(Chest. 2001;119:64S-94S.)
© 2001
American College of Chest Physicians
Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety
Jack Hirsh, MD, FCCP, Chair;
Theodore E. Warkentin, MD;
Stephen G. Shaughnessy, PhD;
Sonia S. Anand, MD;
Jonathan L. Halperin, MD;
Robert Raschke, MD, MS;
Christopher Granger, MD;
E. Magnus Ohman, MBBCh, FCCP and
James E. Dalen, MD, MPH, Master FCCP
Correspondence to: Jack Hirsh, MD, FCCP, Director, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, ON L8V 1C3, Canada
 |
Introduction
|
|---|
Heparin
and its derivative, low-molecular-weight heparin (LMWH), are the
anticoagulants of choice when a rapid anticoagulant effect is required,
because their onset of action is immediate when administered by IV
injection. Both types of heparins are administered in lower doses for
primary prophylaxis than for treatment of venous thrombosis or acute
myocardial ischemia. Heparin has pharmacokinetic
limitations1
not shared by LMWHs. Based on these
pharmacokinetic limitations, heparin therapy is usually restricted to
the hospital setting, where its effect can be monitored and its dosage
adjusted frequently. In contrast, LMWH preparations can be administered
in either the in-hospital or out-of-hospital setting because they can
be administered subcutaneously (sc) without the need for laboratory
monitoring. When long-term anticoagulant therapy is indicated, heparin
or LMWH administration is usually followed by treatment with oral
anticoagulants. However, long-term out-of-hospital treatment with
heparin or LMWH is used when anticoagulant therapy is indicated in
pregnancy and in patients who develop recurrent venous thromboembolism
while treated with appropriate doses of oral anticoagulants.
Since our report in 1998 (Supplement to CHEST, Vol.
114, iss 5), a number of LMWH preparations have been approved
for use for the treatment of venous thrombosis and for the
treatment of unstable angina (UA).
|
Clinical Indications
|
|---|
Heparin is effective and indicated for the prevention of venous
thromboembolism; for the treatment of venous thrombosis and pulmonary
embolism (PE); for the early treatment of patients with UA and acute
myocardial infarction (MI); for patients who undergo cardiac surgery
using cardiac bypass, vascular surgery, and coronary angioplasty; in
patients with coronary stents; and in selected patients with
disseminated intravascular coagulation.
LMWHs are effective and indicated for the prevention of venous
thromboembolism, for the treatment of venous thrombosis, for the
treatment of acute PE, and for the early treatment of patients with UA.
The levels of evidence and grading of recommendations for the clinical
use of heparin and LMWHs are discussed in the chapters that consider
the evidence supporting antithrombotic therapy with these agents for
the various clinical indications.
This chapter will review the mechanisms of action of heparin and LMWHs,
their pharmacokinetics, anticoagulant effects, side effects, and
laboratory monitoring. The clinical uses of heparin and LMWHs and the
results of clinical trials will also be discussed, although more
details appear in other chapters.
|
Historical Highlights
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Heparin was discovered by McLean2
in 1916, and
Brinkhous and associates3
demonstrated that its
anticoagulant effect requires a plasma cofactor later named
antithrombin III (AT-III),4
but is now known simply as
antithrombin (AT). Rosenberg and Lam,1
Rosenberg and
Bauer,5
and Lindahl et al6
elucidated the
mechanisms responsible for the heparin/AT interaction. It is now known
that the active center serine of thrombin and other coagulation enzymes
are inhibited by an arginine-reactive site on the AT molecule and that
heparin binds to lysine site on AT, producing a conformational change
at the arginine-reactive site that converts AT from a slow, progressive
thrombin inhibitor to a very rapid inhibitor of thrombin and factor
Xa.5
AT binds covalently to the active serine centers of
coagulation enzymes; heparin then dissociates from the ternary complex
and can be reutilized (Fig 1
).5
Subsequently, it was discovered1
5
6
that
heparin binds to and potentiates the activity of AT through a unique
glucosamine unit1
5
6
7
contained within a pentasaccharide
sequence,8
the structure of which has been confirmed. A
synthetic pentasaccharide has been developed and is undergoing clinical
evaluation for prevention and treatment of venous
thrombosis.9
10
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Figure 1. Inactivation of clotting enzymes by heparin.
Top panel: AT-III is a slow inhibitor without heparin.
Middle panel: Heparin binds to AT-III through
high-affinity pentasaccharide and induces a conformational change in
AT-III, thereby converting AT-III from a slow to a very rapid
inhibitor. Bottom panel: AT-III binds covalently to the
clotting enzyme, and the heparin dissociates from the complex and can
be reutilized.
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Mechanism of Action
|
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Only about one third of an administered dose of heparin binds to
AT, and this fraction is responsible for most of its anticoagulant
effect.11
12
The remaining two thirds has minimal
anticoagulant activity at therapeutic concentrations, but at
concentrations greater than usually obtained clinically, both
high-affinity and low-affinity heparin catalyze the AT effect of a
second plasma protein, heparin cofactor II (Table 1
).13
The heparin-AT complex inactivates a number of coagulation enzymes,
including thrombin factor (IIa), factors Xa, IXa, XIa, and
XIIa.5
Of these, thrombin and factor Xa are most
responsive to inhibition, and human thrombin is about 10-fold more
sensitive to inhibition by the heparin-AT complex than factor Xa (Fig 2
). To inhibit thrombin, heparin must bind to both the coagulation enzyme
and AT, but binding to the enzyme is less important for the inhibition
of activated factor X (factor Xa; Fig 3
).7
Molecules of heparin containing < 18 saccharides do
not bind simultaneously to thrombin and AT and are therefore unable to
catalyze thrombin inhibition. In contrast, very small heparin fragments
containing the high-affinity pentasaccharide sequence catalyze
inhibition of factor Xa by AT.14
15
16
17
By inactivating
thrombin, heparin not only prevents fibrin formation but also inhibits
thrombin-induced activation of factor V and factor
VIII.18
19
20
Unfractionated heparin (UFH) and LMWH also
induce secretion of tissue factor pathway inhibitor by vascular
endothelial cells that reduce procoagulant activity of tissue factor
VIIa complex, and this could contribute to the antithrombotic action of
heparin and LMWH.21
22
23
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Figure 2. The heparin/AT-III complex inactivates the
coagulation enzymes factor XIIa (XIIa), factor XIa (XIa), factor IXa
(IXa), factor Xa (Xa), and thrombin (IIa). Thrombin and factor Xa are
most sensitive to the effects of heparin/AT-III.
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Figure 3. Inhibition of thrombin requires simultaneous
binding of heparin to AT-III through the unique pentasaccharide
sequence and binding to thrombin through a minimum of 13 additional
saccharide units. Inhibition of factor Xa (Xa) requires binding heparin
to AT-III through the unique pentasaccharide without the additional
requirements for binding to Xa. 5 indicates unique high-affinity
pentasaccharide.
|
|
Heparin is heterogeneous with respect to molecular size, anticoagulant
activity, and pharmacokinetic properties (Table 2
). Its molecular weight ranges from 3,000 to 30,000 d average, with a
mean molecular weight of 15,000 d (approximately 45 monosaccharide
chains; Fig 4
).24
25
26
Its anticoagulant activity varies because only one
third of heparins have anticoagulant function and because its
anticoagulant profile and clearance are influenced by the chain length
of the molecules, with the higher-molecular-weight species cleared from
the circulation more rapidly than the lower-molecular-weight species.
This differential clearance results in accumulation in vivo
of the lower-molecular-weight species, which have a lower ratio of
antifactor IIa to antifactor Xa activity. The lower-molecular-weight
species that are retained in vivo are measured by the
antifactor Xa heparin assay, but these have little effect on the
activated partial thromboplastin time (APTT). Binding of heparin to von
Willebrand factor also inhibits von Willebrand factor-dependent
platelet function.27
Heparin binds to platelets, and depending on the experimental
conditions in vitro, can either induce or inhibit platelet
aggregation.28
29
Heparin prolongs the bleeding time in
humans30
and enhances blood loss from the microvasculature
in rabbits.31
32
33
The interaction of heparin with
platelets31
and endothelial cells32
may
contribute to heparin-induced bleeding by a mechanism independent of
its anticoagulant effect.33
In addition to its anticoagulant effect, heparin increases vessel wall
permeability,32
inhibits the proliferation of vascular
smooth muscle cells,34
and suppresses osteoblast formation
and activates osteoclasts that promote bone loss.35
36
Each of these effects is independent of its anticoagulant activity, but
only the osteopenic effect is likely to be relevant
clinically.37
|
Pharmacology of UFH
|
|---|
The preferred routes of UFH administration are continuous IV
infusion and sc injection. When the sc route is selected, the initial
dose must be sufficient to overcome the lower bioavailability
associated with this route of administration.38
An
immediate anticoagulant effect requires an IV bolus.
In the circulation, heparin binds to a number of plasma proteins (Fig 5
), which reduces its anticoagulant activity at low concentrations,
thereby contributing to the variability of the anticoagulant response
to heparin among patients with thromboembolic disorders39
and to the laboratory phenomenon of heparin resistance.40
Heparin also binds to endothelial cells41
and macrophages,
which further complicates its pharmacokinetics.
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Figure 5. As heparin (small, filled circles) enters the
circulation, it binds to heparin-binding proteins (elongated circles),
endothelial cells (EC), macrophages (M), and AT-III (egg-shaped
circles). Only heparin with the high-affinity pentasaccharide binds to
AT-III, but binding to other proteins and to cells is nonspecific and
occurs independently of the AT-III binding site.
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Heparin clearance involves a combination of a rapid saturable and a
much slower first-order mechanisms (Fig 6
).42
43
44
The mechanism of the saturable phase of heparin
clearance is through binding to receptors on endothelial
cells45
46
and macrophages47
where it is
depolymerized (Fig 5)
,48
49
while the slower unsaturable
mechanism is renal (Fig 6)
. At therapeutic doses, heparin is cleared
predominantly through the rapid saturable, dose-dependent mechanism and
its anticoagulant effects are nonlinear, with both the intensity and
duration of effect rising disproportionately with increasing dose. As a
result, the half-life of heparin increases from approximately 30 min
following an IV bolus of 25 U/kg, to 60 min with a bolus of 100 U/kg,
and to 150 min with a bolus of 400 U/kg.42
43
44
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Figure 6. Low doses of heparin clear rapidly from plasma
through saturable (cellular) mechanism of clearance. Therapeutic doses
of heparin are cleared by a combination of the rapid, saturable
mechanism and the slower, nonsaturable dose-independent mechanism of
renal clearance. Very high doses of heparin are cleared predominantly
through the slower nonsaturable mechanism of clearance.
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Plasma recovery of heparin is reduced50
when administered
by sc injection in low (5,000 U q12h) or moderate (12,500 to
15,000 U q12h) doses.38
51
At high therapeutic doses
(> 35,000 U/24 h), however, plasma recovery is almost
complete.52
The difference between the bioavailability of
heparin administered by sc or IV injection was demonstrated in patients
with venous thrombosis38
randomized to receive either
15,000 q12h by sc injection or 30,000 U by continuous IV infusion; both
regimens were preceded by a 5,000-U bolus. Therapeutic heparin levels
and APTT ratios were achieved at 24 h in only 37% of patients
given sc heparin, compared with 71% of those given the same total dose
by continuous IV infusion.
|
Laboratory Monitoring
|
|---|
Randomized trials show a relationship among heparin dose,
efficacy,38
51
53
and safety.54
55
Since the
anticoagulant response to heparin varies among patients with
thromboembolic disorders,56
57
58
59
60
it is standard practice to
adjust the dose of heparin and monitor its effect by measurement of the
APTT that is sensitive to the inhibitory effects of heparin on
thrombin, factor Xa, and factor IXa. Although a relationship exists
between heparin dose and therapeutic efficacy for patients with venous
thromboembolism, such a relationship has not been established for
patients with acute coronary ischemia, although those receiving
concomitant thrombolytic therapy or glycoprotein (GP) IIb/IIIa
(GPIIb/IIIa) antagonists given heparin in a dose used to treat venous
thrombosis have an unacceptably high rate of bleeding.
Although a close relationship between an effect of heparin ex
vivo on the APTT and its clinical effect in vivo has
been assumed, the data supporting this assumption are derived from
retrospective subgroup analysis of cohort
studies38
51
57
58
60
61
(Table 3 ) and are inconsistent with the results of a randomized
trial62
and meta-analyses of contemporary cohort
studies.63
64
Furthermore, there was no direct
relationship between APTT and efficacy observed in the subgroup
analysis of the GUSTO I study65
in patients with acute MI
who were treated with thrombolytic therapy followed by heparin. And
even if the APTT were predictive of clinical efficacy, its value would
be limited by the variable responsiveness of commercial APTT reagents
to heparin.66
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Table 3. Relation Between Failure to Reach Lower Limit of
Therapeutic Range of APTT and Thromboembolic Events From Subgroup
Analysis of Prospective Studies
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The risk of heparin-associated bleeding increases with
dose67
68
and with concomitant thrombolytic
therapy69
70
71
72
or the GPIIb/IIIa antagonist
abciximab.54
55
The risk of bleeding is also increased by
recent surgery, trauma, invasive procedures, or concomitant hemostatic
defects.73
Despite its limitations, the APTT remains the most frequently used
method for monitoring the anticoagulant response to heparin. The APTT
should be measured approximately 6 h after the bolus dose of
heparin, and the continuous IV dose should be adjusted based on the
result.
When heparin is given by sc injection in a dose of 35,000 U/24 h in two
divided doses,52
the anticoagulant effect is delayed for
approximately 1 h and peak plasma levels occur at approximately
3 h.
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Dosing Nomograms
|
|---|
Audits of physician-directed heparin therapy have demonstrated a
great deal of variability in dosing decisions.74
75
76
77
A
number of methods for standardizing the management of IV heparin
therapy have been published, including heparin dose-adjustment
nomograms56
78
79
80
81
82
83
and computer
algorithms.84
85
Nomograms and computer-assisted dosage
adjustment have also been used to manage heparin in conjunction with
thrombolytic therapy for patients with MI.65
81
85
The
weight-adjusted nomogram has been incorporated into the Agency for
Health Care Policy and Research guideline for treatment of
UA.86
87
A weight-based nomogram using a starting dose of 18 U/kg/h heparin
infusion (1,260 U/h for a 70-kg patient; Fig 7
) reduced recurrent thromboembolism in a randomized controlled trial
(relative risk [RR] = 0.2; 95% confidence interval [CI], 0.05 to
0.91)78
88
; the control group, however, received an
inadequate initial heparin infusion (1,000 U/h). Several other
nomograms utilize initial heparin infusion doses as low as 12
U/kg/h,89
90
but the APTT was determined
unconventionally91
and therefore might not be valid.
Two nomograms have been validated independently92
93
; both
significantly reduced latency to therapeutic APTT levels. Over a 5-year
period, voluntary physician use of the nomogram approached 95% at one
institution and this was associated with significantly higher initial
heparin dosage, shorter time to therapeutic APTT, and no increase in
bleeding.94
Weight-adjusted nomograms have also been evaluated in clinical trials
in patients with UA. These have used a lower initial infusion rate of
15 U/kg/h.95
96
In the OASIS-2 study,95
a
bolus dose of 5,000 U was followed by an infusion of 15 U/kg/h. More
than 80% of patients reached the therapeutic APTT range (60 s and
100 s) within 24 h. In the TIMI-11B
study,96
a 70-U/kg bolus was followed by an
infusion of 15 U/kg/h and the APTT reached 55 to 58 s in 42% of
patients within 12 h. A weight-adjusted nomogram has been
incorporated into the guidelines for treatment of UA promulgated by the
Agency for Health Care Policy and Research.86
87
When a nomogram is used, it is important to determine the appropriate
therapeutic range based on the local laboratory reagent and to adapt
the recommended dosage adjustments accordingly. For patients with
venous thrombosis or PE, the targeted APTT should be equivalent to a
heparin level or 0.3 to 0.7 U/mL by antifactor Xa heparin
levels.97
98
A lower therapeutic range is recommended for
patients with acute myocardial ischemia receiving thrombolytic or
GPIIb/IIIa antagonist agents, since a lower dose of heparin proved
safer and no less effective in these circumstances than the higher-dose
regimen established for patients with venous thrombosis. Recognizing
that the traditional heparin dosing regimens cause excessive bleeding
in patients with acute MI who receive thrombolytic therapy, a
therapeutic range corresponding to antifactor Xa levels of 0.14 to 0.34
seems reasonable.89
Failure to adapt nomograms to the
therapeutic range could result in dangerous errors in heparin therapy.
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Heparin Resistance
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Some patients require higher-than-average doses of heparin to
prolong APTT to the therapeutic range. These patients are designated
heparin resistant if their daily heparin requirement is
> 35,000 U/24 h,62
99
100
and approximately 25% of
patients with venous thromboembolism fulfill this
criterion.38
52
101
102
103
Heparin resistance has been
associated with AT deficiency,5
91
increased heparin
clearance,104
elevations in heparin binding
proteins,40
105
106
and elevations of factor
VIII,62
107
fibrinogen,107
and platelet
factor 4 (PF4).108
Aprotinin and nitroglycerin have been
reported to cause drug-induced heparin resistance,109
110
though the association with nitroglycerin is
controversial.111
Factor VIII or fibrinogen levels are
elevated in response to acute illness or
pregnancy.91
112
113
Elevation of the levels of factor
VIII alters the response of the APTT to heparin without diminishing the
antithrombotic effect,62
as the anticoagulant effect of
heparin (measured by the APTT) and the antithrombotic effect measured
by anti-Xa activity become dissociated.91
100
Studies in
experimental animals demonstrated that the infusion of factor VIII
significantly lowers APTT values without interfering with the
antithrombotic effect of heparin. Under these experimental
circumstances, heparin concentration was unperturbed and was a more
accurate measure of thrombus inhibition than the APTT.114
A randomized, controlled trial has shown that adjusting dosage by
anti-Xa heparin concentrations results in favorable clinical outcomes
in heparin-resistant patients despite lower doses of heparin and
subtherapeutic APTT levels.62
For patients who require > 35,000 U of UFH per 24 h, the dose
should be adjusted to maintain anti-Xa heparin levels of 0.35 to
0.70 IU/mL.91
106
112
In a randomized, controlled trial in
131 patients with venous thromboembolism requiring > 35,000 U of
heparin per day, monitoring the APTT was compared to anti-Xa heparin
activity with no significant differences in clinical outcomes, but the
group monitored using anti-Xa heparin levels required significantly
less heparin with no difference in bleeding.62
This
approach is especially useful for patients at high risk of bleeding
when continued heparin therapy is necessary. Substitution of LMWH may
be inadvisable in such patients due to its long half-life and the lack
of an effective neutralizing agent. Although measurement of AT levels
has also been recommended in the management of heparin
resistance,91
low values are usually secondary to heparin
therapy,115
116
rather than the cause of heparin
resistance.
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Limitations
|
|---|
The limitations of heparin are based on its pharmacokinetic,
biophysical, and its nonanticoagulant biological
properties.117
All of these limitations are caused by the
AT-independent, charge-dependent binding properties of heparin to
proteins and surfaces. Pharmacokinetic limitations are caused by the
following: (1) AT-independent binding of heparin to plasma
proteins,118
to proteins released from
platelets,119
and possibly to endothelial cells, which
result in the variable anticoagulant response to heparin and to the
phenomenon of heparin resistance62
; and (2) AT-independent
binding to macrophages and endothelial cells, which result in its
dose-dependent mechanism of clearance.
The biophysical limitations occur because the heparin/AT complex is
unable to inactivate factor Xa in the prothrombinase complex and
thrombin bound to fibrin or to subendothelial surfaces. The biological
limitations of heparin include osteopenia and heparin-induced
thrombocytopenia (HIT). Osteopenia is caused as a result of the binding
of heparin to osteoblasts,35
which then release factors
that activate osteoclasts, whereas HIT results from heparin binding to
PF4 to form an epitope to which the HIT antibody
binds.120
121
The pharmacokinetic and nonanticoagulant
biological limitations of heparin are less evident with
LMWH,122
while the limited ability of the heparin-AT
complex to fibrin- bound thrombin and factor Xa is overcome by several
new classes of AT-independent thrombin and factor Xa
inhibitors.123
The anticoagulant effect of heparin is modified by platelets, fibrin,
vascular surfaces, and plasma proteins. Platelets limit the
anticoagulant effect of heparin by protecting surface factor Xa from
inhibition by heparin/AT124
125
and by secreting PF4, a
heparin-neutralizing protein.126
Fibrin limits the
anticoagulant effect of heparin by protecting fibrin-bound thrombin
from inhibition by heparin/AT.127
Heparin binds to fibrin
and bridges between fibrin and the heparin binding site on thrombin. As
a result, heparin increases the affinity of thrombin for fibrin, and by
occupying the heparin binding site on thrombin, protects fibrin-bound
thrombin from inactivation by heparin/AT.128
129
Thrombin
also binds to subendothelial matrix proteins, where it is protected
from inhibition by heparin.130
These observations explain
why in experimental animals131
132
heparin is less
effective than the AT-independent thrombin and factor Xa
inhibitors123
at preventing thrombosis at sites of deep
arterial injury and may explain why hirudin is more effective than
heparin in UA and non-Q-wave myocardial infarction
(NQMI).95
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Therapeutic Use
|
|---|
Heparin is indicated for prevention of venous thromboembolism; for
treatment of venous thrombosis and PE for the early treatment of
patients with UA and acute MI; for patients who undergo cardiac surgery
using cardiopulmonary bypass, vascular surgery, coronary angioplasty,
and stents; and in selected patients with disseminated intravascular
coagulation. LMWHs are indicated for prevention of venous
thromboembolism, for treatment of venous thrombosis, for treatment of
acute PE, and for the early treatment of patients with UA. Levels of
evidence and grading of recommendations for the clinical use of heparin
and LMWHs are discussed in the chapters discussing antithrombotic
therapy for the various clinical indications.
In patients with venous thromboembolism or UA, the dose of heparin is
usually adjusted to maintain the APTT at an intensity equivalent to an
antifactor Xa level of 0.35 to 0.7 U/mL. For many APTT reagents, this
is equivalent to a ratio (patient/control APTT) of 1.5 to 2.5. This
therapeutic range38
61
is recommended based on animal
studies114
and subgroup analysis of prospective studies of
patients with established deep vein thrombosis (DVT),38
and studies of prevention of mural thrombosis after MI51
and prevention of recurrent ischemia following coronary
thrombolysis.57
58
Recommended heparin regimens for venous
and arterial thrombosis are summarized in Table 4
.
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Treatment of Venous Thromboembolism
|
|---|
The efficacy and safety of continuous IV infusion of heparin has
been compared with intermittent IV injection in seven
studies135
136
137
138
139
140
141
and with high-dose sc injection in five
studies.52
101
142
143
144
From these studies, it is
difficult to determine the optimal route of heparin administration
because most were underpowered, total doses varied, and disparate
criteria were used to assess outcome. A pooled analysis of 11 clinical
trials involving 15,000 patients treated with either IV UFH
(administered as an initial bolus of 5,000 U followed by 30,000 to
35,000 U/24 h with APTT monitoring) or sc LMWH145
found
the mean incidence of recurrent venous thromboembolism 5.4% (fatal in
0.7%) and major bleeding 1.9% (fatal in 0.2%).
A 5-day course of heparin therapy appears as effective as a 10-day
course for the treatment of DVT (Table 5
),103
146
and brevity has obvious appeal, reducing both
hospital stay and the risk of HIT. While adequate for most patients
with venous thromboembolism, a 5-day course of heparin therapy may not
be sufficient for those with extensive iliofemoral venous thrombosis or
PE who were underrepresented in these studies.103
146
|
Prophylaxis Against Venous Thromboembolism
|
|---|
Heparin in a fixed low dose of 5,000 U sc every 8 to 12 h
results in 60 to 70% risk reduction for venous thrombosis and fatal
PE.147
148
The incidence of fatal PE in general surgical
patients was reduced from 0.7% in control subjects to 0.2% in one
analysis (p < 0.001),147
and from 0.8 to 0.3%
(p < 0.001) in a larger analysis that included orthopedic surgical
patients.148
There was also a statistically significant
decrease in mortality, from 3.3 to 2.4% (p < 0.02).148
The use of low-dose heparin was associated with a small excess of wound
hematoma,147
148
149
but there was no statistically
significant increase in major bleeding. Low-dose heparin therapy is
also effective for prevention of venous thromboembolism in patients
with MI and other serious medical disorders,150
reducing
in-hospital mortality by 31% (p < 0.05) in a study of 1,358 general
medical patients > 40 years old.151
The incidence of DVT
remains substantial (20 to 30%) after hip surgery,148
despite low-fixed-dose heparin prophylaxis, and risk can be reduced
further by administering either adjusted-dose heparin152
or fixed-dose LMWH.122
Moderate-dose warfarin therapy is
also effective in patients undergoing major orthopedic surgical
procedures,153
154
but direct comparisons of low-dose
heparin and warfarin therapy have not been performed in patients
undergoing major orthopedic surgery in sufficiently powered trials.
|
Coronary Artery Disease
|
|---|
Coronary thrombosis is important in the pathogenesis of UA, acute
MI, and sudden cardiac death, and affects the outcomes of patients with
acute MI treated with thrombolytic therapy or percutaneous transluminal
coronary angioplasty (PTCA). Heparin is no longer used as the sole
antithrombotic drug in patients with acute coronary syndromes, but it
is combined with aspirin in eligible patients with acute
MI,155
with thrombolytic therapy in patients with evolving
MI, and with GPIIb/IIIa antagonists in high-risk patients with
UA156
157
or in those undergoing high-risk
PTCA.54
55
157
Heparin increases the risk of bleeding when
given in full doses combined with aspirin,155
158
thrombolytic therapy, and GPIIb/IIIa antagonists, so the dose is
usually reduced in these settings.55
|
Unstable Angina and NQMI
|
|---|
Heparin has been evaluated in a number of randomized,
double-blind, placebo-controlled clinical trials for the short-term
treatment of patients with UA or NQMI.159
160
161
162
When used
alone in patients with UA, heparin reduces the risk of developing
recurrent angina or acute MI.160
161
162
Meta-analysis of
short-term results suggests that the combination of heparin and aspirin
reduces cardiovascular death and MI by about 30% over that
achieved by aspirin alone.159
Theroux et al160
compared the relative efficacy and safety
of heparin, aspirin, or the combination in 479 patients with UA. The
incidence of MI during the acute period was 11.9% in the placebo group
and was reduced to 3.3% in the aspirin group (p = 0.012), 0.8% in
the heparin group (p < 0.0001), and 1.6% with the combination
(p = 0.001; all comparisons to placebo). The incidence of refractory
angina, 22.9% in the placebo group, was reduced to 8.5% with heparin
(p = 0.002), 10.7% with heparin plus aspirin (p = 0.11), but it
was 16.5% in the aspirin group. In a second study,163
these investigators compared heparin with aspirin, eliminating the
placebo and combination therapy groups. Fatal or nonfatal MI occurred
in 4 of 362 heparin-treated patients, compared with 23 of 362 patients
treated with aspirin (odds ratio = 0.16; p < 0.005).
In contrast, the Research Group in Instability in Coronary Artery
Disease Investigators159
found heparin (10,000 U q6h for
24 h and 7,500 U q6h for 5 days thereafter) no more effective than
aspirin (75 mg/d) in 796 men with UA or NQMI. The incidence of MI or
death 5 days after enrollment was significantly reduced only in the
group given the combination of aspirin plus heparin (1.4%,
p = 0.027), and not in the groups receiving either heparin or aspirin
alone. After 30 days and 90 days, both the aspirin and
aspirin-plus-heparin groups fared significantly better than those given
placebo, but the outcome in the group receiving heparin alone was no
different than placebo.
A meta-analysis of published data from six randomized trials, each
relatively small (composite n = 1,353) including the foregoing, found
a risk reduction of 33% in cardiovascular death and MI (95% CI,
2 to 56%) with the combination of IV UFH and aspirin compared to
placebo, but this was of borderline statistical significance (Fig 8
).155
When data from the FRISC
trial,228
which compared LMWH to placebo in
patients treated with aspirin, are also considered, the combination of
heparin and aspirin appears more effective than aspirin alone in
patients with UA.
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Acute MI
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The benefit of heparin in patients with acute MI not given
thrombolytic therapy may not be applicable to the current clinical
practice of treating these patients with aspirin. In randomized trials
before the thrombolytic era, heparin reduced reinfarction by an average
of 22% and mortality by 17%.164
Heparin also reduces the incidence of mural thrombosis.56
A fixed dose of 12,500 U sc q12h reduced the incidence of mural
thrombosis detected by two-dimensional echocardiography by 72%
compared with no treatment,165
and by 58% compared with
low-dose heparin (5,000 U sc q12h; p < 0.06 for each
study).166
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Coronary Thrombolysis
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TOP
Introduction
Clinical Indications
