Enoxaparin

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Enoxaparin Future Prospects in Cardiovascular
Diseases

• David Hasdai, MD
• Rabin Medical Center
• Tel Aviv University

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Antithrombin agents in NSTE ACS and PCI Trials
ISAR-SWEET
GUSTO IIA
SYNERGY
ISAR-REACT
IMPACT 2
ACE
RESTORE
GUSTO IV
TACTICS
CAPRIE
FRIC
BAT
PURSUIT
CADILLAC
ESPRIT
TIMI 8
CREDO
FRISC 2
EPISTENT
FRAXIS
GUSTO IIB
OASIS Pilot
PRISM
PRISM-PLUS
CURE
RITA 3
TIMI 7
INTERACT
FRISC
TIMI 11B
OASIS 2
ACUTE 2
FRISC 2
REPLACE 2
HELVETICA
A to Z
TARGET
ESSENCE
3
Anti-XaAnti-IIa Ratios for LMWHs
Anti-Xa Anti-IIa Ratio (IU/mg dry
substance) (IU/mg dry substance)
Enoxaparin1 102.8 24.9 4.1 Nadroparin1 103.6 29.
9 3.5 Reviparin2 127 36 3.5 Dalteparin1 167.2 64
.2 2.4 Tinzaparin1 99.6 53.7 1.9 Certoparin1 106.
4 44.7 2.4 UFH3 193 193 1.0
1. European Pharmacopeia Commission (March
1994). 2. Knoll Pharma. 3. Hirsh J, et al. Chest.
1998114489S. 4. Bergqvist D, et al. Br J Surg.
199582496.
Anti-Xa activity was measured using an amidolytic
assay (chromogenic substrate S-2222). Anti-IIa
activity was measured using activated partial
thromboplastin time4
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Correlation Between Enoxaparin Dose Anti-Xa
Efficiency Mortality
Anti-Xa level (IU/mL)
30-d mortality ()
0.5 0.6 0.7 0.8 0.9 1.0
Anti-Xa (IU/mL)
Montalescot G, et al. Circulation. 2004
27110392.
5
Release of von Willebrand Factor (vWF)
P 0.0006
NS
Enoxaparin releases less vWF, resulting in
reduced platelet aggregation compared with UFH
or dalteparin at approvedtreatment doses for
UA/NQMI
Enoxaparin 1 mg/kg (100 IU anti-Xa/kg) bid
Dalteparin 120 IU anti-Xa/kg bid
UFH 5,000 IU anti-Xa IV bolus then aPTT-adjusted
continuous infusion
Montalescot G, et al. J Am Coll Cardiol.
200036110.
6
ESSENCE One-year follow-up
Death, MI, recurrent angina
p0.022
UFH
Patients
Enoxaparin
Coronary revascularization
50
40
p0.002
30
20
10
0
0
2
4
6
8
10
12
N3,171
Time since enrollment (months)
Goodman SG, et al. J Am Coll Cardiol
200036693-8.
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TIMI 11BDeath/MI/Urgent Revasc Early Tx Phase


9
7.3
8
UFH
Enoxaparin
7
6
5
Patients
5.5
RRR 23.8 P0.026
4
3
2
1
0
0
8
16
24
32
40
48
56
64
72
Hours from Randomization
Antman EM, et al. Circulation 19991001593-1601.
8
TIMI 11BDeath/MI/Urgent Revasc Day 43
19.7
UFH
ENOXAPARIN
17.3
patients
p0.048RRR 12
Days
Antman EM, et al. Circulation 19991001593-1601.
9
Validation and Treatment Interaction for
Enoxaparin (ESSENCE)
10
Primary Efficacy Outcome
1.0
Hazard Ratio (95 CI)
0.95
30-Day Death/MI
30-Day Death/MI
n
n
Freedom from Death / MI
0.9
0.85
0.8
1
1.2
0.8
1
1.2
1.1
Enoxaparin
Enoxaparin
UFH
UFH
Better
Better
0.8
0
5
10
15
20
25
30
Days from Randomization
Enoxaparin is as effective as UFH in the
treatment of high-risk patients with ACS
undergoing a rapid invasive strategy
SYNERGY Trial Investigators. JAMA 200429245-54.
11
Pre-Specified Analysis N 6138
Randomization
UFH n 1228
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SYNERGY Population, 6-Month Freedom from
Death/MIConsistent Therapy, NO Crossover
HR (95 CI) 0.831 (0.733, 0.942)
Kleiman NS. TCT 2004 Late-Breaking Trials.
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Intention-to-treat PopulationDeath or MI at 30
days
Trial Enox () UFH () Odds ratio 95 CI Odds
ratio (95 CI) ESSENCE 5.8 7.5 0.76 0.58,
1.01 TIMI 11B 7.4 8.3 0.88 0.70, 1.11 ACUTE
II 7.9 8.1 0.97 0.51, 1.83 INTERACT 5.0 9.0 0.
54 0.30, 0.96 A to Z 7.4 7.9 0.94 0.73,
1.20 SYNERGY 14.0 14.5 0.96 0.86, 1.07
Overall 10.1 11.0 0.91 0.83, 0.99
Enoxaparin better
UFH better
Petersen JL, et al. JAMA. 200429289.
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No Prerandomization Therapy PopulationDeath or
MI at 30 Days
Trial Enox () UFH () Odds ratio 95 CI Odds
ratio (95 CI) ESSENCE 5.8 7.5 0.76 0.58,
1.01 TIMI 11B 6.4 7.8 0.81 0.60,
1.10 INTERACT 4.6 8.1 0.55 0.28, 1.08 A to
Z 7.3 6.9 1.06 0.68, 1.67 SYNERGY 12.6 14.8 0.84
0.68, 1.05 Overall 8.0 9.4 0.81 0.70, 0.94
Enoxaparin better
UFH better
Petersen JL, et al. JAMA. 200429289.
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Anti-Xa Activity with LMW Heparin Administration
Enoxaparin 1 mg/kg IV bolus Enoxaparin 0.75 mg/kg
IV bolus Enoxaparin 1 mg/kg SQ
1.5
Sheath removal
1.0
Anti-Xa (U/ml)
0.5
5
10
15
25
20
Time (hours)
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ENOXAPARIN THE ANTICOAGULANT FROM ADMISSION
THROUGH PERCUTANEOUS CORONARY INTERVENTION
WITHOUT CROSSOVER!!!