enoxaparin – future prospects in cardiovascular diseases david hasdai, md rabin medical center tel...
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Enoxaparin – Future Prospects in Cardiovascular
Diseases
David Hasdai, MD
Rabin Medical Center
Tel Aviv University
TIMI 8
BAT
GUSTO IIA
OASIS Pilot
TIMI 7
CURE
CAPRIE
CREDO
ISAR-REACT
EPICEPILOG
CAPTURE
TARGET
GUSTO IVRESTORE
IMPACT 2
ESPRIT
ACE
ISAR-SWEET
EPISTENT
PURSUIT
PRISM PRISM-PLUS
REPLACE 2
OASIS 2
GUSTO IIB
HELVETICA
FRISC
FRIC
RITA 3
A to Z
INTERACT
SYNERGY
CADILLAC
TACTICS
ESSENCE
FRAXIS
FRISC 2
FRISC 2ACUTE 2
TIMI 11B
PROTECT
Antithrombin agents inAntithrombin agents inNSTE ACS and PCI NSTE ACS and PCI
TrialsTrials
Anti-Xa:Anti-IIa Ratios for LMWHs
Anti-XaAnti-Xa Anti-IIaAnti-IIa RatioRatio(IU/mg dry substance)(IU/mg dry substance) (IU/mg dry substance)(IU/mg dry substance)
1. 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.
Anti-Xa activity was measured using an amidolytic assay (chromogenic substrate S-2222). Anti-IIa activity was measured using activated partial thromboplastin time4
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
│ │ │ │ ││ │ │ │ │ ││
0.50.5 0.60.6 0.70.7 0.80.8 0.90.9 1.01.0
Correlation Between Enoxaparin Dose – Anti-Xa Efficiency –
Mortality
An
ti-X
a le
vel
(IU
/mL
)A
nti
-Xa
leve
l (I
U/m
L)
Enoxaparin (mg/kg bid)Enoxaparin (mg/kg bid)
1.8–1.6–1.4–1.2–1.0–0.8–0.6–0.4–0.2–
0–
rr22 = 0.97 = 0.97
0
5
10
15
20
25
< 0.5 0.5 – 1.2 ≥ 1.2
Anti-Xa (IU/mL)Anti-Xa (IU/mL)
30-d
mo
rtal
ity
(%)
30-d
mo
rtal
ity
(%)
Montalescot G, et al. Montalescot G, et al. Circulation. Circulation. 2004; 27;110:392.2004; 27;110:392.
(( vW
FvW
F 48
h48
h –
–
vW
FvW
F 0 h0 h))
vWF
(%)
vWF
(%)
100100
8080
6060
4040
2020
00
P = P = 0.00060.0006
Dalteparin 120 IU anti-Xa/kg bid Dalteparin 120 IU anti-Xa/kg bid
Enoxaparin 1 mg/kg (100 IU anti-Xa/kg) bid Enoxaparin 1 mg/kg (100 IU anti-Xa/kg) bid
UFH 5,000 IU anti-Xa IV bolus then aPTT-adjusted continuous infusion UFH 5,000 IU anti-Xa IV bolus then aPTT-adjusted continuous infusion
NSNS
Release of von Willebrand Factor (vWF)
Enoxaparin releases less Enoxaparin releases less vWF, resulting in reducedvWF, resulting in reduced
platelet aggregation platelet aggregation compared with UFH or compared with UFH or dalteparin at approveddalteparin at approvedtreatment doses for treatment doses for
UA/NQMIUA/NQMI
Montalescot G, et al. Montalescot G, et al. J Am Coll Cardiol. J Am Coll Cardiol. 2000;36:110.2000;36:110.
ESSENCE: One-year follow-upDeath, MI, recurrent angina%
Pat
ien
ts
Coronary revascularization
Time since enrollment (months)
0 2 4 6 8 10 12
0
10
20
30
40
50
Goodman SG, et al. J Am Coll Cardiol 2000;36:693-8.
UFHEnoxaparin
p=0.022
p=0.002
0
10
20
30
40
50
0 2 4 6 8 10 12N=3,171
0
1
2
3
4
5
6
7
8
9
0 8 16 24 32 40 48 56 64 72
% P
atie
nts
Hours from Randomization
7.3 %
5.5 % RRR 23.8%P=0.026
UFHEnoxaparin
TIMI 11BDeath/MI/Urgent Revasc: Early Tx
Phase
Antman EM, et al. Circulation 1999;100:1593-1601.
p=0.048RRR 12 %
UFHUFHENOXAPARINENOXAPARIN
19.7 %
17.3 %
2020
1818
1616
1414
1212
1010
88
66
44
22
0000 44 88 1212 1616 2020 2424 2828 3232 3636 4040 4444
% p
atie
nts
% p
atie
nts
DaysDaysAntman EM, et al. Circulation 1999;100:1593-1601.
TIMI 11BDeath/MI/Urgent Revasc: Day 43
Validation and Treatment Interaction for Enoxaparin (ESSENCE)
19.819.816.616.6
Risk factors
% T
rip
le e
nd
po
int
(14d
)
UFH
Enoxaparin
0
10
20
30
40
50
60
Total 0/1 2 3 4 5 6/7population
p=0.022 for trend
p<0.0012 for trend
Primary Efficacy Outcome
0 5 10 15 20 25 300.8
0.85
0.9
0.95
1.0
Free
dom
from
Dea
th /
MI
Days from Randomization
UFH
Enoxaparin
30-Day Death/MI30-Day Death/MI
0.80.8 11 1.21.2
Hazard Ratio (95% CI)
EnoxaparinBetter
UFHBetter
1.1
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.
UFHUFHn = 2740n = 2740
15.9%15.9% 30d Death/MI30d Death/MI7.9%7.9% TIMI MajorTIMI Major2.1%2.1% GUSTO Severe GUSTO Severe
EnoxaparinEnoxaparinn = 3398n = 3398
13.3%13.3% 30d Death/MI30d Death/MI9.3%9.3% TIMI MajorTIMI Major2.9%2.9% GUSTO Severe GUSTO Severe
Pre-Specified Pre-Specified AnalysisAnalysis
N = 6138N = 6138RandomizationRandomizationPre-randomizationPre-randomization
EnoxaparinN= 4294
No prior therapy
N= 2440
UFHN= 2940
UFHn = 1228
UFHn = 1512
UFHn = 2108
Enoxaparinn = 1212
Enoxaparinn = 1428
Enoxaparinn = 2186
30d Death/MIP = 0.0039RRR = 16.4
**
**
* No Statistical difference* No Statistical difference
SYNERGY Population, 6-Month Freedom from Death/MI
Consistent Therapy, NO Crossover
0 30 60 90 120 150 1800.7
0.75
0.8
0.85
0.9
0.95
1Fr
eedo
m fr
om D
eath
/ M
I at 6
Mon
ths
Days from Randomization
UFH
Enoxaparin
HR (95% CI) = 0.831 (0.733, 0.942)Kleiman NS. TCT 2004 Late-Breaking Trials.
TrialTrial Enox (%)Enox (%) UFH (%)UFH (%) Odds ratio [95% CI]Odds ratio [95% CI] Odds ratio (95% CI)Odds ratio (95% CI)
ESSENCEESSENCE 5.85.8 7.57.5 0.76 [0.58, 1.01]0.76 [0.58, 1.01]
TIMI 11BTIMI 11B 7.47.4 8.38.3 0.88 [0.70, 1.11]0.88 [0.70, 1.11]
ACUTE IIACUTE II 7.97.9 8.18.1 0.97 [0.51, 1.83]0.97 [0.51, 1.83]
INTERACTINTERACT 5.05.0 9.09.0 0.54 [0.30, 0.96]0.54 [0.30, 0.96]
A to ZA to Z 7.47.4 7.97.9 0.94 [0.73, 1.20]0.94 [0.73, 1.20]
SYNERGYSYNERGY 14.014.0 14.514.5 0.96 [0.86, 1.07]0.96 [0.86, 1.07]
OverallOverall 10.110.1 11.0 11.0 0.91 [0.83, 0.99]0.91 [0.83, 0.99]
Enoxaparin betterEnoxaparin better UFH betterUFH better0.20.2 1.01.0 2.02.0
Intention-to-treat Population:Death or MI at 30 days
Petersen JL, et al. Petersen JL, et al. JAMAJAMA. 2004;292:89.. 2004;292:89.
TrialTrial Enox (%)Enox (%) UFH (%)UFH (%) Odds ratio [95% CI]Odds ratio [95% CI] Odds ratio (95% CI)Odds ratio (95% CI)
ESSENCE ESSENCE 5.85.8 7.57.5 0.76 [0.58, 1.01]0.76 [0.58, 1.01]
TIMI 11BTIMI 11B 6.46.4 7.87.8 0.81 [0.60, 1.10]0.81 [0.60, 1.10]
INTERACTINTERACT 4.64.6 8.18.1 0.55 [0.28, 1.08]0.55 [0.28, 1.08]
A to ZA to Z 7.37.3 6.96.9 1.06 [0.68, 1.67]1.06 [0.68, 1.67]
SYNERGYSYNERGY 12.612.6 14.814.8 0.84 [0.68, 1.05]0.84 [0.68, 1.05]
OverallOverall 8.08.0 9.49.4 0.81 [0.70, 0.94]0.81 [0.70, 0.94]
Enoxaparin betterEnoxaparin better UFH betterUFH better0.20.2 1.01.0 2.02.0
No Prerandomization Therapy Population:
Death or MI at 30 Days
Petersen JL, et al. Petersen JL, et al. JAMAJAMA. 2004;292:89.. 2004;292:89.
Anti-Xa Activity with LMW Heparin Administration
An
ti-X
a (
U/m
l)
Time (hours)
5 10 15 20 25
Enoxaparin 1 mg/kg IV bolusEnoxaparin 0.75 mg/kg IV bolusEnoxaparin 1 mg/kg SQ
0.5
1.0
1.5SheathSheathremovalremovalSheathSheathremovalremoval
ENOXAPARIN – THE ANTICOAGULANTFROM ADMISSION THROUGH
PERCUTANEOUS CORONARY INTERVENTION WITHOUT CROSSOVER!!!