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, 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

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

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.


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)

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


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


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


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-

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


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


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


Results: P2Y12 reaction unit (PRU): TAT vs DAT

p < 0.001p < 0.001PRU


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


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


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


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





6.6%

7.2%

8.5%

9.2%

2.0%

2.0%

Results: Clinical outcomes depending on anti-plt regimen


Distribution of PRU in pts with MACCE






PRU value versus Anti-PLT regimen to predict MACCE


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


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


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)


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.

seoul national university hospital cilon-t late breaking trial : randomized prospective trial of...

Documents

phd slide

cilont trial efficacy

korea slide

atorvastatin n

rosuvastatin n

randomization n

eligibility n

mo clinical fu