Presentation on theme: "Seoul National University Hospital CILON-T Late Breaking Trial : Randomized prospective trial of dual vs. triple antiplatelet therapy after DES implantation."— Presentation transcript:
Seoul National University Hospital CILON-T Late Breaking Trial : Randomized prospective trial of dual vs. triple antiplatelet therapy after DES implantation ACC & i2 summit, March 15th 2010, Atlanta, Georgia Hyo-Soo Kim, MD, PhD Seoul National University Hospital Seoul, Korea
Seoul National University Hospital Nothing to disclose
Seoul National University Hospital CILON-T trial CIL ostazol-based triple anti-platelet therapy ON Ischemic Complication after drug-eluting sten T implantation Multicenter, prospective, randomized trial PROBE (Prospective Randomized Open-label Blinded Evaluation) Principal investigator Hyo-Soo Kim, MD, PhD Clinical trials identifier NCT
Seoul National University Hospital CILON-T trial : participating centers CentersInvestigators 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
Seoul National University Hospital Background of the CILON-T trial I.Accumulating evidences suggest the relationship between clopidogrel resistance & clinical events. II.Recent studies reported the value of using VerifyNow (PRU) in predicting clinical events. III.Efficacy of adding cilostazol in reducing clinical events has been reported in the registry or small randomized controlled study of specific subpopulation.
Seoul National University Hospital 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.
TAT (n=457) Randomization (n=960) TAT (n=477) Rosuvastatin (n=236) Atorvastatin (n=241) Atorvastatin (n=242) Rosuvastatin (n=241) DAT (n=483) Assessed for eligibility (n=976) DAT (n=458) 3 Withdrawal at patient request 14 Withdrawal at clinicians judgment 3 Failed PCI 2 Withdrawal at patient request 19 Withdrawal at clinicians judgment 4 Failed PCI 915 patients with successful PCI & follow-up at 6 month - Cardiovascular death, nonfatal MI, ischemic stroke, TLR - Platelet (P2Y12) reaction unit
Seoul National University Hospital 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
Seoul National University Hospital Key participation criteria Inclusion criteria Age 18~80yrs All-comers : patients with native de-novo 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 anti-platelet agents Allergy to study medications
Seoul National University Hospital Profiles of Medication at Discharge TAT (n=457) DAT (n=458) P- value Medication at discharge Aspirin99.8 (449)99.8 (451)0.997 Statin98.9 (451)100 (451)0.259 Beta-blocker52.9 (239)51.6 (232)0.691 ACE inhibitor or ARB37.6 (169)45.8 (207)0.012 Calcium channel blocker26.0 (117)27.2 (123)0.680 Nitrates42.7 (187)42.7 (193)0.728 Proton pump inhibitor2.7 (12)2.0 (9)0.488
Seoul National University Hospital 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%) 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%) Ostial lesions112 (24.5%)109 (23.8%)0.802 Calcified lesions105 (24.1%)128 (29.3%)0.092 Bifurcation lesion145 (31.7%)132 (28.8%)0.556 Thrombus on angiography34 (7.8%)38 (8.7%)0.637
Seoul National University Hospital Procedural profiles of patients TAT (n=457)DAT (n=458)P Lesion length, mm 21.1± ± MLD, mm 0.75± ± Reference vessel diameter, mm 2.96± ± No. of stent / lesion 1.23± ± Post-procedural MLD, mm 2.29± ± Type of stents0.102 Paclitaxel-eluting (TAXUS)228 (49.9%)225(49.1%) Zotarolimus-eluting (Endeavor)194 (42.5%)207 (45.2%) Multi-lesion intervention156 (34.1%)163 (35.6%)0.64
Seoul National University Hospital Results: P2Y12 reaction unit (PRU): TAT vs DAT p < PRU
Seoul National University Hospital Results: Change of PRU for 6 months : TAT vs DAT At discharge 6 mo At discharge 6 mo p < p =0.23 P2Y12 reaction unit (PRU) TATDAT
Seoul National University Hospital Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR Results: Clinical outcomes depending on PRU value p=0.077 p=0.037 p=0.486
Seoul National University Hospital Results: Clinical outcomes depending on anti-plt regimen TAT (n=457)DAT (n=458)p Primary endpoint CD, nonfatal MI, ischemic stroke and TLR39 (8.5%)42 (9.2%)0.73 Secondary endpoint Death from any cause4 (0.9%)6 (1.3%)0.75 Cardiac death03 (0.7%)0.25 Nonfatal MI4 (0.9%)3 (0.7%)0.73 Ischemic stroke5 (1.1%)4 (0.9%)0.75 TLR30 (6.6%)32(7.2%)0.79 Stent thrombosis3 (0.7%)5 (1.1%)0.73 Death, nonfatal MI, ischemic stroke13 (2.8%) 1.0 CD, nonfatal MI, ischemic stroke9 (2.0%)10 (2.0%)1.0
Seoul National University Hospital DAT TAT DAT TAT DAT TAT p=0.818 for log-rank test Double anti-PLT regimen Triple anti-PLT regimen p=0.742 for log-rank test p=0.701 for log-rank test Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR 6.6% 7.2% 8.5% 9.2% 2.0% Results: Clinical outcomes depending on anti-plt regimen
Seoul National University Hospital Distribution of PRU in pts with MACCE
Seoul National University Hospital Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR PRU value versus Anti-PLT regimen to predict MACCE
Seoul National University Hospital Subgroup analysis : TAT vs DAT 012 TAT betterDAT better Baseline characteristics HR95% CI Diabetes Yes No Sex Male Female Lesion length 28mm <28mm Reference vessel diameter <2.75mm 2.75mm Age 65 yr <65 yr
Seoul National University Hospital Results: Safety outcomes : TAT vs DAT VariableTAT (n=457)DAT (n=458)P Bleeding complications0.511 Major Minor 2 (0.4%) 1 (0.2%) 0 (0%) Drug discontinuation30 (6.6%)3 (0.7%)<0.001 Heart rate, /min Baseline 6 months 69.7± ± ± ±13.7, 0.62 <0.001
Seoul National University Hospital Results: Independent predictors for MACCE ( Cox-regression analysis) Risk factorUnadjusted 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 cilostazol0.91 (0.59~1.41)0.88 (0.50~1.56) Diabetes mellitus1.22 (0.78~1.91)1.53 (0.86~2.73) Female0.65 (0.39~1.10)0.64 (0.33~1.24) Hypertension1.31 (0.81~2.13)1.29 (0.67~2.52) Age1.02 (0.99~1.04)1.01 (0.97~1.04) Diagnosis of AMI0.62 (0.25~1.53)1.01 (0.36~2.86)
Seoul National University Hospital Study limitations Open-label study, but with 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
Seoul National University Hospital 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.
Seoul National University Hospital Conclusion of CILON-T randomized controlled trial Tailored decision on the adjunctive use of cilostazol according to PPR (post-treatment platelet reactivity) may be important to reduce clinical events in patients with DES implantation.