GUSTO-IV Pilot Trial,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,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,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,Overview of Trials of Low-Dose Lysis and GP IIb/IIIa Inhibitors,* bolus 0.25 mg/kg; infusion 0.125 mg/kg/min x 12h,Criteria,Age 18 to 75 Symptoms 12 hours, 18 years old Symptoms 6 hours,TIMI -14,SPEED/GUSTO IV AMI Pilot,t-PA, SK, or Reteplase +,Reteplase +,Abciximab* with,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,8%,18%,23%,32%,Gold et al 10 min Circ. 1997; 95: 1755-59 GRAPE 45 min JACC 1999; 33:1528-32 SPEED 60 min EHJ 1999; 20:616 (#3336) TIMI-14 90 min Circ. 1999; 99:2720-32,Ability of Abciximab to Cause Dethrombosis,TIMI Grade 3 flow,25%,50%,Study Time,0,SPEED,Dose Confirmation Protocol,Acute MI,ST elevation,Symptom duration 6 hrs.,Administered in the ED,SPEED,ACC 1999: Oral Presentation,Dose Escalation and Confirmation,Dose Escalation,Control Abciximab Alone n = 63,Control r-PA 10 U + 10 U n = 109,Experimental Abciximab Abciximab + r-PA + r-PA 5 U + 5 U n = 166 60 U heparin n = 76,SPEED,Dose Confirmation,Total,Abciximab + r-PA 5 U+ 5 U + 60U Heparin, n=116,Experimental Abciximab Abciximab + r-PA 5 U + 5 U + r-PA 5 U + 5 U 60 U Heparin 40 U Heparin n = 40 n = 76,ACC 1999; Oral Presentation,Dose Confirmation Acute Cardiac Catheterization,Time from study 60 (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,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 = 107,n = 34,n = 75,n = 109,Total,p = 0.395,SPEED,ACC 1999: Oral Presentation,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 = 107,n = 103,n = 75,n = 66,Abciximab Alone,p = 0.06,SPEED,ACC 1999: Oral Presentation,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,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,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,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,Facilitated PCI,Final diameter stenosis 10 (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),p,Post-Procedure,Pre-Procedure TIMI Grade Flow,Procedural Outcome,SPEED,ACC 1999: Oral Presentation,Facilitated PCI,Clinical Outcome,Death 4.1% 3.0% Reinfarction 2.4% 0.5% Severe ischemia 1.6% 1.5% requiring repeat revascularization Composite 7.3% 4.6% Blood transfusion 7.3% 10.1%,0-1 (n = 123),2-3 (n = 198),TIMI Grade Flow,SPEED,ACC 1999: Oral Presentation,Facilitated PCI,Abciximab alone 52%