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Enoxaparin – Future
Prospects in Cardiovascular
Diseases
David Hasdai, MD
Rabin Medical Center
Tel Aviv University
Antithrombin agents in
NSTE ACS and PCI
Trials
ISAR-SWEET
EPILOG
EPIC
GUSTO IIA
CAPTURE
SYNERGY
IMPACT 2
ACE
RESTORE
BAT
ISAR-REACT
GUSTO IV
CAPRIE
PURSUIT
FRIC
ESPRIT
TIMI 8
CREDO
TACTICS
FRISC 2
EPISTENT
CADILLAC
PROTECT
FRAXIS
PRISM
GUSTO IIB
OASIS Pilot
CURE
PRISM-PLUS
RITA 3
TIMI 7
TIMI 11B
FRISC
OASIS 2
INTERACT
ACUTE 2
FRISC 2
REPLACE 2
HELVETICA
TARGET
A to Z
ESSENCE
Anti-Xa:Anti-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
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
193
193
1.0
Reviparin2
UFH3
Anti-Xa activity was measured using an amidolytic
assay (chromogenic substrate S-2222). Anti-IIa
activity was measured using activated partial
thromboplastin time4
1. European Pharmacopeia Commission (March 1994).
2. Knoll Pharma.
3. Hirsh J, et al. Chest. 1998;114:489S.
4. Bergqvist D, et al. Br J Surg. 1995;82:496.
1.8–
1.6–
1.4–
1.2–
1.0–
0.8–
0.6–
0.4–
0.2–
0│–
0.5
25
r2 = 0.97
30-d mortality (%)
Anti-Xa level (IU/mL)
Correlation Between
Enoxaparin Dose – Anti-Xa Efficiency –
Mortality
20
15
10
5
0
│
│
│
│
0.6
0.7
0.8
0.9
Enoxaparin (mg/kg bid)
│
< 0.5
0.5 – 1.2
≥ 1.2
1.0
Anti-Xa (IU/mL)
Montalescot G, et al. Circulation. 2004; 27;110:392.
Release of von Willebrand Factor (vWF)
P = 0.0006
NS
100
Enoxaparin releases less
vWF, resulting in reduced
platelet aggregation
compared with UFH or
dalteparin at approved
treatment doses for
UA/NQMI
vWF (%)
80
60
40
20
0
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. 2000;36:110.
ESSENCE: One-year follow-up
Death, MI, recurrent angina
50
40
p=0.022
30
% Patients
20
UFH
Enoxaparin
10
0
0
2
4
6
8
10
12
Coronary revascularization
50
40
p=0.002
30
20
10
0
N=3,171
0
2
4
6
8
10
12
Time since enrollment (months)
Goodman SG, et al. J Am Coll Cardiol 2000;36:693-8.
TIMI 11B
Death/MI/Urgent Revasc: Early Tx
Phase
9
7.3 %
8
UFH
Enoxaparin
% Patients
7
6
5
5.5 %
4
RRR 23.8%
P=0.026
3
2
1
0
0
8
16
24
32
40
Hours from Randomization
Antman EM, et al. Circulation 1999;100:1593-1601.
48
56
64
72
TIMI 11B
Death/MI/Urgent Revasc: Day 43
19.7 %
20
UFH
ENOXAPARIN
18
% patients
16
17.3 %
14
12
p=0.048
RRR 12 %
10
8
6
4
2
0
0
4
8
12
16
20
24
Days
Antman EM, et al. Circulation 1999;100:1593-1601.
28
32
36
40
44
Validation and Treatment Interaction
for Enoxaparin (ESSENCE)
p<0.001
2 for trend
60
50
UFH
Enoxaparin
40
p=0.02
2 for trend
30
20
19.8
16.6
10
0
Total
population
0/1
2
3
Risk factors
4
5
6/7
Primary Efficacy Outcome
Freedom from Death / MI
1.0
Hazard Ratio (95% CI)
0.95
30-Day Death/MI
n
n
0.9
0.85
0.8
Enoxaparin
UFH
0.8
0
5 10 15 20 25
Days from Randomization
Enoxaparin
Better
1
1.1
1.2
UFH
Better
30
Enoxaparin is as effective as UFH in the treatment of high-risk
patients with ACS undergoing a rapid invasive strategy
SYNERGY Trial Investigators. JAMA 2004;292:45-54.
Pre-randomization
Randomization
Pre-Specified
Analysis
N = 6138
No prior
therapy
N= 2440
UFH
N= 2940
UFH
n = 1228
Enoxaparin
n = 1212
UFH
n = 2740
15.9% 30d Death/MI
7.9% TIMI Major *
2.1% GUSTO Severe
UFH
n = 1512
Enoxaparin
n = 1428
UFH
Enoxaparin
n = 2108
N= 4294
Enoxaparin
n = 2186
* No Statistical difference
Enoxaparin
n = 3398
13.3% 30d Death/MI
9.3% TIMI Major *
2.9% GUSTO Severe
30d Death/MI
P = 0.0039
RRR = 16.4
Freedom from Death / MI at 6 Months
SYNERGY Population, 6-Month Freedom from
Death/MI
Consistent Therapy, NO Crossover
1
Enoxaparin
0.95
UFH
0.9
0.85
0.8
0.75
0.7
0
30
60
90
120
150
180
Days from Randomization
Kleiman NS. TCT 2004 Late-Breaking Trials.
HR (95% CI) = 0.831 (0.733, 0.942)
Intention-to-treat Population:
Death or MI at 30 days
Trial
Enox (%) UFH (%)
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]
Odds ratio (95% CI)
0.2
1.0
Enoxaparin better
2.0
UFH better
Petersen JL, et al. JAMA. 2004;292:89.
No Prerandomization Therapy Population:
Death or MI at 30 Days
Trial
Enox (%) UFH (%)
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]
Odds ratio (95% CI)
0.2
1.0
Enoxaparin better
2.0
UFH better
Petersen JL, et al. JAMA. 2004;292:89.
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
0.5
5
10
Time (hours)
15
20
25
ENOXAPARIN – THE ANTICOAGULANT
FROM ADMISSION THROUGH
PERCUTANEOUS CORONARY INTERVENTION
WITHOUT CROSSOVER!!!