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!!!