extract-timi 25
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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
Antman EM et al. N Engl J Med. 2006;354:1477-88.LMWH = low-molecular-weight heparinUFH = unfractionated heparin
ExTRACT-TIMI 25: Study design
*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.
N = 20,506 fibrinolytic eligible, STEMI <6 hours
Primary end points:Efficacy: Death, MI in 30 days
Safety: TIMI major bleeding
Net clinical benefit:Death, MI, disabling stroke, nonfatal major bleed, ICH
Randomized, double-blind, double-dummy
ASA 150–325 mg, fibrinolytic (TNK, tPA, rPA, SK)
Enoxaparin 30 mg IV bolus, 1.0 mg/kg sc q12h*
median 7 days
UFH 60 U/kg IV bolus, 12 U/kg/h
median 2 days
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
Prior PCI 3.3 3.1
Long-term ASA 13.6 13.3
UFH <3 h prior to randomization 15.9 15.7
LMWH <7 d prior to randomization 0.4 0.5
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
Weight (lb) 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
Antman EM et al. N Engl J Med. 2006;354:1477-88.
ExTRACT-TIMI 25: Baseline treatmentEnoxaparin(n = 10,256)
UFH(n = 10,223)
Time from symptom onset to startof fibrinolytic therapy (hr) 3.1 3.2
Fibrinolytic therapy (%)
Tenecteplase 19.3 19.7
Alteplase 54.7 54.5
Reteplase 5.5 5.5
Streptokinase 20.3 20.1
None 0.3 0.3
Time from fibrinolytic therapy to study drug (%)
≤30 min 97.0 97.1
>30 min 3.1 2.8Antman 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
Antman EM et al. N Engl J Med. 2006;354:1477-88.
15
12
9
6
3
0
255 10 15 200 30
End point(%)
Days after randomization
Enoxaparin
UFH
RR 0.83(0.77–0.90)P < 0.001
ExTRACT-TIMI 25: Significant reduction in major secondary end point
Death, MI, urgent revascularization at 30 days
Antman EM et al. N Engl J Med. 2006;354:1477-88.
15
12
9
6
3
0
255 10 15 200 30
Enoxaparin
RR 0.81(0.75–0.87)P < 0.001
RR (48 hr) 0.88(0.79–0.98)
P = 0.02
End point(%)
UFH
2
Days after randomization
ExTRACT-TIMI 25: Safety outcomes at 30 days
Enoxaparin(n = 10,176)
UFH(n = 10,151)
Major bleeding* 2.1 1.4
Intracranial hemorrhage (ICH)
0.8 0.7
Minor bleeding 2.6 1.8
Major or minor bleeding
4.6 3.1
%
Antman EM et al. N Engl J Med. 2006;354:1477-88.*Primary safety outcome (includes ICH)
P
<0.001
0.14
<0.001
<0.001
0 1 2Relative risk (95% CI)
Favorsenoxaparin
FavorsUFH
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
Death, MI, major bleeding
11.0 12.8
Death, MI, ICH 10.1 12.2
%
Antman EM et al. N Engl J Med. 2006;354:1477-88.
P
<0.001
<0.001
<0.001
0.75 1 1.25
Relative risk (95% CI)
Favorsenoxaparin
FavorsUFH
ExTRACT-TIMI 25: Overall results
• Primary efficacy end pointRate of death or MI was significantly lower with enoxaparin vs UFH (P < 0.001)
• Major secondary end pointRate of death, MI or urgent revascularization was significantly lower with enoxaparin vs UFH (P < 0.001)
• Safety outcomeRate of major bleeding* in both groups: 2.1% enoxaparin vs 1.4% UFH (P < 0.001)
Antman EM et al. N Engl J Med. 2006;354:1477-88.*TIMI criteria
ExTRACT-TIMI 25: Summary
• In STEMI patients, treatment with enoxaparin throughout the index of hospitalization vs UFH for48 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
-15
-7-6
+4
-20
-15
-10
-5
0
5
Events per1000 patients
Antman EM et al. N Engl J Med. 2006;354:1477-88.
Nonfatal MI
Urgentrevascularization Death
Nonfatal major
bleeding
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