1. SPEED : GUSTO-IV PILOT GUSTO-IV Pilot Trial

2. SPEED : GUSTO-IV PILOT Rationale for Combination Therapy in AMI Enhance Incidence and Speed of Reperfusion Reduced Mortality Safer Therapy - Less IC bleed Facilitate Early Percutaneous Interventions SPEED ACC 1999: Oral Presentation

3. SPEED : GUSTO-IV PILOT Rationale for Combination Therapy in AMI Improved Reperfusion –Only 40-50% achieve normal perfusion (TIMI grade 3 flow) with fibrinolytic therapy alone Reduced Mortality –30% 1-year mortality among the elderly (> 75 years) in GUSTO-III ACC 1999: Oral Presentation SPEED

4. SPEED : GUSTO-IV PILOT Rationale for Combination Therapy in AMI Facilitate Early Percutaneous Interventions –Improved mortality with primary PCI is limited to hospitals where procedure and expertise is available Reduced ICH Rates –21% increase in IC bleed from GUSTO-I to GUSTO-III with t-PA SPEED ACC 1999: Oral Presentation

5. Overview of Trials of Low-Dose Lysis and GP IIb/IIIa Inhibitors * bolus 0.25 mg/kg; infusion 0.125  g/kg/min x 12h CriteriaAge 18 to 75 Symptoms < 12 hours > 18 years old Symptoms < 6 hours TIMI -14SPEED/GUSTO IV AMI Pilot t-PA, SK, or Reteplase +Reteplase + Abciximab* with Heparin 60 U/kg 30 U/kg Heparin 60 U/kg 40 U/kg TIMI grade 3 flow at 90 minutes TIMI grade 3 flow at 60-90 minutes (avg. was 62 min) Rescue only “Encouraged” -Facilitated PCI Combination Therapies Studied 1° Endpoint PCI Control Arm(s) Accelerated t-PA and 10 U +10 U Reteplase Standard Reteplase 10 U +10 U SPEED ACC 1999: Oral Presentation

6. SPEED : GUSTO-IV PILOT 8% 18% 23% 32% Gold et al10 min Circ. 1997; 95: 1755-59 GRAPE45 min JACC 1999; 33:1528-32 SPEED60 min EHJ 1999; 20:616 (#3336) TIMI-1490 min Circ. 1999; 99:2720-32 Ability of Abciximab to Cause Dethrombosis TIMI Grade 3 flow 25% 50% StudyTime 0 SPEED

7. SPEED : GUSTO-IV PILOT Dose Confirmation Protocol  Acute MI  ST elevation  Symptom duration < 6 hrs. 1:1 Randomization r-PA 10 + 10 U Heparin 70 U/kg Abciximab standard dose r-PA 5 + 5 U Heparin 60 U/kg / 40 U/kg  60-90 Minute Angiography PTCA + Stent as indicated Administered in the ED SPEED ACC 1999: Oral Presentation

8. SPEED : GUSTO-IV PILOT Dose Escalation and Confirmation Dose Escalation Control Abciximab Alone n = 63 Control r-PA 10 U + 10 U n = 109 Experimental Abciximab + r-PA + r-PA 5 U + 5 U n = 166 60 U heparin n = 76 SPEED Dose Confirmation TotalAbciximab + r-PA 5 U+ 5 U + 60U Heparin, n=116 Experimental Abciximab + r-PA 5 U + 5 U 60 U Heparin 40 U Heparin n = 40 n = 76 ACC 1999; Oral Presentation

9. Dose Confirmation Acute Cardiac Catheterization Time from study60 (50,65)55 (48,61)60 (48,67) drug to cath (min)* Infarct-related artery: LAD 41% 32% 45% LCX 14% 16% 9% RCA 44% 49% 45% PCI of IRA 83% 70% 94% at 60-90 min * median (25th, 75th) r-PA Alone (n = 109) Abciximab r-PA 5 + 5 60 U Hep (n = 40) Abciximab r-PA 5 + 5 40 U Hep (n = 76) ACC 1999: Oral Presentation

10. SPEED : GUSTO-IV PILOT TIMI Grade 3 Flow at 60-90 Min Angiographic Core Lab Reading by Treatment Recieved r-PA Alone 60 U Hep Abciximab + r-PA 5 + 5 40 U Hep Abciximab + r-PA 5 + 5 n = 107n = 34n = 75n = 109 Total p = 0.395 SPEED ACC 1999: Oral Presentation

11. SPEED : GUSTO-IV PILOT TIMI Grade 3 Flow at 60-90 Min Angiographic Core Lab Reading r-PA Alone 60 U Hep Abciximab + r-PA 5 + 5 40 U Hep Abciximab + r-PA 5 + 5 p = 0.2 n = 107n = 103n = 75n = 66 Abciximab Alone p = 0.06 SPEED ACC 1999: Oral Presentation

12. Median TIMI Frame Count by Treatment Received Dose escalation and confirmation r-PA Alone 60 U Hep Abciximab + r-PA 5 + 5 40 U Hep Abciximab + r-PA 5 + 5 Abciximab Alone p = 0.87 p = 0.43 43 33 100 36 SPEED ACC 1999 : Oral Presentation

13. SPEED : GUSTO-IV PILOT Clinical Outcomes* Death 5.6%4.4%2.6%3.2% Reinfarction 2.8%1.7%1.3% 0% Severe ischemia 2.8%4.3%2.6%6.4% requiring urgent revascularization Composite 11.2%9.6%5.3%9.5% * to 30 days post randomization r-PA Alone Abciximab r-PA 5 + 5 60 U Hep Abciximab r-PA 5 + 5 40 U Hep Abciximab Alone SPEED ACC 1999: Oral Presentation

14. SPEED : GUSTO-IV PILOT Rationale for Facilitated PCI Meta-analyses suggest improved survival with primary PTCA over lysis Procedural success lower in vessels with TIMI Grade 0-1 vs. 2-3 Limitations to primary PTCA include access (minority of hospitals can perform PCI) and delay in restoring flow (few hospitals < 60 min to cath) SPEED ACC 1999: Oral Presentation

15. SPEED : GUSTO-IV PILOT Facilitated PCI 530 Patients 464 Patients 60-90 min cath 323 Patients PCI TIMI Grade 0-1 (n = 136) TIMI Grade 2-3 (n = 324) PCI 91% No PCI 9% PCI 61% No PCI 39% SPEED ACC 1999: Oral Presentation

16. SPEED : GUSTO-IV PILOT Facilitated PCI Final diameter stenosis10 (0, 25)0 (0, 20)0.0001 TIMI grade 3 flow 83% 95% 0.001 Stents 73% 81% 0.09 Procedural success* 81% 93% 0.001 * < 50% diameter stenosis with TIMI grade 3 flow 0-1 (n = 123) 2-3 (n = 198) pPost-Procedure Pre-Procedure TIMI Grade Flow Procedural Outcome SPEED ACC 1999: Oral Presentation

17. SPEED : GUSTO-IV PILOT Facilitated PCI Clinical Outcome Death4.1%3.0% Reinfarction2.4%0.5% Severe ischemia1.6%1.5% requiring repeat revascularization Composite7.3%4.6% Blood transfusion7.3%10.1% 0-1 (n = 123) 2-3 (n = 198) TIMI Grade Flow SPEED ACC 1999: Oral Presentation

18. SPEED : GUSTO-IV PILOT Facilitated PCI Abciximab alone52%83%3% (n = 66) Abciximab + r-PA 5 + 576%66%11% (n = 192) r-PA alone73%61%10% (n = 109) * > 24 hours after randomization TIMI GRADE 2-3 Flow Early (60-90 min) PCI Late* PCI SPEED ACC 1999: Oral Presentation

19. SPEED : GUSTO-IV PILOT Facilitated PCI Final diameter stenosis10 (0, 25)5 (0, 25)5(0, 20) 0.41 TIMI grade 3 flow 95% 90% 85% 0.16 Stents 75% 75% 90% 0.02 Procedural success* 95% 88% 85% 0.35 * < 50% diameter stenosis with TIMI grade 3 flow ** compares any abciximab to r-PA alone Abciximab Alone (n = 40) Abciximab + r-PA 5 + 5 (n = 114) p** Post-Procedure Procedural Outcome r-PA Alone (n = 60) SPEED ACC 1999: Oral Presentation

20. SPEED : GUSTO-IV PILOT Facilitated PCI Death5.0%5.3%3.3% Reinfarction 0%1.8%1.7% Severe ischemia5.0%0.9%1.7% requiring repeat revascularization Composite10.0%6.1%6.7% Blood transfusion 5.0%9.7%6.7% Abciximab Alone (n = 40) Abciximab + r-PA 5 + 5 (n = 114) Clinical Outcomes r-PA Alone (n = 60) SPEED ACC 1999: Oral Presentation

21. SPEED : GUSTO-IV PILOT Conclusion Low dose fibrinolytic therapy in addition to abciximab improves reperfusion rates Heparin dose with the combination is also important to maximize reperfusion rates with abciximab + low-dose r-PA Combination therapy appears to facilitate early PCI in AMI

22. SPEED : GUSTO-IV PILOT Results in a Perspective 31% 54% 0% 25% 50% 75% 100% SKt-PA Abciximab r-PA 5 + 5 GUSTO-1 90-min Meta-analysis 60-min SPEED 60-min 23% 14% p < 0.001p = 0.06 ACC 1999: Oral Presentation

23. SPEED : GUSTO-IV PILOT Trial Protocol (n = 16,600) ST, lytic eligible, < 6 h ASA No Abciximab 2 x 10 U bolus (30’) Reteplase Abciximab* Low Dose Heparin: 60 U/kg bolus followed by a 7 U/kg/h infusion 1º endpoint: mortality at 30 days 2º endpoint: clinical and safety events at 30 days 2 x 5 U bolus (30’) Reteplase Standard Heparin: 5,000 U bolus followed by either 800 U/hr (pts < 80 kg) or 1,000 U/hr (pts > 80 kg) infusion * 0.25mg/kg bolus followed by 0.125  g/kg/min infusion for 12 hours GUSTO-IV AMI