1. 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

2. Nothing to disclose

3. 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
NCT

4. 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

5. 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.

6. 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.

7. 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

8. 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

9. 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

10. 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

11. RESULTS

12. 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

13. 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

14. 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

15. 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)

16. 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)

17. 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)

18. 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

19. 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)

20. 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

21. Distribution of PRU in pts with MACCE

22. 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

23. Subgroup analysis : TAT vs DAT1 2
TAT better
DAT better
Baseline characteristics HR
95% CI
Diabetes
Yes No
0.78
1.02
Sex
Male
Female
0.66
3.41
Lesion length
≥ 28mm
<28mm
0.79
0.70
Reference vessel diameter
<2.75mm
≥2.75mm
0.80
0.85
Age
≥ 65 yr
<65 yr
1.34
0.64

24. 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

25. 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)

26. 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

27. 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.

28. 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.