1. Rationale for the Clinical Evaluation of Combination GP IIb-IIIa Inhibitor and Low-Dose Fibrinolytic Therapy in ST-Elevation Myocardial Infarction

2. Acute ST-Elevation MI n Over 1.5 million patients suffer an acute ST-elevation MI in the U.S. each year n ST-elevation MI is still the leading cause of mortality in the U.S. —over 500,000 deaths each year n 200,000 of all ST-elevation MI patients receive fibrinolytic therapy n 5-6% of patients receiving fibrinolytic therapy die within 30 days n 1% of patients receiving fibrinolytic therapy experience an intracranial hemorrhage during hospitalization

3. IssuesIssues n Can the still unacceptably high incidence of mortality among patients with ST-elevation MI treated with despite fibrinolytic therapy be reduced? n Can the risk of intracranial hemorrhage with fibrinolytic therapy be reduced?

4. Pathophysiology of ST-Elevation Myocardial Infarction Results from stabilization of a platelet aggregate at site of plaque rupture by fibrin mesh platelet RBC fibrin mesh GP IIb-IIIa Generally caused by a completely occlusive thrombus in a coronary artery

5. Mechanism of Action of Fibrinolytic Therapy Indirect fibrin degradation Plasminogen Plasmin Fibrinolytic

6. Goals of Fibrinolytic Therapy n Break-up fibrin mesh that stabilizes the clot n Allow normal hemostatic processes to break down remaining clot n Restore normal blood flow (TIMI 3 blood flow) through the coronary artery

7. Effect of Fibrinolytic Therapy on TIMI-3 Flow at Ninety Minutes Alteplase (tPA) 58% 30% 48% % patients with TIMI 3 flow restored Streptokinase (SK) Retaplase (rPA)

8. Clinical Outcomes with Fibrinolytic Therapy in ST-Elevation MI 1.0%  ( P  0.001) 1.9%  ( P  0.01) 11.5% 9.6% 7.3% 6.3% Heparin % death at 30 days (n=60,000) 1 (n=30,647) 2 Pooled thrombolytics Accelerated alteplase Streptokinase 1. Fibrinolytic therapy trialists’ collaborative group et al. Lancet.1994; 343: 311-322. 2. The GUSTO investigators. N Engl Med. 1993; 329: 673-682.

9. Rationale for Failed Fibrinolysis Microembolization and Non-ST elevation MI Platelet aggregation enhanced by thrombin generation stimulated by fibrinolytic Intraluminal”red” thrombus (fibrin and erythrocytes) Transitional zone (fibrin and platelets) Intraplaque “white” thrombus (platelet rich) Atheromatous plaque

10. Rationale for Combination GP IIb-IIIa Inhibitor and Fibrinolytic Therapy in ST-Elevation MI n GP IIb-IIIa inhibitors could help prevent fibrinolysis- induced platelet aggregation and arterial re-occlusion n GP IIb-IIIa inhibitors could help prevent microembolization and occlusion of down-stream arterioles n GP IIb-IIIa inhibitors may allow for a reduction in the dose of fibrinolytic therapy needed, perhaps reducing the incidence of fibrinolytic-induced intracranial hemorrhage

11. Study Overview n Design: –Open-label, angiographic study –Sequential design, dose escalation –International, multicenter enrollment n Enrollment: –Acute MI with ST elevation of less than 6 hours duration –60-minute angiography –PTCA for TIMI 1-2 flow or if clinically indicated n Endpoints: –TIMI 3 flow at 60 and 90 minutes –TIMI bleeding during initial hospitalization

12. Study Protocol Heparin: IV bolus 4000 IU followed by an IV infusion of 800 IU/hr. Anticoagulation adjusted to aPTT 50-70 seconds

13. TIMI-3 Flow at Ninety Minutes 58% 78% 75% % patients with TIMI 3 flow restored at 90 minutes Historical Control: Full-dose tPA Eptifibatide 180/90/1.33 + Half-dose tPA Eptifibatide 180/180/1.33 + Half-dose tPA

14. On-going Dose Confirmation Phase

15. Combination Studies Underway

16. ConclusionConclusion n Clinical trials completed to date have demonstrated improved TIMI 3 flow with combination GP IIb-IIIa inhibitor and low-dose fibinolytic therapy versus full-dose fibrinolysis alone n Large-scale studies focused on mortality and safety need to be completed before adopting a combination strategy