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Transcript of Seoul National University Hospital CILON-T Late Breaking Trial : Randomized prospective trial of...
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
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
Seoul National University Hospital
CILON-T trial : participating centers
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
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.
Seoul National University Hospital
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)
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 request14 Withdrawal at clinician’s judgment3 Failed PCI
2 Withdrawal at patient request19 Withdrawal at clinician’s judgment4 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
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 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
Seoul National University Hospital
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
Seoul National University Hospital
Profiles of Medication at Discharge
TAT
(n=457)DAT
(n=458)P-
valueMedication 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
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%)
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%) 0.802Calcified lesions 105 (24.1%) 128 (29.3%) 0.092Bifurcation lesion 145 (31.7%) 132 (28.8%) 0.556Thrombus on angiography 34 (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±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
Seoul National University Hospital
Results: P2Y12 reaction unit (PRU): TAT vs DAT
p < 0.001p < 0.001PRU
Seoul National University Hospital
Results: Change of PRU for 6 months : TAT vs DAT
At discharge 6 mo At discharge 6 mo
p < 0.001 p =0.23
P2Y1
2 re
actio
n un
it (P
RU)
TAT DAT
Seoul National University Hospital
Composite of CD, nonfatal MI,
ischemic stroke & TLR
Composite of CD, nonfatal MI
& ischemic strokeTLR
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 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 0 3 (0.7%) 0.25
Nonfatal MI 4 (0.9%) 3 (0.7%) 0.73
Ischemic stroke 5 (1.1%) 4 (0.9%) 0.75
TLR 30 (6.6%) 32(7.2%) 0.79
Stent thrombosis 3 (0.7%) 5 (1.1%) 0.73
Death, nonfatal MI, ischemic stroke 13 (2.8%) 13 (2.8%) 1.0
CD, nonfatal MI, ischemic stroke 9 (2.0%) 10 (2.0%) 1.0
Seoul National University Hospital
DAT 458 452 450 425 416
TAT 457 450 449 428 418
DAT 458 452 451 449 447
TAT 457 452 452 451 448
DAT 458 458 449 426 418
TAT 457 450 449 429 421
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 strokeTLR
6.6%
7.2%
8.5%
9.2%
2.0%
2.0%
Results: Clinical outcomes depending on anti-plt regimen
Seoul National University Hospital
Composite of CD, nonfatal MI,
ischemic stroke & TLR
Composite of CD, nonfatal MI
& ischemic strokeTLR
PRU value versus Anti-PLT regimen to predict MACCE
Seoul National University Hospital
Subgroup analysis : TAT vs DAT
0 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
Seoul National University Hospital
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%)
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
<0.001
Seoul National University Hospital
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)
Seoul National University Hospital
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
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) can
be helpful to reduce adverse clinical outcomes in
patients who undergo DES implantation.