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Gurbel PA, Bliden KP, DiChiara J, Bassi A, Herzog WR, Gesheff TB, Tantry US

Bivalirudin With and Without Eptifibatide for Elective Stenting: A Pharmacodynamic Study of Platelet Reactivity in Relation to the Occurrence of Periprocedural Myocardial Infarction (The CLEAR PLATELETS-2 Study). Gurbel PA, Bliden KP, DiChiara J, Bassi A, Herzog WR, Gesheff TB, Tantry US

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Gurbel PA, Bliden KP, DiChiara J, Bassi A, Herzog WR, Gesheff TB, Tantry US

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  1. Bivalirudin With and Without Eptifibatide for Elective Stenting:A Pharmacodynamic Study of Platelet Reactivity in Relation to the Occurrence of Periprocedural Myocardial Infarction(The CLEAR PLATELETS-2 Study) Gurbel PA, Bliden KP, DiChiara J, Bassi A, Herzog WR, Gesheff TB, Tantry US Sinai Center for Thrombosis Research, Sinai Hospital of BaltimoreBaltimore, Maryland, U.S.A.

  2. Disclosures Dr. Paul A. Gurbel has received research grants and honoraria from: Haemoscope Astra Zeneca Schering Plough Medtronic Daiichi/Sankyo Lilly Sanofi-Aventis Boston Scientific Bayer Portola

  3. Background The optimal antiplatelet and anticoagulant strategy for elective coronary stenting remains controversial. Elective stenting is commonly performed in the presence of only aspirin and an anticoagulant, without clopidogrel pretreatment or GPIIb/IIIa inhibition. In the CLEAR PLATELETS Study the addition of the GPIIb/IIIa inhibitor, eptifibatide to low or high loading dose clopidogrel + heparin administered at the time of stenting (no pretreatment) produced: - superior platelet inhibition and lower myocardial necrosis than 300 mg or 600 mg clopidogrel + heparin. High platelet reactivity was associated with peri-procedural myocardial necrosis. (Threshold for MI ?) 1 1. Gurbel PA et al. Circulation. 2005;111:1153-9

  4. High periprocedural platelet reactivity and high platelet-fibrin clot strength are risk factors for short and long-term ischemic events. 1-3 It has been proposed that bivalirudin, a direct thrombin inhibitor, may be a superior antithrombotic agent compared to heparin for stenting.4 There are no randomised data on platelet reactivity and clot characteristics in elective stent patients treated with bivalirudin vs. bivalirudin + eptifibatide. CLEAR PLATELETS-2 Objectives: Compare in elective stenting the effect of: bivalirudin (B) + eptifibatide (E) vs. bivalirudin alone on: 1) platelet reactivity (aggregometry) 2) physical characteristics of clot (thrombelastography) Relation of platelet reactivity to post-stent myonecrosis Background 1. Gurbel PA, et al. Circulation. 2005; 111:1153-9 2. Gurbel PA, et al. J Am Coll Cardiol. 2005; 46:1820-6 3. Bliden KP, et al. J Am Coll Cardiol. 2007; 49:657-66 4. Lincoff M, et al. JAMA . 2003; 289:853-63

  5. Methods Elective coronary stenting, open label, randomised, 2 center study (n = 200)- Sinai Hospital of Baltimore - University of Oklahoma Health Sciences Center - J Saucedo Exclusion Criteria: Bleeding diathesis , MI < 48hrs, CVA within 3 months, EF < 25%Platelets < 100,000/mm3, Hct < 30%, Cr > 2.0 mg/dlGPIIb/IIIa or anticoagulant use prior to the procedure Clopidogrel 600 mg in lab [clopidogrel naïve (n=128)]On 75 mg clopidogrel maintenance, no load (n=72) ASA 325 mg Bivalirudin(1mg/kg bolus; 2.5 mg/kg/hr) + Eptifibatide (n = 98)(180 g/kg bolus x 2, 2.0 g/kg/min infusion x 18h) - Eptifibatide (n = 102) Blood Samples:Pre-PCI; 2 hrs, 6-8hrs and 18hrs post-PCI

  6. Methods:Laboratory Studies Light Transmittance Aggregometry - (Chronolog) - PPACK tubes (75 M) - 5 and 20uM ADP, 15 and 25uM TRAP, 2ug/mL Collagen, 2mM AA Flow Cytometry (FACScan, BD Biosciences)- PPACK tubes (75 M)-Non-stimulated and ADP-stimulated (1 M):P-selectin expression (% positive cells), Activated GPIIb/IIIa (MFI) Thrombelastography (Haemoscope)- Maximum platelet - fibrin clot strength stimulated by kaolin (MA, mm)- Time to initial platelet-fibrin clot formation (R, min.) Triage Meter (Biosite)- CKMB, Troponin-I, Myoglobin

  7. Methods: Clinical Outcomes • In-hospital and up to 12 month ischemic and bleeding events • Definition ofIschemic Events:- Death (secondary to cardiovascular cause) - MI (symptoms and Tn I >ULN and/or CKMB > 3x ULN) - Stroke - Definite stent thrombosis (angiographically documented) - Any unplanned coronary intervention • Bleeding Events • TIMI Major (intracranial, a fall in Hgb>5g/dL or a fall in Hct of >15%)1 • TIMI Minor (fall in Hgb of 3-5g/dL or a fall in Hct of 9-15%)1 1. Bovill EG, et al. Ann Intern Med. 1991;115:256-65.

  8. Results: Patient Demographics

  9. Results: Patient Demographics

  10. Results: Procedural Characteristics

  11. Results: Aggregation 100 600 C+B +E 600 C+B +E 600 mg C+B 600 mg C+B 75 mg C+B 75 mg C+B 75 mg C+B+E 75 mg C+B+E + 80 + + 60 40 20 * * * 0 Baseline 2 hrs 6-8 hrs 18 hrs 100 + + 80 + 60 40 20 * * * 0 Baseline 2 hrs 6-8 hrs 18 hrs 5 M ADP-InducedAggregation (%) + p<0.05, 600 mg C+B vs. 75 mg C+B * p<0.001, B+E vs. E 20 M ADP-InducedAggregation (%)

  12. Results:Aggregation 100 600 C+B + E 600 mg C+B 75 mg C+B 75 mg C+B+E 80 + + 60 + 40 20 * * * 0 Baseline 2 hrs 6-8 hrs 18 hrs 100 600 mg C+B 600 C+B + E 75 mg C+B 75 mg C+B+E 80 60 40 * * * 20 0 Baseline 2 hrs 6-8 hrs 18 hrs 2 ug/ml Collagen-InducedAggregation (%) + p<0.05, 600 mg C+B vs. 75 mg C+B * p<0.001, B+E vs. E 25 uM TRAP-InducedAggregation (%)

  13. 600mg C+B 600mg C+B+E 75 75mg C+B 75mg C+B+E 75 70 * * 70 65 65 60 60 55 55 50 Baseline 2 hr 6-8hr 18 hr 50 Baseline 2 hr 6-8hr 18 hr 25 600mg C+B 600mg C+B+E 25 75mg C+B 75mg C+B+E 20 20 15 15 10 10 5 5 0 Baseline 2 hr 6-8 hr 18 hr 0 Baseline 2 hr 6-8 hr 18 hr Results: Thrombelastography Platelet-Fibrin Clot Strength Clopidogrel Naïve Chronic Clopidogrel * p<0.05 (mm) Time to Initial Platelet-Fibrin Clot Formation Clopidogrel Naïve Chronic Clopidogrel (min)

  14. Clopidogrel Naive Chronic Clopidogrel 75 75 Baseline 18 hr Baseline 18 hr 60 60 45 Mean Fluorescence Intensity 45 * 30 30 * * 15 15 0 0 C+B C+B+E C+B+E C+B Clopidogrel Naive Chronic Clopidogrel Baseline 18 hr Baseline 18 hr 45 45 36 36 * * 27 27 Positive Cells (%) 18 18 9 9 0 0 C+B C+B+E C+B C+B+E Results- Flow Cytometry ADP-Stimulated GPIIb/IIIa Expression *p<0.001 ADP-Stimulated P-Selectin Expression *p<0.001

  15. Relation of Platelet Reactivity (5M ADP) to Myocardial Necrosis 100 p<0.0001 90 80 p=0.8 p<0.0001 70 60 Mean Post-Treatment Aggregation (%) 50 40 30 20 10 0 NL >1-3 ULN >3X ULN CKMB

  16. p=0.02 p=0.04 Patient (%) Cardiac Marker 600C+B 75C+B 600C+B+E 75C+B+E Troponin-I (>ULN), % 12 17 3 6 Myoglobin (>2XULN), % 12 11 3 6 Relation of Myonecrosis Marker Release to Treatment

  17. Relation of Platelet-Fibrin Clot Strengthto Myocardial Necrosis p=0.02 85 p=NS p=0.04 80 75 70 Clot Strength (mm) 65 60 ~ 25% greater clot strength 55 50 NL (>1-3X ULN) (>3X ULN) CKMB

  18. Relation of Platelet-Fibrin Clot Strength (G) to MA Clot Strength Increases: ~ 1.8x Between MA 62- MA 74 (MI range) ~ 4.0x Between MA 50- MA 80 (total range) 14200 8160 Data on file from Haemoscope Corp.

  19. Results: Clinical Outcomes

  20. Conclusions 1) Eptifibatide + bivalirudin = 1) superior platelet inhibition irrespective of agonist 2) lower platelet-fibrin clot strength (most pronounced in clopidogrel naïve) These 2 properties may explain lower periprocedural Ischemic events in patients treated with eptifibatide + bivalirudin vs. bivalirudin. 2) CLEAR PLATELETS 2 further supports a link between high platelet reactivity and the occurrence of post-stent infarction. 3) The addition of eptifibatide may reduce periprocedural MI in selected patients with high platelet reactivity on bivalirudin + clopidogrel therapy 4) Selection of patients for adjunctive GPIIb/IIIa blockade may be facilitated in future studies by individualized platelet function measurements- ? Target pt. with high on-clopidogrel treatment platelet reactivity • In elective stenting in clopidogrel naïve and chronic clopidogrel treated pts:

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