Download - The Evolving Role of LMWH in ACS
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The Evolving Role of
LMWH in ACS
The Evolving Role of
LMWH in ACS
James J. Ferguson, MD
Texas Heart InstituteHouston, TX
James J. Ferguson, MD
Texas Heart InstituteHouston, TX
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ObjectivesObjectives
• Assist peers in overcoming gaps in awareness of LMWH therapy in ACS
• Review emerging data for ACS• NICE-3• GUSTO-IV
• Discuss strategies for increasing early administration of LMWH therapy
• Discuss future directions for LMWH therapy in ACS
• Assist peers in overcoming gaps in awareness of LMWH therapy in ACS
• Review emerging data for ACS• NICE-3• GUSTO-IV
• Discuss strategies for increasing early administration of LMWH therapy
• Discuss future directions for LMWH therapy in ACS
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TIMI 11B-ESSENCE Meta-Analysis Death/MITIMI 11B-ESSENCE Meta-Analysis Death/MI
0.5 1 20.6 0.7 0.8 0.9
Odds RatioEnox Better UFH Better
DayOR p
N UFH(%)
Enox (%)
OVERALL
ESSENCE8
0.77(0.62-0.96)
23 0.027081
3910
3171
B
B
5.3 4.1
OVERALL
ESSENCE14
0.79(0.65-0.96)
21 0.027081
3910
3171 B
B
6.5 5.2
OVERALL
ESSENCE430.82
(0.69-0.98)18 0.027081
3910
3171 B
B
8.6 7.1
%TIMI 11B
TIMI 11B
TIMI 11B
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The ESSENCE Trial: 1-YearTime to First Triple Endpoint
The ESSENCE Trial: 1-YearTime to First Triple Endpoint
0
5
10
15
20
25
30
35
40
0 2 4 6 8 10 12 14
Months
Cu
mu
lati
ve e
ve
nt
rate
(%
)
Heparin
Enoxaparin
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ParadoxParadox
• We have data strongly supporting a better form of therapy
• We are still not using it widely
Why?
• We have data strongly supporting a better form of therapy
• We are still not using it widely
Why?
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Unfractionated HeparinUnfractionated Heparin LMW HeparinLMW Heparin
IIaATIIaAT
XaAT XaAT
UpstreamUpstreamUpstreamUpstream
DownstreamDownstreamDownstreamDownstream
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0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
1.21.2
1.41.4
1.61.6
1.81.8
2.02.0
22 66 1010 1414 1818 2222 2626 3030 3434Time (h)Time (h)
An
ti-X
a a
cti
vit
y (
IU/m
l)A
nti
-Xa
ac
tiv
ity
(IU
/ml) 1.0 mg/kg1.0 mg/kg 1.25 mg/kg1.25 mg/kg
1.5 mg/kg1.5 mg/kg 2.0 mg/kg2.0 mg/kg
Plasma Anti-Xa Activity after Ascending Single Doses ofPlasma Anti-Xa Activity after Ascending Single Doses of Subcutaneous Enoxaparin in Healthy VolunteersSubcutaneous Enoxaparin in Healthy Volunteers
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% P
ts
Hours from Randomization
0
1
2
3
4
5
6
7
8
9
0 8 16 24 32 40 48 56 64 72
UFHUFH
ENOXENOX
5.2 %5.2 %
4.2 %4.2 %
RRR 18%RRR 18%P=0.21P=0.21
% P
ts%
Pts
Hours from RandomizationHours from Randomization
00
11
22
33
44
55
66
77
88
99
00 88 1616 2424 3232 4040 4848 5656 6464 7272
7.3 %7.3 %
5.5 %5.5 %
RRR 24%RRR 24%P=0.03P=0.03
UFHUFH
ENOXENOX
ESSENCEESSENCE TIMI 11BTIMI 11B
Death/MI/Urgent RevascDeath/MI/Urgent RevascEarly Rx PhaseEarly Rx Phase
Early Benefit
AventisParsippany, NJ
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TIMI 11BTriple Endpoint at Day 43
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Discussion Discussion
• How are you currently using LMWHs?
• What are you using?• When are you using it?• Why? Why not?
• How are you currently using LMWHs?
• What are you using?• When are you using it?• Why? Why not?
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CAPTURE
GUSTO IV†
PRISM
PRISM-Plus
PURSUIT
PARAGON
Trial (LMWH)
ESSENCE
TIMI 11B
TESSMA‡
Trial (IIb/IIIa) Placebo IIb/IIIa
1252
7800
3231
1570
10,948
2282
3171
3910
7,081
N
9.0
8.0
7.0
11.9
15.7
11.7
Heparin
7.7
8.3
8.6
4.8
~8.6
5.7
8.7
14.2
10.3
Enoxaparin
6.2
7.4
7.1
Better Worse0.1 1 10
Clinical Event Rates in Unstable Angina Trials
Death / MI at 30 days
Odds Ratio & 95% CI
N
† Preliminary results - placebo vs abciximab bolus plus 24 and 48 hr infusion‡ Meta-analysis of TIMI 11B and ESSENCE at Day 43
(%) (%)
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NICE-3NICE-3NNational ational IInvestigators nvestigators CCollaborating on ollaborating on
EEnoxaparinnoxaparin
NICE-3NICE-3NNational ational IInvestigators nvestigators CCollaborating on ollaborating on
EEnoxaparinnoxaparin
XXIIXXIIndnd Congress of the European Congress of the European Society of CardiologySociety of Cardiology
August 30, 2000August 30, 2000
Amsterdam, The NetherlandsAmsterdam, The Netherlands
XXIIXXIIndnd Congress of the European Congress of the European Society of CardiologySociety of Cardiology
August 30, 2000August 30, 2000
Amsterdam, The NetherlandsAmsterdam, The Netherlands
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NICE-3 ObjectivesNICE-3
Objectives
• To assess the safety profile (primarily with respect to bleeding) of enoxaparin and a IIb/IIIa antagonist (abciximab, eptifibatide or tirofiban) in patients with ACS
• To assess the feasibility and safety of bringing patients to the cath laboratory on combination therapy (without the use of UFH)
• To assess the safety profile (primarily with respect to bleeding) of enoxaparin and a IIb/IIIa antagonist (abciximab, eptifibatide or tirofiban) in patients with ACS
• To assess the feasibility and safety of bringing patients to the cath laboratory on combination therapy (without the use of UFH)
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NICE-3 Inclusion Criteria
NICE-3 Inclusion Criteria
• Recent (w/in 24 hours) unprovoked or rest angina
• Documented ischemic CAD• ECG changes• Abnormal biomarkers• Previously documented CAD
• Patients on prior UFH could be included
• Recent (w/in 24 hours) unprovoked or rest angina
• Documented ischemic CAD• ECG changes• Abnormal biomarkers• Previously documented CAD
• Patients on prior UFH could be included
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NICE-3 Exclusion Criteria
NICE-3 Exclusion Criteria
• Evolving Q-wave MI
• Fibrinolytic Rx w/in 48 hours
• Cardiogenic shock
• Left main disease
• Valvular disease
• CABG w/in 2 mos.; revasc w/in 1 week
• Thrombocytopenia
• Evolving Q-wave MI
• Fibrinolytic Rx w/in 48 hours
• Cardiogenic shock
• Left main disease
• Valvular disease
• CABG w/in 2 mos.; revasc w/in 1 week
• Thrombocytopenia
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NICE-3ProtocolNICE-3Protocol
Study Study Initiated Initiated
January 2000January 2000
46 clinical sites 46 clinical sites in US/Canadain US/Canada
In-hospital, 14-day, In-hospital, 14-day, and 30-day follow-and 30-day follow-
upup
661 patients 661 patients enrolledenrolled
[Enoxaparin [Enoxaparin alone]alone]
(n=45)(n=45)
Data Data available available
August 2000August 2000
All IIb/IIIa patientsAll IIb/IIIa patients(n=616)(n=616)
Enrollment Enrollment Completed May Completed May
20002000
AbciximabAbciximab
(n=147)(n=147)
EptifibatideEptifibatide
(n=252)(n=252)
TirofibanTirofiban
(n=217)(n=217)
All treated All treated with with
EnoxaparinEnoxaparin
If patients went to the cath lab, combination Rx continued; no UF heparin
used
If within 8 hrs of last enoxaparin, no additional
Rx
If > 8 hrs from last dose, 0.3 mg/kg enoxaparin iv
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NICE-3ProtocolNICE-3Protocol
• Primary Endpoint• Non-CABG major bleeding (TIMI
criteria) during hospitalization
• Secondary Endpoints• Minor bleeding (TIMI criteria)• Clinical efficacy
•Composite of death, MI, ischemia-driven TVR
• Primary Endpoint• Non-CABG major bleeding (TIMI
criteria) during hospitalization
• Secondary Endpoints• Minor bleeding (TIMI criteria)• Clinical efficacy
•Composite of death, MI, ischemia-driven TVR
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NICE-3Sample Size
NICE-3Sample Size
• Primary Hypothesis
• The 95% CI for major bleeding will not exceed the historical rate
• Agents examined as a whole and separately
• Example (Assuming major bleed rate of 2%):
• A 200 patient sample size has a 95% CI of approx 0.1-3.9%
• A 150 patient sample size has a 95% CI of approx 0-4.2%
• Primary Hypothesis
• The 95% CI for major bleeding will not exceed the historical rate
• Agents examined as a whole and separately
• Example (Assuming major bleed rate of 2%):
• A 200 patient sample size has a 95% CI of approx 0.1-3.9%
• A 150 patient sample size has a 95% CI of approx 0-4.2%
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NICE-3Demographics
NICE-3Demographics
AgeAge 62.9 62.9 12.2 years12.2 years
WeightWeight 83.9 83.9 18.5 kg18.5 kg
M/F M/F approx 2:1approx 2:1
LOSLOS 5.9 5.9 4.2 days 4.2 days
AgeAge 62.9 62.9 12.2 years12.2 years
WeightWeight 83.9 83.9 18.5 kg18.5 kg
M/F M/F approx 2:1approx 2:1
LOSLOS 5.9 5.9 4.2 days 4.2 days
HistoryHistory
HTNHTN 63.5%63.5% Prior PCIPrior PCI 30.7%30.7%
DMDM 30.0%30.0% Prior CABGPrior CABG 20.9%20.9%
SmokingSmoking 28.1%28.1% Prior MIPrior MI 36.2%36.2%
CHF (on admin) 4.5%CHF (on admin) 4.5%
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NICE-3Bleeding (%)
NICE-3Bleeding (%)
AbciximabAbciximab
(n=147)(n=147)
EptifibatideEptifibatide
(n=252)(n=252)
TirofibanTirofiban
(n=217)(n=217)
EnoxapariEnoxaparinn
[Enoxaparin [Enoxaparin alone]alone]
(n=45)(n=45)
All All IIb/IIIaIIb/IIIa
(n=616)(n=616)
AllAll 17.817.8
Major Major 6.76.7
non-CABGnon-CABG
4.4 4.4
MinorMinor 13.313.3
XfusionXfusion 8.98.9
AllAll 27.227.2
Major Major 5.15.1
non-CABGnon-CABG
1.4 1.4
MinorMinor 24.024.0
XfusionXfusion 10.610.6
AllAll 30.630.6
Major Major 4.44.4
non-CABGnon-CABG
3.2 3.2
MinorMinor 27.227.2
XfusionXfusion 10.310.3
AllAll 24.524.5
Major Major 4.14.1
non-CABGnon-CABG
0.70.7
MinorMinor 22.422.4
XfusionXfusion 10.910.9
AllAll 27.9 27.9
Major Major 4.5 4.5
non-CABG 1.9non-CABG 1.9
MinorMinor 25.0 25.0
XfusionXfusion 10.5 10.5
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NICE-3In-Hospital Clinical Outcomes
(%)
NICE-3In-Hospital Clinical Outcomes
(%)
AbciximabAbciximab
(n=147)(n=147)
EptifibatideEptifibatide
(n=252)(n=252)
TirofibanTirofiban
(n=217)(n=217)
[Enoxaparin [Enoxaparin alone]alone](n=45)(n=45)
All IIb/IIIaAll IIb/IIIa
(n=616)(n=616)
DeathDeath 0 0
MI MI 2.2 2.2
uTVRuTVR 2.2 2.2
D/MI/uTVR 4.4D/MI/uTVR 4.4
D/MID/MI 2.2 2.2
DeathDeath 0.30.3
MI MI 3.43.4
uTVRuTVR 2.1 2.1
D/MI/uTVR 5.7D/MI/uTVR 5.7
D/MID/MI 3.63.6
DeathDeath 0.5 0.5
MI MI 4.1 4.1
uTVRuTVR 3.2 3.2
D/MI/uTVR 7.8D/MI/uTVR 7.8
D/MID/MI 4.6 4.6
DeathDeath 0.40.4
MI MI 3.23.2
uTVRuTVR 2.0 2.0
D/MI/uTVR 5.2D/MI/uTVR 5.2
D/MID/MI 3.23.2
DeathDeath 0 0
MI MI 2.7 2.7
uTVRuTVR 0.7 0.7
D/MI/uTVR 3.4D/MI/uTVR 3.4
D/MID/MI 2.7 2.7
EnoxapariEnoxaparinn
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NICE-330% in Platelet Count
NICE-330% in Platelet Count
9.4
4.7
3.8
5.5
00
2
4
6
8
10
Abciximab Eptifibatide Tirofiban All I Ib/ I I Ia No I Ib/ I I Ia
9.4
4.7
3.8
5.5
00
2
4
6
8
10
Abciximab Eptifibatide Tirofiban All I Ib/ I I Ia No I Ib/ I I Ia
0<100K 0.85%<100K 1.44%<100K 0.86%<100K
(n=138)(n=138) (n=235)(n=235) (n=208)(n=208) (n=581)(n=581) (n=38)(n=38)
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NICE-3All Major Bleeding (%)
NICE-3All Major Bleeding (%)
1
4.8
3.6
4.8
3.1
0.9
4.3
1.7
0
2
4
6
Abciximab Eptifibatide Tirofiban All IIb/IIIa
Patients undergoing PCIPatients undergoing PCI Patients not undergoing PCI or CABG
Patients not undergoing PCI or CABG
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NICE-3PCI Patients (n=292)
NICE-3PCI Patients (n=292)
Tirofiban 0.9%
Eptifibatide2.4%
Abciximab 0
All IIb/IIIa1.0%
Tirofiban 0.9%
Eptifibatide2.4%
Abciximab 0
All IIb/IIIa1.0%
Non-CABG Major BleedingNon-CABG Major Bleeding
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NICE-3Conclusions
NICE-3Conclusions
• Combination of enoxaparin and IIb/IIIa• Does not result in excess major bleeding • Events (non-CABG)
• Patients on combination Rx can safely undergo PCI
• Clinical outcomes in NICE-3 were comparable to those noted in prior studies
• Therefore, not necessary to use UFH in:• UA/NSTEMI patients undergoing coronary • intervention who are treated with enoxaparin
and an IV IIb/IIIa antagonist
• Combination of enoxaparin and IIb/IIIa• Does not result in excess major bleeding • Events (non-CABG)
• Patients on combination Rx can safely undergo PCI
• Clinical outcomes in NICE-3 were comparable to those noted in prior studies
• Therefore, not necessary to use UFH in:• UA/NSTEMI patients undergoing coronary • intervention who are treated with enoxaparin
and an IV IIb/IIIa antagonist
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NICE-3Clinical Implications
NICE-3Clinical Implications
• Real-world study• Broad distribution of patients and institutions• Safety data for all 3 commercially available
• IIb/IIIa antagonists
• Addresses safety concerns about combining enoxaparin and a IIb/IIIa antagonist
• Addresses logistical concerns about transition to cath lab
• Foundation for future investigations
• Real-world study• Broad distribution of patients and institutions• Safety data for all 3 commercially available
• IIb/IIIa antagonists
• Addresses safety concerns about combining enoxaparin and a IIb/IIIa antagonist
• Addresses logistical concerns about transition to cath lab
• Foundation for future investigations
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Is it safe to combine enoxaparin Is it safe to combine enoxaparin
with IIb/IIIa blockers?with IIb/IIIa blockers?
How do we make the transition How do we make the transition
from the floor to the cath lab?from the floor to the cath lab?
Is it safe to combine enoxaparin Is it safe to combine enoxaparin
with IIb/IIIa blockers?with IIb/IIIa blockers?
How do we make the transition How do we make the transition
from the floor to the cath lab?from the floor to the cath lab?
No safety issues at No safety issues at presentpresent
Potential synergismPotential synergism
Good regimen for PCIGood regimen for PCI
No safety issues at No safety issues at presentpresent
Potential synergismPotential synergism
Good regimen for PCIGood regimen for PCI
Carefully but confidently, Carefully but confidently, within the limits of our within the limits of our
experienceexperience
Carefully but confidently, Carefully but confidently, within the limits of our within the limits of our
experienceexperience
Issues for Enoxaparin in ACS
Issues for Enoxaparin in ACS
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Discussion Discussion
• How does NICE-3 help you?
• What questions doesn’t it answer?
• Is it going to affect your practice?
• What additional information do we
need?
• How does NICE-3 help you?
• What questions doesn’t it answer?
• Is it going to affect your practice?
• What additional information do we
need?
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NICE-1NICE-1
NICE-4NICE-4
NICE-3NICE-3
? ? ?? ? ?
PI: Cindy GrinesPI: Cindy Grines
Enoxaparin (1 mg/kg iv) for PCIEnoxaparin (1 mg/kg iv) for PCI
PI: Cindy GrinesPI: Cindy Grines
Enoxaparin (1 mg/kg iv) for PCIEnoxaparin (1 mg/kg iv) for PCI
PI: Dean KereiakesPI: Dean Kereiakes
Enoxaparin (0.75 mg/kg iv) Enoxaparin (0.75 mg/kg iv)
with abciximab for PCIwith abciximab for PCI
PI: Dean KereiakesPI: Dean Kereiakes
Enoxaparin (0.75 mg/kg iv) Enoxaparin (0.75 mg/kg iv)
with abciximab for PCIwith abciximab for PCI
PI: James FergusonPI: James Ferguson
Enoxaparin (1 mg/kg sq) Enoxaparin (1 mg/kg sq)
with IIb/IIIa blocker for ACSwith IIb/IIIa blocker for ACS
(including PCI)(including PCI)
PI: James FergusonPI: James Ferguson
Enoxaparin (1 mg/kg sq) Enoxaparin (1 mg/kg sq)
with IIb/IIIa blocker for ACSwith IIb/IIIa blocker for ACS
(including PCI)(including PCI)
The NICE Trials TogetherThe NICE Trials Together
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DiscussionDiscussion
Patient management strategies
when an ACS patient, who is a
candidate for LMWH, proceeds
to the cath lab
Patient management strategies
when an ACS patient, who is a
candidate for LMWH, proceeds
to the cath lab
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Future DataFuture Data
GUSTO-IV ACSGUSTO-IV ACS
A to ZA to Z
ACUTE-2ACUTE-2
INTERACTINTERACT
CRUISECRUISE
[Pilot trial LMWH vs combo Rx][Pilot trial LMWH vs combo Rx]
[Efficacy trial LMWH vs UFH][Efficacy trial LMWH vs UFH]
GUSTO-IV ACSGUSTO-IV ACS
A to ZA to Z
ACUTE-2ACUTE-2
INTERACTINTERACT
CRUISECRUISE
[Pilot trial LMWH vs combo Rx][Pilot trial LMWH vs combo Rx]
[Efficacy trial LMWH vs UFH][Efficacy trial LMWH vs UFH]
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GUSTO-IV ACSSimoons, ESC 2000GUSTO-IV ACS
Simoons, ESC 2000
• Multicenter study (458 sites in 24 countries)• ACS patients not undergoing
revascularization• Treated with ASA and UFH• Scandanavian subset got LMWH• 7800 patients randomized to
• abciximab (24 hours)• abciximab (48 hours) • placebo
• Primary Endpoint: Death or MI at 30 days
• Multicenter study (458 sites in 24 countries)• ACS patients not undergoing
revascularization• Treated with ASA and UFH• Scandanavian subset got LMWH• 7800 patients randomized to
• abciximab (24 hours)• abciximab (48 hours) • placebo
• Primary Endpoint: Death or MI at 30 days
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GUSTO-IV ACSSimoons, ESC 2000GUSTO-IV ACS
Simoons, ESC 2000
• Definition of ACS: Rest angina with ST-segment (1/2 mm) or (+) troponin
• Coronary angiography only for recurrent ischemia• ~ 28% had evolving MI• 14% from US, 48% from Western Europe• ~80% had ST-segment • ~59% had + troponin• ~32% had both• Revasc performed in ~30% by day 30• Only 1.4% revasc in first 48 hours
• Definition of ACS: Rest angina with ST-segment (1/2 mm) or (+) troponin
• Coronary angiography only for recurrent ischemia• ~ 28% had evolving MI• 14% from US, 48% from Western Europe• ~80% had ST-segment • ~59% had + troponin• ~32% had both• Revasc performed in ~30% by day 30• Only 1.4% revasc in first 48 hours
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GUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACS
Placebo Abcix (24) Abcix (48)
Death/MI 1.5 1.9 2.2
Death 0.3 0.7 0.9
Placebo Abcix (24) Abcix (48)
Death/MI 1.5 1.9 2.2
Death 0.3 0.7 0.9
Placebo Abcix (24) Abcix (48)
Death/MI 4.5 4.0 4.1
Death 1.8 1.5 2.0
Placebo Abcix (24) Abcix (48)
Death/MI 4.5 4.0 4.1
Death 1.8 1.5 2.0
Placebo Abcix (24) Abcix (48)
Death/MI 8.0 8.2 9.1
Death 3.9 3.4 4.2
Placebo Abcix (24) Abcix (48)
Death/MI 8.0 8.2 9.1
Death 3.9 3.4 4.2
48 Hours48 Hours
7 Days7 Days
30 Days30 Days
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GUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACS
UFH
Placebo (n = 2270)
Abciximab (n = 4556)
0.1% 0.15%
0.5% 0.5%
UFH
Placebo (n = 2270)
Abciximab (n = 4556)
0.1% 0.15%
0.5% 0.5%
ICHICH
Ischemic Stroke
Ischemic Stroke
LMWH SubstudyLMWH Substudy
Dalteparin
Placebo (n = 328)
Abciximab (n = 646)
0 0.3%
1.2% 0.8%
Dalteparin
Placebo (n = 328)
Abciximab (n = 646)
0 0.3%
1.2% 0.8%
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