CILON-T Late Breaking Trial : Randomized prospective trial of dual vs CILON-T Late Breaking Trial : Randomized prospective trial of dual vs. triple antiplatelet therapy after DES implantation Presented at ACC & i2 summit, March 15th 2010, Atlanta, Georgia Published in Trials 2010, JACC 2011. Hyo-Soo Kim, MD, PhD Seoul National University Hospital, Seoul, Korea

Nothing to disclose

CILON-T trial CILostazol-based triple anti-platelet therapy ON Ischemic Complication after drug-eluting stenT implantation Multicenter, prospective, randomized trial PROBE (Prospective Randomized Open-label Blinded Evaluation) Principal investigator Hyo-Soo Kim, MD, PhD Clinical trials identifier NCT00776828

CILON-T trial : participating centers Investigators Seoul National University Hospital Hyo-Soo Kim, MD, PhD Seoul National University Bundang Hospital In-Ho Chae, MD, PhD Konyang University Hospital Jang-Ho Bae, MD, PhD Korea University Guro Hospital Seung-Woon Rha, MD, PhD Chungbuk University Hospital Myeong-Chan Cho, MD, PhD

Background of the CILON-T trial Accumulating evidences suggest the relationship between clopidogrel resistance & clinical events. Recent studies reported the value of using VerifyNow (PRU) in predicting clinical events. Efficacy of adding cilostazol in reducing clinical events has been reported in the registry or small randomized controlled study of specific subpopulation.

Background of the CILON-T trial Efficacy of adding cilostazol on DAT in reducing clinical events or PRU value has not been tested in the real-world all-comer patients with DES implantation at the level of large randomized controlled study.

CILON-T Clinical Trial Design Comparison of two anti-platelet regimens with random assignment of statin type (atorva-20 & rosuva-10) 960 patients randomized (Sep 2006~June 2009) TAT group (477) versus DAT group (483) Five centers in Korea Follow-up requirements P2Y12 reaction unit (VerifyNow TM P2Y12) at discharge & 6 mo Clinical F/U at 1, 3 and 6 mo Angiographic F/U (recommended) SP Lee, JW Suh,, HS Kim. Trials 2010

TAT (n=477) DAT (n=483) TAT (n=457) DAT (n=458) Randomization (n=960) Rosuvastatin (n=236) Atorvastatin (n=241) (n=242) DAT (n=483) Assessed for eligibility (n=976) DAT (n=458) 3 Withdrawal at patient request 14 Withdrawal at clinician’s judgment 3 Failed PCI 2 Withdrawal at patient request 19 Withdrawal at clinician’s judgment 4 Failed PCI 915 patients with successful PCI & follow-up ** Primary endpoint : at 6 month Cardiovascular death, nonfatal MI, ischemic stroke, TLR Platelet (P2Y12) reaction unit

CILON-T Trial Endpoints Primary Endpoint Composite of clinical outcomes within six months (cardiac death, MI, ischemic stroke & TLR) Secondary endpoint PRU level measured at discharge & 6 mo after the index procedure All cause of death, stent thrombosis, and each component of primary endpoint at six months Safety Endpoint Bleeding complications according to TIMI criteria The incidence of drug discontinuation Heart rate JW Suh,, HS Kim. JACC 2011

Key participation criteria Inclusion criteria Age 18~80yrs All-comers : patients with native coronary artery lesions for which DES implantation was feasible Exclusion criteria Hepatic dysfunction (GOT/GPT >*3 UNL) Renal dysfunction (Scr>2.0mg/dl or on dialysis) LV dysfunction (EF <30%) Uncontrolled hematological disease Patients taking warfarin or other antiplatelet agents Allergy to study medications JW Suh,, HS Kim. JACC 2011

RESULTS

Clinical profiles of patients TAT (n=457) DAT (n=458) p Age, yrs 62.8±9.6 62.8±9.2 0.999 Men 321 (68.6%) 326 (68.3%) 0.935 Hypertension 291 (64.5%) 305 (66.9%) 0.454 Diabetes mellitus 160 (35.5%) 147 (32.2%) 0.303 Diet 24 (5.3%) 17 (3.7%) OHA 103 (22.8%) 116 (25.4%) Insulin 33 (7.3%) 14 (3.1%) Current smoker 107 (23.7%) 122 (26.8%) 0.470 Previous PCI 29 (6.4%) 39 (8.6%) 0.225 Previous CABG 8 (1.8%) 13 (2.7%) 0.281 Clinical diagnosis 0.748 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%) Total cholesterol 176.1±39.4 177.4±4.31 0.62 LDL cholesterol 104.7±34.6 107.9±40.2 0.20

Profiles of Medication at Discharge TAT (n=457) DAT (n=458) P-value Medication at discharge Aspirin 99.8 (449) 99.8 (451) 0.997 Statin 98.9 (451) 100 (451) 0.259 Beta-blocker 52.9 (239) 51.6 (232) 0.691 ACE inhibitor or ARB 37.6 (169) 45.8 (207) 0.012 Calcium channel blocker 26.0 (117) 27.2 (123) 0.680 Nitrates 42.7 (187) 42.7 (193) 0.728 Proton pump inhibitor 2.7 (12) 2.0 (9) 0.488 JW Suh,, HS Kim. JACC 2011

Angiographic profiles of patients TAT (n=457) DAT (n=458) p Lesion locations LAD LCx RCA Left main 220 (48.4%) 91 (20.2%) 105 (23.1%) 23 (5.1%) 222 (49.3%) 107 (23.5%) 124 (27.6%) 13 (2.9%) 0.166 ACC-AHA lesion classification A B1 B2 C 12 (2.8%) 126 (29.7%) 55 (13.0%) 231 (54.5%) 10 (2.3%) 126 (29.1%) 46 (10.6%) 251 (58.0%) 0.633 Ostial lesions 112 (24.5%) 109 (23.8%) 0.802 Calcified lesions 105 (24.1%) 128 (29.3%) 0.092 Bifurcation lesion 145 (31.7%) 132 (28.8%) 0.556 Thrombus on angiography 34 (7.8%) 38 (8.7%) 0.637 TAT (n=457) DAT (n=458) JW Suh,, HS Kim. JACC 2011

Procedural profiles of patients TAT (n=457) DAT (n=458) P Lesion length, mm 21.1±13.4 22.2±13.9 0.244 MLD, mm 0.75±0.49 0.79±0.50 0.246 Reference vessel diameter, mm 2.96±0.52 2.93±0.52 0.416 No. of stent / lesion 1.23±0.51 1.18±0.44 0.164 Post-procedural MLD, mm 2.29±0.51 2.23±0.51 0.107 Type of stents 0.102 Paclitaxel-eluting (TAXUS) 228 (49.9%) 225(49.1%) Zotarolimus-eluting (Endeavor) 194 (42.5%) 207 (45.2%) Multi-lesion intervention 156 (34.1%) 163 (35.6%) 0.64 TAT (n=457) DAT (n=458)

Results: P2Y12 reaction unit (PRU): TAT vs DAT JW Suh,, HS Kim. JACC 2011 PRU p < 0.001 p < 0.001 TAT (n=457) DAT (n=458)

Results: Change of PRU for 6 months : TAT vs DAT At discharge 6 mo p < 0.001 p =0.23 P2Y12 reaction unit (PRU) TAT DAT TAT (n=457) DAT (n=458)

Results: Clinical outcomes depending on PRU value Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR p=0.077 p=0.486 p=0.037 JW Suh,, HS Kim. JACC 2011

Results: Clinical outcomes depending on anti-plt regimen TAT (n=457) DAT (n=458) p Primary endpoint CD, nonfatal MI, ischemic stroke and TLR 39 (8.5%) 42 (9.2%) 0.73 Secondary endpoint Death from any cause 4 (0.9%) 6 (1.3%) 0.75 Cardiac death 3 (0.7%) 0.25 Nonfatal MI Ischemic stroke 5 (1.1%) TLR 30 (6.6%) 32(7.2%) 0.79 Stent thrombosis Death, nonfatal MI, ischemic stroke 13 (2.8%) 1.0 CD, nonfatal MI, ischemic stroke 9 (2.0%) 10 (2.0%) TAT (n=457) DAT (n=458)

Results: Clinical outcomes depending on anti-plt regimen Double anti-PLT regimen Triple anti-PLT regimen Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR p=0.818 for log-rank test p=0.742 for log-rank test p=0.701 for log-rank test 9.2% TAT (n=457) DAT (n=458) 7.2% 8.5% 6.6% 2.0% 2.0% DAT 458 452 450 425 416 TAT 457 449 428 418 DAT 458 452 451 449 447 TAT 457 448 DAT 458 449 426 418 TAT 457 450 429 421

Distribution of PRU in pts with MACCE

PRU value versus Anti-PLT regimen to predict MACCE Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR JW Suh,, HS Kim. JACC 2011

Subgroup analysis : TAT vs DAT 1 2 TAT better DAT better Baseline characteristics HR 95% CI Diabetes Yes No 0.78 0.37-1.60 1.02 0.57-1.83 Sex Male Female 0.66 0.39-1.13 3.41 1.12-10.4 Lesion length ≥ 28mm <28mm 0.79 0.34-1.84 0.70 0.38-1.31 Reference vessel diameter <2.75mm ≥2.75mm 0.80 0.85 0.38-1.69 0.45-1.60 Age ≥ 65 yr <65 yr 1.34 0.64 0.69-2.58 0.32-1.29

Results: Safety outcomes : TAT vs DAT Variable TAT (n=457) DAT (n=458) P Bleeding complications 0.511 Major Minor 2 (0.4%) 1 (0.2%) 0 (0%) Drug discontinuation 30 (6.6%) 3 (0.7%) <0.001 Heart rate, /min Baseline 6 months 69.7±11.9 73.3±12.0 69.2±12.7 68.4±13.7, 0.62 TAT (n=457) DAT (n=458) JW Suh,, HS Kim. JACC 2011

Results: Independent predictors for MACCE (Cox-regression analysis) Risk factor Unadjusted HR (95% CI) Adjusted HR (95% CI) Lesion length ≥28mm (vs. <28mm) 1.75 (1.07~2.86) 1.90 (1.05~3.43) High PRU level (every increase of tertile) 1.42 (1.04~1.93) 1.63 (1.12~2.37) Use of cilostazol 0.91 (0.59~1.41) 0.88 (0.50~1.56) Diabetes mellitus 1.22 (0.78~1.91) 1.53 (0.86~2.73) Female 0.65 (0.39~1.10) 0.64 (0.33~1.24) Hypertension 1.31 (0.81~2.13) 1.29 (0.67~2.52) Age 1.02 (0.99~1.04) 1.01 (0.97~1.04) Diagnosis of AMI 0.62 (0.25~1.53) 1.01 (0.36~2.86) TAT (n=457) DAT (n=458)

Study limitations Open-label study, but blinded evaluation Platelet reactivity measured by single method Not powered to verify the effect of cilostazol on the hard endpoint, such as CD, nonfatal MI or stent thrombosis

Summary of CILON-T randomized controlled trial TAT achieved lower PPR (post-treatment platelet reactivity) than DAT. But it did not necessarily reduce MACCE within six months after DES implantation, because there were substantial numbers of hypo-responders even to TAT. The importance of PPR is reflected by the finding that the patients with low PPR (PRU < 210 unit) did not develop any thrombotic event (CD, MI, or ischemic stroke) irrespective of anti-platelet regimen.

Conclusion of CILON-T randomized controlled trial Tailored decision on the adjunctive use of cilostazol according to PPR (post-treatment platelet reactivity) can be helpful to reduce adverse clinical outcomes in patients who undergo DES implantation.