Enoxaparin and Thrombolysis
Reperfusion for Acute
Myocardial Infarction
ExTRACT-TIMI 25
ACC 2006
Atlanta, GA
Disclosure Statement:
Dr. Antman received research grant support via the
Brigham and Women’s Hospital from sanofi-aventis
1
Background
• Advantages of ENOX over UFH
Greater anti Xa:anti IIa activity
Reliable A/C without monitoring
Convenient sc administration
• Prior trials suggest
ENOX may be superior to UFH
• Pharmacologic reperfusion remains the
most common treatment for STEMI
Definitive evaluation of
ENOX vs UFH needed
2
Primary Hypothesis
Compared to UFH, adjunctive
antithrombin therapy with ENOX
reduces the composite end
point of all-cause mortality or
non-fatal re-MI within 30 days in
patients with STEMI who are
eligible to receive fibrinolytic
therapy.
3
Trial Organization
TIMI Study Group
Eugene Braunwald
David A. Morrow
Sabina Murphy
Elliott M. Antman
Carolyn H. McCabe
Susan McHale
Sponsor: sanofi-aventis
Frank Jiang
Paul Chew
Lu Cui
Christophe Gaudin
Sylvie Fontecave
Kim Giordano
Data Safety Monitoring Board
Frans Van de Werf (Chair)
Desmond Julian
J. Ward Kennedy
David DeMets
Jean Rouleau
Jeffrey Anderson
4
Protocol Design
STEMI < 6 h
Lytic eligible
ASA
Lytic choice by MD
(TNK, tPA, rPA, SK)
Double-blind, double-dummy
ENOX
< 75 y: 30 mg IV bolus
SC 1.0 mg / kg q 12 h (Hosp DC)
≥ 75 y: No bolus
SC 0.75 mg / kg q 12 h (Hosp DC)
UFH
60 U / kg bolus (4000 U)
Inf 12 U / kg / h (1000 U / h)
Duration: at least 48 h
Cont’d at MD discretion
CrCl < 30: 1.0 mg / kg q 24 h
Day 30
1° Efficacy Endpoint: Death or Nonfatal MI
1° Safety Endpoint: TIMI Major Hemorrhage
5
Enrollment: Oct 2002 - Oct 2005
N = 20,479 (ITT)
Argentina
Finland
Latvia
Singapore
Australia
France
Lebanon
Slovakia
Austria
Germany
Lithuania
South Africa
Belarus
Greece
Malaysia
Spain
Belgium
Hong Kong
Mexico
Sweden
Brazil
Hungary
Netherlands
Switzerland
Bulgaria
India
New Zealand
Thailand
Canada
Ireland
Norway
Turkey
Chile
Israel
Poland
Ukraine
China
Italy
Portugal
United Kingdom
Croatia
Jordan
Romania
United States
Estonia
Republic of
Korea
Russian
Federation
Uruguay
48 Countries
674 Sites
6
Baseline Characteristics
ITT
N = 20,479
Age (yrs)-median
59
CrCl (ml/min)-median 82
Male (%)
77
UFH within 3 h (%)
Hypertension (%)
44
LMWH within 7 d (%) 0.5
Hyperlipidemia (%)
18
Killip Class I (%)
Current smoker (%)
47
TIMI Risk Score (STEMI)
Diabetes (%)
15
< 3 (%)
64
Prior MI (%)
13
> 3 (%)
36
Anterior MI (%)
44
ALL P = NS
16
89
7
Medications
ITT
N = 20,479
Fibrinolytic
20
SK (%)
Fibrin-specific (%) 80
ASA (%)
Beta Blocker (%)
ACEI / ARB (%)
Statin (%)
ALL P = NS
95
86
80
70
8
Primary End Point (ITT)
Death or Nonfatal MI
Primary End Point (%)
15
UFH
12
12.0%
17% RRR
9
9.9%
ENOX
Relative Risk
0.83 (0.77 to 0.90)
P<0.0001
6
3
Lost to follow up = 3
0
0
5
10
15
Days
20
25
30
9
Treatment Benefit over Time (ITT)
Death or Nonfatal MI
Primary End Point (%)
15
48 h
UFH
12
206 events
9
ENOX
12.0%
(1223)
9.9%
(1017)
5.2%
6
4.7%
RR
0.90
(0.80 to 1.01)
P=0.08
3
0
0 UFH
5
ENOX
10
15
Days
20
25
30
10
Major Secondary End Point
Death or Nonfatal MI
or Urgent Revascularization (ITT)
Secondary End Point (%)
15
48 h
UFH
280 events
19% RRR
12
14.5%
(1479)
11.7%
(1199)
ENOX
9
RR 0.81
(0.75 to 0.87)
P<0.0001
6.1%
6
5.3%
12% RRR
3
0
RR 0.88
(0.79 to 0.98)
P=0.02
0UFH
5
ENOX
10
15
Days
20
25
30
11
Outcomes at 30 Days (ITT)
8%
8
7
UFH
ENOX
7.5
6.9
33%
6
%
4.5
5
26%
4
3
3
2.8
2.1
2
1
0
Death
Nonfatal MI
Urg Revasc
RR
0.92
0.67
0.74
P value
0.11
<0.0001
0.0008
12
Death or Nonfatal MI - Day 30
Major Subgroups
Reduction In Risk (%)
Male
SEX
All Interaction Tests
P = NS
Female
20
6
< 75
AGE (y)
>= 75
INFARCT
LOCATION
Anterior
DIABETES
No DM
11
23
Other
B
17
21
B
17
20
DM
No Prior MI
PRIOR MI
Prior MI
FIBRINOLYTIC
13
18
Streptokinase
Fibrin-specific
23
12
< Median
TIME TO Rx
B
> Median
20,479
OVERALL
18
16
0.5
ENOX Better
P < 0.0001
1
Relative Risk
17
2
UFH Better
Death or Nonfatal MI - Day 30
Medical Rx vs Any PCI
13.8
15
% Events
11.4
10
5
10.7
9.7
RRR
23%
RRR
16%
0
AnyPCI
PCI
N = 4,676 (23%)
P Value
0.001
UFH
UFH
ENOX
ENOX
Medical Rx
Medical
Rx
N = 15,223 (75%)
0.0004
14
Death or Nonfatal MI - Day 30
Clopidogrel Use
% Events
15
10
5
12.2
11.4
10.4
RRR
15%
8.7
RRR
24%
0
UFH
UFH
ENOX
ENOX
Clop Used*
No Clop
No Clopidogrel
Clopidogrel
N = 14,752 (78%) N = 5,727 (28%)
P Value
0.0005
0.0006
* 2546 clopidogrel treated
patients did not undergo PCI
15
Bleeding Endpoints (TIMI)
30 Days
10
UFH
ENOX
% Events
8
6
4
2
0
ARD 0.7%
RR 1.53
ARD 0.4%
RR 1.39
ARD 0.1%
RR 1.27
P<0.0001
P = 0.014
P = 0.14
0.9 1.3
0.7 0.8
1.4
2.1
Major Bleed
(fatal + nonfatal)
Nonfatal
Major Bleed
ICH
16
Net Clinical Benefit
at 30 Days
Prespecified Definitions
Death or Nonfatal MI or
Nonfatal Disabl. Stroke
Death or Nonfatal MI or
Nonfatal Major Bleed
Death or Nonfatal MI or
Nonfatal ICH
UFH (%) ENOX (%) RRR (%)
12.3
10.1
18
12.8
11.0
14
12.2
10.1
17
P <0.0001
P <0.0001
P <0.0001
0.8
0.9
ENOX Better
1
RR
1.25
UFH Better
17
For Every 1000 Pts
Treated with Enoxaparin
+
Events / 1000 Pts
5
4
0
(No increase in
nonfatal ICH)
-5
-7
-10
-6
-15
-15
-20
Nonfatal
reMI
Urgent
Revasc.
Death
Nonfatal TIMI
Major Bleed
18
Clinical Implication
A strategy of ENOX is
clearly preferable to the
current standard of UFH as
the antithrombin to support
fibrinolysis, the most
common form of reperfusion
for STEMI used worldwide.
19
Publication of Primary Results
www.NEJM.org
Slides and Full Listing of Trial Participants at www.TIMI.org
21
Trial Results In Perspective:
Major Bleeding Rates
% Pts with Major Bleed
10
Major Bleeds in Prior Trials
Pooled Data
8
6
UFH
5
LMWH
4
UFH
3.3
2.5
2
ENOX
UFH
2.1
1.4
UFH
0.9
ENOX
1.3
0
Keeley
Lancet 2003
Lytic Arms
Eikelboom
Circ. 2005
Major Bleed
(Total)
Nonfatal
Major Bleed
22
Trial Results In Perspective:
PCI vs Lysis for STEMI
10
(30-42 Days)
% Events
8
Overview of 23 RCTs
Keeley Lancet 2003
7
6
4
2
0
Lytic
Arms
(UFH)
3.4
2.2
PCI
Arms
ENOX
Reinfarction
The significant advance in adjunctive therapy with enoxaparin has
narrowed the gap between PCI and Lysis as reperfusion for STEMI.
23