acute myocardial infarction are thrombolitics enough ?
TRANSCRIPT
Acute Myocardial Infarction are Thrombolitics Enough ?
Augustin J. DeLago M.D.,F.A.C.C.Director,Catheterization LaboratoryDirector,Invasive CardiologyThe Heart Institute Albany Medical Center
Early evidence of reduced mortality
after IC SK
Evidence of mortality benefit
after IV SK(GISSI)
GUSTO-I, TIMI:•Lytics, 90-min CBF
reduce mortality•New lytics created
Management Strategies in AMI
8.9
4.4
TIMI 2TIMI 0-1
30-d
ay m
ort
alit
y (%
)
1010
88
66
44
00
22
7.4
TIMI 390-minute angiography
P=0.08
P=0.009
Patency ~ Mortality
Ross AM et al. N Engl J Med. 1993;329:1615–1622.
The Open Artery
Hypothesis
• Reperfusion of the IRA results in LV preservation
• Open the artery early to improve outcomes
GUSTO-I: The Benefit of Reperfusion
INFARCT
ASSENT-2• Designed to test the superior fibrin specificity of tenecteplase vs alteplase
(equivalence study)• Outcome: No difference in mortality
The Mortality Ceiling With ModernFibrinolytics
Percentage of survival
AlteplaseTenecteplase
Su
rviv
al p
rob
abili
ty
Innovations in the Managementof AMI
INFARCT
• Designed to test the theory that reteplase would be superior to alteplasebecause of its superior angiographic data
• Outcome: No difference in mortality
The Mortality Ceiling With ModernFibrinolytics
Ohman EM. Oral presentation, ACC 1999.
GUSTO-III Survival Curve
AlteplaseReteplase
Alteplase mortality rate (11.0%)Reteplase mortality rate (11.21%)P=0.6630
days
mo
rtality
(%
)16
12
8
4
0
Innovations in the Managementof AMI
• Mortality ceiling (6% to 7%)
• Successful reperfusion (45% to 60%)
• ICH risk (0.5% to 1.5%)
• Approximately 40% of patients do not achieve TIMI-3 flow at 90 minutes
• Critical time dependence for reperfusion to achieve optimal outcomes
Limitations of Fibrinolysis
Innovations in the Managementof AMI
GP IIb/IIIa Inhibitors
Steric hindranceNonspecificBinds with 3 chain on GP IIb/IIIa,
v33
Competitive blockadeHighly specific for GP IIb/IIIaMimic amino acid sequences
AbciximabSmall molecule
Artist’s conception
Binding Competitive Competitive
Half-lifePlasma ~2 h ~2 h
<10 minBiologic ~2 h ~2 h
Days
Clearance Renal Renal Renal/Spleen
GP IIb/IIIa Inhibitors
EptifibatideAbciximab Tirofiban
Benefits of GP IIb/IIIa Inhibition in AMI:
Review of Clinical Trials
GP IIb/IIIa Inhibitors
EPIC: AMI Subset – Post Hoc Analysis
Lefkovits J et al. Am J Cardiol. 1996;77:1045–1051.
Dea
th/r
e-M
I/u
rgen
t T
VR
(%
)
30 days 6 months0
102030405060708090
100
26.121.1
4.5
47.8
32.3
4.5
Placebo (n=23) Abciximab bolus(n=19)
Abciximab bolus + infusion (n=22)
P=0.06
P=0.002
83%
91%
TIMI 3 Flow : 90 TIMI 3 Flow : 90 minmin
627470 73
0
20
40
60
80
100
215 148 88
tPA50 mg
rPA5 + 5 U
% Pts
n =
Full Dose Lytic 50% Lytic+ Abx
87
tPA100 mg
rPA10 + 10 U
p=0.014p=0.014
TIMI 14TIMI 14
tPA +tPA + rPA PhasesrPA Phases
Abciximab Improves ST Res-Abciximab Improves ST Res-90 min90 min
40
58
0
20
40
60
80
100
Lytic Lytic +Abx
de Lemos et al AHA 1999
Complete (> 70%)ST Res
P<0.0005
N=179 N=329
tPA + rPA pooledtPA + rPA pooled
TIMI 14TIMI 14
GP IIb/IIIa Inhibitors in Primary PTCA
RAPPORT
ObjectiveEvaluate safety and efficacyof abciximab as adjunctive therapy to primary PTCA
End Points• Primary: Composite of
any-cause death, recurrentMI, repeat TVR within
6 months•Secondary: Composites ofdeath, MI, urgent TVR at
7 days and 30 days
Brener SJ et al. Circulation. 1998;98:734–741.
RAPPORT30-Day End Points (Intent-to-Treat)
P=0.03%
of
Pat
ien
ts
Death, re-MI, orurgent
intervention
Urgentintervention
Death or re-MI
P=0.52P=0.006
0
5
10
15
11.2
5.8 5.84.6
6.6
1.7
Placebo (n=242)
Abciximab (n=241)
48%
74%
Brener SJ et al. Circulation. 1998;98:734–741.
N: 64 392/83 200 403 300
Random: No No Yes YesYes
PCI: PTCA PTCA Stent PTCAStent
P: 0.06 0.04 0.03 <0.05<0.05
26.1
4.5
9.7
3.6
9.2
2
11.2
5.8
15.3
7.3
0
10
20
30
Control
Abciximab
30-d Mortality, MI, Urgent ReV
PCI with Adjunctive GP IIb/IIIa
Per
cen
t
Trial EPIC GUSTO-III Neumann RAPPORT ADMIRAL
.
6.5
2.6
7
1.0*
3.64.3
75.7 5.6 5.5
11.9
8.7*
6.5
4.4*
0
5
10
15
PAMI ZWOLLE MAYO GUSTO-IIb MITI CCP Weaver
Lytic PTCA
*P<0.05
30-d Mortality or Discharge
N 395 395 103 1138 3145 20,683 2606
Herrmann HC. Am J Cardiol. 2000;85:10C-16C.
Lysis vs Primary PTCA
Per
cen
t
Reperfusion in AMI
FIBRINOLYSIS
PRIMARY PTCA
• Reduces mortalityReduces mortality
• Well studiedWell studied
• Widely availableWidely available
• Lower mortalityLower mortality
• Anatomic definitionAnatomic definition
• Avoids hemorrhageAvoids hemorrhage
Facilitated Percutaneous Coronary Intervention:
Evidence for the Efficacy of a New Approach
Potential Benefits of Facilitated PCI
• May be cost-effective if combination pharmacologic therapy lessens the need for PCI
• Improves patient stability during intervention
– Patients with open arteries have less shock, IABP, pacemaker, arrest
– Higher technical success due to less hectic procedure, better distal vessel visualization
• Fuses best aspects of fibrinolysis and primary PCI
– Earlier and greater TIMI-3 flow rates
– May improve myocardial tissue perfusion
Nonqualifying PCI (n=43)
SPEED study (n=528)
Primary end point= TIMI-3 flow
Dose-finding (n=305)
Confirmation (n=223)
60-90 min angiogram
(n=466) No early PCI (n=162)
Facilitated PCI
(n=323)
Abciximab + reteplase
Abciximab + reteplase (5+5 U) vs full-dose reteplase (10+10 U)
Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489–1496.
SPEED: Study Population
TIMI Grade 3 Flow at 60-90 Min
29%
51%
62%
48%
0
50
100
Angiographic Core Lab ReadingAngiographic Core Lab Reading
r-PAAlone
60 U HepAbciximab+ r-PA 5 + 5
40 U HepAbciximab+ r-PA 5 + 5
p = 0.2
n = 107 n = 103 n = 75 n = 66
AbciximabAlone
p = 0.06
SPEEDSPEED
ACC 1999: Oral Presentation
Freedom From Mortality, MI, Urgent ReV at 30 days
Early PCI No Early PCI
80
85
90
95
100
0 10 20 30
94.4%
83.8%
P<0.05
SPEED: Clinical Success
Pe
rce
nt
Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489–1496.
Days
Results in a Perspective
31%
54%
0%
25%
50%
75%
100%
SK t-PA
22%
45%
0%
25%
50%
75%
100%
SK t-PA
48%
62%
0%
25%
50%
75%
100%
r-PA Abciximabr-PA 5 + 5
GUSTO-190-min
Meta-analysis60-min
SPEED60-min
23% 23%14%
p < 0.001 p = 0.06
ACC 1999: Oral Presentation
Trial Protocol (n = 16,600)
ST , lytic eligible, < 6 hASA
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 days2º 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 AMIGUSTO-IV AMI
Suggested Treatment Strategy
Abciximab
Low Dose Heparin:
60 U/kg bolus followed by a 7 U/kg/h infusion
Half Dose Lytic
URGENT PCI IF PERSISTENT CHEST PAIN OR ST ELEVATION
Future Studies
• FASTER
• ASSENT III
• GUSTO V - MI
• INTEGRITI
• FINESSE
TNK + TirofibanTNK + Tirofiban
Phase IIbPhase IIb
[ Spring 2001 ][ Spring 2001 ]
TNK + TirofibanTNK + Tirofiban
Phase IIbPhase IIb
[ Spring 2001 ][ Spring 2001 ]TNK + AbciximabTNK + Abciximab
TNK + heparinTNK + heparin
TNK + LMW heparinTNK + LMW heparin
approx 6000 ptsapprox 6000 pts
Phase IIbPhase IIb
[ Spring 2001 ][ Spring 2001 ]
TNK + AbciximabTNK + Abciximab
TNK + heparinTNK + heparin
TNK + LMW heparinTNK + LMW heparin
approx 6000 ptsapprox 6000 pts
Phase IIbPhase IIb
[ Spring 2001 ][ Spring 2001 ]
r-PA + Abciximabr-PA + Abciximab
r-PA + heparinr-PA + heparin
16,600 pts16,600 pts
Phase IIIPhase III
[ Spring 2001 ][ Spring 2001 ]
r-PA + Abciximabr-PA + Abciximab
r-PA + heparinr-PA + heparin
16,600 pts16,600 pts
Phase IIIPhase III
[ Spring 2001 ][ Spring 2001 ]
TNK + EptifibatideTNK + Eptifibatide
Phase IIbPhase IIb
[ Starting now ][ Starting now ]
TNK + EptifibatideTNK + Eptifibatide
Phase IIbPhase IIb
[ Starting now ][ Starting now ]
Abciximab + PCIAbciximab + PCI
Abciximab + r-PA + PCIAbciximab + r-PA + PCI
2700 pts; starting now2700 pts; starting now
Abciximab + PCIAbciximab + PCI
Abciximab + r-PA + PCIAbciximab + r-PA + PCI
2700 pts; starting now2700 pts; starting now
Summary
• Several aspects of combined fibrinolytic and GP IIb/IIIa inhibition reperfusion strategy remain to be clarified
• Further reductions in mortality should be expected with more inclusion of platelet inhibition in reperfusion strategies for ST-elevation MI
• Combined pharmacologic and catheter-based reperfusion approaches will offer optimal treatment to more patients
• Optimal dosing of unfractionated heparin added to combined fibrinolysis and GP IIb/IIIa inhibition
• Clinical importance of differences among GP IIb/IIIa antagonists in potency, effects on other adhesion molecules, and efficacy in protecting microvasculature
• Validation of the safety and efficacy of early invasive management combined with potent platelet inhibition
Evolving Questions