From Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.
Correspondence to Jack Hirsh, MD, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, Ontario, Canada L8V 1C3.
Low-molecular-weight heparins (LMWHs) are a new class of
anticoagulants derived from unfractionated heparin (UFH). They have a
number of advantages over UFH that have led to their increasing use for
a number of thromboembolic indications.1 This
article will review the limitations of UFH and the mechanisms by which
LMWHs overcome these limitations and discuss the results of recent
clinical trials evaluating LMWHs for the treatment of venous
thrombosis, pulmonary embolism, and unstable angina.
Limitations of UFH
Heparin has pharmacokinetic, biophysical, and biological
limitations.2 LMWHs overcome the pharmacokinetic
and some of the biological limitations of UFH, but they share the same
biophysical limitations.
Pharmacokinetic Limitations of UFH
The variability in plasma levels of heparin-binding proteins in
patients with thromboembolic diseases4 is
responsible for both the unpredictable anticoagulant response to
UFH4 and the very high heparin requirements in
some of these patients (heparin resistance).5
Biophysical Limitations
Biological Limitations
Thrombocytopenia
There is evidence from a large randomized trial that the incidences of
heparin-associated IgG and of HIT are less in patients treated with
prophylactic doses of LMWH than those treated with low-dose
UFH.10 However, there are reports that the
administration of LMWHs can be associated with the development of
thrombocytopenia both in previously unexposed individuals and in those
with a history of HIT.12 There is also evidence
that LMWH cross-reacts with plasma from patients with recent
HIT.13 In contrast to the LMWHs, the
heparinoid danaparoid sodium, which is said to be free of
contaminating heparin, exhibits minimal cross-reactivity in in vitro
assays for HIT13 and has been used successfully
in patients with a history of HIT.13 14
Osteoporosis
In a series of studies, Shaughnessy and
associates18 reported that UFH produces a
concentration-dependent effect on various indexes of bone
metabolism in rats. Thus, UFH (1) increases bone resorption
from cultured fetal calvariae, (2) decreases cancellous bone
volume,19 and (3) decreases osteoblast and
osteoid surface and increases osteoclast surface in rats. All these
effects are heparin chain length–dependent and are less marked with
LMWH.18 19
Initial case reports of successful use of LMWH in patients whose
treatment with heparin was complicated with symptomatic
osteoporosis20 have been supported by the results
of a small randomized study that showed that the incidence of bone
fracture was less in patients assigned LMWH than those assigned
UFH.16
LMWHs
LMWHs are derived from UFH by chemical or enzymatic
depolymerization to yield fragments that are
approximately one third the size of heparin. Like UFH, they are
heterogeneous with respect to molecular size and
anticoagulant activity. LMWHs have a mean molecular weight of 4000 to
5000, with a molecular weight distribution of 1000 to 10 000.
Depolymerization of UFH into lower-molecular-weight
fragments results in 5 main changes in its properties; all are due to
reduced binding of LMWH to proteins or cells (Table 1
Compared with UFH, LMWHs have (1) reduced ability to catalyze
inactivation of thrombin because the smaller fragments cannot bind to
thrombin but retain their ability to inactivate factor
Xa21 22 23 24 ; (2) reduced nonspecific binding to
plasma proteins, with a corresponding improvement in the predictability
of their dose-response relationship25 ; (3)
reduced binding to macrophages and endothelial
cells, with an associated increase in their plasma half-life; (4)
reduced binding to platelets8 and PF4, which
may explain the lower incidence of HIT10 ; and (5)
possibly reduced binding to osteoblasts, which results in less
activation of osteoclasts and an associated reduction in bone loss
(Table 1
The LMWHs approved for use in Europe, Canada, and the United States are
shown in Table 2
Anticoagulant Effects of LMWHs
Clinical Experience With LMWH Preparations
Treatment of Venous Thromboembolism
A number of LMWH preparations have been compared with UFH in
hospitalized patients in many well-designed studies. The results of
studies published up to 1995 have been summarized in a
meta-analysis33 (Tables 3
The results indicate that all 4 LMWH preparations evaluated are as
effective and safe as intravenous UFH and that event rates
(recurrent thromboembolism and major bleeding) are low and similar with
all the LMWHs. It is noteworthy that the LMWHs were administered by
subcutaneous injection in unmonitored weight-adjusted doses, whereas
UFH was monitored by the activated partial thromboplastin time
(APTT).
The study evaluating Tinzaparin (Innohep)34
stands out because it was double blind and relatively large and used a
once-daily dosing regimen (175 anti-Xa units/kg). Major bleeding was
less with Tinzaparin than UFH. However, whether the observed difference
in bleeding reflects a safety advantage of Tinzaparin or is the result
of the unusually high rate of major bleeding in the UFH group (5%) is
uncertain. In this context, the study reported by Simmoneau and
associates35 comparing the efficacy and safety of
Tinzaparin with UFH in acute pulmonary embolism (described in
detail below), which used an identical once-daily regimen of
Tinzaparin, reported equal efficacy and safety for the Tinzaparin LMWH
and UFH.
Since the publication of the pooled analysis, 4 large
randomized trials have been completed35 36 37 38 39 : 2 of
patients with venous thrombosis,36 37 1 of
patients with venous thrombosis or pulmonary
embolism,38 and 1 of patients with
pulmonary embolism.35 The design used in
3 of the studies36 37 38 capitalized on the more
predictable anticoagulant response of LMWH by encouraging patients
assigned to LMWH to be treated at home, while those assigned to UFH
were treated in the standard manner in hospital with a continuous
intravenous infusion.
In the study by Levine and associates,36 eligible
patients with proximal vein thrombosis were randomly assigned to
intravenous heparin in hospital or a strategy of LMWH
(enoxaparin sodium) 1 mg/kg (100 anti-Xa units/kg SC) twice daily
administered primarily at home. The design allowed patients assigned
LMWH to be treated at home without admission and hospitalized patients
to be discharged early. Thirteen of 247 LMWH patients (5.3%) developed
recurrent thromboembolism compared with 17 of 253 patients (6.7%) in
the heparin group (P=0.57). Five LMWH patients developed
major bleeding compared with 3 heparin patients. After randomization,
the mean length of hospital stay for the LMWH group was 1.1 days
compared with 6.5 days for the heparin group.
In the study by Koopman and associates,37
patients with deep venous thrombosis were randomly assigned to
intravenous heparin in hospital (5000 IU as a bolus
followed by 1250 U/h) with APTT or LMWH (nadroparine calcium) twice
daily subcutaneously with a weight-adjusted dosage regimen. Patients
weighing <50 kg received a daily dose of 8200 anti-Xa units; those
weighing between 50 and 70 kg received 12{ths}300 anti-Xa units;
and those weighing >70 kg received 18{ths}400 anti-Xa units. The
design allowed outpatients to go home immediately on LMWH and
hospitalized patients to be discharged early on LMWH. Fourteen of 202
LMWH patients (6.9%) developed recurrent thromboembolism compared with
17 of 198 patients (8.6%) in the heparin group (P>0.5).
One LMWH patient developed major bleeding compared with 4 heparin
patients.
A comparison of the results of the studies reported by Levine et
al36 and by Koopman et al37
is shown in Table 5
Both of these studies36 37 excluded patients with
symptomatic pulmonary embolism or a history of
recent previous venous thrombosis. To address this, both groups
collaborated to perform the COLUMBUS
study38 (Table 6
Of the 510 patients assigned to LMWH, 5.3% had recurrent
thromboembolic events over the 3 months of treatment compared with
4.9% of the 511 patients assigned to UFH. Major bleeding occurred in
3.1% of patients assigned to LMWH compared with 2.3% assigned to
receive UFH (P=0.63). The mortality rates were 7.1% and
7.6%, respectively (P=0.89). This study confirms the
efficacy and safety of out-of-hospital LMWH for the treatment of
symptomatic venous thrombosis and was the first large study
to demonstrate the efficacy and safety of LMWH for the treatment of
patients with acute pulmonary embolism.
The effectiveness and safety of unmonitored subcutaneous LMWH
(riviparin) in symptomatic pulmonary embolism
reported in the COLUMBUS study were confirmed in a study of 612
patients with symptomatic pulmonary embolism
reported by Simonneau and associates,35 who used
a different LMWH (Tinzaparin). Patients who did not require
thrombolytic therapy or pulmonary embolectomy
were randomly allocated to receive LMWH (175 anti-Xa units/kg SC once
daily) or UFH (50 U/kg bolus followed by a continuous infusion of 500
U · kg-1 ·
d-1) adjusted to obtain an APTT ratio of 2.0 to
3.0.
The outcome measure, a composite of recurrent thromboembolism, major
bleeding, and death, was assessed on days 8 and 90. On day 8, 9 of 308
patients (2.9%) assigned to UFH and 9 of 304 patients (3.0%) assigned
to LMWH reached at least 1 of the primary end points. By day 90, 22
patients (7.1%) patients to UFH and 18 patients (5.9%) assigned to
LMWH reached 1 of the primary end points (P=0.54) (Table 6
The findings of this study, combined with those of the COLUMBUS study,
indicate that subcutaneous weight-adjusted LMWH is as effective and
safe as intravenous UFH. LMWH, however, is much more
convenient.
Most of these studies evaluating LMWH preparations for the treatment of
venous thromboembolism used a twice-daily weight-adjusted regimen.
However, 2 studies, 1 of patients with acute venous
thrombosis34 and 1 of patients with acute
pulmonary embolism,35 used a once-daily
dose (175 anti-Xa units/kg) of the same LMWH (Tinzaparine). Both
studies reported that the LMWH (Tinzaparin) was likely to be as
effective UFH.
LMWH in Unstable Angina
Currently, the combination of heparin and aspirin is
standard antithrombotic treatment for patients with unstable angina and
non–Q-wave myocardial infarction. Although the value of aspirin is
well established for this indication, the evidence supporting a benefit
for heparin is less certain.39 The increased
convenience and recent success of LMWHs for the treatment of venous
thromboembolism have led to their evaluation, administered
subcutaneously without laboratory monitoring, in patients with unstable
angina and non–Q-wave myocardial infarction. To date, 4 randomized
trials comparing LMWHs with UFH have been reported.
The first, which was a small open trial comparing LMWH
(nadraparine) and aspirin with UFH and aspirin or aspirin alone,
reported that the LMWH reduced the risk of acute myocardial
infarction.40 This promising report was followed
by three larger studies in patients with unstable angina.
The first large randomized study41 was a
double-blind, placebo-controlled trial of 1506 patients with unstable
angina or non–Q-wave myocardial infarction performed by the FRISC
study group. The experimental group received LMWH (dalteparin) 120 U/kg
twice daily for 6 days followed by 7500 anti-Xa units of dalteparin
once daily for 35 to 45 days, whereas the control group received
placebo injections; all patients received aspirin. LMWH was shown to
reduce the risk of death or myocardial infarction by >60% at 6 days.
Thus, of the 741 patients allocated to receive LMWH, 13 (1.8%) died or
developed myocardial infarction compared with 36 of 758 (4.7%) of
those who received placebo. The composite end point of death,
myocardial infarction, and need for
revascularization also showed a significant
difference in favor of LMWH (5.4% versus 10.3%). At 40 days, the
difference in rates of death and myocardial infarction and of the
composite end point persisted. However, there was a cluster of events
in the patients assigned LMWH after the high initial dose was replaced
by the lower maintenance dose, suggesting that a dose of 7500
anti-Xa units of dalteparin once daily produces inadequate protection
even after a 6-day course of high-dose LMWH. At 4 to 5 months of
follow-up, the significant difference between the 2 groups in the rates
of death, myocardial infarction, or
revascularization was no longer evident. The rates
for death or myocardial infarction in the control and experimental
groups were 15.3% and 14.0% respectively (P=0.41); for
death, myocardial infarction, or revascularization,
43.6% and 42.7% (P=0.18), respectively.
The results of this study established the short-term value of LMWH
(dalteparin) for the treatment of unstable angina but suggested that
protection with high-dose treatment is required for >6 days. Although
all patients received aspirin, the control group did not receive UFH,
which is the standard treatment in most countries.
A second study, the FRIC study,42 was then
performed. In the first phase, 1482 patients with unstable angina or
non–Q-wave infarction were assigned to receive the LMWH dalteparin
(120 anti-Xa units/kg twice daily) or UFH (5000 U bolus followed by
1000 U/h) by continuous infusion for 6 days in an open randomized
design. In the second phase, which was double blind, patients assigned
to LMWH were continued at a dose of 7500 IU once daily or placebo. The
results showed that the treatment regimens were equivalent in efficacy
and safety (Table 7
The results of this study are consistent with the
hypothesis that dalteparin (administered in a dose of 120 anti-Xa IU SC
twice daily) is as effective as UFH. It is noteworthy, however, that
after 6 days, dalteparin administered in a dose of 7500 U SC once daily
is no more effective than placebo, findings that are consistent
with the results of the FRISC study.
The third study, the ESSENCE trial,43
included 3171 patients with unstable angina or non–Q-wave myocardial
infarction (Table 7
There was no difference in the incidence of major bleeding at 30 days
(6.5% with LMWH versus 7.0% with UFH), but the incidence of total
bleeding was higher in the LMWH group (18.4% versus 14.2%), primarily
because of bruising at injection sites.
The reason for the differences between the results of the FRIC and
ESSENCE studies is uncertain, but there are a number of potential
explanations (Table 8
Dalteparin and enoxaparin are depolymerized by different chemical
methods and have different molecular weight distributions. However,
these differences are unlikely to explain the more favorable results
seen in the ESSENCE study, because patients assigned to receive LMWH in
the FRIC study were given a more aggressive anticoagulant regimen (both
in terms of anti-Xa and anti-IIa units) than those assigned enoxaparin
in the ESSENCE study.
Although the inclusion criteria were similar for both studies, the
event rates in the patients assigned UFH appeared to be higher in the
ESSENCE study, possibly accounting for the more favorable results in
patients assigned LMWH in this study. Alternatively, the observed
differences in the efficacy of LMWH in the 2 studies could be due to
the play of chance. Further information will be forthcoming from the
TIMI 11B trial, which is testing a longer duration of treatment with
enoxaparin versus UFH in a similar patient group.
Controversial Issues
A number of controversial issues remain, including the relative
costs of LMWH and UFH and the possibility that the efficacy and safety
of LMWH might be improved if laboratory monitoring is performed.
Although LMWH preparations are more convenient to use than UFH, they
have the disadvantage of being more expensive. Because LMWH
preparations have not received approval for use for the treatment of
venous thrombosis, pulmonary embolism, or unstable angina in
the United States, their cost for these indications is unknown. In
addition, the higher cost of LMWH preparations cannot be considered in
isolation, because they might well be offset by the savings derived
from reduced hospital stay and the subcutaneous route of
administration.
One appealing feature of LMWH is their more predictable dose response,
which has been translated clinically into treatment with
weight-adjusted dosing without laboratory monitoring. The only study
that compared the predictability of the dose response of LMWH with that
of UFH44 demonstrated less variability with LMWH
than with UFH. However, even LMWH produced a somewhat variable
anticoagulant response, thereby raising the possibility that both the
efficacy and safety of LMWH might be improved if the anti-factor Xa
level were monitored. It is likely, however, that if monitoring
produces improvement in clinical outcome, the effects would be marginal
and therefore would be offset by the loss of convenience and increased
expense. Weight-adjusted dosing could be misleading in renal
insufficiency or in the very obese, and studies are required to
determine if monitoring is necessary in such patients. However, on the
basis of current information, when indicated, LMWH preparations should
be administered with weight-adjusted dosing in most patients.
Summary
LMWHs are a new class of anticoagulants that have pharmacokinetic
and biological advantages over UFH. These advantages are translated
clinically into (1) greater convenience afforded by the ability to
administer LMWH by subcutaneous injection without laboratory monitoring
and the associated cost reduction resulting from reduced hospital stay
and (2) a lower incidence of HIT and possibly a lower risk of
osteopenia. LMWHs appear to be as safe and effective as UFH for
the treatment of venous thrombosis and pulmonary embolism and
at least as safe and effective as UFH for the treatment of patients
with unstable angina. Whether 1 LMWH preparation is more effective than
others remains an open question that can be answered only by direct
comparison of different LMWH preparations in randomized trials.
Acknowledgments
I would like to thank Dr Jeffrey Weitz for critically reviewing
this document.
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J Med. 1997;337:447–452.
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Handeland GF, Abildgaard U, Holm HA, Arnesen K-E. Dose
adjusted heparin treatment of deep venous thrombosis: a comparison of
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© 1998 American Heart Association, Inc.
Cardiovascular Drugs
Low-Molecular-Weight Heparin
A Review of the Results of Recent Studies of the Treatment of Venous Thromboembolism and Unstable Angina
Key Words: heparin • angina • venous thrombosis
The pharmacokinetic limitations of heparin are caused by its
nonspecific binding to proteins and cells.2 3
Because heparin is highly negatively charged, it binds in a
pentasaccharide-independent fashion to a variety of plasma
proteins (including histidine-rich glycoprotein,
vitronectin, lipoproteins, fibronectin, and fibrinogen) and
to proteins secreted by platelets (platelet factor 4 [PF4]
and high-molecular-weight von Willebrand factor) and
endothelial cells (high-molecular-weight von
Willebrand factor).2 Some heparin-binding
proteins are acute-phase reactants, the levels of which are elevated in
sick patients.4 In addition, during the clotting
process, PF4 and von Willebrand factor are released from
platelets and endothelial cells, respectively.
The biophysical limitations of heparin reflect the inability of
the heparin-antithrombin complex to inactivate
thrombin-bound to fibrin6 and factor Xa bound to
phospholipid surfaces within the prothrombinase
complex.7 The inability of heparin to
inactivate surface-bound thrombin and factor Xa may explain
why heparin is of only limited efficacy in unstable angina, high-risk
coronary angioplasty, and coronary
thrombolysis.
Apart from the well-known complication of bleeding, which is
common to all anticoagulants, UFH can produce thrombocytopenia and
osteoporosis.
Heparin binds to platelets, causing
activation8 and release of PF4. Heparin complexes
PF4 and stimulates the formation of antibodies that cause
heparin-induced thrombocytopenia (HIT).9 The
reported incidence of HIT varies widely, but in a recent large
randomized trial,10 it was 
3%.
Thrombocytopenia usually begins between 5 and 15 days after heparin is
begun (median, 10 days)11 but can occur within
hours in patients who have been previously exposed to
heparin.11 The incidence of arterial
or venous thrombosis with HIT is unknown but has been estimated to
occur in 
20% of patients with HIT. Thrombosis is thought to be
triggered by immune complex–induced platelet activation.
Osteoporosis is a well-recognized complication of long-term
heparin treatment.15 16 17 Reports from recent
clinical studies suggest that 2% to 3% of patients receiving UFH for
>3 months develop symptomatic bone fractures and that up
to one third have had an asymptomatic reduction in bone
density as determined by dual-photon
absorptiometry.15 16 17 
).
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Table 1. Biological Consequences of Reduced Binding of LMWH
to Proteins and Cells 
). LMWHs are cleared principally by the renal route, and their
biological half-life is increased in patients with renal
failure.26 27 28 . Because some of these
LMWHs are prepared by different methods of
depolymerization and differ to some extent in their
pharmacokinetic properties and anticoagulant profiles, they may not be
clinically interchangeable.
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Table 2. Comparison of LMWH
Preparations
Like UFH, LMWHs produce their major anticoagulant effect by
activating antithrombin (AT). Their interaction with AT is mediated by
a unique pentasaccharide sequence29 30
found on fewer than one third of LMWH molecules. Because a minimum
chain length of 18 saccharides (including the
pentasaccharide sequence) is required for ternary complex
formation, only the 25% to 50% of LMWH species that are above this
critical chain length are able to inactivate thrombin. In
contrast, all LMWH chains that contain the high-affinity
pentasaccharide catalyze the inactivation of factor Xa.
Consequently, commercial LMWHs have ratios of anti-factor Xa to
anti-IIa that vary between 4:1 and 2:1, depending on their molecular
size distribution (the Figure). In
contrast to LMWH, virtually all UFH molecules contain 18
saccharide units.31 32 Therefore, UFH has
a ratio of anti-factor Xa to anti-factor IIa of 1:1.
View larger version (25K):
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Figure 1. LMWH activity. Approximately 25% to 50% of LMWH molecules
of different commercial preparations contain 18 saccharide
units; these molecules inhibit both thrombin and factor Xa. Remaining
50% to 75% of LMWH molecules contain <18 saccharide units
and inhibit only factor Xa.
LMWHs have been evaluated in a large number of randomized clinical
trials and have been shown to be safe and effective for the prevention
and treatment of venous thrombosis. More recently, LMWH preparations
have also been evaluated in patients with acute pulmonary
embolism and those with unstable angina. and 4) in
which the data for each of the 4 LMWHs have been pooled separately.
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Table 3. LMWH Versus Heparin in the Treatment of Deep Venous
Thrombosis: Symptomatic Recurrent Venous Thromboembolic Complications
During Initial Treatment and 3- to 6-Month
Follow-Up
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Table 4. LMWH Versus Heparin: Incidence of Major Bleeding
Complications During Initial Heparin Treatment, Including 48 Hours
After Heparin Cessation . The results are
similar and indicate that LMWH administered on an out-of-hospital basis
in eligible patients with deep venous thrombosis is as effective and
safe as intravenous heparin administered in hospital. These
findings have the potential to change our current approach to the
treatment of venous thrombosis, with improved patient convenience and
reduced health care costs.
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Table 5. Efficacy and Safety of 2 Trials Using Outpatient
LMWH ),
which was a randomized study of 1021 patients with
symptomatic venous thromboembolism. Patients with venous
thrombosis or pulmonary embolism were randomly allocated to
receive either subcutaneous LMWH (riviparin sodium) or adjusted-dose
intravenous UFH. Warfarin was started concomitantly and
continued for 3 months. The dosage regimen for LMWH was 6300 anti-Xa
units twice daily for patients weighing >60 kg, 4200 anti-Xa units
twice daily for persons weighing 46 to 60 kg, and 3500 anti-Xa units
twice daily for those weighing 35 to 45 kg. Approximately one third of
the patients had associated pulmonary embolism, and most were
treated in hospital. Of the patients with venous thrombosis, 27% were
treated out of hospital, and an additional 15% were discharged during
the first 3 days of treatment. As a result, the mean hospital stay was
3 days shorter for patients assigned to LMWH.
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Table 6. Relative Efficacy and Safety of LMWH and Heparin in
2 Trials That Included Patients With Pulmonary
Embolism ).
The rate of major bleeding was similar in both groups (2.6% and 2.0%,
respectively). There were 3 deaths at 8 days and 14 deaths at 90 days
(4.5%) in patients assigned to UFH and 4 deaths at 8 days and 12
deaths at 90 days (3.9%) in patients assigned to LMWH. Five deaths
were treatment related in the UFH group (3 from pulmonary
embolism and 2 from major bleeding), and 4 were treatment related in
the LMWH group (3 from pulmonary embolism and 1 from
bleeding). ). At 6 days, the
composite outcome of death, myocardial infarction, or recurrent angina
was 7.6% in the UFH group and 9.3% in the LMWH group. The
corresponding rates of the composite end point of death or myocardial
infarction were 3.6% and 3.9%, respectively. Between days 6 and 45,
the rate of death, myocardial infarction, or recurrence was
12.3% in both groups. There was no difference in the incidence of
major bleeding, which was very low in both groups.
View this table:
[in a new window]
Table 7. Relative Efficacy and Safety of Heparin and LMWH in
2 Trials That Included Patients With Unstable
Angina ). Patients were randomized in a double-blind
fashion to 1 mg/kg (100 anti-Xa IU) SC of LMWH (enoxaparin) every 12
hours or UFH administered as an intravenous bolus followed
by a continuous infusion for 2 to 8 days. The median duration of
treatment in both groups was 2.6 days. There was a significant
reduction in the primary end point of death, myocardial infarction, or
recurrent angina at 14 days in patients assigned to LMWH: 19.8% in the
UFH group and 16.5% in the LMWH group, for a 17% relative risk
reduction (P=0.019). The 30-day incidence of the composite
end point was 23.3% in the UFH group and 19.8% in the LMWH group,
which represents a significant difference (P=0.016).
This difference was accounted for mainly by a lower incidence of
recurrent angina in patients assigned to LMWH, although there was a
nonsignificant trend in reduction of death or myocardial
infarction. ).
View this table:
[in a new window]
Table 8. Comparison of LMWH Treatment Characteristics and
Some Patient Characteristics of the FRIC and ESSENCE
Studies
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