Drugs 2008; 68 (5): 691-710

ADIS DRUG EVALUATION 0012-6667/08/0005-0691/$53.45/0

© 2008 Adis Data Information BV. All rights reserved.

Enoxaparin
A Review of its Use in ST-Segment Elevation
Myocardial Infarction
Natalie J. Carter, Paul L. McCormack and Greg L. Plosker
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Conshohocken, Pennsylvania, USA

Various sections of the manuscript reviewed by:

E.M. Antman, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA; E.R.
Bates, Institute of Medical/Cardiology, University of Michigan, Ann Arbor, Michigan, USA; R. Corbalan,
Hospital Clinico de la Universidad Catolica de Chile, Piso, Chile; J. Lopez-Sendon, Cardiology Department,
Hospital Universitario La Paz, Madrid, Spain; I.B.A. Menown, Craigavon Cardiac Centre, Craigavon Area
Hospital, Craigavon, Northern Ireland; J.C. Nicolau, Heart Institute, University of São Paulo Medical School,
São Paulo, Brazil; F. Van de Werf, Department of Cardiology, University of Leuven, Leuven, Belgium.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘enoxaparin’, identified using MEDLINE and EMBASE, supplemented
by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of
published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing
the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘enoxaparin’ and ‘ST-segment elevation myocardial infarction’,
‘ST-elevation myocardial infarction’ or ‘STEMI’. Searches were last updated 12 March 2008.
Selection: Studies in patients with ST-segment elevation myocardial infarction who received enoxaparin. Inclusion of studies was based
mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were
preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Enoxaparin, ST-segment elevation myocardial infarction, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
2. Overview of Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
2.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
3.1 The ExTRACT-TIMI 25 Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
3.1.1 Primary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
3.1.2 Subgroup Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
3.2 Other Randomized Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
3.2.1 Clinical Efficacy versus Unfractionated Heparin (UFH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
3.2.2 Angiographic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
3.3 Meta-Analysis of All Randomized Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
692 Carter et al.

5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706

6. Place of Enoxaparin in the Management of Patients with ST-Segment Elevation Myocardial
Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706

Summary
Abstract Enoxaparin (enoxaparin sodium; Lovenox®) is a low-molecular-weight heparin
(LMWH) that has recently been approved by the US FDA for use in patients with
medically managed ST-segment myocardial infarction (STEMI), or STEMI with
subsequent percutaneous coronary intervention (PCI). It binds to and potentiates
the action of antithrombin, and inhibits coagulation factors XIa, IXa, Xa and IIa
(thrombin), thereby preventing formation of blood clots. Unfractionated heparin
(UFH) has long been regarded as the antithrombotic agent of choice in the
adjunctive treatment of patients with STEMI. However, compared with UFH,
enoxaparin has many advantages in terms of its pharmacodynamic profile and,
potentially, also its efficacy.
Enoxaparin was significantly more effective than UFH in patients presenting
with STEMI who underwent fibrinolytic therapy in terms of the 30-day combined
incidence of all-cause mortality plus recurrent nonfatal myocardial infarction (MI)
[primary endpoint], and all-cause mortality plus recurrent nonfatal MI plus urgent
revascularization (secondary endpoint) in the ExTRACT-TIMI 25 trial. The
significant difference in the incidence of the composite primary endpoint between
these two groups was maintained at the 1-year follow-up. Although bleeding was
reported more frequently with enoxaparin than with UFH in the ExTRACT-TIMI
25 trial, enoxaparin was associated with a net clinical benefit relative to UFH.
Patients in this trial received enoxaparin as an initial 30 mg intravenous bolus,
followed by 1 mg/kg subcutaneously within 15 minutes and then every 12 hours
for up to 8 days; the first two subcutaneous dosages were not to exceed 100 mg.
Patients ≥75 years of age did not receive the initial bolus of enoxaparin and the
12-hourly dosages were reduced to 0.75 mg/kg; the dose was also reduced to 1
mg/kg every 24 hours in patients of any age who had an estimated creatinine
clearance (CLCR) of <30 mL/min. Data from several earlier randomized, multi-
centre, phase III trials support these results.

Pharmacological Enoxaparin is an LMWH of a variable size, with an average molecular weight of

Properties 4–5 kD. It prevents the formation of blood clots by binding to antithrombin and
potentiating its action, as well as by inhibiting coagulation factors XIa, IXa, Xa
and IIa (thrombin). The pharmacodynamic profiles of LMWHs, such as enox-
aparin, have many advantages when compared with that of UFH. Advantages
include minimal plasma binding, leading to more reliable anticoagulant effects
(thereby eliminating the need for therapeutic monitoring), a greater capacity to
release tissue factor pathway inhibitor, a higher anti-factor Xa : IIa ratio, a lower
propensity to inhibit platelet aggregation, less inhibition by platelet factor 4,
potential antiplatelet effects via higher degrees of suppression of von Willebrand
factor and a lesser propensity to cause heparin-induced thrombocytopenia and
osteoporosis.
Following subcutaneous administration, enoxaparin demonstrates high bio-
availability and has a linear pharmacokinetic profile over the normal therapeutic

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (5)
Enoxaparin: A Review
Therapeutic Efficacy
Tolerability
© 2008 Adis Data Information BV. All rights reserved.
693
dose range. The pharmacokinetics of enoxaparin are based on anti-factor Xa
activity. Following administration of subcutaneous enoxaparin 1.5 mg/kg once
daily for 5 days, the mean peak plasma anti-factor Xa activity was 1.37 IU/mL and
the steady-state area under the plasma activity-time curve was 14.26 IU • h/mL;
the apparent volume of distribution has been reported as 4.3–9.3 L.
Enoxaparin is predominantly metabolized by the liver and is eliminated
renally. The clearance of anti-factor Xa activity at steady state has been shown to
decline with increasing renal dysfunction and hence, the dosage of enoxaparin
must be reduced in patients with severe renal impairment (CLCR <30 mL/min).
The pharmacokinetics of a non-weight-adjusted single subcutaneous 40-mg dose
of enoxaparin differ depending upon the weight of the patient.
In patients with STEMI who received fibrinolytic therapy, enoxaparin was
significantly more effective than UFH in reducing the 30-day combined incidence
of all-cause mortality plus recurrent nonfatal MI (primary endpoint), and all-cause
mortality plus recurrent nonfatal MI plus urgent revascularization (secondary
endpoint) in the ExTRACT-TIMI 25 trial. Moreover, the significant difference
between the two groups at the primary endpoint was still evident 1 year later. In
addition, enoxaparin was superior to UFH as adjunctive therapy in patients with
STEMI in terms of the incidence of three combined efficacy-safety endpoints.
When data was stratified according to baseline CLCR levels, there was no
difference in the incidence of the primary endpoint between enoxaparin and UFH
recipients in those with severe renal dysfunction, but a difference in favour of
enoxaparin emerged as renal function improved. The incidence of the primary
endpoint was lower in fibrin-specific lytic recipients who received enoxaparin
than UFH; however, there was no statistically significant difference between the
two groups in those who received streptokinase as their lytic therapy. In those
patients who underwent PCI, the incidence of the primary endpoint was signifi-
cantly lower in enoxaparin than UFH recipients, and fewer patients receiving
enoxaparin than UFH underwent PCI.
In this randomized, double-blind, double-dummy, parallel-group, multicentre,
phase III trial, enoxaparin was administered as an initial 30 mg intravenous bolus,
followed by 1 mg/kg subcutaneously within 15 minutes and then every 12 hours
for up to 8 days; the first two subcutaneous dosages were not to exceed 100 mg.
Patients ≥75 years of age did not receive the initial bolus of enoxaparin and the
12-hourly dosages were reduced to 0.75 mg/kg; the dose was also reduced to
1 mg/kg every 24 hours if patients of any age had an estimated CLCR of <30 mL/
min. Efficacy outcomes from this study have been supported by the results of
several earlier randomized, double-blind, phase III trials that compared enox-
aparin with UFH or placebo, and established both its clinical and angiographic
efficacy.
As expected, bleeding complications were the most frequently occurring adverse
events associated with enoxaparin use in clinical trials. Minor bleeding accounted
for the majority of events and occurred at a significantly greater incidence in
enoxaparin recipients than in UFH recipients in the ExTRACT-TIMI 25 trial. The
incidence of major bleeds also occurred at a higher incidence in enoxaparin
recipients than in UFH recipients in this trial. However, intracranial haemorrhage
occurred at a similar incidence in the two groups.
Drugs 2008; 68 (5)
694 Carter et al.

Other adverse effects associated with enoxaparin use include local reactions,
such as mild local irritation, pain, haematoma, ecchymosis and erythema. In
addition, fully reversible elevations in AST or ALT levels have been reported in
patients receiving enoxaparin; these laboratory abnormalities have also been seen
in patients receiving heparin and other LMWHs in clinical trials.

1. Introduction tithrombin therapies, and unfractionated heparin

The development of reperfusion strategies over
the last three decades has resulted in considerable
advances in the management of patients presenting
with ST-segment elevation myocardial infarction
(STEMI).[1,2] Despite there being a reduction in in-
hospital mortality levels over this time, there has
been little improvement in the overall survival of
patients with STEMI in the past decade, possibly
reflecting in part the suboptimal improvement in
coronary reperfusion, the recurrence of myocardial
infarction (MI) and the bleeding complications, such
as intracranial haemorrhage (ICH), that can occur as
a result of fibrinolytic therapy.[1,3,4] As a result,
STEMI remains a significant public health issue in
all industrialized countries and is becoming more so
in developing countries.[2] US estimates predict
565 000 first-time cases, and 300 000 recurrent
cases, of MI annually.[5] It has also been estimated
that the number of years of life lost due to an MI can
be as many as 15 years, and that those patients with a
history of previous STEMI have a sudden death rate
that is 4- to 6-fold higher than that of the general
population.[5] Therefore, there remains a need for
new and improved treatment strategies for patients
with STEMI.
Current US[2,6] and European[7] guidelines recom-
mend a multimodal approach for the treatment of
STEMI that includes reperfusion (either medical or
via subsequent percutaneous coronary intervention
[PCI]), along with adjuvant antiplatelet and
antithrombin agents. Despite there having been a
number of advances with respect to the first two
modalities in recent years, there has been relatively
little progress in the development of new an-
(UFH) has long been the agent of choice.[2,6-8] How-
ever, UFH has a number of potential limitations,
such as the difficulty in maintaining therapeutic
plasma levels necessitating frequent monitoring and
dose adjustment (section 6).[8,9]
The use of enoxaparin (enoxaparin sodium;
Lovenox®),1 a low-molecular-weight heparin
(LMWH), has recently been studied in patients with
STEMI[3,4,8-12] and may offer benefits over UFH as
the adjuvant antithrombotic of choice in these pa-
tients. This article reviews the pharmacological
properties, clinical efficacy and tolerability of sub-
cutaneous enoxaparin in adult patients with STEMI.
2. Overview of Pharmacology
Enoxaparin is an LMWH produced by controlled
depolymerization of a benzyl ester of UFH using
sodium hydroxide.[13] It has a variable size, with an
average molecular weight of 4–5 kD.[13] The phar-
macodynamic and pharmacokinetic properties of
enoxaparin have been reviewed previously.[13-16]
This section provides a brief overview of its major
pharmacological properties.
2.1 Pharmacodynamics
Enoxaparin, like UFH, binds to and potentiates
the action of antithrombin, which is an endogenous
inhibitor of coagulation factors XIa, IXa, Xa and IIa
(thrombin). Inhibition of these serine proteases in-
hibits the coagulation cascade and prevents forma-
tion of blood clots.[14] Enoxaparin has also been
shown to cause the release of tissue factor pathway
inhibitor (TFPI) and to inhibit the generation of
factor VIIa.[16] While the interaction of enoxaparin

1 Other trade names include Clexane®, Decipar® and Klexane®. The use of trade names is for identification purposes
only and does not imply endorsement.

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (5)
Enoxaparin: A Review
with the coagulation cascade is complex, inhibition
of factors Xa (which converts prothrombin to throm-
bin) and IIa (which converts fibrinogen to fibrin) are
central to its action.[13]
As a result of its low molecular weight, enox-
aparin has markedly lower anti-factor IIa activity
than UFH, while its anti-factor Xa activity is not
affected.[14] Therefore, enoxaparin has a higher ratio
of anti-factor Xa to IIa activity (variously estimated
between 3.6 : 1 and 14 : 1) than UFH (1 : 1).[13,16] A
high ratio of anti-factor Xa to IIa activity has been
linked to a lesser tendency to cause bleeding.[14]
However, this has not been borne out in clinical
studies (section 4).
Although enoxaparin and UFH produce similar
increases in free TFPI concentrations following sin-
gle-dose administration, total TFPI activity is par-
tially depleted after continuous, multiple-dose, sub-
cutaneous administration of UFH, but not of enox-
aparin.[14]
The effects of enoxaparin on platelets (either
platelet activation or inhibition of platelet aggrega-
tion) are less pronounced than those of UFH.[14,15]
Although the lower propensity of enoxaparin to
inhibit platelet aggregation suggests a lower tenden-
cy to cause bleeding, this has not been shown in
clinical studies (section 4). Platelet factor 4, which is
released by activated platelets, almost completely
inactivates UFH, but has only minor effects on
enoxaparin. The anti-factor Xa activity of enox-
aparin is almost completely retained and the anti-
factor IIa activity is only partially reduced.[14] The
reduced interaction with platelets may be responsi-
ble for the reduced incidence of heparin-induced
thrombocytopenia observed with enoxaparin.[14]
Furthermore, unlike UFH, enoxaparin does not pro-
mote platelet retention in fibrin clots.[14]
Enoxaparin binds with lower affinity than UFH
to endothelial cells, which may explain its higher
bioavailability following subcutaneous administra-
tion. The lower propensity of enoxaparin than UFH
to bind nonspecifically to a variety of plasma pro-
teins may explain its lower variability in pharmaco-
dynamic effects relative to UFH.[14]
© 2008 Adis Data Information BV. All rights reserved.
695
Enoxaparin appears to inhibit bone formation to a
much lesser extent than UFH, indicating a lower
propensity to produce osteoporotic effects.[14] Enox-
aparin has also been shown to differ from UFH in
that it reduces the release of von Willebrand factor,
which mediates platelet adhesion to exposed suben-
dothelium and, thereby, protects patients with acute
coronary syndromes.[14]
2.2 Pharmacokinetics
The pharmacokinetics of enoxaparin are based on
anti-factor Xa activity, rather than direct detection
of the molecular species, and have predominantly
been determined using the 100 mg/mL formulation.
Following subcutaneous administration, enox-
aparin demonstrates high bioavailability
(≈100%).[17] The pharmacokinetics of subcutaneous
enoxaparin are linear over the normal therapeutic
dosage range and steady state is normally achieved
by the second day of treatment.[13,17] Single-dose
pharmacokinetics of enoxaparin are a good indicator
of the steady-state activity levels. Peak plasma anti-
factor Xa activity (Amax) generally occurs 3–5 hours
after single-dose subcutaneous administration.[17]
The mean Amax values in healthy volunteers re-
ceiving single-dose subcutaneous enoxaparin 20 and
40 mg were 0.16 and 0.38 IU/mL, while the Amax
following subcutaneous enoxaparin 1.5 mg/kg once
daily for 5 days was 1.37 IU/mL and the steady-state
area under the plasma activity-time curve (AUC)
was 14.26 IU • h/mL.[17] Following a 30 mg intrave-
nous bolus, immediately followed by 1 mg/kg sub-
cutaneously, then 1 mg/kg subcutaneously every
12 hours, the initial Amax was 1.16 IU/mL and
the average exposure was 84% of steady-state
levels.[17] The apparent volume of distribution of
enoxaparin has been reported to be between 4.3 and
9.3 L.[13,15-17]
Enoxaparin is predominantly metabolized in the
liver by desulfation or depolymerization to lower
molecular weight species with substantial loss of
biological activity and is eliminated renally.[17] After
intravenous administration of radiolabelled enox-
aparin, 40% of the radioactivity and 8–20% of the
anti-factor Xa activity were recovered in the urine
Drugs 2008; 68 (5)
696
within 24 hours.[17] The total body clearance of
intravenous enoxaparin is 26 mL/min, while the
apparent clearance of subcutaneous enoxaparin is
about 15 mL/min.[17] The elimination half-life of
enoxaparin is ≈4.5 hours after a single subcutaneous
dose and ≈7 hours at steady state; however, substan-
tial anti-factor Xa activity remains in plasma for
≈12 hours after the administration of subcutaneous
enoxaparin 40 mg once daily.[17]
The clearance of anti-factor Xa activity at steady
state declines with increasing renal dysfunction, ne-
cessitating dosage reduction in patients with severe
renal impairment (creatinine clearance [CLCR]
<30 mL/min) [section 5].[17] The maximum plasma
activity and clearance of subcutaneous enoxaparin
in elderly subjects were similar to those in young
subjects. The AUC at steady state (day 10) in elderly
subjects was ≈15% higher than the AUC on day
1.[17]
The pharmacokinetics of weight-adjusted dos-
ages of enoxaparin at steady state were generally
similar in obese and non-obese volunteers, but with
a non-weight-adjusted single subcutaneous 40 mg
dose, the exposure to enoxaparin was 52% higher in
low-weight women (<45 kg) and 27% higher in low-
weight men (<57 kg) than in normal-weight volun-
teers.[17]
3. Therapeutic Efficacy
The efficacy of enoxaparin in patients with
STEMI has been evaluated in several fully pub-
lished, randomized, multicentre, phase III clinical
trials (see table I for acronyms).[3,4,8-12] The majority
of data in this section are from a large, randomized,
double-blind, double-dummy, parallel-group, multi-
centre, phase III trial, known as the ExTRACT-
TIMI 25 study. Overall results of this study are
available in one main article (section 3.1)[10] and a
further seven articles[18-24] report data from pre-spec-
ified subgroup analyses (section 3.1.1). Additional
ExTRACT-TIMI 25 trial data are from an abstract
reporting 1-year results,[25] as well as from the man-
ufacturer’s prescribing information.[17]
Supplementary data from six other randomized
trials are also discussed (section 3.2),[3,4,8,9,11,12] as
© 2008 Adis Data Information BV. All rights reserved.
Carter et al.
Table I. Enoxaparin clinical trial acronyms
AMI-SK Acute Myocardial Infarction-StreptoKinase
ASSENT-3 and ASsessment of the Safety and Efficacy of a
ASSENT-3 PLUS New Thrombolytic regimen
ENTIRE-TIMI 23 ENoxaparin and TNK-tPA with or without GP
IIb/IIIa Inhibitor as REperfusion strategy in
ST-elevation myocardial infarction-
Thrombolysis In Myocardial Infarction
ExTRACT-TIMI 25 Enoxaparin and Thrombolysis Reperfusion
for Acute Myocardial Infarction Treatment-
Thrombolysis in Myocardial Infarction
HART II Heparin and Aspirin Reperfusion Therapy
well as results of a large meta-analysis of random-
ized trials in patients with STEMI who received
either enoxaparin or UFH (section 3.3).[26]
Patients eligible for these trials were
≥18 years,[3,4,8-11] had symptoms of ischaemia that
lasted for ≥30 minutes[8,9,12] and occurred ≤6[3,4,8,10]
to 12[11] hours prior to randomization, had ST-seg-
ment elevation of ≥0.1 mV in two or more limb
leads,[3,4,8-10] ≥0.2 mV in two or more contiguous
precordial leads,[3,4,8-10] or ≥1 mm in two or more
contiguous leads,[12] or a left bundle branch
block.[3,4,10] In one study, patients with a left bundle
branch block on ECG were excluded from the
trial.[8] In the ExTRACT-TIMI 25 trial,[10] patients
were eligible for inclusion only if they had planned
reperfusion with streptokinase, tenecteplase, al-
teplase or reteplase.
Patients were excluded from the trials if they had
a cardiovascular, haematological or other disorder,
or had received prior or concomitant pharmacologi-
cal therapy that would place them at an unacceptable
risk of serious bleeding from the administration of a
fibrinolytic agent.[3,4,8,10,11] Patients with known re-
nal insufficiency (serum creatinine >2.5 mg/dL for
men and >2.0 mg/dL for women)[3,4,8,10,11] or other
serious medical illness[10] were also excluded.
3.1 The ExTRACT-TIMI 25 Study
In addition to fibrinolytic therapy, patients were
randomized 1 : 1 to receive enoxaparin 30 mg as an
initial intravenous bolus, followed within 15 min-
utes by a 1 mg/kg subcutaneous dose that was re-
peated every 12 hours (maximum dose for first two
subcutaneous dosages was 100 mg) for 8 days or
Drugs 2008; 68 (5)
Enoxaparin: A Review 697

until hospital discharge (whichever occurred earli-
er), or UFH 60 U/kg (up to a maximum of 4000 U)
as an initial intravenous bolus, followed by an intra-
venous infusion of 12 U/kg/h (up to a maximum of
1000 U/h) for at least 48 hours.[10] To minimize the
risk of enoxaparin accumulation in patients aged
≥75 years, the 12-hourly subcutaneous dosages of
enoxaparin were reduced from 1 to 0.75 mg/kg and
the initial 30 mg intravenous bolus was omitted in
this age group.[10] The dose was also reduced to
1 mg/kg every 24 hours in patients of any age who
had an estimated CLCR of <30 mL/min.[10] Study
medication was administered between 15 minutes
prior to, and 30 minutes following, the commence-
ment of fibrinolytic therapy.[10] All patients received
aspirin (acetylsalicylic acid) or an alternative anti-
platelet agent.[10]
The primary efficacy endpoint was the composite
of all-cause mortality and nonfatal recurrent MI in
the first 30 days following randomization.[10] The
main secondary endpoint was the composite of
30-day all-cause mortality, nonfatal recurrent MI
and recurrent myocardial ischaemia leading to ur-
gent revascularization.[10] Other endpoints included
the individual components of the primary and secon-
dary endpoints, as well as three combined efficacy-
safety endpoints that were designed to give an indi-
cation of the net clinical benefit of enoxaparin rela-
tive to UFH.[10]
A total of 20 506 patients were randomized in the
ExTRACT-TIMI 25 study and 20 479 were includ-
ed in the intention-to-treat population.[10] Baseline
characteristics were similar between the enoxaparin
(n = 10 256) and UFH (n = 10 223) groups. The
mean treatment duration was 6.6 days for enox-
aparin recipients and 2.2 days for UFH recipients.[17]
3.1.1 Primary Analysis
At day 30, the combined incidence of all-cause
mortality plus nonfatal recurrent MI (primary end-
point), and all-cause mortality plus nonfatal recur-
rent MI plus urgent revascularization (secondary
endpoint), was significantly lower in patients who
received enoxaparin than in those who received
UFH (both p < 0.001; table II).[10] When each com-
ponent of these endpoints was analysed separately, a
significant difference was seen between enoxaparin
and UFH for the endpoints of nonfatal recurrent MI
and urgent revascularization (both p < 0.001), but
not for the endpoint of all-cause mortality (table
II).[10]
In addition, enoxaparin was superior to UFH with
respect to net clinical benefit, as evidenced by the
lower incidence of the three pre-specified combined

Table II. Efficacy of enoxaparin (ENO) as an adjunct to fibrinolytic therapy in ST-segment elevation myocardial infarction: results of the
randomized, double-blind ExTRACT-TIMI 25 study.[10] See text for trial design and dosage details
Study endpoint Incidence 30 d after randomization (% of pts) Relative risk
ENO UFH (95% CI)
(n = 10 256) (n = 10 223)
Primary efficacy endpoint
Death or nonfatal reMI 9.9* 12.0 0.83 (0.77, 0.90)

Secondary efficacy endpoint

Death, nonfatal reMI or urgent revascularization 11.7* 14.5 0.81 (0.75, 0.87)
Other efficacy endpoints
Death 6.9 7.5 0.92 (0.84, 1.02)
Nonfatal reMI 3.0* 4.5 0.67 (0.58, 0.77)
Urgent revascularization 2.1* 2.8 0.74 (0.62, 0.88)
Net-clinical-benefit endpoints
Death, nonfatal reMI or nonfatal disabling stroke 10.1* 12.3 0.82 (0.76, 0.89)
Death, nonfatal reMI or nonfatal major bleeding 11.0* 12.8 0.86 (0.80, 0.93)
Death, nonfatal reMI or nonfatal ICH 10.1* 12.2 0.83 (0.77, 0.90)
ICH = intracranial haemorrhage; reMI = recurrent myocardial infarction; UFH = unfractionated heparin; * p < 0.001 vs UFH.

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (5)
698
efficacy-safety endpoints in enoxaparin recipients
than in UFH recipients (table II).[10]
At 1 year following randomization into the Ex-
TRACT-TIMI 25 trial, the incidence of the primary
endpoint and the net-clinical-benefit endpoint of all-
cause mortality, nonfatal recurrent MI or nonfatal
disabling stroke remained significantly lower in pa-
tients who had received enoxaparin than in those
who had received UFH (15.8% vs 17.0%, p < 0.01;
16.0% vs 17.3%, p = 0.007).[25] When the compon-
ents of the primary endpoint were analysed separate-
ly, the incidence of nonfatal recurrent MI remained
significantly lower in enoxaparin recipients than in
UFH recipients (5.7% vs 6.7%, p < 0.001), and no
statistical difference had emerged between the inci-
dence of all-cause mortality in enoxaparin and UFH
recipients (10.5% vs 10.6%).[25] The incidence of
urgent revascularisation at 1 year was not report-
ed.[25]
3.1.2 Subgroup Analyses
Renal dysfunction
Because of the potential for enoxaparin to accu-
mulate in patients with renal dysfunction (section
2.2), patients with known poor renal function were
excluded from the ExTRACT-TIMI 25 trial, and
those with a degree of renal dysfunction received
reduced dosages of enoxaparin (see section 3.1). In a
subgroup analysis, the effect of enoxaparin was
stratified according to the estimated baseline CLCR
of patients.[21] Baseline characteristics between the
strata varied greatly, with patients in each lower
stratum being older (p < 0.001) with a higher inci-
dence of hypertension, diabetes mellitus, previous
MI and a higher baseline mortality risk (higher
thrombolysis in myocardial infarction [TIMI] risk
score) [all p < 0.001] than patients in the strata
above.[21]
In those patients with severe renal dysfunction,
there was no significant difference in the incidence
of the primary endpoint between patients who re-
ceived enoxaparin and those who received UFH.[21]
However, a significant difference in favour of enox-
aparin appeared as renal function improved (table
III).
© 2008 Adis Data Information BV. All rights reserved.
Carter et al.
Similarly, there was no statistical difference in
the incidence of the net-clinical-benefit endpoint of
all-cause mortality, nonfatal recurrent MI or nonfa-
tal major bleeding between enoxaparin and UFH
recipients who had a CLCR of <30 mL/min (34.9%
vs 37.7%) or 30–60 mL/min (21.3% vs 20.6%), but
there was a statistically significant difference in
favour of enoxaparin for this endpoint in those with
a CLCR of >60–90 mL/min (10.7% vs 13.0%,
p < 0.01) or >90 mL/min (5.7% vs 7.9%,
p < 0.001).[21]
Type of Lytic Therapy
In this subgroup analysis,[18] data were analysed
according to the type of fibrinolytic therapy that
patients received: fibrin-specific lytic (alteplase,
reteplase or tenecteplase; n = 16 283) or streptoki-
nase (n = 4139). The type of fibrinolytic therapy
administered was not a randomized procedure, but
occurred at the physician’s discretion. Patients who
received streptokinase were older (p < 0.001) and
had a higher incidence of diabetes (p = 0.008) than
those who received fibrin-specific lytics; other base-
line characteristics were similar between the two
groups.[18]
The incidence of the primary endpoint was sig-
nificantly lower in patients who received a fibrin-
specific lytic and enoxaparin than in those who
received a fibrin-specific lytic and UFH; however,
there was no significant difference between these
two groups in those patients who received streptoki-
nase as their lytic therapy (table III).[18] The benefits
of enoxaparin over UFH for the prevention of the
primary endpoint translated into a number of pa-
tients who need to be treated (NNT) to prevent one
event of 48 and 67 for the fibrin-specific lytic cohort
and the streptokinase cohort, respectively.[18]
When data from each fibrin-specific lytic was
analysed separately, the difference in the incidence
of the primary endpoint between enoxaparin and
UFH recipients was significant in patients who re-
ceived alteplase (10.1% vs 12.2%, p < 0.001;
n = 5605 and 5570) and reteplase (8.4% vs 11.4%,
p = 0.05; n = 561 in both groups), but not for those
who received tenecteplase (9.4% vs 11.5%;
n = 1976 and 2010); however, the study was not
Drugs 2008; 68 (5)
Enoxaparin: A Review 699

Table III. Efficacy of enoxaparin (ENO) in patients (pts) with ST-segment myocardial infarction (MI): primary endpoint results of pre-
specified comparative subgroup analyses[18,20-24] of the randomized, double-blind ExTRACT-TIMI 25 trial.[10] See text for trial design and
dosage details
Comparative subgroup Stratification factor 30-Day all-cause mortality or nonfatal recurrent MI (% of pts)
analysis ENO [no. of pts] UFH [no. of pts]
Fox et al.[21] CLCR <30 mL/min 33.0 [106] 37.7 [106]
CLCR 30–60 mL/min 19.4 [1813] 19.4 [1858]
CLCR >60–90 mL/min 9.6* [3583] 12.1 [3620]
CLCR >90 mL/min 5.1** [3739] 7.3 [3723]
Gibson et al.[19] Underwent PCIa 10.7** [2272] 13.8 [2404]
Giraldez et al.[18] Received fibrin-specific lytic 9.8** [8142] 12.0 [8141]
Received streptokinase 10.2 [2083] 11.8 [2056]
Mega et al.[24] Women 15.4* [2415] 18.3 [2368]
Men (15 696)b 8.2** 10.1
Sabatine et al.[20] Clopidogrel 7.3 [1083] 7.8 [1090]
No clopidogrel 9.9c [6528] 12.0 [6390]
Scirica et al.[22] Complete STRd 4.4** [575] 9.9 [525]
Partial STRd 14.2 [422] 12.5 [408]
No STRd 16.2 [167] 15.9 [201]
White et al.[23] Aged <75 y 7.9*** [9015] 9.9 [8932]
Aged ≥75 y 24.8 [1241] 26.3 [1291]
a Corresponding values for pts who did not undergo PCI are not available.
b Total no. of men in study; no. in each treatment arm not specified.
c No p-value available for this result; adjusted odds ratio = 0.79 (95% CI 0.70, 0.90).
d On ECG at 180 mins after fibrinolytic therapy. Initial ECG was conducted at onset of fibrinolytic therapy.
CLCR = creatinine clearance; PCI = percutaneous coronary intervention; STR = ST-segment resolution; UFH = unfractionated heparin;
* p < 0.01, ** p ≤ 0.001, *** p < 0.0001 vs UFH.

powered to detect differences between the sub-
groups.[18]
Similar to the primary endpoint data, there was
also a significantly lower incidence of all-cause
mortality, nonfatal recurrent MI or urgent revascu-
larization (secondary endpoint) with enoxaparin
than with UFH in patients who received fibrin-
specific lytics (11.6% vs 14.4%, p < 0.001).[18] This
difference was seen in those who received alteplase
(11.3% vs 14.0%, p < 0.001) and tenecteplase
(12.5% vs 15.7%, p = 0.05), but not in those who
received reteplase (11.1% vs 14.4%, p = 0.07).[18]
However, unlike primary endpoint data, the inci-
dence of the secondary endpoint was significantly
lower in streptokinase recipients who received
enoxaparin than in those who received UFH (12.2%
vs 14.5%, p = 0.01).[18]
In addition, the incidence of the net-clinical-
benefit endpoint of all-cause mortality, nonfatal re-
current MI or nonfatal major bleeding was signifi-
cantly lower in fibrin-specific lytic recipients who
received adjuvant enoxaparin than in those who
received UFH (10.8% vs 12.7%, p < 0.001).[18] The
difference between these two groups of patients in
the streptokinase cohort was not significant (11.8%
vs 13.0%).[18]
Sex of Patient
As a subgroup, women were older, were more
likely to have hypertension, diabetes or prior angina
pectoris, were at a higher baseline mortality risk
(TIMI risk score >3), experienced a longer delay
from symptom onset to fibrinolytic therapy, were
less likely to be prescribed antiplatelet agents, β-
adrenergic antagonists or HMG-CoA reductase in-
hibitors (statins), and underwent significantly fewer
cardiac procedures (all p < 0.001).[24]
The incidence of the primary endpoint was sig-
nificantly lower in the subgroups of women and men
receiving enoxaparin than in the corresponding sub-
groups receiving UFH (table III). The relative risk

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (5)
700
reduction (RRR) in women and men was 16% and
19%, and the absolute risk difference (ARD) was
2.9% and 1.9%.[24]
Women and men had a similar relative benefit
(both RRR 14%) with enoxaparin over UFH for the
net-clinical-benefit endpoint of all-cause mortality,
nonfatal recurrent MI or nonfatal major bleeding
(incidence in women 16.4% vs 19.0%; men 9.3% vs
10.9%).[24] Because of their higher baseline risk,
women received a numerically greater absolute ben-
efit than men with enoxaparin relative to UFH
(ARD 2.6% vs 1.6%) and this translated into a NNT
to prevent one episode of the net-clinical-benefit
endpoint of 38 for women and 63 for men.[24]
Clopidogrel Use
In patients who received a fibrinolytic and aspirin
on presentation, and who did not undergo PCI
during the index hospital stay, 2173 also received
clopidogrel and 12 918 did not.[20] The decision to
commence clopidogrel treatment was not a random-
ized procedure, but occurred at the discretion of the
treating physician. Whilst treatment was similar be-
tween the two groups, clopidogrel recipients were
younger (p < 0.001), were more likely to be male
(p < 0.001), have hyperlipidaemia (p = 0.008) or
diabetes (p < 0.001) and have had previous PCI
(p < 0.001), but less likely to be Caucasian
(p < 0.001), have prior angina pectoris (p < 0.001) or
a previous MI (p = 0.025).[20]
In this subgroup analysis,[20] enoxaparin was sig-
nificantly more effective than UFH in decreasing the
incidence of the primary endpoint in patients who
did not receive clopidogrel, but not in those who
received clopidogrel (table III).
ST-Segment Elevation Resolution
ECGs were obtained in 3208 patients at the onset
of fibrinolytic therapy (baseline ECG) and then
again at 180 minutes after the administration of
fibrinolytic therapy.[22] Of the 2298 patients who
had ECGs that were valid for calculation of ST-
segment elevation resolution, baseline characteris-
tics were similar between those who received enox-
aparin and those who received UFH.[22]
When compared with UFH, enoxaparin signifi-
cantly reduced the incidence of the primary endpoint
© 2008 Adis Data Information BV. All rights reserved.
Carter et al.
in patients with complete ST-segment elevation res-
olution at 180 minutes following fibrinolytic ther-
apy, but not in those with partial or no ST-segment
elevation resolution (table III).[22]
These results suggest that enoxaparin acts to pre-
vent the reocclusion of the vessel after successful
reperfusion with fibrinolytic therapy.[22]
Age of Patient
In a previous study,[3] enoxaparin was associated
with an increased risk of bleeding in elderly pa-
tients.[23] Because of this, patients ≥75 years of age
received reduced dosages of enoxaparin in the Ex-
TRACT-TIMI 25 trial (see section 3.1). Baseline
characteristics varied considerably between patients
who were aged ≥75 years (n = 2532) and those who
were aged <75 years (17 947).[23] In particular, pa-
tients aged ≥75 years were significantly (p < 0.001)
more likely to have hypertension, diabetes, prior MI
or angina pectoris, have been receiving long-term
aspirin therapy, or have a greater baseline mortality
risk (assessed by Killip class, TIMI risk score and
TIMI risk index) than their younger counterparts. In
addition, patients aged ≥75 years were significantly
(p < 0.001) less likely to receive aspirin, clopidogrel,
β-adrenergic antagonists and statins during the in-
dex hospital stay.[23] Baseline characteristics were
similar between the enoxaparin and UFH treatment
arms of each subgroup.[23]
The incidence of the primary endpoint was sig-
nificantly lower in enoxaparin than UFH recipients
in the subgroup of patients aged <75 years, but not
in the subgroup of those aged ≥75 years (table
III).[23] The ARD was 1.5% and 2.0% for ≥75-year
olds and <75-year olds, respectively, and was in
favour of enoxaparin. This corresponded to a NNT
to prevent one primary endpoint event of 67 in
patients aged ≥75 and 50 in those aged <75 years.[23]
A statistical difference was reported between
enoxaparin and UFH recipients who were aged
<75 years (9.7% vs 12.4%, p < 0.001), but not
between the two groups in patients ≥75 years
(26.0% vs 28.4%, p = 0.18) for the secondary end-
point of all-cause mortality, nonfatal recurrent MI
and urgent revascularization.[23] This corresponded
with an ARD in favour of enoxaparin of 2.7% in
Drugs 2008; 68 (5)
Enoxaparin: A Review
patients aged <75 years and 2.4% in those aged ≥75
years, with NNT to prevent one secondary endpoint
event of 37 and 42, respectively.[23]
Similarly, a statistical difference favouring enox-
aparin over UFH was seen for the net-clinical-bene-
fit endpoint of all-cause mortality, nonfatal recurrent
MI or nonfatal major bleeding in patients <75 years
of age (9.0% vs 10.7%, p < 0.001), but not in those
aged ≥75 years (25.8% vs 27.3%).[23]
Percutaneous Coronary Intervention
All patients who subsequently underwent PCI
during their index hospital stay were continued on
their double-blind study medication for antithrom-
botic support.[19] In those patients whose last subcu-
taneous dosage of enoxaparin had been adminis-
tered >8 hours prior to PCI, an additional intrave-
nous bolus of enoxaparin (or matched placebo) of
0.3 mg/kg was administered; those who had re-
ceived their last dose of study medication <8 hours
previously did not receive this additional dose. UFH
(or matched placebo) was dosed according to the
activated partial thromboplastin time (aPTT).[19] If
PCI occurred after day 8 or hospital discharge, all
patients received antithrombotic support with open-
label UFH.
Significant differences in baseline characteristics
of patients who did and did not undergo PCI by day
30 were identified in this subgroup analysis and a
propensity score was calculated to adjust for the
differences.[19]
In the subgroup of patients who underwent PCI
by day 30, the combined incidence of the primary
endpoint was 10.7% in enoxaparin recipients com-
pared with 13.8% in UFH recipients (p = 0.001).[19]
In addition, PCI was performed less frequently in
patients in the enoxaparin group than in those in the
UFH group (22.8% vs 24.2%, p = 0.027) and was
delayed longer in enoxaparin recipients than in UFH
recipients (121.7 vs 109.2 hours, p = 0.006).[19]
Moreover, enoxaparin was also superior to UFH
for the net-clinical-benefit endpoint of all-cause
mortality, nonfatal MI or nonfatal major bleeding
with the incidence being 11.5% in enoxaparin recip-
ients compared with 14.8% in UFH recipients
(p < 0.001).[19]
© 2008 Adis Data Information BV. All rights reserved.
701
3.2 Other Randomized Studies
A number of earlier randomized studies have also
compared the efficacy of enoxaparin with that of
UFH or placebo. Efficacy was established using
clinical[3,4,12] and/or angiographic[8,9,11] endpoints;
data in this section are discussed according to the
nature (clinical or angiographic) of the primary end-
point.
3.2.1 Clinical Efficacy versus Unfractionated
Heparin (UFH)
The clinical efficacy of enoxaparin compared
with UFH was established in two pivotal (AS-
SENT-3[4] and ASSENT-3 PLUS[3]) randomized
trials.
A total of 6095 patients were enrolled in the
ASSENT-3 trial and 5989 patients received fibrino-
lytic therapy with tenecteplase and were randomized
to receive enoxaparin, full-dose UFH or low-dose
UFH plus abciximab.[4] Enoxaparin was adminis-
tered as an intravenous bolus of 30 mg, followed by
a 1 mg/kg subcutaneous dose that was repeated
every 12 hours until hospital discharge or revascu-
larization for a maximum of 7 days; the first two
subcutaneous dosages were not to exceed 100 mg.
Full-dose UFH was administered as an intravenous
bolus of 60 U/kg (up to a maximum of 4000 U)
followed by a 12 U/kg/h infusion (up to a maximum
of 1000 U/h) for ≥48 hours; the infusion dosage was
adjusted according to the aPTT. In the third group,
low-dose UFH was administered as an intravenous
bolus of 40 U/kg (up to a maximum of 3000 U),
followed by a 7 U/kg/h infusion (up to a maximum
of 800 U/h) adjusted as per aPTT for ≥48 hours, and
patients received abciximab as a 0.25 mg/kg bolus,
followed by a 0.125 µg/kg/min infusion (up to a
maximum of 10 µg/min) for 12 hours.[4] Half-dose
tenecteplase was administered to patients in the
abciximab treatment arm, whereas all other patients
received full-dose tenecteplase. All patients in the
study received aspirin.
As an extension of the ASSENT-3 trial,[4] the
ASSENT-3 PLUS[3] trial was performed to assess
the efficacy of enoxaparin versus UFH when admin-
istered in conjunction with tenecteplase in the pre-
hospital (patient’s home or ambulance) setting. Dos-
Drugs 2008; 68 (5)
702 Carter et al.

Table IV. Clinical efficacy of enoxaparin (ENO) in patients (pts) with ST-segment elevation myocardial infarction (MI): results of random-
ized, multicentre, phase III trials[3,4,12] comparing the efficacy of ENO with that of unfractionated heparin (UFH). See text for trial design and
dosage details. The primary endpoint was the 30[3,4] or 90[12] day composite of mortality (all-cause[3,4] or cardiac only[12]), nonfatal recurrent
MI (reMI) or refractory ischaemia
Trial Treatment No. of pts Incidence (% of pts)
death, nonfatal death nonfatal reMI refractory
reMI or refractory ischaemia
ischaemia
Efficacy at 30 d
ASSENT-3 Investigators ENO 2040 11.4**a 5.4 2.7**a,b 4.6***a,b
[4] a a
(ASSENT-3 trial) UFH 2038 15.4 6.0 4.2 6.5a
a a ,b
UFH + ABC 2017 11.1*** 6.6 2.2** 3.2***a,b
Wallentin et al.[3] ENO 818 14.2 7.5 3.5*a 4.4a
(ASSENT-3 PLUS trial) UFH 821 17.4 6.0 5.8a 6.5a
Efficacy at 90 d
Baird et al.[12] ENO 149 25.5*c,d 6.0c 14.8 4.7d
UFH 151 36.4c,d 10.6c 19.9 6.0d
a Includes only those pts with in-hospital events.
b It was unclear from the source article as to whether p-value referred to ENO vs UFH and/or UFH + ABC vs UFH for this parameter.
c Incidence of cardiac death only.
d Includes only those pts who were re-admitted as a result of unstable angina pectoris.
ABC = abciximab; * p < 0.05, ** p < 0.001, *** p ≤ 0.0001 vs UFH.

ages were identical to those administered in the
ASSENT-3 trial.[3,4]
In the ASSENT-3 trial, the incidences of the
primary endpoint and two of its three components
were significantly lower in the patient groups that
received enoxaparin or low-dose UFH plus abcix-
imab than in those that received UFH (table IV).[4]
In addition, patients who received adjuvant therapy
with either enoxaparin or low-dose UFH plus abcix-
imab had a lower incidence of the efficacy-safety
endpoint of death, in-hospital nonfatal recurrent MI,
refractory ischaemia, ICH or major bleeding than
those who received UFH (13.7% and 14.2% vs
17.0%, p = 0.0037 and 0.0142, respectively).[4]
Despite there not being a significant difference in
the incidence of the primary endpoint between enox-
aparin recipients and UFH recipients in the AS-
SENT-3 PLUS trial, when each component of the
primary endpoint was analysed separately, a signif-
icant difference in favour of enoxaparin was seen for
in-hospital recurrent MI (table IV).[3] There was also
no significant difference in the incidence of the
efficacy-safety endpoint of 30-day death, in-hospital
nonfatal recurrent MI, in-hospital refractory ischae-
mia, in-hospital ICH or in-hospital major bleeding
(excluding ICH) between those who received enox-
aparin and those who received UFH (18.3% vs
20.3%).[3]
Results of the ASSENT-3 and ASSENT-3 PLUS
trials are supported by those of a smaller random-
ized trial (Baird et al.)[12] In this trial, patients re-
ceived fibrinolytic therapy and were then random-
ized prospectively to receive enoxaparin (initial in-
travenous bolus of 40 mg followed by a 40 mg
subcutaneous dose every 8 hours) or UFH (initial
intravenous bolus of 5000 U followed by an infusion
of 30 000 U/24 h adjusted as per aPTT) for 4 days in
conjunction with other standard therapy, including
aspirin (24% were already taking aspirin on ad-
mission), which was administered only after the
study period was over.[12]
In the study by Baird et al.,[12] enoxaparin was
significantly more effective than UFH in lowering
the rates of the composite primary endpoint of death,
nonfatal recurrent MI and readmission with unstable
angina pectoris (table IV).[12] Univariate predictors
of the occurrence of a recurrent cardiac event after
administration of enoxaparin compared with UFH
included left ventricular failure (28% vs 46%,
p = 0.01), hypertension (27% vs 43%, p = 0.01) and

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (5)
Enoxaparin: A Review
a family history of heart disease (26% vs 37%,
p = 0.033).[12]
3.2.2 Angiographic Efficacy
Compared with UFH
The angiographic efficacy of enoxaparin has
been compared with that of UFH in two randomized
trials (HART II[9] and ENTIRE-TIMI 23[8]), one of
which was also a noninferiority trial.[9] In HART II,
patients received aspirin and alteplase and were
randomized to receive adjuvant enoxaparin (intrave-
nous 30 mg bolus followed by 1 mg/kg subcutane-
ously every 12 hours) or UFH (intravenous weight-
dependent bolus of 4000 or 5000 U followed by an
infusion of 15 U/kg/h [adjusted according to aPTT])
for at least 3 days.[9] An angiogram was performed
90 minutes after the initial bolus of alteplase was
administered and again 5–7 days later. A total of
380 patients had assessable angiograms and 259
with TIMI grade 2 or 3 flow on initial angiogram
were eligible for follow-up angiography.[9]
Patients in the ENTIRE-TIMI 23 trial were ran-
domized to receive either standard reperfusion with
full-dose tenecteplase or combination therapy with
half-dose tenecteplase plus abciximab.[8] In addi-
tion, patients were also randomized to receive enox-
aparin (intravenous 30 mg bolus followed by two
dose-ranging subcutaneous injections 12 hours apart
and then a fixed 1 mg/kg subcutaneous dose every
Table V. Angiographic efficacy of enoxaparin (ENO) in patients (pts) with ST-segment elevation myocardial infarction: results of random-
ized, multicentre phase III trials comparing the efficacy of ENO with that of unfractionated heparin (UFH) or placebo (PL).[8,9,11] See text for
trial design and dosage details
Trial Comparator
Antman et al.[8] ENO vs UFH (evaluable n = 275
(ENTIRE-TIMI 23 trial) and 140)
Ross et al.[9] ENO vs UFH (total evaluable for
(HART II trial) primary and secondary endpoints
n = 380 and 259; no. of evaluable
pts in each treatment group not
specified)
Simoons et al.[11] ENO vs PL (evaluable n = 389; no.
(AMI-SK trial) of evaluable pts in each treatment
group not specified)
TIMI = thrombolysis in myocardial infarction.
© 2008 Adis Data Information BV. All rights reserved.
703
12 hours for the duration of hospital stay up to a
maximum of 8 days) or UFH (with standard reperfu-
sion [intravenous bolus of 60 U/kg followed by an
infusion of 12 U/kg/h for ≥36 hours] or with combi-
nation therapy [intravenous bolus of 40 U/kg fol-
lowed by an infusion of 7 U/kg/h for ≥36 hours]) at a
ratio of either 2 : 1 or 3 : 1.[8] Angiography was
performed 60 minutes after initiation of fibrinolytic
therapy. Of the 483 patients who were treated,
415 had an angiogram at 60 minutes that was assess-
able.
The noninferiority of the efficacy of enoxaparin
to UFH (determined by the TIMI 2 and 3 reperfusion
rates at 90 minutes in all randomized patients with a
technically adequate coronary angiogram) in pa-
tients with STEMI was verified in the HART II trial
with the between-group difference being within the
limits for noninferiority (–10%) and nearing that of
superiority (lower limit of 95% CI –2.1%).[9] Results
pertaining to the incidence of the primary and secon-
dary endpoints of the HART II study are shown in
table V.
In the ENTIRE-TIMI 23 trial, there was no statis-
tically significant difference in the incidence of the
primary endpoint between enoxaparin and UFH re-
cipients; pooled primary endpoint results are shown
in table V.[8] When data were stratified according to
the receipt of standard or combination reperfusion,
the rate of TIMI 3 flow (primary endpoint) was 50%
Incidence (% of pts)
primary endpoint secondary endpoint
TIMI grade 3 flow at 60 min in TIMI grade 2 or 3 flow at 60 min in
infarct-related artery: 50.9 vs 77.5 infarct-related artery on initial
angiogram: 77.5 vs 75.0
TIMI grade 2 or 3 flow at 90 min in Reocclusion rates (defined as the
infarct-related artery on initial deterioration from TIMI grade 2 or
angiogram: 80.1 vs 75.1 3 flow at 90 min to grade 0 or 1 at
follow-up) on repeat angiogram in
pts with TIMI grade 2 or 3 flow on
initial (90 min) angiogram: 5.9 vs
9.8
TIMI grade 3 flow on day 8 TIMI grade 2 or 3 flow on day 8
angiogram: 70.3 vs 57.9; p = 0.01 angiogram: 87.6 vs 71.7;
p = 0.001
Drugs 2008; 68 (5)
704
in enoxaparin recipients compared with 52% in
UFH recipients who received full-dose tenecteplase,
and 52% and 48% in those who received half-dose
tenecteplase and abciximab.[8] In addition, the inci-
dence of the composite clinical endpoint of death or
nonfatal recurrent MI in patients who received full-
dose tenecteplase plus either enoxaparin or UFH
was 4.4% vs 15.9% (p = 0.005) with corresponding
values being 5.5% and 6.5% (p-value not reported)
in patients who received half-dose tenecteplase plus
abciximab; the overall incidence of death or nonfatal
recurrent MI was 4.9% and 11.3% in enoxaparin and
UFH recipients, respectively (p = 0.01).[8]
Compared with Placebo
The angiographic efficacy of enoxaparin was
compared with that of placebo in a randomized trial
(AMI-SK).[11] All patients in the AMI-SK study
received streptokinase and aspirin, and were ran-
domly assigned to either enoxaparin (intravenous 30
mg bolus followed by 1 mg/kg [maximum of
100 mg for first two subcutaneous injections] subcu-
taneously every 12 hours for ≥3 days up to angiogra-
phy or day 8) or placebo.[11] Study drug was given at
the same time as, or within 1 hour of, streptokinase.
Compared with patients who received placebo,
significantly more enoxaparin recipients had a TIMI
flow of grade 3 (primary endpoint), or grade 2 or 3
(secondary endpoint), in the infarct-related artery on
day 8 angiography [table V].[11] In addition, enox-
aparin recipients also had a lower incidence of the
composite clinical endpoint of death, recurrent MI
or refractory ischaemia than UFH recipients (13.4%
vs 21.0%, p = 0.03); however, there was no statisti-
cally significant between-group difference when
each of the clinical endpoint components were
analysed separately.[11]
3.3 Meta-Analysis of All Randomized Studies
Data from patients with STEMI who received
either enoxaparin or UFH in randomized trials have
been collated in a meta-analysis.[26] Aside from the
AMI-SK study,[11] all the trials discussed in sections
3.1 and 3.2[3,4,8-10,12] were included in this meta-
analysis.[26] The primary endpoint of the meta-ana-
lysis was net clinical events, which was a composite
© 2008 Adis Data Information BV. All rights reserved.
Carter et al.
of mortality, non-fatal recurrent MI or non-fatal
major bleeding at 30 days, or the closest timepoint to
30 days.[26] A total of 27 131 patients with STEMI
received enoxaparin or UFH in these trials.[26]
The incidence of the primary endpoint was sig-
nificantly lower in enoxaparin recipients than in
UFH recipients according to the meta-analysis
(11.1% vs 12.9%, p = 0.018).[26] When the largest
trial (ExTRACT-TIMI 25) was excluded from the
analysis, the incidence of the primary endpoint was
11.5% in enoxaparin recipients compared with
13.2% in UFH recipients; however this difference
was no longer significant (p = 0.09).[26]
When each component of the primary endpoint
was analysed separately, the incidences of non-fatal
recurrent MI and non-fatal major bleeding were
significantly lower in enoxaparin recipients than in
UFH recipients (3.4% vs 5.1% and 2.6% vs 1.8%,
respectively; p < 0.001 for both); however, there
was no significant between-group difference in the
incidence of mortality (6.6% and 7.1%).[26]
4. Tolerability
As expected, bleeding complications were the
most frequently occurring adverse events associated
with enoxaparin use in clinical trials.[3,4,8-12] Given
that tolerability data were generally similar among
all the trials discussed in section 3,[3,4,8-12] this sec-
tion focuses on tolerability data from the largest trial
(ExTRACT-TIMI 25; section 3.1)[10] including a
number of its subgroup analyses.[18-24] Supporting
data are from the manufacturer’s prescribing infor-
mation.[17] In addition, pivotal tolerability data in
patients >75 years of age from the ASSENT-3[4] trial
are also presented.
Minor bleeding (defined by the TIMI Haemor-
rhage Criteria[27] as a spontaneous onset of gross
haematuria, haemoptysis or haematemesis, or a drop
in haemoglobin of >3 g/dL, but ≤5 g/dL, with bleed-
ing from a known site) accounted for the majority of
haemorrhagic adverse events at day 30 in the Ex-
TRACT-TIMI 25 trial and occurred in 2.6% of
patients with STEMI who received enoxaparin com-
pared with 1.8% of those who received UFH
(p < 0.001; table VI).[10] When data from this trial
Drugs 2008; 68 (5)
Enoxaparin: A Review 705

Table VI. Tolerability of enoxaparin (ENO) as an adjunct to fibrinolytic therapy in patients (pts) with ST-segment elevation myocardial
infarction: bleeding complications in the ExTRACT-TIMI 25 trial[10,21,23] at day 30 unless otherwise specified. See text for trial design and
dosage details
Stratification factor Treatment regimen Bleeding complications (% of pts)
(no. of pts) TIMI major bleed TIMI minor bleed ICH
(including ICH)
Overall
At 48 h ENO (10 176) 1.4 1.6 0.7
UFH (10 151) 1.0** 1.2* 0.6
At 30 d ENO (10 176) 2.1 2.6 0.8
UFH (10 151) 1.4*** 1.8*** 0.7

Stratified according to baseline creatinine clearance (CLCR)

CLCR <30 mL/min ENO (106) 5.7 7.6 1.9
UFH (106) 2.8 3.7 0.9
CLCR 30–60 mL/min ENO (1813) 3.5 5.0 1.2
UFH (1858) 1.9** 3.6* 1.2
CLCR >61–90 mL/min ENO (3583) 2.3 2.3 1.2
UFH (3620) 1.6* 1.6* 0.9
CLCR >90 mL/min ENO (3739) 1.2 1.6 0.3
UFH (3723) 0.8 1.2 0.2

Stratified according to pt age

Aged <75 y ENO 1.9 0.7
(n = 17 947)a UFH 1.1**** 0.5
Aged ≥75 y ENO 3.3 1.6
(n = 2532)a UFH 2.9 1.7
a Total no. of pts aged <75 years (17 947) or aged ≥75 years (2532); no. of pts in each treatment arm not specified.
ICH = intracranial haemorrhage; TIMI = thrombolysis in myocardial infarction; UFH = unfractionated heparin; * p < 0.05, ** p < 0.01,
*** p < 0.001, **** p < 0.0001 vs ENO.

were stratified according to pre-specified subgroup
analyses (section 3.1.1), minor bleeding was report-
ed in 1.6–7.6% of enoxaparin recipients and
1.2–3.7% of UFH recipients.[10,18-24] The highest
incidence of events in enoxaparin recipients was
reported in the subgroup of patients with a CLCR of
<30 mL/min (7.6%)[21] and that consisting of
women (4.4%);[24] the corresponding incidences in
patients in these two subgroups who received UFH
were 3.7% (between-group difference not statistical-
ly significant)[21] and 2.9% (p = 0.006 vs enox-
aparin).[24]
The incidence of major bleeds in the ExTRACT-
TIMI 25 trial (defined by the TIMI Haemorrhage
Criteria[27] as an ICH, cardiac tamponade or drop in
haemoglobin of >5 g/dL with or without an identi-
fied site of bleeding) at day 30 was 2.1% in enox-
aparin recipients and 1.4% in UFH recipients
(p < 0.001; table VI).[10] Taking into account stratifi-
cation factors, major bleeds at 30 days occurred at a
rate of 1.2–5.7% in patients who received enox-
aparin compared with 0.8–2.9% in those who re-
ceived UFH.[10,18-24] The highest incidence of events
in enoxaparin recipients was reported in patients
aged ≥75 years (3.3%),[23] and those with a CLCR of
<30 mL/min (5.7%) or 30–60 mL/min (3.5%);[21]
corresponding values for UFH recipients in these
subgroups were 2.9% (between-group difference not
significant),[23] 2.8% (between-group difference not
significant) and 1.9% (p < 0.01 vs enoxaparin).[21]
ICH alone occurred at a similar rate in enox-
aparin and UFH recipients 0.8% vs 0.7%; table
VI).[10]
In the ASSENT-3 PLUS trial,[3] the incidences of
total stroke (2.9% vs 1.3%, p = 0.026) and in-
hospital ICH (2.2% vs 1.0%, p = 0.047) were signif-
icantly higher in enoxaparin recipients than in UFH
recipients. This difference was attributed to the sig-

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (5)
706
nificantly (p = 0.01) greater incidences of these
endpoints (total stroke 9.4% vs 2.3%; ICH 6.7% vs
0.8%) in the predefined subgroup of patients
>75 years of age.[3] Because of this finding, patients
≥75 years of age in the ExTRACT-TIMI 25 trial
received reduced dosages of enoxaparin (section 3.1
and 3.1.1).
In addition, patients with some degree of renal
dysfunction have been shown to be at an increased
risk of bleeding with enoxaparin use in previous
studies;[17] as a result, patients in this subgroup
received reduced dosages of enoxaparin in the Ex-
TRACT-TIMI 25 trial (section 3.1). However, de-
spite this adjustment, the risk of major or minor
bleeding increased by ≈50% with each increase in
CLCR of 30 mL/min in both enoxaparin and UFH
recipients in a subgroup analysis,[21] in which data
were stratified according to baseline CLCR (table
VI). In addition, even a modest degree of renal
dysfunction was associated with an increased risk of
major or minor bleeding irrespective of enoxaparin
or UFH use in this subgroup analysis (table VI).
In general, enoxaparin has been associated with
local reactions, such as mild local irritation, pain,
haematoma, ecchymosis and erythema.[17]
In addition, fully reversible elevations in ALT or
AST levels to ≥3-fold that of normal have been
reported in up to 5.9% and 6.1% of patients who
received enoxaparin in clinical trials.[17] Such labor-
atory abnormalities have also been reported in
healthy volunteers and patients receiving heparin or
other LMWHs in clinical trials.[17]
5. Dosage and Administration
Enoxaparin is approved by the US FDA for use in
patients with STEMI. Although not currently ap-
proved for this indication in other countries, an
application has been filed for approval in Europe.
In the US, enoxaparin is indicated for the treat-
ment of medically managed patients with acute
STEMI and in those with STEMI who undergo
subsequent PCI.[17] The recommended dosage in this
indication in patients <75 years of age is an initial
30 mg intravenous bolus plus a 1 mg/kg subcutane-
ous dosage followed by 1 mg/kg subcutaneously
© 2008 Adis Data Information BV. All rights reserved.
Carter et al.
every 12 hours with adjuvant aspirin; in patients of
this age group with severe renal impairment (CLCR
<30 mL/min), the recommended dosage is an initial
30 mg intravenous bolus plus a 1 mg/kg subcutane-
ous bolus followed by 1 mg/kg subcutaneously once
daily.[17] In patients ≥75 years of age, it is recom-
mended that 0.75 mg/kg of enoxaparin is adminis-
tered subcutaneously every 12 hours, with the nota-
ble exclusion of the initial intravenous bolus; those
in this age group with severe renal impairment have
a recommended dosage of 1 mg/kg subcutaneously
once daily.[17]
In patients who subsequently undergo PCI, an
additional 0.3 mg/kg intravenous bolus of enox-
aparin should be administered to patients whose last
dosage of enoxaparin was administered >8 hours
prior to balloon inflation; in those whose last dosage
was administered <8 hours prior to balloon inflation,
no additional dosage is required.[17]
Local prescribing information should be con-
sulted for additional information, including dosage
and administration, contraindications, warnings and
precautions, adverse reactions, drug interactions and
use in special populations.
6. Place of Enoxaparin in the
Management of Patients with
ST-Segment Elevation
Myocardial Infarction
Time to reperfusion is one of the major determi-
nants of mortality in patients with STEMI; there-
fore, treatment of STEMI centres on achieving early
and persistent reperfusion of the infarct-related ar-
tery.[1,3,22] Although there is increasing interest in a
catheter-based approach to reperfusion,[8] fibrinolyt-
ic therapy remains the leading reperfusion strategy
around the globe in patients with STEMI.[18] Fol-
lowing fibrinolytic therapy, there is potential for
reocclusion of the infarct-related artery when throm-
bin, which was previously bound up in clots, is
exposed and released; this, in turn, may activate the
coagulation cascade.[12,28] Therefore, adjuvant anti-
platelet and antithrombin therapies also play an im-
portant role in medical reperfusion.[28]
Drugs 2008; 68 (5)
Enoxaparin: A Review
The choice of reperfusion strategy is dependent
upon availability and timing, as well as the per-
ceived benefit versus risk for each individual pa-
tient.[2,7] Current US[2,6] and European[7] guidelines
recommend PCI if a skilled laboratory with surgical
backup is available and medical contact-to-balloon
or door-to-balloon time is <90 minutes,[2,6,7] the
patient is in cardiogenic shock or otherwise at high
risk,[2,6,7] fibrinolytic therapy is contraindicated,[2,6,7]
the patient is presenting >3 hours after the onset of
symptoms[2,6] or the diagnosis of STEMI is un-
clear.[2,6]
Fibrinolytic therapy, on the other hand, is the
preferred method of reperfusion in the US[2,6] if
patients present within 3 hours of the onset of symp-
toms and a delay to mechanical reperfusion is ex-
pected, mechanical reperfusion is not an option or
there is a delay to mechanical reperfusion as a result
of prolonged transport, the door-to-balloon minus
door-to-needle time of >1 hour, or there is a medical
contact-to-balloon or door-to-balloon time of
>90 minutes. In Europe,[7] fibrinolytic therapy is
preferred when PCI cannot be performed within
90 minutes after first medical contact by an experi-
enced team. However, a more fibrin-specific agent,
such as tenecteplase or alteplase, is preferred in
patients who present >4 hours after the onset of
symptoms.[7] A number of fibrinolytic agents are
approved for use in patients with STEMI in the US
and Europe, but the specific choice of agent is
dependent upon the individual assessment of benefit
and risk, as well as the likelihood of complications
and cost.[2,6,7]
Adjuvant therapy with aspirin and/or clopidogrel,
and other myocardial protective agents such as β-
adrenergic antagonists and angiotensin-converting
enzyme inhibitors, is also strongly recommended for
use in patients presenting with STEMI.[2,6,7]
UFH is recommended in US[2,6] and European[7]
guidelines for use in patients undergoing PCI or
surgical revascularization,[2,6] and in those undergo-
ing medical reperfusion with alteplase, reteplase or
tenecteplase.[2,6,7] In the US,[2,6] UFH is recommen-
ded in patients receiving nonselective fibrinolytic
agents if they are at high risk of developing systemic
© 2008 Adis Data Information BV. All rights reserved.
707
emboli and, in Europe,[7] UFH is optional in patients
who are receiving nonselective fibrinolytic agents,
such as streptokinase. Unfortunately, UFH has
many potential limitations, including the need for
frequent monitoring and dose adjustment, the need
for antithrombin as a cofactor, a non-specific plasma
protein binding that results in an unpredictable anti-
coagulant response, an inability to inhibit fibrin-
bound thrombin or platelet-bound factor Xa, neu-
tralization by platelet factor 4, activation of platelets
and a rebound increase in thrombogenicity after
cessation of the infusion.[29]
Compared with UFH, LMWHs may offer several
advantages when administered to patients with
STEMI. Such advantages include the following:
(i) a simpler administration route; (ii) a high bio-
availability and minimal plasma binding leading to
more reliable anticoagulant effects, thereby elimi-
nating the need for therapeutic monitoring; (iii) a
greater capacity to release TFPI, a higher anti-factor
Xa : IIa ratio and a lower propensity to inhibit plate-
let aggregation, leading to a lesser tendency to cause
bleeding; (iv) less inhibition by platelet factor 4;
(v) potential antiplatelet effects via higher degrees
of suppression of von Willebrand factor; and (vi) a
lesser propensity to cause osteoporosis (section 2.1).
A recent meta-analysis[30] of randomized trials
comparing LMWHs with UFH demonstrated reduc-
tions in the rate of recurrent MI and death of ≈25%
and ≈10% with LMWHs relative to placebo; com-
pared with UFH, LMWHs reduced the rate of recur-
rent MI by ≈ 50%. However, whilst all LMWHs are
similar, they all differ in their physical and pharma-
cological properties and, therefore, may differ in
relative clinical efficacies.[14]
In light of the limitations of UFH, and the prom-
ising results demonstrated in the recent trials of
enoxaparin, a recent focused update[6] of the US
treatment guidelines[2] now also recommends enox-
aparin as an alternative to UFH in patients with
STEMI.
Despite the increased risk of bleeding associated
with enoxaparin use, a summary of trial observa-
tions presented in the updated US guidelines[6] sug-
gests that enoxaparin may be superior to UFH in
Drugs 2008; 68 (5)
708
patients with STEMI receiving fibrinolytic therapy,
and may also be used as a sole antithrombin agent to
support PCI after fibrinolysis. Enoxaparin may be
administered regardless of patient age, providing
serum creatinine levels are <2.5 mg/dL in men and
<2.0 mg/dL in women.[6]
Based upon the results of the OASIS-6 (Organi-
zation for the Assessment of Strategies for Ischemic
Syndromes) trial,[31] fondaparinux sodium (hence-
forth fondaparinux), a synthetic, sulfated penta-
saccharide, selective factor Xa inhibitor, is now also
recommended alongside UFH and enoxaparin in the
updated US guidelines[6] for use in patients with
STEMI (providing serum creatinine level is
<3.0 mg/dL), particularly in those receiving fibrino-
lytic therapy; however, fondaparinux does not ap-
pear to be superior to control therapy (UFH/placebo)
in patients undergoing primary PCI, and additional
anticoagulant support is also required when patients
receiving fondaparinux undergo PCI following fi-
brinolysis.[6] Reviparin sodium, another LMWH,
has also demonstrated promising efficacy results in
the CREATE (Clinical Trial of Reviparin and Meta-
bolic Modulation in Acute Myocardial Infarction
Treatment Evaluation) trial[32] according to the up-
dated guidelines.[6] Although this agent is approved
for use as an antithrombotic agent in some European
countries, it is not currently approved in the US.
No one anticoagulant agent is recommended over
another in the treatment of patients with STEMI in
the updated US guidelines.[6]
Although there have been no direct head-to-head
comparative trials between enoxaparin and other
LMWHs in patients with STEMI, no other LMWH
has been evaluated as extensively as enoxaparin in
this patient population. Moreover, enoxaparin has
demonstrated clear benefits over UFH in several
well designed randomized trials and a large meta-
analysis (section 3).
In comparative studies in patients with STEMI
receiving fibrinolytic therapy, adjunctive therapy
with enoxaparin was associated with better efficacy
than UFH (section 3). The pivotal ExTRACT-TIMI
25 trial reported a significantly greater reduction in
the combined 30-day incidence of all-cause mor-
© 2008 Adis Data Information BV. All rights reserved.
Carter et al.
tality and nonfatal MI (primary endpoint) as well as
the combined 30-day incidence of all-cause mor-
tality, nonfatal recurrent MI and urgent revascu-
larization (secondary endpoint) in patients receiving
enoxaparin than in those receiving UFH (section
3.1). Furthermore, the difference between the two
groups for the primary endpoint remained signif-
icant at the 1-year follow-up. In addition, a signifi-
cantly lower incidence of three pre-specified com-
bined efficacy-safety endpoints was reported in
enoxaparin than UFH recipients in this study. The
FDA approval of enoxaparin in patients with medi-
cally managed STEMI, or STEMI with subsequent
PCI, is based upon these results. However, the use of
enoxaparin in patients with STEMI undergoing pri-
mary PCI has not yet been adequately studied.
The findings of the ExTRACT-TIMI 25 trial are
supported by subgroup analyses of the trial (section
3.1.1), as well as earlier randomized, double-blind,
phase III trials comparing enoxaparin with UFH or
placebo (section 3.2).
As expected, bleeding complications were the
most frequently occurring adverse events associated
with enoxaparin use in clinical trials (section 4).
Minor bleeding accounted for the majority of events
and occurred with a significantly higher incidence in
enoxaparin than UFH recipients in the ExTRACT-
TIMI 25 trial. The incidence of major bleeds was
also higher in enoxaparin recipients than in UFH
recipients in this trial. However, ICH occurred at a
similar incidence in the two groups.
Despite there being a significantly higher inci-
dence of bleeding episodes reported in enoxaparin
recipients than in UFH recipients in the ExTRACT-
TIMI 25 trial, enoxaparin remained superior to UFH
in terms of the combined efficacy-safety endpoints
(section 3.1).
Previous studies have shown an increased num-
ber of bleeding events with antithrombin (including
enoxaparin) use in elderly patients and in those with
renal dysfunction, and for this reason, patients in
these subgroups in the ExTRACT-TIMI 25 trial
received reduced dosages of enoxaparin (section
3.1). Despite this adjustment, even a modest degree
of renal dysfunction was associated with an in-
Drugs 2008; 68 (5)
Enoxaparin: A Review
creased risk of major or minor bleeding irrespective
of enoxaparin or UFH use (table VI). An assessment
of risk versus benefit is therefore important when
deciding upon a regimen for the treatment of STEMI
in these patient groups.
In conclusion, enoxaparin was significantly more
effective than UFH in patients presenting with
STEMI in terms of the 30-day combined incidence
of all-cause mortality plus recurrent nonfatal MI
(primary endpoint), and all-cause mortality plus re-
current nonfatal MI plus urgent revascularization
(secondary endpoint), in the ExTRACT-TIMI 25
trial. The significant difference in the incidence of
the composite primary endpoint between these two
groups was maintained at the 1-year follow-up. Al-
though bleeding was reported more frequently with
enoxaparin than with UFH in the ExTRACT-TIMI
25 trial, enoxaparin was associated with a net clin-
ical benefit compared with UFH. Data from several
earlier randomized, multicentre, phase III trials sup-
port these results.
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manu-
facturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from comments
received were made on the basis of scientific and editorial
merit.
References
1. Hahn SA, Chandler C. Diagnosis and management of ST eleva-
tion myocardial infarction: a review of the recent literature and
practice guidelines. Mt Sinai J Med 2006 Jan; 73 (1): 469-81
2. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guide-
lines for the management of patients with ST-elevation myo-
cardial infarction: executive summary. A report of the Ameri-
can College of Cardiology/American Heart Association Task
Force on Practice Guidelines (writing committee to revise the
1999 guidelines for the management of patients with acute
myocardial infarction). Circulation 2004 Aug 3; 110 (5):
588-636
3. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and
safety of tenecteplase in combination with the low-molecular-
weight heparin enoxaparin or unfractionated heparin in the
prehospital setting: the asssessment of the safety and efficacy
of a new thrombolytic regimen (ASSENT)-3 PLUS random-
ized trial in acute myocardial infarction. Circulation 2003 Jul
15; 108 (2): 135-42
4. ASSENT-3 investigators. Efficacy and safety of tenecteplase in
combination with enoxaparin, abciximab, or unfractionated
© 2008 Adis Data Information BV. All rights reserved.
709
heparin: the ASSENT-3 randomised trial in acute myocardial
infarction. Lancet 2001 Aug 25; 358 (9282): 605-13
5. Heart disease and stroke statistics: 2007 update. Dallas (TX):
American Heart Association, 2007
6. Antman EM, Hand M, Armstrong PW, et al. 2007 focused
update of the ACC/AHA 2004 guidelines for the management
of patients with ST-elevation myocardial infarction: a report of
the American College of Cardiology/American Heart Associa-
tion Task Force on Practice Guidelines. J Am Coll Cardiol
2008 Jan; 51 (2): 210-47
7. Van de Werf F, Ardissino D, Betriu A, et al. Management of
acute myocardial infarction in patients presenting with ST-
segment elevation: the task force on the management of acute
myocardial infarction of the European Society of Cardiology.
Eur Heart J 2003 Jan; 24 (1): 28-66
8. Antman EM, Louwerenburg HW, Baars HF, et al. Enoxaparin
as adjunctive antithrombin therapy for ST-elevation myocardi-
al infarction: results of the ENTIRE-thrombolysis in myocar-
dial infarction (TIMI) 23 trial. Circulation 2002 Apr 9; 105
(14): 1642-9
9. Ross AM, Molhoek P, Lundergan C, et al. Randomized compar-
ison of enoxaparin, a low-molecular-weight heparin, with un-
fractionated heparin adjunctive to recombinant tissue plasmi-
nogen activator thrombolysis and aspirin: second trial of hepa-
rin and aspirin reperfusion therapy (HART II). Circulation
2001 Aug 7; 104 (6): 648-52
10. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin
versus unfractionated heparin with fibrinolysis for ST-eleva-
tion myocardial infarction. N Engl J Med 2006 Apr 6; 354
(14): 1477-88
11. Simoons M, Krzemiñska-Pakula M, Alonso A, et al. Improved
reperfusion and clinical outcome with enoxaparin as an adjunct
to streptokinase thrombolysis in acute myocardial infarction.
The AMI-SK study. Eur Heart J 2002 Aug; 23 (16): 1282-90
12. Baird SH, Menown I, McBride SJ, et al. Randomized compari-
son of enoxaparin with unfractionated heparin following fibri-
nolytic therapy for acute myocardial infarction. Eur Heart J
2002 Apr; 23: 627-32
13. Noble S, Peters DH, Goa KL. Enoxaparin: a reappraisal of its
pharmacology and clinical applications in the prevention and
treatment of thromboembolic disease. Drugs 1995; 49 (3):
388-410
14. Fareed J, Hoppensteadt D, Walenga J, et al. Pharmacodynamic
and pharmacokinetic properties of enoxaparin: implications
for clinical practice. Clin Pharmacokinet 2003; 42 (12):
1043-57
15. Ibbotson T, Goa KL. Enoxaparin: an update of its clinical use in
the management of acute coronary syndromes. Drugs 2002; 62
(9): 1407-30
16. Siddiqui MAA, Wagstaff AJ. Enoxaparin: a review of its use as
thromboprophylaxis in acutely ill, nonsurgical patients. Drugs
2005; 65 (7): 1025-36
17. Lovenox® (enoxaparin sodium injection): US prescribing infor-
mation. Bridgewater (NJ): Sanofi-Aventis US LLC, 2007
18. Giraldez RR, Nicolau JC, Corbalan R, et al. Enoxaparin is
superior to unfractionated heparin in patients with ST elevation
myocardial infarction undergoing fibrinolysis regardless of the
choice of lytic: an ExTRACT-TIMI 25 analysis. Eur Heart J
2007 Jul; 28 (13): 1566-73
19. Gibson CM, Murphy SA, Montalescot G, et al. Percutaneous
coronary intervention in patients receiving enoxaparin or un-
fractionated heparin after fibrinolytic therapy for ST-segment
elevation myocardial infarction in the ExTRACT-TIMI 25
trial. J Am Coll Cardiol 2007 Jun 12; 49 (23): 2238-46
Drugs 2008; 68 (5)
710
20. Sabatine MS, Morrow DA, Dalby A, et al. Efficacy and safety of
enoxaparin versus unfractionated heparin in patients with ST-
segment elevation myocardial infarction also treated with
clopidogrel. J Am Coll Cardiol 2007 Jun 12; 49 (23): 2256-63
21. Fox KAA, Antman EM, Montalescot G, et al. The impact of
renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial.
J Am Coll Cardiol 2007 Jun 12; 49 (23): 2249-55
22. Scirica BM, Morrow DA, Sadowski Z, et al. A strategy of using
enoxaparin as adjunctive antithrombin therapy reduces death
and recurrent myocardial infarction in patients who achieve
early ST-segment resolution after fibrinolytic therapy: the
ExTRACT-TIMI 25 ECG study. Eur Heart J 2007 Jun; 28
(17): 2070-6
23. White HD, Braunwald E, Murphy SA, et al. Enoxaparin vs.
unfractionated heparin with fibrinolysis for ST-elevation myo-
cardial infarction in elderly and younger patients: results from
ExTRACT-TIMI 25. Eur Heart J 2007 May; 28 (9): 1066-71
24. Mega JL, Morrow DA, Ostor E, et al. Outcomes and optimal
antithrombotic therapy in women undergoing fibrinolysis for
ST-elevation myocardial infarction. Circulation 2007 Jun 5;
115 (22): 2822-8
25. Morrow D, Wallentin L. Enoxaparin versus unfractionated he-
parin for STEMI: one year results from ExTRACT-TIMI 25
(abstract plus slide presentation) [online]. Available from
URL: http://www.escardio.org/knowledge/congresses/Con-
gressReports/2007/hl-ctu/1027-morrow-wallentin-ctu1.htm
[Accessed 2007 Sep 10]
26. Murphy SA, Gibson CM, Morrow DA, et al. Efficacy and safety
of the low-molecular weight haparin enoxaparin compared
with unfractionated heparin across the acute coronary syn-
drome spectrum: a meta-analysis. Eur Heart J 2007 Sep; 28
(17): 2077-86
© 2008 Adis Data Information BV. All rights reserved.
Carter et al.
27. Classification of hemorrhagic events according to TIMI criteria
[online]. Available from URL: http://www.aggrastat.com.sa/
secure/keystudies/timi_criteria/timi_criteria.html [Accessed
2007 Oct 12]
28. Cohen M. Low-molecular-weight heparin in patients with acute
ST-segment elevation myocardial infarction. Am Heart Hosp J
2005; 3 (2): 82-7
29. Bates ER. New anticoagulant options for ST-elevation myocar-
dial infarction and unstable angina pectoris/non-ST-elevation
myocardial infarction. Curr Cardiol Rep 2007 Jul; 9 (4):
289-97
30. Eikelboom JW, Quinlan DJ, Mehta SR, et al. Unfractionated
and low-molecular-weight heparin as adjuncts to thrombolysis
in aspirin-treated patients with ST-elevation acute myocardial
infarction: a meta-analysis of the randomized trials. Circula-
tion 2005 Dec; 112 (25): 3855-67
31. The OASIS-6 Trial Group. Effects of fondaparinux on mortality
and reinfarction in patients with acute ST-segment elevation
myocardial infarction. JAMA 2006 Apr 5; 295 (13): 1519-30
32. The CREATE Trial Group Investigators. Effects of reviparin, a
low-molecular-weight heparin, on mortality, reinfarction, and
strokes in patients with acute myocardial infarction presenting
with ST-segment elevation. JAMA 2005 Jan 26; 293 (4):
427-36
Correspondence: Natalie J. Carter, Wolters Kluwer
Health | Adis, 41 Centorian Drive, Private Bag 65901,
Mairangi Bay, North Shore 0754, Auckland, New Zealand.
E-mail: demail@adis.co.nz
Drugs 2008; 68 (5)