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INCITE Study

INCITE. INCITE Study. IN flammatory C essation with abc I ximab or I n TE grilin. Co-PI: Frederick Welt, M.D. Co-PI: Daniel I. Simon, M.D. Brigham and Women’s Hospital West Roxbury VA Medical Center Harvard Medical School Boston, MA. CD40L.

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INCITE Study

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  1. INCITE INCITE Study INflammatory Cessation with abcIximab or InTEgrilin Co-PI: Frederick Welt, M.D. Co-PI: Daniel I. Simon, M.D. Brigham and Women’s Hospital West Roxbury VA Medical Center Harvard Medical School Boston, MA

  2. CD40L Acute Coronary Syndromes Evolving Understanding of Pathophysiology Inflammation Atherosclerosis Quiescent plaque Plaque rupture Platelets and thrombin Thrombus Thrombosis

  3. CD40L in Immunity:Isotype Switching Helper T cell B cell CD40 CD40L TNF Homology TM CD40L N C sCD40L

  4. Cells Blood 3 300 P=0.016 2 200 CD40L Units/mL blood CD40L Units/1x106 cells 1 100 0 0 Platelets Lymphocytes Platelets Lymphocytes CD40L Distribution Henn et al., Blood, 2001, 98, 1047 Lindmark et al. ATVB, 2000, 20, 2322 Andre et al., Nature Med., 2002, 8, 247

  5. CD40L in Vascular Disease • CD40L antibody inhibits atherosclerotic lesion progression in LDLR -/- mice • CD40L gene deletion inhibits lesion progression in Apo E-/-mice • Soluble form detected in ACS and PCI • Elevated plasma levels of sCD40L identify healthy women at risk for CV events. Nature 1998;391:591 PNAS 2000;97:7458 Circulation 1999;100:614 Circulation 2001;104:2266 Nature Med 1999;5:1313

  6. Platelet CD40L-Induced Inflammation thrombin CD40L CD40L sCD40L MCP-1 ICAM-1 VCAM-1 IL-8 TF Cultured HUVECs Modified from: Nature 1998;391:591

  7. CD40L-/- + rsCD40L sCD40L Promotes Thrombosis: Delayed Arterial Occlusion in CD40L-/- Mice 30 min after FeCl3 Time to reach occlusion * 40 WT 30 20 (min) 10 0 CD40L-/- WT CD40 -/- CD40L-/- * P < 0.0005 † P < 0.02 Nature Med, 2002, v.8, 247-52

  8. 125 125 100 100 75 75 50 50 25 25 % aggregation % sCD40L Release 0 0 0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 0 1 2 3 4 5 Eptifibatide (mM) Abciximab (mM) Tirofiban (mM) GP IIb-IIIa Antagonism:sCD40L Release and Aggregation Circulation, Supplement. 2001;104:II-318, 1533

  9. Thrombosis GP IIb/IIIa sCD40L Inflammation Functions of Released sCD40L sCD40L

  10. Abciximab: Anti-Inflammatory Action AM Lincoff at al. Circ 2001;104:163

  11. GP IIb-IIIa Inhibitors: Specificity/Selectivity IIb/IIIa xxx xxx xxx V3 xxx ?x Mac-1 x Abciximab Eptifibatide Tirofiban Charo IF et al. Proc Natl Acad Sci. 1986;83:835 Coller BS et al. Blood. 1991;77:75 Altieri DC et al. J Immunol. 1988;141:2656 Simon DI et al. Arterioscler Thromb Vasc Biol 1997;17:528 Lele M et al. Circ 2001;104:582

  12. INCITE INCITE: Hypothesis • Our central hypothesis is that GP IIb-IIIa inhibitors will modulate peri-PCI inflammation by virtue of their effect on platelet-induced leukocyte activation.

  13. INCITE INCITE: Study Design Elective PCI ASA, heparin (50-70 U/kg) Abciximab 0.25 mg/kg 0.1 mg/kg/min (n=15) Eptifibatide 180/180 mg/kg 2 mg/kg/min (n=15) No GP IIb-IIIa (n=15) RPFA baseline and 10 min post-bolus ELISA: sCD40L, RANTES, IL-6, sICAM-1 Timepoints: Baseline, 30 min, 2 hrs, 24 hrs

  14. Exclusion Criteria -Patients already on GP IIb/IIIa inhibitor -Patients with clear indications for GP IIb/IIIa: -Acute ST elevation MI or non q-wave MI with CPK elevation -Pain at rest with EKG changes < 24 hours -Visible Thrombus -Pain refractory to heparin -Lesions located in vascular grafts or at sites of prior intervention -Bleeding disorder -Thrombocytopenia (plts< 100) -History of GI bleeding -History of stroke or intracranial bleed -Uncontrolled hypertension (SBP > 200 mm Hg, DBP> 100 mm Hg) -Condition requiring oral anticoagulation -History of allergy or contraindication for aspirin or heparin

  15. Baseline Characteristics

  16. Procedural Characteristics

  17. INCITE Plasma sCD40L Post-PCI 0.1 None Eptifibatide Abciximab 0.05 Delta Plasma Concentration (ng/ml) 0 -0.05 -0.1 24 hour 30 min 2 hour ANOVA P=0.018 P<0.03 None vs Eptifibatide

  18. INCITE Plasma RANTES Post-PCI(Pro-inflammatory Platelet derived chemokine) 100 None Eptifibatide 50 Abciximab 0 Delta Plasma Concentration (ng/ml) -50 -100 -150 24 hour 30 min 2 hour ANOVA P=0.006 P<0.005 None vs Eptifibatide

  19. INCITE Plasma sICAM-1 Post-PCI 100 None Eptifibatide Abciximab 50 Delta Plasma Concentration (ng/ml) 0 -50 -100 24 hour 30 min 2 hour ANOVA P=0.23

  20. INCITE Plasma IL-6 Post-PCI 6 None 5 Eptifibatide Abciximab 4 3 Delta Plasma Concentration (ng/ml) 2 1 0 24 hour 30 min 2 hour ANOVA P=0.1

  21. INCITE Summary • GP IIb/IIIa inhibition lowers levels of sCD40L and RANTES post stenting, possibly conferring anti-inflammatory as well as anti-thrombotic effects.

  22. INCITE Conclusion • These findings may have significant implications for long term benefits associated with GP IIb/IIIa inhibitor use. • The findings of this pilot study need to be examined in a larger clinical trial that confirms these findings and correlates reduction in inflammation with improved clinical outcome.

  23. Procedural Characteristics

  24. 0.7 2 6 12 24 Platelet aggregation inhibition with abciximab, eptifibatide, and tirofiban RIAR Study (Keriakes. Am J Cardiol 1999) abciximab 0.25/0.125 (n=10) eptifibatide 180/2 (n=10) tirofiban 0.4/0.1 (n=9) 0.7 2 6 18 24 0.7 2 6 18 24 Time from bolus (h)

  25. INCITE CRP Preliminary Results

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