1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

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

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

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

18. 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.

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