameter, mm 2.24 ( ) 2.23 ( ) 0.15 Number of stents per lesion 1.0 ( ) 1.0 ( ) 0.84 Type of stents* 0.53 Paclitaxel-eluting stent (TAXUS) 223 (49.1%) 233 (51.4%) Zotarolimus-eluting stent (Endeavor) 212 (46.7%) 196 (43.3%) Multilesion intervention 156 (34.1%) 163 (35.6%) 0.64 Data are n (%) or median (interquartile range). *Other stents were sirolimus-eluting stent (Cypher, Cordis, Miami Lakes, Florida) and everolimuseluting stent (Xience, Abbott Vascular, Santa Clara, California). ACC/AHA American College of Cardiology/American Heart Association; other abbreviations as in Table 1. group showed significantly lower PPR compared with the DAT group both at discharge ( vs , p 0.001) and at 6 months ( vs , p 0.001) after DES implantation (Fig. 2). The PRU level in the DAT group significantly increased for 6 months between 2 time points, at discharge and 6 months after index procedure (p 0.001). In the TAT group, however, the PRU level did not change between the 2 time points (p 0.23). There was a significant difference in changes in PRU level between the 2 groups (p for interaction 0.046). The level of % inhibition was also significantly different at each time point between the 2 groups (at discharge after PCI, TAT: % vs. DAT: %, p ; at 6 months, TAT: % vs. DAT: %, p ). Profiles Table 3of Medication Profiles ofat Medication Dischargeat Discharge TAT (n 457) DAT (n 458) p Value Aspirin 449 (98.2%) 451 (98.5%) Statin CYP3A4 metabolized 234 (51.2%) 230 (50.2%) Non-CYP3A4 metabolized 223 (48.8%) 228 (49.8%) Beta-blocker 239 (52.2%) 232 (50.7%) ACE inhibitor or ARB 169 (37.0%) 207 (45.2%) Calcium channel blocker 117 (26.0%) 123 (26.9%) Nitrates 187 (40.9%) 193 (42.1%) Proton pump inhibitor 12 (2.6%) 9 (2.0%) Values are n (%). ACE angiotensin-converting enzyme; ARB angiotensin II receptor blocker; other abbreviations as in Table 1. Figure 2 PPR in DAT Versus TAT Measured by the VerifyNow P2Y12 Assay This figure shows P2Y 12 reaction unit (PRU) level in both the dual antiplatelet therapy (DAT) and triple antiplatelet therapy (TAT) groups at discharge and 6 months after the index procedure. The TAT group shows significantly lower post-treatment platelet reactivity (PPR) than the DAT group in both stages. Data represent mean and 95% confidence interval of the PRU of each group.

6 JACC Vol. 57, No. 3, 2011 January 18, 2011:280 9 Suh et al. Cilostazol and Ischemic Events After PCI 285 Clinical Table 4Outcomes Clinical During Outcomes Follow-Up During Follow-Up TAT (n 457) DAT (n 458) p Value OR 95% CI Primary end point Cardiac death, nonfatal MI, ischemic stroke, and TLR 39 (8.5%) 42 (9.2%) Secondary end point Death from any cause 4 (0.9%) 6 (1.3%) Cardiac death 0 3 (0.7%) 0.25 Nonfatal MI 4 (0.9%) 3 (0.7%) Ischemic stroke 5 (1.1%) 4 (0.9%) TLR 30 (6.6%) 32(7.2%) Stent thrombosis 3 (0.7%) 5 (1.1%) Death, nonfatal MI, ischemic stroke 13 (2.8%) 13 (2.8%) Cardiac death, nonfatal MI, ischemic stroke 9 (2.0%) 10 (2.0%) CI confidence interval; MI myocardial infarction; OR odds ratio; TLR target lesion revascularization; other abbreviations as in Table 1. Clinical outcomes with DAT versus TAT. All (100%) of the patients enrolled were followed up throughout the duration of the study period. Angiographic follow-up was done in 85.2% of the TAT and in 84.9% of the DAT groups (p 0.93), and there were no differences in the clinical and angiographic characteristics between patients with or without angiographic follow-up. The clinical outcomes are summarized in Table 4. The primary end point, composite of cardiac death, MI, ischemic stroke, and TLR, was reached in 39 patients (8.5%) in the TAT group and 42 patients (9.2%) in the DAT group, which did not show statistical significance (p 0.74) (Table 4). In addition, there were no differences between the 2 groups in the secondary end points, such as death, MI, ischemic stroke, TLR, or any of these events combined. Subgroup analysis according to clinical and angiographic characteristics demonstrated no significant differences in clinical outcomes between the 2 groups, except in female patients, in whom TAT showed a higher rate of adverse cardiac events than DAT (Fig. 3). Clinical outcomes depending on PPR. To evaluate the influence of PPR on clinical outcomes, we categorized all the patients into 3 groups ( 184, 184 to 264, and 264 PRU) depending on the PRU value at discharge. Patients tended to have a different incidence of primary end point according to tertile distribution of PRU levels during follow-up (p 0.077) (Fig. 4A). Atherothrombotic complications, such as cardiac death, nonfatal MI, and ischemic stroke, were significantly different among the 3 tertile groups of PPR (2.9% in the highest vs. 2.0% in the middle vs. 0% in the lowest, p 0.037) (Fig. 4B). The incidence of TLR had no association with tertile distribution of PRU (p 0.49) (Fig. 4C). Baseline characteristics HR 95% CI Diabetes Yes No Age 65 yr <65 yr Sex Male Female Lesion length 28mm <28mm Reference vessel diameter <2.75mm 2.75mm TAT better DAT better Figure 3 HR Between DAT and TAT for Composite Cardiovascular Events in Patients Grouped by Baseline Characteristics All data were presented on a logarithmic scale. HR hazards ratio; CI confidence interval; other abbreviations as in Figure 2.

7 286 Suh et al. JACC Vol. 57, No. 3, 2011 Cilostazol and Ischemic Events After PCI January 18, 2011:280 9 The tertile distribution of percentage inhibition ( 16%, 16% to 36%, 36%) at discharge was not associated with atherothrombotic complications (2.1% in the lowest vs. 2.7% in the middle vs. 0.4% in the highest, p 0.133). ROC curve analysis of PPR demonstrated that posttreatment PRU measured at discharge was able to distinguish between patients with and without atherothrombotic events (area under the curve, 0.670, 95% confidence interval [CI]: to 0.762, p 0.043) (Fig. 5). A PRU was identified as the optimal cutoff value to predict postdischarge 6-month atherothrombotic events, providing a sensitivity of 75%, specificity of 62%, positive predictive value (PPV) of 3.2%, and negative predictive value (NPV) of 99.3%. Patients with PPR greater than the cutoff value had significantly higher rates of the primary end point (11.8% vs. 7.1%, p 0.030) and atherothrombotic complications (3.2% vs. 0.7%, p 0.014). Multivariate analysis. Independent predictors of primary outcome were lesion length ( 28 mm, hazard ratio [HR]: 1.90, 95% CI: 1.05 to 3.43) and the PRU level at discharge (every increase in tertile, HR: 1.63, 95% CI: 1.12 to 2.37) in the Cox regression analysis, which included age, sex, diabetes mellitus, hypertension, hypercholesterolemia, previous MI, clinical diagnosis, lesion length, reference vessel diameter, multivessel intervention, type of DES, the use of cilostazol, and PRU level at discharge. However, the use of cilostazol was not an independent predictor of atherothrombotic events (HR: 0.88, 95% CI: 0.50 to 1.56) (Table 5). Figure 4 Differences in Cardiovascular Events According to Tertile Distribution of PRU Value (A) Composite major adverse cardiovascular outcomes (cardiac death, nonfatal myocardial infarction [MI], ischemic stroke, and target lesion revascularization [TLR]) showed a tendency for association with tertile distribution of PRU. (B) Atherothrombotic events (cardiac death, nonfatal MI, and ischemic stroke) were significantly associated with tertile distribution of PRU. (C) The rate of TLR, however, was not associated with tertile distribution of PRU. Low indicates PRU 0 to 164; Middle, PRU 165 to 264; and High, 265. Abbreviations as in Figure 2. Figure 5 ROC Curve for the VerifyNow P2Y12 Assay The optimal cutoff for the atherothrombotic events (cardiac death, myocardial infarction, and ischemic stroke) was a post-treatment platelet reactivity at discharge P2Y 12 reaction units (area under the curve [AUC]: 0.670, 95% confidence interval [CI]: to 0.762, p 0.043). AUC area under the curve; ROC receiver-operator characteristic.

8 JACC Vol. 57, No. 3, 2011 January 18, 2011:280 9 Suh et al. Cilostazol and Ischemic Events After PCI 287 Cox Predictors Regression ofcox Composite Analysis: Regression Clinical Analysis: Outcomes Table 5 Predictors of Composite Clinical Outcomes Adverse drug effects. At 6 months, there was no difference in the use of nonstudy drugs except beta-blockers. Betablockers were used more frequently in the TAT group (61% vs. 55%, p 0.048). Despite the more frequent use of beta-blockers, TAT group showed a higher heart rate than the DAT group at 6 months (TAT group, beats/min vs. DAT group, beats/min, p 0.001), which was more pronounced in females ( heart rate, beats/min in male, beats/min in female, p 0.01) (Online Fig. 1). Cilostazol was stopped in 30 patients (6.6%) of the TAT group due to adverse reactions, in contrast to 3 patients (0.7%) in the DAT group. Common side effects were palpitation (n 13, 2.8%), headache (n 11, 2.4%), and gastrointestinal trouble (n 3, 0.7%). Bleeding complications did not differ between the 2 groups. The safety profiles are summarized in Table 6. Discussion Risk Factor Unadjusted HR (95% CI) Adjusted HR (95% CI) Lesion length 28 mm (vs. 28 mm) 1.75 ( ) 2.10 ( ) High PRU level (every increase of tertile) 1.42 ( ) 1.61 ( ) Use of cilostazol 0.91 ( ) 0.90 ( ) Female 0.65 ( ) 0.63 ( ) Multilesion PCI 1.80 ( ) 1.57 ( ) AMI acute myocardial infarction; CI confidence interval; HR hazard ratio; PCI percutaneous coronary intervention; PRU P2Y 12 reaction unit. Despite the superiority of TAT to DAT in reducing PPR ex vivo, this study suggests that TAT does not reduce the adverse cardiovascular events after DES implantation. In addition, this study confirms that high residual platelet reactivity assessed by the VerifyNow system is a predictor of ischemic events (8 10). Comparison of platelet inhibition between 2 antiplatelet regimens. Cilostazol rapidly lowers PPR by increasing cyclic adenosine monophosphate levels by means of phosphodiesterase III inhibition in platelets (18). We verified this effect both at discharge and at 6 months after index PCI in this study. The PRU level in the DAT group in this study was higher than that of Caucasians in previous studies (7 9). This finding is consistent with previous Korean results, and it may be attributed to the high prevalence of CYP2C19 loss-of-function alleles that are associated with poor metabolic activation of clopidogrel in the Korean population, reported to be 26.4% to 29.8% (*2) and 6.6% to 7.1% (*3) in previous studies (28,29). Interestingly, the PRU level in the DAT group increased significantly at 6 months compared with that measured at discharge after the index procedure. Drug compliance was periodically checked, and there were no differences between the 2 groups. Pharmacodynamic tachyphylaxis has been reported for aspirin (30,31). However, this phenomenon and its underlying mechanism have not been well evaluated in clopidogrel therapy. Further studies are needed to clarify this observation. Our results suggest that the adjunctive use of cilostazol may overcome this delayed hyporesponsiveness to clopidogrel, since the TAT group did not show this result. Comparison of clinical outcomes between the 2 antiplatelet regimens. To date, CILON-T trial is the largest prospective randomized study to assess efficacy of cilostazol on clinical events. It did not show superiority of TAT to DAT with respect to ischemic clinical outcomes after DES implantation in a real-world setting. These results are contradictory to the results of previous smaller randomized trial enrolling specific populations, such as diabetes and long lesions, which demonstrated that cilostazol is useful for reducing late luminal loss and thrombotic complications after DES implantation. There may be several possible explanations for this discrepancy. First, the CILON-T trial had a different composition of patients and primary end point from previous trials. This trial enrolled all-comers who underwent DES implantation, and reflected real-world clinical settings, which included about 30% patients with diabetes mellitus and about 50% those with acute coronary syndrome. It was designed to verify the superiority of TAT to DAT in the clinical outcome after DES implantation. In contrast, in the DECLARE-DIABETES and DECLARE-LONG studies (15,16), investigators enrolled only high-risk subsets, such as diabetes mellitus or long lesions, and reported that TAT reduced angiographic late loss and the occurrence of TLR after DES implantation. Importantly, the primary end point of those studies was angiographic late loss, and they were not powered to show the clinical superiority of TAT to DAT. Another Chinese study reported that TAT reduced long-term cardiac and cerebral events after PCI in patients with acute coronary syndrome (26). However, the population of this study did not include patients with DES only, but also included those with bare metal stents in about 50%. Second, intensity of risk factor control in this study was different from previous ones. We prescribed statin to nearly all patients at discharge. At 6 months, mean low-density lipoprotein cholesterol levels of both groups were about 60 mg/dl (data not shown). Tight control of cholesterol can reduce platelet reactivity and neointimal hyperplasia in Safety TableAssessments 6 Safety Assessments in 2 Groups in 2 Groups Variable TAT (n 457) DAT (n 458) p Value Bleeding complications TIMI major 2 (0.4%) 1 (0.2%) TIMI minor 1 (0.2%) 0 (0%) Drug discontinuation 30 (6.6%) 3 (0.7%) Heart rate, beats/min Baseline 69.7 (11.9) 69.2 (12.7) months 73.3 (12.0) 68.4 (13.7) Data are mean (SD) or n (%). TIMI Thrombolysis In Myocardial Infarction; other abbreviations as in Table 1.

9 288 Suh et al. JACC Vol. 57, No. 3, 2011 Cilostazol and Ischemic Events After PCI January 18, 2011:280 9 patients with coronary heart disease (32,33), and thus might dilute the potential benefit of cilostazol. Third, we used zotarolimus-eluting and paclitaxel-eluting stents in most of the patients, whereas previous trials exclusively used sirolimus-eluting and paclitaxel-eluting stents (15,16). The effect of cilostazol on the angiographic outcome of zotarolimus-eluting stents has not been reported. Fourth, the TAT group showed significantly higher heart rates at follow-up despite higher use of beta-blockers. Clinical implication of positive chronotropic effect of cilostazol has not been well assessed in the previous clinical trials. Considering the high portion of patients with acute coronary syndrome in this study, we cannot exclude the possibility that positive chronotropic effects of cilostazol may be associated with higher cardiovascular event rates, leading to the negative result of this study. Interestingly, within the female subgroup, TAT had significantly more cardiovascular events than DAT, which may be partially explained by the finding that cilostazol induces a more pronounced chronotropic effect in female patients. Further studies are warranted to confirm this finding. Although recent registry data suggested that the addition of cilostazol in patients with acute MI is beneficial (34), it needs cautious interpretation considering the positive chronotropic effect of cilostazol, especially in patients with significant left ventricular dysfunction. Finally, we cannot exclude selection bias of previous randomized trials and confounders of previous registry studies. In addition, we cannot rule out publication bias which arises from the tendency for researchers and editors to favor clinical results that are positive rather than negative or inconclusive. Importance of platelet reactivity. In the Cox regression analysis, platelet reactivity measured at discharge was 1 of 2 independent predictors of composite cardiovascular events. Tertile distribution of PRU level rather than that of percentage inhibition was significantly associated with atherothrombotic events. ROC curve analysis of PPR demonstrated that a PRU was the optimal cutoff value to predict post-discharge 6-month atherothrombotic events. This is in line with previous studies (8 10) and adds new evidence about the importance of PPR in Asians. The cutoff level was higher than in previous results, which were reported to be 230 to 240 PRU (7 9). This may also be associated with a high prevalence of loss-of-function alleles of CYP2C19 in Koreans as previously described. If we applied 235 and 240 PRU, which were suggested as cutoff levels in studies of Western countries, to our model, sensitivity values were both 75%, but specificity values decreased to 54.5% and 57.0%. PPV decreased to 2%, and NPV was 99% in both cutoff levels. Although the TAT group had a lower mean PRU level than the DAT group as a whole, a significant number of patients (30.4%, 108 of 355) in the TAT group still belonged to the highest tertile level of PRU ( 264 PRU). This suggests that many patients still have high PPR even with TAT. The presence of this subgroup, hyporesponders to TAT, may be an explanation of the finding that enhanced platelet inhibition or lower mean PRU value as a whole with TAT did not decrease the actual number of clinical events. These hyporesponders to TAT may be the toughest group, one that has little additional benefit from cilostazol therapy and also, the target population in need of another adjunctive or alternative pharmacologic intervention. These findings suggest that not the antiplatelet regimen but the achievement of low PPR is important. This study was not designed to evaluate the benefit of the personalized antiplatelet therapy based on PPR, such as addition of cilostazol on top of DAT in patients showing high PPR. Ongoing studies that are designed to decide antiplatelet regimen based on the platelet function test may show whether tailored therapy according to PPR can improve clinical outcomes in patients with PCI (35 37). Study limitations. First, despite its prospective and randomized design, this study was open label. To compensate for this limitation, the platelet function test was performed in a blinded manner, and assessment of the clinical outcomes was adjudicated by a separate board. Second, there might be a possible bias associated with clinical decisions related to TLR. Third, we measured platelet reactivity with only one method, the VerifyNow P2Y12 assay. Fourth, this study was not powered to verify the effect of cilostazol on hard end points, such as cardiac death and nonfatal MI. Fifth, bleeding end points were assessed by TIMI criteria, such as the occurrence of the composite of TIMI major or TIMI minor bleeding. We did not compare insignificant bleeding complications between the 2 groups. Thus, the rate of bleeding complications was too low to analyze clinical or laboratory predictors of hemorrhagic events. Conclusions TAT did not show superiority to DAT in reducing the ischemic events after DES implantation although it achieved lower PPR. The PPR was more important in predicting adverse clinical events after DES implantation rather than the type of antiplatelet regimen. Further studies are needed to warrant these findings. Acknowledgment The authors appreciate the cordial support of the research coordinator, Tae-Eun Kim, RN. 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APPENDIX For a supplementary figure, please see the online version of this article.