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) Patients 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 sufficient 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.

Introduction (cont’d) Mechanisms of clopidogrel nonresponse/resistance are incompletely defined ? Due to inadequate levels of active metabolite ? Overcome by a higher dose 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;85:92.

Introduction (cont’d) 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 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.

Objectives of CLEAR PLATELETS Trial Compare platelet reactivity following 4 treatments in low- 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 postprocedural myocardial necrosis Analyze the relation of platelet reactivity to postprocedural inflammation Gurbel et al. Circulation. 2005;111:1153.

Methods Consecutive patients undergoing elective coronary stenting Exclusion criteria Chest pain <24 h AMI <48 h Chronic occlusion Illicit drug use PT >1.5 × Platelets <100,000/mm3 Creatinine >4.0 mg/dL Thienopyridine or GP IIb/IIIa use Elevated cardiac markers CVA <3 mo Visible thrombus Hct <30% Bleeding diathesis Gurbel et al. Circulation. 2005;111:1153.

Methods (cont’d) Heparin per ESPRIT dosing Clopidogrel 75 mg qd Treatment regimens 2 × 2 factorial study 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 mg qd ASA 325 mg qd Gurbel et al. Circulation. 2005;111:1153.

Methods (cont’d) Platelet aggregation (5 and 20 µM ADP) Flow cytometry BL, 3 h, 8 h, 18-24 h, 5 d poststenting Flow cytometry P-selectin expression stimulated by 5 µM ADP BL, 18-24 h poststenting Cardiac markers Troponin-I, CKMB, myoglobin BL, 8 h, 18-24 h poststenting Inflammation markers LDLox, hsCRP, ICAM-1, VCAM-1, TNF, sP-selectin, sTNF RI Gurbel et al. Circulation. 2005;111:1153.

Results: Demographics Clopidogrel 300 mg (n=30) Clopidogrel 600 mg (n=30) Clopidogrel 300 mg + Eptifibatide (n=30) Clopidogrel 600 mg + Eptifibatide (n=30) Age (y) 67  20 55  29 58  11 64  9 Race (cauc. %) 69 87 84 64 Gender (male %) 43 65 72 59 Risk factors (%) Smoker 67 46 Family history of CAD 52 62 31 71 Hypertension 68 91 Hyperlipidemia 77 88 86 Diabetes 30 40 36 Prior MI 35 28 27 Prior CABG 17 20 9 CAD = coronary artery disease; MI = myocardial infarction. Gurbel et al. Circulation. 2005;111:1153.

Results: Demographics (cont’d) Clopidogrel 300 mg (n=30) Clopidogrel 600 mg (n=30) Clopidogrel 300 mg + Eptifibatide (n=30) Clopidogrel 600 mg + Eptifibatide (n=30) Baseline medications (%) Beta blockers 90 83 92 100 ACE inhibitors 68 64 80 82 Calcium blockers 15 23 8 14 Lipid-lowering agents (%) 3A4 52 72 36 Non-3A4 24 22 20 33 Laboratory data WBCs 8.2  3.8 8.3  3.6 7.9  2.5 7.2  1.8 Platelets 249  106 229  89 231  70 203  33 Hemoglobin 12.4  2.0 12.9  1.8 13.7  1.6 12.7  2.0 Creatinine 1.2  1.1 1.2  0.4 0.9  0.2 1.0  0.2 Gurbel et al. Circulation. 2005;111:1153.

Results: Angiographic Data Clopidogrel 300 mg (n=30) Clopidogrel 600 mg (n=30) Clopidogrel 300 mg + Eptifibatide (n=30) Clopidogrel 600 mg + Eptifibatide (n=30) Length of procedure (min) 72  38 62  19 67  37 54  17 Ejection fraction 53  8 55  8 49  11 53  9 No. of vessels treated 1.3  0.5 1.3  0.6 1.4  0.6 1.5  0.7 Lesion morphology (%) De novo 97 87 90 Restenotic 3 13 10 Lesion location (%) LAD 33 30 43 CX 14 27 RCA 46 37 17 40 SVG 7 Reference vessel diam. (mm) 2.9  0.5 3.2  0.5 3.0  0.4 Total lesion length (mm) 19  10 22  15 20  12 Prestenosis (%) 81 85 88 83 Poststenosis (%) 2 4 5 Gurbel et al. Circulation. 2005;111:1153.

Results: Clinical Outcomes (24 hours) No. of Patients Clopidogrel 300 mg (n=30) Clopidogrel 600 mg (n=30) Clopidogrel 300 mg + Eptifibatide (n=30) Clopidogrel 600 mg + Eptifibatide (n=30) Death STEMI 1 SAT Urgent TVR Bleeding complications* Minor Major *TIMI criteria. Gurbel et al. Circulation. 2005;111:1153.

RESULTS: PLATELET REACTIVITY * †P0.001 for C600 alone vs C300 alone. + * ‡ Relative Inhibition (%) Relative Inhibition (%) + ‡ .05 0.09 ‡P0.001 for C300+E and C600+E vs C300 alone and C600 alone. †P0.001 for C600 alone vs C300 alone. +P=0.01 for C600 alone vs C300 alone. Gurbel et al. Circulation. 2005;111:1153.

Results: Stimulated P-Selectin (5 uM ADP) + * % Positive Cells * * * *P0.02 vs baseline. †P0.03 vs C600 alone, C600+E and C300+E. Gurbel et al. Circulation. 2005;111:1153.

Mean platelet reactivity (%) Relation of Platelet Reactivity to Necrosis Marker Release ( 5 µM ADP ) P≤0.001 P≤0.001 P=0.15 Mean platelet reactivity (%) CKMB (normal) CKMB (>1-3 × ULN) CKMB (>3 × ULN) Gurbel et al. Circulation. 2005;111:1153.

Relation of Mean Posttreatment Aggregation to Occurrence of MI (n=120) 5 µM ADP-Induced Aggregation 20 µM ADP-Induced Aggregation P≤0.01 P≤0.01 Mean platelet reactivity (%) Mean platelet reactivity (%) No MI MI No MI MI Gurbel et al. Circulation. 2005;111:1153.

RELATION OF PLATELET REACTIVITY TO MYOCARDIAL NECROSIS Patients (%) * * CKMB ( >1- 3 X ULN ) CKMB ( > 3X ULN ) *P<0.05 for C300+E and C600+E vs C300 alone and C600 alone. Gurbel et al. Circulation. 2005;111:1153.

EARLY CLINICAL RELEVANCE OF PLATELET REACTIVITY: MYOCARDIAL INFARCTION Patients (%) Troponin - I ( > ULN ) Myoglobin ( > 2X ULN ) Gurbel et al. Circulation. 2005;111:1153.

Conclusions Platelet reactivity correlates strongly with the development of periprocedural myocardial necrosis in elective 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 alone 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.

Exposing the Clopidogrel Myths Uniform inhibition Rapid inhibition Potent inhibition Adequate protection