Transcript PCI ExTract - Clinical Trial Results

PCI in Patients Receiving Enoxaparin
or UFH Following Fibrinolytic Therapy
for STEMI:
PCI ExTRACT-TIMI 25
C. Michael Gibson, Sabina A. Murphy, David A. Morrow,
Carolyn H. McCabe, Dietrich C. Gulba, Gilles Montalescot, Servet Cetin,
Oscar H. Kracoff, Basil S. Lewis, Nathan Roguin, Elliott M. Antman,
Eugene Braunwald, for the ExTRACT-TIMI 25 Investigators
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Disclosure
The TIMI Study Group has received research / grant support in the past 2 yrs
through the Brigham & Women’s Hospital with funding from (in alphabetical order):
Accumetrics, Inc.
Amgen, Inc.
AstraZeneca Pharmaceuticals LP
Baxter
Bayer Healthcare LLC
Beckman Coulter, Inc.
Biosite Incorporated
Bristol-Myers Squibb
CardioKinetix
CV Therapeutics, Inc.
Eli Lilly and Company
FoldRx
GlaxoSmithKline
INO Therapeutics LLC
Inotek Pharmaceuticals Corporation
Integrated Therapeutics Corporation
KAI Pharmaceuticals
Merck & Co., Inc.
Millennium Pharmaceuticals, Inc.
Novartis Pharmaceuticals
Nuvelo, Inc.
Ortho-Clinical Diagnostics, Inc.
Pfizer, Inc.
Roche Diagnostics Corporation
Roche Diagnostics GmbH
Sanofi-Aventis
Sanofi-Synthelabo Recherche
Schering-Plough Research Institute
St Jude Medical
The National Institutes of Health
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Background: Main Results
ExTRACT-TIMI 25
Main Secondary Endpoint:
Death, non-fatal re-MI, urgent
revascularization by 30 days
Primary Endpoint:
Death or non-fatal re-MI by 30 days
UFH
UFH
12.0
11.7
9.9
ENOX
ENOX
%
RR = 0.83
p = 0.000003
Days
14.5
%
RR = 0.81
p = 0.000001
Days
N Engl J Med 2006;354:1477-88.
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Objective
To determine whether ENOX is
superior to UFH as adjunctive
therapy for patients undergoing PCI
for STEMI who initially received
fibrinolytic therapy.
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Study Profile
20,479 Patients Randomized into
ExTRACT-TIMI 25
10,256 Assigned ENOX
10,223 Assigned UFH
2,272 Underwent
PCI by 30 days
22.8%
2,404 Underwent
PCI by 30 days
24.2%
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Anticoagulation for PCI
ONLY blinded study drug to be used
All Pts receive BOTH blinded Enox/Plac AND UFH/Plac
< 8h since SC dose
Additional Enox/Plac
NO
> 8 h since SC dose
0.3 mg/kg IV
Additional UFH/Plac
GP IIb/IIIa
ACT 200 s*
ACT 200 s*
No GP IIb/IIIa
ACT 250 s*
ACT 250 s*
*ACT TESTING ONLY BY UNBLINDED MEDICAL PROFESSIONAL
Sheath Removal
Closure Device
No Closure Device
After PCI
+ Groin Hemostasis
End of PCI
Wait 6 hours after last sc/IV dose
STUDY MEDICATION SHOULD NOT BE
STARTED UNLESS CLINICALLY INDICATED
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Baseline Characteristics
PCI Cohort N = 4,676
Age (yrs)-median
57
CrCl (ml/min)-median 87
Male (%)
82
UFH within 3 h (%)
Hypertension (%)
37
LMWH within 7 d (%) 0.7
Hyperlipidemia (%)
23
Killip Class I (%)
Current smoker (%)
51
TIMI Risk Score (STEMI)
Diabetes (%)
16
Prior MI (%)
11
Anterior MI (%)
41
> 3 (%)
ALL P = NS for ENOX vs UFH
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92
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Medications During Hospitalization
PCI Cohort
N = 4,676
Fibrinolytic
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SK (%)
Fibrin-specific (%) 79
ASA (%)
Beta Blocker (%)
ACEI / ARB (%)
Statin (%)
Clopidogrel (%)
98
86
80
85
68
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UFH
13.8%
10
ENOX
10.7%
5
RR 0.77
p=0.001
0
Death or MI (%)
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PCI Cohort: Primary Endpoint
Death or Nonfatal MI by 30 days
0
5
10
15
20
25
30
Days
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PCI Cohort: Safety
Event
ENOX
n=2,238
UFH
RR
P-Value
n=2,377
TIMI Major Bleed 1.4%
1.6%
0.87 (0.55-1.39)
0.56
TIMI Minor Bleed 3.3%
2.4%
1.34 (0.95-1.88)
0.09
TIMI Major or
Minor Bleed
4.6%
4.0%
1.15 (0.88-1.51)
0.31
ICH
0.2%
0.4%
0.42 (0.13-1.35)
0.18
Stroke
0.3%
0.9%
0.30 (0.12-0.75)
0.006
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PCI Cohort: Death or Nonfatal reMI Major Subgroups
Subgroup
No hx diabetes
Hx diabetes
Enox (%)
10.3
12.5
UFH (%)
13.2
17.3
Non-anterior MI
Anterior MI
9.4
12.3
13.4
14.5
Sx onset to Lytic <=median
Sx onset to Lytic >median
10.3
11.5
15.1
11.8
SK
Fibrin specific
10.2
10.9
11.7
14.3
Time to PCI >=5 days
Time to PCI 2-<5 days
Time to PCI <48 hrs
7.8
8
20.8
9.2
13.9
23.2
No GP IIb/IIIa Inhibitor
GP IIb/IIIa Inhibitor
9.5
17.1
12.3
20.2
No Clopidogrel
Clopidogrel
12.4
9.8
13
14.2
0.25
0.5
ENOX Better
0.75
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Odds
Ratio
1.25
1.5
UFH Better
11
10
UFH
10.9%
ENOX
7.8%
5
RR 0.72
p<0.001
0
Non-Fatal MI (%)
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PCI Cohort:
Nonfatal Recurrent MI by 30 days
0
5
10
15
20
25
30
Days
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Incidence and Relative Timing of
PCI
Incidence of PCI:
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Median time to PCI:
p=0.006
5
10
UFH (n=2,404): 109 hours
Enox (n=2,272): 122 hours
0
PCI (%)
20
25
UFH
24.2%
p=0.027
ENOX
22.8%
0
5
10
15
Days
20
25
30
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Relative Timing of PCI:
Urgent vs Non-Urgent PCI
UFH
ENOX
p=0.31
p=0.006
140
120
122.0
109.0
126.0
p=0.08
100
Hours
120.0
80
n=1885
67.0
79.0
n=278
n=442
60
40
20
0
n=2,404
n=2,272
All PCI
Urgent PCI
n=1,829
n=1,885
Non- Urgent PCI
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Outcomes by 30 Days in Patients
Undergoing PCI on Blinded Study Drug
UFH (n=1,075)
ENOX (n=1,103)
RR 0.77
P=0.002
% Events
20
15
16.7
RR 0.75
P=0.33
13.0
10
5
0
2.4
Death or Nonfatal reMI
1.8
Major Bleed
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PCI Performed on Blinded
Study Drug
Two scenarios in which a patient
underwent PCI on study drug:
1) Blinded study drug never
discontinued and PCI performed
on blinded study drug
2) Blinded study drug
discontinued prior to PCI and
then resumed at time of PCI
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15
UFH
18.9%
ENOX
14.2%
5
10
RR 0.75
p=0.018
0
Death or MI (%)
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Death or Nonfatal MI by 30 days Among PCI
Patients in Whom Study Drug Was
Not Discontinued (n=1501)
0
5
10
15
Days
20
25
30
17
15
RR 0.41
p=0.004
10
UFH
14.4%
5
ENOX
5.9%
0
Death or MI (%)
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Death or Nonfatal MI by 30 days Among PCI
Patients in Whom Study Drug Was
Discontinued and Resumed For PCI (n=677)
0
5
10
15
Days
20
25
30
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Conclusion
• When compared to UFH as adjunctive
therapy among patients undergoing PCI,
ENOX:
• Reduced death or MI
• Reduced stroke
• No difference in bleeding
Conclusion (cont.)
• ENOX was associated with ↓ risk of
death or reMI both among patients in
whom antithrombin was continued as
well as discontinued prior to PCI.
• ENOX associated with both delayed
onset and ↓ occurrence of reMI, both of
which may expand window of
opportunity to perform PCI following
fibrinolytic administration.
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Clinical Implications
• Among STEMI pts treated with lytic,
ENOX can be administered as the sole
antithrombin therapy before and
during PCI without the need for
additional antithrombin inhibition.
• Periprocedural ENOX is preferable to
UFH in the management of these
patients.
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Back Up Slides
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10
5
p=0.07 for ENOX vs UFH in no PCI cohort
p=0.93 for ENOX vs UFH in PCI cohort
0
Death (%)
15
Death at 30 days by PCI and
randomization group
0
5
10
15
Days
ENOX/PCI
UFH/PCI
20
25
30
ENOX/no PCI
UFH/no PCI
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