CIT2016-CREATIVE trial-v2

1、Clopidogrel Response Evaluation and AnTi-platelet InterVEntion in High Thrombotic Risk PCI Patients CREATIVE trialYi-Da Tang, Yuejin YangDisclosuresFunding:Sponsors: Capital Research and Development of Special 2011-4003-03. Haemonetics Corporation (US) Zhejiang Otsuka Pharmaceutical Co., Ltd.Backgro

2、und Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is the standard treatment to prevent the ischemic events after PCI. Current “one size fits all” dosing strategy has limitations: wide variability in response to clopidogrel Patients with low responsiveness to clopidogrel have a

3、higher incidence of stent thrombosis and cardiac ischemic events. Low responsiveness to Clopidogrel is mainly identified through the platelet function testTantry US, et al. J Am Coll Cardiol. 2013 Dec 17;62(24):2261-73.Background Pilot trials with limited samplw exploring new antiplatelet strategies

4、: Triple antiplatelet therapy (Clopidogrel + Aspirin + Cilostazol) Double-dosage Clopidogrel (150mg/d) + Aspirin There have yet been any head-to-head clinical trials to compare the two approaches in high risk population. Lower platelet reactivity: confirmed Reduce clinical events: not consistent low

5、 percentage of high-risk cases included in previous studiesBackgroundMA(ADP) 预测预后的价值预测预后的价值明显，预测指标在明显，预测指标在46.6mm处明显处明显ADP 抑制率在抑制率在50.9%的预测价值明显的预测价值明显MA(thrombin) 未未显示出显著的预警显示出显著的预警价值价值BackgroundWith the cut-off value of 47mm, MA(ADP) shows predicting value for ischemic eventsWith the cut-off value

6、of 50.9%, ADP inhibition rate also shows predicting value for ischemic eventsDesign Single center (Fuwai Hospital), randomized control trial Definition of low clopidogrel responsiveness ADP inhibition rate 47 mm Patients who fulfill the inclusion criteria were randomised into three groups in 1:1:1 r

7、atio (350 Pts in each): STANDARD (ASA 100mg QD+ Clopidogrel 75mg QD) DOUBLE (ASA 100mg QD+ Clopidogrel 150mg QD) TRIPLE (ASA 100mg QD+ Clopidogrel 150mg QD+ Cilostazol 100mg BID)Gurbel PA, et al. Am Heart J. 2010 Aug;160(2):346-54.DesignPatients undergoing PCI procedureASA+ Clopidogrel 75mg Qd （n=35

8、0）ASA+ Clopidogrel 75mg Qd+ Cilostazol 100mg Bid(n=350)ASA+ Clopidogrel 150mg Qd (n=350)TEG test to identify low clopidogrel responsiveness:ADP%（ADP-induced platelet aggregation）MA（ADP）（）（ADP-induced MA）30 day3 month6 month9 month12 month18 monthTelephone Follow-upTelephone Follow-upTelephone Follow

9、-upTelephone Follow-upOnsite visit: TEG test; acquire drug use condition; acquire Endpoints Events and Adverse EventsOnsite visit: TEG test; acquire drug use condition; acquire Endpoints Events and Adverse EventsTherapy maintain for 12 months Endpoints Primary endpoints: Major adverse cardiac and ce

10、rebrovascular events (MACCE, includes cardiac death, myocardial infarction, target vessel revascularization and cerebrovascular events) Secondary endpoints: ARC-defined stent thrombosis Other endpoints: Platelet function BARC-defined bleeding Net adverse cardiac and cerebrovascular events (NACCE, in

11、cludes cardiac death, myocardial infarction, cerebrovascular events and major bleeding)Population Characteristics STANDARDN=362DOUBLEN=359TRIPLEN=355P valueGender (male)198 (54.7%)234 (65.2%)216 (60.8%)0.015 Age (year)59.398.6957.199.0658.469.020.004 BMI (kg/m2)25.783.1226.353.3225.693.040.010 SBP (

12、mmHg)128.117.5127.216.4126.915.40.599 DBP (mmHg)77.610.778.610.577.39.30.197 Diabetez melletus121 (33.4%)115 (32.0%)121 (34.1%)0.838 Hypertension 243 (67.1%)219 (61.0%)229 (64.5%)0.228 Dislypidemia233 (64.4%)246 (68.5%)229 (64.5%)0.408 Pre-stroke39 (10.8%)37 (10.3%)46 (13.0%)0.503 Smoking124 (34.3%)

13、137 (38.2%)137 (38.6%)0.320 Pre-MI57 (15.7%)59 (16.4%)44 (12.4%)0.260 Pre-CABG8 (2.2%)7 (1.9%)4 (1.1%)0.495 Pre-PCI72 (19.9%)77 (21.4%)67 (18.9%)0.688 Atrial fibrillation353 (97.5%)355 (98.9%)348 (98.0%)0.367 Procedural CharacteristicsSTANDARDDOUBLETRIPLEP valueProcedure time26.3416.1029.7721.0528.5

14、520.850.061 No. of stents1.650.751.730.85 1.730.840.215 Length of stents31.8616.8932.7918.6631.7117.160.672 Transradial approach 339 (94.4%)338 (94.2%)330 (93.5%)0.635 Pre-dilation254 (70.2%)264 (73.5%)258 (72.7%)0.578 B2/C type lesions282 (78.8%)297 (83.9%)277 (78.7%)0.128 No. of target lesions0.06

15、4 1274 (75.7%)242 (67.4%)235 (66.2%) 274 (20.4%)101 (28.1%)105 (29.6%) 314 (3.9%)15 (4.2%)15 (4.2%) 40 (0.0%)1 (0.3%)0 (0.0%)PreprocedureTIMI flow0.741 TIMI 048 (13.4%)56 (15.6%)47 (13.3%)TIMI 18 (2.2%)10 (2.8%)8 (2.3%)TIMI 238 (10.6%)34 (9.5%)28 (7.9%)TIMI 3264 (73.5%) 257 (71.8%)269 (76.2%)Baselin

16、e MedicationSTANDARDN=362DOUBLEN=359TRIPLEN=355P valueClopidogrel regimen0.579 Loading dose, 300 mg135 (37.3%)146 (40.7%)133 (37.5%) Maintenance, 75 mg5d227 (62.7%)213 (59.3%)222 (62.5%)Perioperative anticoagulation LMWH197 (54.4%)192 (53.5%)195 (54.9%)0.925 Fondaparinux111 (30.7%)118 (32.9%)107 (30

17、.1%)0.706 Unfractionated heparin138 (38.1%)134 (37.3%)140 (39.4%)0.843 IIb/IIIa inhibitors44 (12.2%) 52 (14.5%)44 (12.4%)0.598Statin1818 (86.7)1895 (89.2)1761 (90.6)0.625Calcium-channel blocker480 (22.9)514 (24.2)418 (21.5)0.081Proton pump inhibitor41 (11.3%) 29 (8.1%)35 (9.9%)0.028Distribution of C

18、YP2C19 Genotype37.02%37.04%36.88%45.60%46.50%49.02%17.40%16.46%14.10%0.00%10.00%20.00%30.00%40.00%50.00%60.00%STANDARDDOUBLETRIPLEExtensive MetabolizerIntermediate MetabolizerPoor MetabolizerChange of Platelet Function53.754.853.550.941.944.5STANDARDDOUBLETRIPLEMA()ADPBaseline3-6 month14.8%14.6%15.0

19、%16.3%21.8%21.8%STANDARDDOUBLETRIPLEADP抑制率抑制率Baseline3-6 monthTotal Clinical Events 1.7%6.1%1.9%4.4%10.2%.6%3.9%.8%3.3%19.7%0.0%3.1%1.1%3.4%18.8%0.0%5.0%10.0%15.0%20.0%25.0%DeathMIIn-stent thrombosisTVRBleedingSTANDARDDOUBLETRIPLEAll-cause DeathSTANDARD 1.66%DOUBLE 0.56%DOUBLE vs STANDARDHR: 0.309,

20、95%CI: 0.062-1.540, P=0.1520TRIPLE 0TRIPLE: no deathMISTANDARD 6.04%DOUBLE 3.86%TRIPLE 3.08%DOUBLE vs STANDARDHR: 0.702,95%CI: 0.357-1.378, P=0.3039TRIPLE vs STANDARDHR: 0.547, 95%CI: 0.264-1.131, P=0.1034TVRSTANDARD 4.44%DOUBLE 3.34%TRIPLE 3.37%DOUBLE vs STANDARDHR: 0.701, 95%CI: 0.330-1.488, P=0.3

21、544TRIPLE vs STANDARDHR: 0.734, 95%CI: 0.346-1.558, P=0.4211StrokeSTANDARD 1.94%DOUBLE 2.51%TRIPLE 1.13%DOUBLE vs STANDARDHR: 1.294, 95%CI: 0.482-3.473, P= 0.6096TRIPLE vs STANDARDHR: 0.579, 95%CI: 0.170-1.978, P=0.3835Major Bleeding （BARC 3 grade）STANDARD 1.93%DOUBLE 3.34%TRIPLE 2.53%DOUBLE vs STAN

22、DARDHR: 1.734, 95%CI: 0.683-4.405, P=0.2470TRIPLE vs STANDARDHR: 1.310, 95%CI: 0.488-3.518, P= 0.5918MACCESTANDARD 12.93%DOUBLE 9.70%TRIPLE 6.74%DOUBLE vs STANDARDHR: 0.736, 95%CI: 0.475-1.140, P=0.1698TRIPLE vs STANDARDHR: 0.506, 95%CI: 0.309,0.827, P=0.0066NACCESTANDARD 10.45%DOUBLE 9.13%TRIPLE 5.

23、89%DOUBLE vs STANDARDHR: 0.869, 95%CI: 0.545-1.385, P=0.5554TRIPLE vs STANDARDHR: 0.553, 95%CI: 0.324-0.942, P=0.0291DiscussionAradi D, et al. Euro Heart J (2015) 36, 176271The cut-off values for on-treatment optimal platelet reactivity are highly heterogeneous in published studiesLeading to controversies on the prognostic relevance of platelet function testing in patients undergoing PCI. Leading to fail