Efficacy and Safety of Enoxaparin vs UFH in ST-elevation MI: A Meta-Analysis of 27,000 Patients

1
Efficacy and Safety of Enoxaparin vs UFH in
ST-elevation MIA Meta-Analysis of 27,000
Patients

• Sabina A Murphy
• C Michael Gibson, David A Morrow, Carolyn H
  McCabe, Frans Van de Werf, Ian B Menown, Frank
  Jiang, Elliott M Antman
• TIMI Study Group
• Boston, MA

2
STEMI Anti-thrombin Meta-AnalysisBackground

• Antithrombin therapy established, guideline
  recommended treatment central to management of ST
  elevation MI patients
• Optimal antithrombin agent still debated
• Several trials have shown improved efficacy with
  LMWH enoxaparin compared to UFH, but safety
  concerns of increased bleeding with enoxaparin
  also reported
• Sought to determine whether enoxaparin remains
  favorable compared with UFH among patients with
  STEMI when incorporating efficacy and safety
  profile using a meta-analysis with net clinical
  benefit endpoint

Presented at AHA 2006
3
STEMI Anti-thrombin Meta-AnalysisMethods

• We performed a PubMed search for randomized
  clinical trials comparing ENOX with UFH among
  patients with STEMI trials were restricted to
  those in which patients were treated with aspirin
  and fibrinolytic therapy
• Trials included ASSENT 3, HART II, Baird et al,
  ENTIRE-TIMI 23, ASSENT 3 Plus, and ExTRACT-TIMI
  25
• Net clinical benefit Death, nonfatal
  reinfarction or nonfatal major bleeding by 30
  days, or the closest timepoint available to 30
  days.
• Components of net clinical benefit composite
  endpoint also evaluated individually

Presented at AHA 2006
4
STEMI Anti-thrombin Meta-Analysis Trial Designs
Trial N Year Published Blinding Randomization Arms Randomization Arms Endpoint Description
Trial N Year Published Blinding Enoxaparin UFH Endpoint Description
ASSENT 3 4075 2001 Open-label 30 mg bolus 1 mg/kg BID for 7 d 60 U/kg bolus, 12 U/kg/h for 48 h to aPTT 50-70 sec Death 30 days MI in-hospital major bleeding (requiring transfusion or intervention due to hemodynamic compromise or ICH) in-hospital
HART II 400 2001 Open-label 30 mg bolus, 1 mg/kg BID for 3 d 4000-5000 U bolus, 15 U/kg/h for 3 d to aPTT 2.0-2.5 x control Death 30 days MI 30 days TIMI major bleeding in-hospital
Baird et al 300 2002 Open-label 40 mg bolus, 40 mg TID for 4 d 5000 U bolus, 30000 U infusion over 24 h for 4 d to aPTT 2.0-2.5 x control Death 90 days MI 90 days major bleeding (clinically significant hemorrhage or ICH) on study drug
ENTIRE-TIMI 23 242 2002 Open-label 0 or 30 mg bolus 1 mg/kg BID for 8 d 60 U/kg bolus, 12 U/kg/h for 3 d to aPTT 1.5-2.5 x control Death 30 days MI 30 days TIMI major bleeding 30 days
ASSENT 3 Plus 1635 2003 Open-label 30 mg bolus 1 mg/kg BID for 7 d 60 U/kg bolus, 12 U/kg/h for 48 h to aPTT 50-70 sec Death 30 days MI in-hospital major bleeding (requiring transfusion or intervention because of hemodynamic compromise or ICH) in-hospital
ExTRACT-TIMI 25 20479 2006 Double-blind 30 mg bolus (if age lt75) 1 mg/kg BID (if age lt75) or 0.75 mg/kg BID (if age 75) for 8 d 60 U/kg bolus (omitted if open-label UFH received within 3 h), 12 U/kg/h for 3 d to aPTT 1.5-2.0 x control Death 30 days MI 30 days TIMI major bleeding 30 days
TIMI major bleeding defined as decrease in
hemoglobin of more than 5 mg/dL or intracranial
or pericardial bleeding
5
Death or Reinfarction
Odds ratio
Enox ()
UFH ()
(95 CI)
0.78 (0.63,0.98)
ASSENT 3
7.7
9.6
8.0
8.0
1.00 (0.49,2.06)
HART II
20.8
30.5
0.60 (0.35,1.01)
BAIRD
0.24 (0.09,0.64)
ENTIRE-TIMI 23
4.4
15.9
0.89 (0.65,1.22)
ASSENT 3 Plus
10.3
11.4
0.81 (0.74,0.88)
ExTRACT-TIMI 25
9.9
12.0
0.78 (0.67,0.91)
Overall
9.6
11.7
p0.002
.2
1
5
Odds ratio
Presented at AHA 2006
Favors Enox
Favors UFH
6
Major Bleeding
Odds ratio
(95 CI)
Enox ()
UFH ()
1.27 (0.90,1.79)
ASSENT 3
3.8
3.0
1.18 (0.39,3.57)
HART II
3.6
3.0
0.84 (0.25,2.81)
BAIRD
3.4
4.0
0.76 (0.13,4.67)
ENTIRE-TIMI 23
1.9
2.4
1.70 (1.07,2.68)
ASSENT 3 Plus
6.2
3.8
1.54 (1.24,1.91)
ExTRACT-TIMI 25
2.1
1.4
1.45 (1.23,1.72)
2.6
1.8
Overall
plt0.001
.2
1
5
Odds ratio
Presented at AHA 2006
Favors Enox
Favors UFH
7
Death, Reinfarction, or Major Bleed
Odds ratio
Enox ()
UFH ()
(95 CI)
0.87 (0.71,1.06)
ASSENT 3
10.2
11.5
0.94 (0.49,1.83)
HART II
9.5
10.0
0.59 (0.35,0.99)
BAIRD
22.1
32.5
6.3
17.1
0.32 (0.14,0.77)
ENTIRE-TIMI 23
1.00 (0.76,1.32)
ASSENT 3 Plus
14.3
14.3
0.84 (0.78,0.92)
ExTRACT-TIMI 25
11.0
12.8
Overall
0.84 (0.73,0.97)
11.1
12.9
p0.018
.2
1
5
Odds ratio
Presented at AHA 2006
Favors Enox
Favors UFH
8
STEMI Anti-thrombin Meta-AnalysisConclusions

• When compared with UFH, enoxaparin offered
  superior net clinical benefit as adjunctive
  antithrombin therapy for fibrinolysis in STEMI
• While bleeding ? with enoxaparin, increase was
  offset by ? death or reinfarction

Presented at AHA 2006
9
STEMI Anti-thrombin Meta-AnalysisConclusions

• For every 1000 patients treated with enoxaparin
  instead of UFH, 21 death or reinfarction events
  were prevented, at the cost of an increase of 4
  major bleeds

Presented at AHA 2006