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
CILON-T trial • CILostazol-based triple anti-platelet therapy ON Ischemic Complication after drug-eluting stenT implantation • Multicenter, prospective, randomized trial • Principal investigator • Hyo-Soo Kim, MD, PhD • Clinical trials identifier • NCT00776828
Backgroundof 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
Backgroundof the CILON-T trial Efficacy of adding cilostazol on DAT in reducing PRU value or clinical events 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 • 2*2 design: Antiplatelet regimen & statin type • 960 patients randomized (Sep 2006~June 2009) • TAT group (477) • DAT group (483) • Five centers in Korea • Follow-up requirements • P2Y12 reaction unit (VerifyNow TM P2Y12) at 6 mo • Clinical F/U at 1, 3 and 6 mo • Angiographic F/U (recommended)
CILON-T : Statistical overview • Co-primary end-point : PRU, composite of major adverse clinical outcomes • Superiority design • Comparison of PRU between DAT & TAT • To show 10% decrease of PRU level in the TAT group (80% power, bilateral risk at 5%, drop out rate 20%) • Estimated number of patients (n=288) • Comparison of clinical outcomes between DAT & TAT • To show 5% difference between two groups (80% power, bilateral risk at 5%, drop out rate 10%) • Estimated number of patients (n=960)
Assessed for eligibility (n=976) Randomization (n=960) DAT (n=483) TAT (n=477) Atorvastatin (n=241) Rosuvastatin (n=236) Atorvastatin (n=242) Rosuvastatin (n=241) 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 TAT (n=457) DAT (n=458) 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) • PRU (VerifyNow TM P2Y12 assay) at 6 mo • Safety Endpoint • Bleeding complications according to TIMI criteria • The incidence of drug discontinuation • Heart rate
CILON-T Trial Endpoints • Secondary endpoint • All cause of death, stent thrombosis, and each component of primary endpoint at six months • PRU level measured at discharge after the index procedure
Key participation criteria • Inclusion criteria • Age 18~80yrs • 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
Results: P2Y12 reaction unit (PRU): TAT vs DAT PRU p < 0.001 p < 0.001
Results: Change of PRU for 6 months : TAT vs DAT DAT TAT 255.7 ±73.7 210.7 ±87.9 232.2 ±80.3 206.6 ±90.3 At discharge 6 mo Atdischarge 6 mo p for interaction=0.046
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
Results: Clinical outcomes depending on anti-plt regimen Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR Double anti-PLT Double anti-PLT Double anti-PLT Triple anti-PLT Triple anti-PLT Triple anti-PLT p=0.818 for log-rank test p=0.742 for log-rank test p=0.701 for log-rank test
PRU value vs Anti-plt regimen to predict MACCE Composite of CD, nonfatal MI, ischemic stroke & TLR Composite of CD, nonfatal MI & ischemic stroke TLR
Subgroup analysis : TAT vs DAT Baseline characteristics HR 95% CI Diabetes 0.37-1.60 0.78 Yes 1.02 0.57-1.83 No Age ≥ 65 yr 1.34 0.69-2.58 0.64 0.32-1.29 <65 yr Sex 0.66 0.39-1.13 Male 3.41 1.12-10.4 Female Lesion length 0.79 0.34-1.84 ≥ 28mm 0.70 0.38-1.31 <28mm Reference vessel diameter <2.75mm 0.80 0.38-1.69 ≥2.75mm 0.85 0.45-1.60 0 1 2 TAT better DATbetter
The change of heart rate by cilostazol min-1 Δ HR p =0.85 p < 0.01 p < 0.001 p =0.69 ΔHR=6mo HR – baseline HR
Results: Independent predictors for MACCE (Cox-regression analysis)
Study limitations • Open-label study • 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 patients with low PPR (PRU < 210 unit) did not develop any thrombotic event like cardiac death, myocardial infarction 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.