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
Fa