Transcript Study acronym: full name - Vascular Biology Working Group

ExTRACT-TIMI 25
Enoxaparin and Thrombolysis Reperfusion
for ACute Myocardial Infarction Treatment–
Thrombolysis In Myocardial Infarction Study 25
ExTRACT-TIMI 25: Background
• In STEMI patients, prolonged infusion of UFH has not been shown to
prevent reocclusion following angiographically successful fibrinolytic
therapy
– Therefore, current recommendations limit duration of infusion to 48 hours
• LMWH vs UFH provides a reliable level of anticoagulation without the need
for therapeutic monitoring and with relatively greater proximal inhibition of
the coagulation cascade
• ExTRACT-TIMI 25 compared LMWH (enoxaparin) and UFH as adjunctive
therapy for fibrinolysis in STEMI
– Enoxaparin was administered for duration of hospitalization and dosed according
to age and renal function
LMWH = low-molecular-weight heparin
UFH = unfractionated heparin
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Study design
N = 20,506 fibrinolytic eligible, STEMI <6 hours
Randomized, double-blind, double-dummy
ASA 150–325 mg, fibrinolytic (TNK, tPA, rPA, SK)
Enoxaparin
UFH
30 mg IV bolus, 1.0 mg/kg sc q12h*
median 7 days
60 U/kg IV bolus, 12 U/kg/h
median 2 days
Primary end points:
Efficacy: Death, MI in 30 days
Safety: TIMI major bleeding
Net clinical benefit:
Death, MI, disabling stroke, nonfatal major bleed, ICH
*Aged ≥75 yr: no IV bolus, 0.75 mg/kg sc q12h;
CrCl <30 mL/min: ± IV bolus, 1.0 mg/kg sc q24h
Antman EM et al. Am Heart J. 2005;149:217-26.
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Medical history and prior
treatments
%
Enoxaparin
(n = 10,256)
UFH
(n = 10,223)
Hypertension
44.5
43.6
Hyperlipidemia
18.3
18.2
Smoking
47.3
47.4
Diabetes
15.2
15.0
Prior MI
13.2
12.9
Prior angina
28.1
28.0
3.3
3.1
Long-term ASA
13.6
13.3
UFH <3 h prior to randomization
15.9
15.7
0.4
0.5
Prior PCI
LMWH <7 d prior to randomization
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Baseline characteristics
Enoxaparin
(n = 10,256)
UFH
(n = 10,223)
Age (years)
59.0
60.0
Age ≥75 years (%)
12.1
12.6
Male (%)
76.5
76.8
White race (%)
87.1
87.3
167.0
167.0
CrCl (mL/min)
82.3
82.0
Anterior MI (%)
43.6
44.2
Killip class I/II (%)
99.0
98.9
TIMI risk score ≤3 (%)
64.4
64.3
TIMI risk score >3 (%)
35.6
35.7
Weight (lb)
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Baseline treatment
Enoxaparin
(n = 10,256)
UFH
(n = 10,223)
3.1
3.2
Tenecteplase
19.3
19.7
Alteplase
54.7
54.5
Reteplase
5.5
5.5
20.3
20.1
0.3
0.3
≤30 min
97.0
97.1
>30 min
3.1
2.8
Time from symptom onset to start
of fibrinolytic therapy (hr)
Fibrinolytic therapy (%)
Streptokinase
None
Time from fibrinolytic therapy to
study drug (%)
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Cardiac medications during
hospitalization
%
Enoxaparin
(n = 10,256)
UFH
(n = 10,223)
Aspirin
94.8
95.4
Clopidogrel
27.2
28.7
β-Blocker
85.9
85.5
ACEI or ARB
80.0
79.3
Statin
69.5
69.5
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Significant reduction in
primary end point
Death, MI at 30 days
15
UFH
12
9
Enoxaparin
End point
(%)
6
RR 0.83
(0.77–0.90)
P < 0.001
3
0
0
5
10
15
20
25
30
Days after randomization
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Significant reduction in major
secondary end point
Death, MI, urgent revascularization at 30 days
UFH
15
12
Enoxaparin
9
End point
(%)
RR 0.81
(0.75–0.87)
P < 0.001
6
RR (48 hr) 0.88
(0.79–0.98)
P = 0.02
3
0
0
2
5
10
15
20
25
30
Days after randomization
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Safety outcomes at 30 days
%
Enoxaparin
(n = 10,176)
UFH
(n = 10,151)
Major bleeding*
2.1
1.4
<0.001
Intracranial
hemorrhage (ICH)
0.8
0.7
0.14
Minor bleeding
2.6
1.8
<0.001
Major or minor
bleeding
4.6
3.1
<0.001
Favors Favors
enoxaparin UFH
0
1
P
2
Relative risk (95% CI)
*Primary safety outcome (includes ICH)
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Net clinical benefit at 30 days
%
Enoxaparin
(n = 10,256)
UFH
(n = 10,223)
Death, MI,
disabling stroke
10.1
12.3
<0.001
Death, MI, major
bleeding
11.0
12.8
<0.001
Death, MI, ICH
10.1
12.2
<0.001
Favors
enoxaparin
0.75
Favors
UFH
1
P
1.25
Relative risk (95% CI)
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Overall results
• Primary efficacy end point
Rate of death or MI was significantly lower with enoxaparin vs
UFH (P < 0.001)
• Major secondary end point
Rate of death, MI or urgent revascularization was significantly
lower with enoxaparin vs UFH (P < 0.001)
• Safety outcome
Rate of major bleeding* in both groups:
2.1% enoxaparin vs 1.4% UFH (P < 0.001)
*TIMI criteria
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Summary
• In STEMI patients, treatment with enoxaparin
throughout the index of hospitalization vs UFH for
48 hours demonstrated:
– Superior reduction in ischemic events
– Increase in episodes of major bleeding
• ExTRACT-TIMI 25 results show that treatment strategy
with enoxaparin is preferable to the current standard of
UFH to support fibrinolysis
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Clinical implications
+4
5
Nonfatal
MI
Urgent
revascularization
Death
0
Nonfatal
major
bleeding
-5
Events per
1000 patients
-7
-6
-10
-15
-15
-20
Antman EM et al. N Engl J Med. 2006;354:1477-88.