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1、1,CLEAR PLATELETS:,Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets,2,Introduction,We have previously reported a significant incidence of clopidogrel resistance in patients post-elective coronary stenting treated with a standard 300-mg loading dose1 (31% at 24 hours) Patie
2、nts with clopidogrel resistance/high post-stent platelet reactivity may be at greatest risk of SAT and ischemic events2-4 Relation of peri-procedural platelet reactivity to myocardial necrosis has never been prospectively studied These data suggest that 300 mg clopidogrel/75 mg qd does not provide s
3、ufficient inhibition in some patients undergoing elective coronary stenting,1. Gurbel et al. Circulation. 2003;107:2908. 2. Muller et al. Thromb Haemost. 2003;89:783. 3. Barragan et al. Catheter Cardiovasc Interv. 2003;59:295. 4. Matetzky et al. Circulation. 2004;109:3171.,3,Introduction (contd),Mec
4、hanisms of clopidogrel nonresponse/resistance are incompletely defined,Study of 30 pts (n=10 for ticlodipine, n=10 for clopidogrel 300 mg, n=10 for clopidogrel 600 mg) suggested better inhibition with 600 mg at 4 hours but no difference at 24 hours with 600-mg dose1,1. Muller et al. Heart. 2001;85:9
5、2.,4,Introduction (contd),A large prospective pharmacodynamic study of clopidogrel 300 mg vs 600 mg is not available The effect of adding eptifibatide to these regimens is unknown ISAR REACT suggested no benefit of adding abciximab to patients loaded with 600 mg clopidogrel1 Patients all pretreated
6、for 2 hours (median 7.4 hours) Risk of bleeding with CABG in patients on clopidogrel therapy2 Low-risk group,1. Kastrati et al. N Engl J Med. 2004;350:232. 2. Hongo et al. J Am Coll Cardiol. 2002;40:231.,5,Objectives of CLEAR PLATELETS Trial,Compare platelet reactivity following 4 treatments in low-
7、 to moderate-risk patients undergoing elective stenting Without pretreatment (CRUSADE) coronary anatomy unknown prior to procedure DOSING 600 mg Clopidogrel 600 mg Clopidogrel + eptifibatide 300 mg Clopidogrel 300 mg Clopidogrel + eptifibatide Analyze the relation of platelet reactivity to postproce
8、dural myocardial necrosis Analyze the relation of platelet reactivity to postprocedural inflammation,Gurbel et al. Circulation. 2005;111:1153.,6,Methods,Consecutive patients undergoing elective coronary stenting Exclusion criteria Chest pain 1.5 Platelets 4.0 mg/dL Thienopyridine or GP IIb/IIIa use,
9、Elevated cardiac markers CVA 3 mo Visible thrombus Hct 30% Bleeding diathesis,Gurbel et al. Circulation. 2005;111:1153.,7,Clopidogrel 300 mg (n=60),Clopidogrel 600 mg (n=60), Eptifibatide (n=30),+ Eptifibatide (n=30), Eptifibatide (n=30),+ Eptifibatide (n=30),Heparin per ESPRIT dosing Clopidogrel 75
10、 mg qd ASA 325 mg qd,Methods (contd),Treatment regimens,2 2 factorial study,Gurbel et al. Circulation. 2005;111:1153.,8,Results: Demographics,CAD = coronary artery disease; MI = myocardial infarction. Gurbel et al. Circulation. 2005;111:1153.,9,Results: Demographics (contd),Gurbel et al. Circulation
11、. 2005;111:1153.,10,Results: Angiographic Data,Gurbel et al. Circulation. 2005;111:1153.,11,Results: Clinical Outcomes (24 hours),*TIMI criteria. Gurbel et al. Circulation. 2005;111:1153.,12,RESULTS: PLATELET REACTIVITY,P0.001 for C300+E and C600+E vs C300 alone and C600 alone. P0.001 for C600 alone
12、 vs C300 alone. +P=0.01 for C600 alone vs C300 alone. Gurbel et al. Circulation. 2005;111:1153.,Relative Inhibition (%),13,Results: Platelet Reactivity,Clopidogrel 300 mg Clopidogrel 300 mg + eptifibatide Clopidogrel 600 mg Clopidogrel 600 mg + eptifibatide,5 M ADP,*P0.001 for C300+E and C600+E vs C
13、300 alone and C600 alone. P0.001 for C600 alone vs C300 alone. Gurbel et al. Circulation. 2005;111:1153.,14,Results: Platelet Reactivity (contd),0.09,20 M ADP,.05,*,*,*,Hours,Relative inhibition (%),Clopidogrel 300 mg Clopidogrel 300 mg + eptifibatide Clopidogrel 600 mg Clopidogrel 600 mg + eptifiba
14、tide,*P0.001 for C300+E and C600+E vs C300 alone and C600 alone. P=0.01 for C600 alone vs C300 alone. Gurbel et al. Circulation. 2005;111:1153.,15,% Positive Cells,+ *,*,*,*,*P0.02 vs baseline. P0.03 vs C600 alone, C600+E and C300+E. Gurbel et al. Circulation. 2005;111:1153.,Results: Stimulated P-Se
15、lectin (5 uM ADP),16,Results: Stimulated P-Selectin (5 M ADP),Positive cells (%),0,10,20,30,40,50,60,70,Baseline,18-24 h poststenting,Clopidogrel 300 mg,Clopidogrel 600 mg,Clopidogrel 300 mg + eptifibatide,Clopidogrel 600 mg + eptifibatide,*,*,*P0.02 vs baseline. P0.03 vs C600 alone, C600+E and C300
16、+E. Gurbel et al. Circulation. 2005;111:1153.,*,*,17,Relation of Platelet Reactivity to Necrosis Marker Release ( 5 M ADP ),P0.001,P=0.15,P0.001,Mean platelet reactivity (%),CKMB (3 ULN),CKMB (1-3 ULN),CKMB (normal),Gurbel et al. Circulation. 2005;111:1153.,18,No MI,MI,5 M ADP-Induced Aggregation,Me
17、an platelet reactivity (%),P0.01,Relation of Mean Posttreatment Aggregation to Occurrence of MI (n=120),No MI,MI,20 M ADP-Induced Aggregation,Mean platelet reactivity (%),P0.01,Gurbel et al. Circulation. 2005;111:1153.,19,CKMB ( 1- 3 X ULN ),Patients (%),CKMB ( 3X ULN ),*,*,*P0.05 for C300+E and C60
18、0+E vs C300 alone and C600 alone. Gurbel et al. Circulation. 2005;111:1153.,RELATION OF PLATELET REACTIVITY TO MYOCARDIAL NECROSIS,20,CKMB (1 - 3 ULN ),CKMB (3 ULN ),*,*,Patients (%),Relation of Platelet Reactivity to Myocardial Necrosis,0,10,20,30,*P0.05 for C300+E and C600+E vs C300 alone and C600
19、 alone. Gurbel et al. Circulation. 2005;111:1153.,21,Patients (%),Troponin - I ( ULN ),Myoglobin ( 2X ULN ),P = 0.08,P = 0.04,P = 0.006,P = 0.09,Gurbel et al. Circulation. 2005;111:1153.,EARLY CLINICAL RELEVANCE OF PLATELET REACTIVITY: MYOCARDIAL INFARCTION,22,Troponin-I ( ULN ),Myoglobin (2 ULN ),P
20、=0.08,P=0.04,P=0.006,P=0.09,Patients (%),Early Clinical Relevance of Platelet Reactivity: Myocardial Infarction,0,10,20,30,40,50,Gurbel et al. Circulation. 2005;111:1153.,0,0,23,Conclusions,Platelet reactivity correlates strongly with the development of periprocedural myocardial necrosis in elective
21、 stenting When clopidogrel pretreatment is not possible or when the duration of pretreatment is inadequate, a strategy of eptifibatide administration should be considered since it is associated with superior platelet inhibition and lower myocardial necrosis than either 300 mg or 600 mg clopidogrel a
22、lone In the absence of eptifibatide, a strategy of clopidogrel 600 mg clearly provides superior platelet inhibition compared with the standard 300-mg dose A 600-mg loading dose should become the new standard loading strategy for clopidogrel in coronary stenting,Gurbel et al. Circulation. 2005;111:1153.,24,Exposing the Clopidogrel Myths,Uniform inhibition Rapid inhibition Potent inhibition Adequate protection,