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Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular Research Hotel Dieu de France Hospital Associate Professor of Medicine Saint Joseph University School of Medicine Beirut, Lebanon NSTEMI: GPIIB/IIIA Inhibitors & Emerging Antiplatelets: Where Do We Stand? Slide 2 Role of the Platelets in Thrombosis UA/NQMI: Partially-occlusive thrombus (primarily platelets) Intra-plaque thrombus (platelet dominated) Plaque core ST MI: occlusive thrombus (platelets, red blood cells, and fibrin) Intra-plaque thrombus (platelet dominated) Plaque core SUDDEN DEATH Adapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46. Slide 3 GP IIb/IIIa Receptor Activation Pathway ASPIRIN ASPIRIN HEPARINS ASPIRIN ASPIRIN ASPIRIN ASPIRIN GP IIb/IIIa Thickness of line indicates strength of activator 5HT PAF Epi Thrombin ADP TXA 2 ASPIRIN Vasopressin Collagen Fibrinogen PLATELET PLATELET CLOPIDOGREL Slide 4 Platelet-fibrinogen interaction Slide 5 5 Time after bolus (minutes) 15304560120 0 60 80 100 abciximab plus infusion tirofiban 10 g/kg bolus plus infusion 85% Inhibition of Light Transmission Aggregation Induced by 20 M ADP After Treatment with Tirofiban or Abciximab Inhibition of Maximal Aggregation (%) TARGET DOSE Slide 6 6 Time after bolus (minutes) 15304560120 0 60 80 100 abciximab plus infusion tirofiban 10 g/kg bolus plus infusion tirofiban 20 g/kg bolus plus infusion tirofiban 25 g/kg bolus plus infusion 85% Inhibition of Light Transmission Aggregation Induced by 20 M ADP After Treatment with Tirofiban or Abciximab Inhibition of Maximal Aggregation (%) TARGET DOSE SHBD Slide 7 EPIC: 3-year Outcome JAMA 1997;278:478 Slide 8 8 PRISM-PLUS: Study Design Endpoints Primary: Composite death, MI, refractory ischemia, rehospitalization at 7 days Secondary: Death, MI, refractory ischemia, rehospitalization at 48 h, 30 days, and 6 months Safety: Major bleeding (>4.0 g/dL decrease in Hb, blood transfusion >2 U, need for corrective surgery, or intracranial or retroperitoneal hemorrhage, or any combo) Endpoints Primary: Composite death, MI, refractory ischemia, rehospitalization at 7 days Secondary: Death, MI, refractory ischemia, rehospitalization at 48 h, 30 days, and 6 months Safety: Major bleeding (>4.0 g/dL decrease in Hb, blood transfusion >2 U, need for corrective surgery, or intracranial or retroperitoneal hemorrhage, or any combo) AGGRASTAT 0.4 g/kg/min for 30 min, then 0.10 g/kg/min maintenance + heparin (n=773) AGGRASTAT 0.4 g/kg/min for 30 min, then 0.10 g/kg/min maintenance + heparin (n=773) Heparin 5000 U loading, then 1000 U maintenance (n=797) Heparin 5000 U loading, then 1000 U maintenance (n=797) Randomization UA or NSTEMI patients Chest pain within 12 h and ECG abnormalities or elevated CK-MB UA or NSTEMI patients Chest pain within 12 h and ECG abnormalities or elevated CK-MB 48 h PRISM-PLUS Study Investigators. N Engl J Med. 1998;338(21):1488-1497. Slide 9 PRISM PLUS: Results NEJM 1998;338:1488 Slide 10 Slide 11 Slide 12 Brenner et al. Circulation 1998;98:734 RAPPORT: Abciximab in primary PTCA reduces death/MI/urgent TVR at 30 days Slide 13 Synergy between abciximab and stenting in primary angioplasty for acute MI. Event free suvival (death, acute coronary syndromes, TVR) Azar et al. J Am Coll Cardiol 1998;32:1996 Slide 14 GP IIb/IIIa Receptor Activation Pathway ASPIRIN ASPIRIN HEPARINS ASPIRIN ASPIRIN ASPIRIN ASPIRIN GP IIb/IIIa Thickness of line indicates strength of activator 5HT PAF Epi Thrombin ADP TXA 2 ASPIRIN Vasopressin Collagen Fibrinogen PLATELET PLATELET CLOPIDOGREL Slide 15 Slide 16 Slide 17 Does Clopidogrel Eliminate the Need for GPIIb/IIIa Antogonists? Slide 18 Treatment with AGGRASTAT provides greater flexibility for early surgical procedures, transfer, or discharge Adapted from Kereiakes DJ et al. Am Coll Cardiol 1996;27(3):536-542 0.5 60 100 % inhibition Fast-On Approximate % platelet aggregation blocked Fast-Off Return to baseline of platelet function Hours of infusionHours postinfusion 80 40 20 122448 0 60 100 80 40 20 248 0 End infusion 3567 % inhibition Slide 14 Slide 19 Slide 20 Slide 21 EPISTENT: Effect of Thienopyridine Pretreatment Placebo No Pretreat Placebo Pretreat Abcix No Pretreat Abcix Pretreat 42% (P=0.028 ) 33% (P=0.033 ) Steinhubl S et al. Circulation 2001;103:1403-9 Slide 22 Slide 23 Slide 24 Slide 25 Slide 26 Slide 27 Slide 28 28 Slide 29 29 Tirofiban vs Placebo 00 22 44 66 Death 30 Days Death Death 5 Months Death 3.03.0 2.02.0 OR= 0.66 P