Acute Myocardial Infarction are Thrombolitics Enough

1
Acute Myocardial Infarction are Thrombolitics
Enough ?

• Augustin J. DeLago M.D.,F.A.C.C.
• Director,Catheterization Laboratory
• Director,Invasive Cardiology
• The Heart Institute
• Albany Medical Center

2
Management Strategies in AMI
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

3
GUSTO-I The Benefit of Reperfusion
Patency Mortality
P0.009
P0.08
8.9

• The Open Artery Hypothesis
• Reperfusion of the IRA results in LV preservation
• Open the artery early to improve outcomes

7.4
30-day mortality ()
4.4
TIMI 2
TIMI 0-1
TIMI 3
90-minute angiography
Ross AM et al. N Engl J Med. 199332916151622.
4
Innovations in the Managementof AMI
5
Innovations in the Managementof AMI
6
Innovations in the Managementof AMI
Limitations of Fibrinolysis
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
7
GP IIb/IIIa Inhibitors

Abciximab
Small molecule
Artists conception
Steric hindrance Nonspecific Binds with ?3 chain
on GP IIb/IIIa, ?v?3
Competitive blockadeHighly specific for GP
IIb/IIIaMimic amino acid sequences
8
GP IIb/IIIa Inhibitors

Abciximab

• Binding Competitive Competitive
• Half-life Plasma 2 h 2 h lt10
  minBiologic 2 h 2 h Days
  
• Clearance Renal Renal
  Renal/Spleen

Tirofiban
Eptifibatide
9
GP IIb/IIIa Inhibitors
Benefits of GP IIb/IIIa Inhibition in
AMI Review of Clinical Trials
10
EPIC AMI Subset Post Hoc Analysis
P0.002
91
P0.06
83
47.8
Death/re-MI/urgent TVR ()
32.3
26.1
21.1
4.5
4.5
30 days
6 months
Lefkovits J et al. Am J Cardiol.
19967710451051.
11
TIMI 3 Flow 90 min
TIMI 14
tPA rPA Phases
12
Abciximab Improves ST Res-90 min
TIMI 14
tPA rPA pooled
Complete (gt 70)ST Res
Plt0.0005
N329
N179
de Lemos et al AHA 1999
13
GP IIb/IIIa Inhibitors in Primary PTCA RAPPORT

• End Points
• Primary Composite of
• any-cause death, recurrentMI, repeat TVR
  within6 months
• Secondary Composites ofdeath, MI, urgent TVR
  at7 days and 30 days

Objective Evaluate safety and efficacy of
abciximab as adjunctive therapy to primary PTCA
Brener SJ et al. Circulation. 199898734741.
14
RAPPORT30-Day End Points (Intent-to-Treat)
Placebo (n242)
P0.03
Abciximab (n241)
11.2
48
P0.006
P0.52
6.6
of Patients
5.8
5.8
74
4.6
1.7
Death, re-MI, or urgent intervention
Urgent intervention
Death or re-MI
Brener SJ et al. Circulation. 199898734741.
15
PCI with Adjunctive GP IIb/IIIa
30-d Mortality, MI, Urgent ReV
30
26.1
Control
20
Abciximab
Percent
15.3
11.2
9.7
9.2
10
7.3
5.8
4.5
3.6
2
0
Trial
EPIC
GUSTO-III
Neumann
RAPPORT
ADMIRAL
N 64 392/83 200 403 300 Random No No Yes Yes
Yes PCI PTCA PTCA Stent PTCA Stent P 0.06 0.0
4 0.03 lt0.05 lt0.05
.
16
Lysis vs Primary PTCA
30-d Mortality or Discharge
Lytic
PTCA
11.9

P
lt0.05
8.7
7
7
6.5
Percent
6.5
5.7
5.6
5.5
4.4
4.3
3.6
2.6
1.0
PAMI
ZWOLLE
MAYO
GUSTO-IIb
MITI
CCP
Weaver
N 395 395 103 1138
3145 20,683 2606
Herrmann HC. Am J Cardiol. 20008510C-16C.
17
Reperfusion in AMI
FIBRINOLYSIS
PRIMARY PTCA

• Reduces mortality
• Well studied
• Widely available

• Lower mortality
• Anatomic definition
• Avoids hemorrhage

18
Facilitated Percutaneous Coronary Intervention
Evidence for the Efficacy of a New Approach
19
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

20
SPEED Study Population
Dose-finding (n305)
Abciximab reteplase
SPEED study (n528) Primary
end point TIMI-3 flow
Abciximab reteplase (55 U) vs full-dose
reteplase (1010 U)
Confirmation (n223)
60-90 min angiogram (n466)
Nonqualifying PCI (n43)
No early PCI (n162)
Facilitated PCI (n323)
Herrmann HC et al. J Am Coll Cardiol.
20003614891496.
21
TIMI Grade 3 Flow at 60-90 Min
SPEED
Angiographic Core Lab Reading
p 0.2
p 0.06
n 107
n 103
n 75
n 66
r-PA Alone
60 U Hep Abciximab r-PA 5 5
40 U Hep Abciximab r-PA 5 5
Abciximab Alone
ACC 1999 Oral Presentation
22
SPEED Clinical Success
94.4
Plt0.05
Percent
83.8
0
10
20
30
Days
Early PCI
No Early PCI
Herrmann HC et al. J Am Coll Cardiol.
20003614891496.
23
Results in a Perspective
GUSTO-1 90-min
Meta-analysis 60-min
SPEED 60-min
100
p lt 0.001
p 0.06
14
23
23
75
54
50
31
25
0
Abciximab r-PA 5 5
SK
t-PA
ACC 1999 Oral Presentation
24
GUSTO-IV AMI
Trial Protocol (n 16,600)
ST , lytic eligible, lt 6 h
ASA
No Abciximab
Abciximab
2 x 10 U bolus (30) Reteplase
2 x 5 U bolus (30) Reteplase
Low Dose Heparin 60 U/kg bolus followed by
a 7 U/kg/h infusion
Standard Heparin 5,000 U bolus followed by
either 800 U/hr (pts lt 80 kg) or 1,000 U/hr
(pts gt 80 kg) infusion
1º endpoint mortality at 30 days 2º endpoint
clinical and safety events at 30 days
0.25mg/kg bolus followed by 0.125 ?g/kg/min
infusion for 12 hours
25
Suggested Treatment Strategy
Abciximab
Half Dose Lytic
Low Dose Heparin 60 U/kg bolus followed by
a 7 U/kg/h infusion
URGENT PCI IF PERSISTENT CHEST PAIN OR ST
ELEVATION
26
Future Studies
TNK Tirofiban Phase IIb Spring 2001

• FASTER
• ASSENT III
• GUSTO V - MI
• INTEGRITI
• FINESSE

TNK Abciximab TNK heparin TNK LMW
heparin approx 6000 pts Phase IIb Spring 2001
r-PA Abciximab r-PA heparin 16,600 pts Phase
III Spring 2001
TNK Eptifibatide Phase IIb Starting now
Abciximab PCI Abciximab r-PA PCI 2700 pts
starting now
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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

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Innovations in the Managementof AMI
GP IIb/IIIa Inhibition Improves Primary
PCI Outcomes by

• Increasing TIMI-3 flow rates prior to and post
  PCI
• Improving cardiac function
• Improving procedural success
• Reducing short- and long-term ischemic events

30
Reasons for Better Results With Contemporary
Facilitated PCI

• Abciximab blocks platelet activation produced by
  fibrinolytic agents and PCI
• RAPPORT and ADMIRAL trials
• Intracoronary stents improve PTCA outcome by
  reducing dissection, reocclusion
• FRESCO, ZWOLLE, GRAMI, PAMI trials
• Increased operator experience
• PACT trial
• The specific fibrinolytic agent utilized (ie,
  reteplase)
• GUSTO-IIIrescue PCI

31
Evolving Questions

• 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

32
Hypothetical TIMI-3 Flow
Percent of patients with TIMI-3 flow
100
90
80
70
60
50
40
30
20
10
0
30
0
30
60
90
Early
Later
Begin Rx
Arrive ED
Time (min)
33
GP IIB/IIIa Inhibitor Use in PCI Summary

• Optimal inhibition of platelet aggregation can be
  attained with GP IIb/IIIa receptor inhibitors
• Target inhibition of the platelet GP IIb/IIIa
  receptor reduces ischemic events associated with
  PCI
• The relative efficacy of GP IIb/IIIa receptor
  inhibitors is difficult to judge from different
  clinical trials, given the differences in study
  design and end-point adjudication

34
Munich ExperiencePrimary Stenting With or
Without Abciximab

P0.024
P0.007
P0.003

62
18.1
56
0.44
Change in wall motion index (SD/chord)
Global LVEF ()
Change in peak flow velocity (cm/s)
10.4
0.15
(n72)
(n80)
(n72)
(n79)
(n72)
(n79)
No abciximab
Abciximab
Neumann FJ et al. Circulation. 19989826952701.
35
Facilitated PCI Trial
FINESSE
N 2700 Inclusion AMI (6 h) Exclusion Low
risk Age lt60 y and local inferior
infarction Design Open-label Facilitated
PCI Reteplase/abciximab Stent/clopidogrel Control
Primary PCI abciximab Heparin 60 U/kg Primary
end point D/ReMI/CHF (30 d) Secondary end
points ST segment resolution/ 1-y follow-up
36
SWIFT Trial of Anistreplase
Conventional care group
Intervention group
Survival
Freedom from MI
Patients alive without reinfarction ()
Patients surviving ()
Days from onset of symptoms
Days from onset of symptoms
SWIFT Trial Study Group. Br Med J.
1991302550-560.
37
SPEED Adverse Events at 30 Days
Early PCI (n323)
No Early PCI (n62)
30
30
Plt0.05
20
16.0
15
Percent
9.3
9.0
8.6
10
6.5
4.9
3.7
3.4
1.6
1.2
0
Death ReMI UR Bleed Trans
All
Herrmann HC et al. J Am Coll Cardiol.
2000361489-1496.
38
GP IIb/IIIa Inhibitors in AMIMunich
Experience (Neumann et al)

• Conclusions
• Improvements in cardiac
• function significantly greater in stent pts
  receiving abciximab
• vs heparin-only pts
• Abciximab improved
• microvascular reperfusion
• Abciximab improved
• restoration of LV function
• in infarct area

Objective Evaluate cardiac function inpts given
adjunctive abciximab stenting vs pts
given standard heparin only
39
GP IIb/IIIa Inhibitors in AMI ADMIRAL

• Conclusions
• Significant improvement inLV function at 24
  hours
• TIMI-3 flow significantly
• higher in abciximab-treated
• group than placebo groupprior to and post PCI
• Significant reduction in death/MI/urgent TVR
  through 30 days

Objective Compare pts given abciximab vs
placebo in primary stenting
40
Thrombogenesis
Platelet Aggregation
GP IIb/IIIa
Fibrinogen
41
Thrombogenesis
Platelet Adhesion
GP IIb/IIIa
GP Ib/IX
von WillebrandFactor
GP Ia/IIa
Collagen
42
Thrombogenesis
Platelet Activation
TxA2
Strong Agonists
TxA2 thrombin collagen (high level)
TxA2
G protein
Prostaglandins G2/H2
Activated phospholipase C
Arachidonic acid
Calcium release
Phospholipase A2
PKC
Weak Agonists Epinephrine, ADP, serotonin,
collagen
Activation of GP IIb/IIIa
43
TIMI-14
90-Minute TIMI 3 Flow (Core Lab)
100
Abx .3 mg/kg
Abx tPA
tPA
75
76
74
73
63
61
59
57
50
53
38
25
0
Antman et al. Circulation 1999992720-2732
44
TIMI Myocardial Perfusion Grade 2/3 at 90 min
TIMI 14
p0.08
Pts
33
66
rPA 1010 U
? rPA Abx
45
Innovations in the Managementof AMI
Limitations of Primary PCI
Longer time to TIMI-3 flow Availability of
catheterization laboratory