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(Circulation. 2001;103:2994.)
© 2001 American Heart Association, Inc.
AHA Scientific Statement |
Guide to Anticoagulant Therapy: Heparin
A Statement for Healthcare Professionals From the American Heart Association
Key Words: AHA Scientific Statement • anticoagulants • heparin
 |
Introduction |
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Top
Introduction
Clinical Consequences of...Thrombi are composed of fibrin and blood cells and may form in any part of the cardiovascular system, including veins, arteries, the heart, and the microcirculation. Because the relative proportion of cells and fibrin depends on hemodynamic factors, the proportions differ in arterial and venous thrombi.1 2 Arterial thrombi form under conditions of high flow and are composed mainly of platelet aggregates bound together by thin fibrin strands.3 4 5 In contrast, venous thrombi form in areas of stasis and are predominantly composed of red cells, with a large amount of interspersed fibrin and relatively few platelets. Thrombi that form in regions of slow to moderate flow are composed of a mixture of red cells, platelets, and fibrin and are known as mixed platelet-fibrin thrombi.4 5 When a platelet-rich arterial thrombus becomes occlusive, stasis occurs, and the thrombus can propagate as a red stasis thrombus. As thrombi age, they undergo progressive structural changes.6 Leukocytes are attracted by chemotactic factors released from aggregated platelets2 or proteolytic fragments of plasma proteins and become incorporated into the thrombi. The aggregated platelets swell and disintegrate and are gradually replaced by fibrin. Eventually, the fibrin clot is digested by fibrinolytic enzymes released from endothelial cells and leukocytes. The complications of thrombosis are caused either by the effects of local obstruction of the vessel, distant embolism of thrombotic material, or, less commonly, consumption of hemostatic elements.
Arterial thrombi usually form in regions of disturbed flow and at sites of rupture of an atherosclerotic plaque, which exposes the thrombogenic subendothelium to platelets and coagulation proteins; plaque rupture may also produce further narrowing due to hemorrhage into the plaque.7 8 9 10 11 Nonocclusive thrombi may become incorporated into the vessel wall and can accelerate the growth of atherosclerotic plaques.9 12 13 When flow is slow, the degree of stenosis is severe, or the thrombogenic stimulus is intense, the thrombi may become totally occlusive. Arterial thrombi usually occur in association with preexisting vascular disease, most commonly atherosclerosis; they produce clinical tissue ischemia either by obstructing flow or by embolism into the distal microcirculation. Activation both of blood coagulation and of platelets is important in the pathogenesis of arterial thrombosis. These 2 fundamental mechanisms of thrombogenesis are closely linked in vivo, because thrombin, a key clotting enzyme generated by blood coagulation, is a potent platelet activator, and activated platelets augment the coagulation process. Therefore, both anticoagulants and drugs that suppress platelet function are potentially effective in the prevention and treatment of arterial thrombosis, and evidence from results of clinical trials indicates that both classes of drugs are effective.
Venous thrombi usually occur in the lower limbs; although often silent, they can produce acute symptoms due to inflammation of the vessel wall, obstruction of flow, or embolism into the pulmonary circulation. They can produce long-term complications due to venous hypertension by damaging the venous valves. Activation of blood coagulation is the critical mechanism in pathogenesis of venous thromboembolism, whereas platelet activation is less important. Anticoagulants are therefore very effective for prevention and treatment of venous thromboembolism, and drugs that suppress platelet function are of less benefit.
Intracardiac thrombi usually form on inflamed or damaged valves, on endocardium adjacent to a region of myocardial infarction (MI), in a dilated or dyskinetic cardiac chamber, or on prosthetic valves. They are usually asymptomatic when confined to the heart but may produce complications due to embolism to the cerebral or systemic circulation. Activation of blood coagulation is more important in the pathogenesis of intracardiac thrombi than platelet activation, although the latter plays a contributory role. Anticoagulants are effective for prevention and treatment of intracardiac thrombi, and in patients with prosthetic heart valves, the efficacy of anticoagulants is augmented by drugs that suppress platelet function.
Widespread microvascular thrombosis is a complication of disseminated intravascular coagulation or generalized platelet aggregation. Microscopic thrombi can produce tissue ischemia, red cell fragmentation leading to a hemolytic anemia, or hemorrhage due to consumption of platelets and clotting factors. Anticoagulants are effective in selected cases of disseminated intravascular coagulation.
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Clinical Consequences of Thrombosis |
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It has been estimated that venous thromboembolism is responsible for more than 300 000 hospital admissions per year in the United States14 and that pulmonary embolism (PE) causes or contributes to death in
12% of hospitalized patients and is responsible for 50 000 to
250 000 deaths annually in the United States. The burden of illness
produced by venous thromboembolism includes death from PE (either acute
or, less commonly, chronic), long-term consequences of the
postthrombotic syndrome, the need for hospitalization, complications of
anticoagulant therapy, and the psychological impact of a potentially
chronic, recurrent illness. Arterial thrombosis is responsible for many of the acute manifestations of atherosclerosis and contributes to the progression of atherosclerosis. The burden of illness from atherosclerosis is enormous. As a generalized pathological process, atherosclerosis affects the arteries supplying blood to the heart, brain, and abdomen or legs, causing acute and chronic myocardial ischemia, including sudden death, MI, unstable angina, stable angina, ischemic cardiomyopathy, chronic arrhythmia, and ischemic cerebrovascular disease (including stroke, transient ischemic attacks, and multi-infarct dementia). In addition, atherosclerosis can cause renovascular hypertension, peripheral arterial disease with resulting intermittent claudication and gangrene, and bowel ischemia, and it can compound the complications of diabetes mellitus and hypertension. Thromboembolism that originates in the heart can cause embolic stroke and peripheral embolism in patients with atrial fibrillation (AF), acute MI, valvular heart disease, and cardiomyopathy.
The second version of "A Guide to Anticoagulant Therapy" was published in 1994. Since then, the following important advances have been made: (1) low-molecular-weight heparin (LMWH) preparations have become established anticoagulants for treatment of venous thrombosis and have shown promise for the treatment of patients with acute coronary syndromes; (2) direct thrombin inhibitors have been evaluated in venous thrombosis and acute coronary syndromes; (3) important new information has been published on the optimal dose/intensity for therapeutic anticoagulation with coumarin anticoagulants; and (4) the dosing of heparin for adjunctive therapy in patients with acute coronary syndromes has been reduced because conventional doses cause serious bleeding when combined with thrombolytic therapy or glycoprotein (GP) IIb/IIIa antagonists.
Whenever possible, the recommendations in this review of anticoagulant therapy are based on results of well-designed clinical trials. For some indications or clinical subgroups, however, recommendations are of necessity based on less solid evidence and are therefore subject to revision as new information emerges from future studies.
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Historical Highlights |
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Heparin was discovered by McLean in 1916.15 More than 20 years later, Brinkhous and associates16 demonstrated that heparin requires a plasma cofactor for its anticoagulant activity; this was named antithrombin III by Abildgaard in 196817 but is now referred to simply as antithrombin (AT). In the 1970s, Rosenberg, Lindahl, and others elucidated the mechanisms responsible for the heparin/AT interaction.18 19 20 It is now known that the active center serine of thrombin and other coagulation enzymes is inhibited by an arginine reactive center on the AT molecule and that heparin binds to lysine sites on AT, producing a conformational change at the arginine reactive center that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor.18 AT binds covalently to the active serine center of coagulation enzymes; heparin then dissociates from the ternary complex and can be reutilized18 (Figure 1
). Subsequently, it was
discovered18 19 20
that heparin binds to and potentiates the activity of AT through a
unique glucosamine
unit18 19 20 21
contained within a pentasaccharide
sequence,22 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.23 24
|
) and induces a conformational change in AT-III, thereby converting AT-III from a slow to a very rapid inhibitor. Bottom, AT-III binds covalently to the clotting enzyme, and the heparin dissociates from the complex and can be reused. Reprinted with permission from Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 suppl):64S–94S. |
Mechanism of Action of Heparin |
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Only approximately one third of an administered dose of heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect.25 26 The remaining two thirds has minimal anticoagulant activity at therapeutic concentrations, but at concentrations greater than those usually obtained clinically, both high- and low-affinity heparin catalyze the AT effect of a second plasma protein, heparin cofactor II27 (Table 1
).
|
The heparin-AT complex inactivates a number of
coagulation enzymes, including thrombin factor (IIa) and factors Xa,
IXa, XIa, and XIIa.18
Of these, thrombin and factor Xa are the most responsive to inhibition,
and human thrombin is 10-fold more sensitive to inhibition by the
heparin-AT complex than factor Xa
(Figure 2). For inhibition of thrombin, heparin must bind to
both the coagulation enzyme and AT, but binding to the enzyme is less
important for inhibition of activated factor X (factor Xa;
Figure 3).21
Molecules of heparin with fewer than 18 saccharides do not bind
simultaneously to thrombin and AT and therefore are unable
to catalyze thrombin inhibition. In contrast, very small heparin
fragments containing the high-affinity pentasaccharide sequence
catalyze inhibition of factor Xa by
AT.28 29 30 31
By inactivating thrombin, heparin not only prevents fibrin formation
but also inhibits thrombin-induced activation of factor V and factor
VIII.32 33 34
|
|
Heparin is heterogeneous with respect to
molecular size, anticoagulant activity, and pharmacokinetic properties
(Table 2). Its molecular weight ranges from 3000 to 30 000
Da, with a mean molecular weight of 15 000 Da (45
monosaccharide chains;
Figure 4).35 36 37
The anticoagulant activity of heparin is heterogeneous,
because only one third of heparin molecules administered to patients
have anticoagulant function, and the anticoagulant profile and
clearance of heparin 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 of the
lower-molecular-weight species, which have a lower ratio of AT to
anti-factor Xa activity, in vivo. This effect is responsible for
differences in the relationship between plasma heparin concentration
(measured in anti-factor Xa units) and the activated partial
thromboplastin time (aPTT). The lower-molecular-weight species that are
retained in vivo are measured by the anti-factor Xa heparin assay, but
these have little effect on the aPTT.
|
|
In vitro, heparin binds to platelets and, depending on
the experimental conditions, can either induce or inhibit platelet
aggregation.38 39
High-molecular-weight heparin fractions with low affinity for AT have a
greater effect on platelet function than LMWH fractions with high
AT affinity40
(Table 1
). Heparin prolongs bleeding time in
humans41 and enhances blood
loss from the microvasculature in
rabbits.42 43 44
The interaction of heparin with
platelets42 and
endothelial
cells43 may contribute to
heparin-induced bleeding by a mechanism independent of its
anticoagulant
effect.44
In addition to anticoagulant effects, heparin increases vessel wall permeability,43 suppresses the proliferation of vascular smooth muscle cells,45 and suppresses osteoblast formation and activates osteoclasts, effects that promote bone loss.46 47 Of these 3 effects, only the osteopenic effect is relevant clinically, and all 3 are independent of the anticoagulant activity of heparin.48
|
Pharmacology of Unfractionated Heparin |
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The 2 preferred routes of administration of unfractionated heparin (UFH) are continuous intravenous (IV) infusion and subcutaneous (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.49 If an immediate anticoagulant effect is required, the initial dose should be accompanied by an IV bolus injection, because the anticoagulant effect of SC heparin is delayed for 1 to 2 hours.
After entering the bloodstream, heparin binds to a number of
plasma proteins
(Figure 5), which reduces its anticoagulant activity at low
concentrations, thereby contributing to the variability of the
anticoagulant response to heparin among patients with thromboembolic
disorders50 and to the
laboratory phenomenon of heparin
resistance.51 Heparin also
binds to endothelial
cells52 and
macrophages, properties that further complicate its
pharmacokinetics. Binding of heparin to von Willebrand factor
also inhibits von Willebrand factor–dependent platelet
function.53
|
). Only heparin with high-affinity pentasaccharide binds to AT-III, whereas binding to other proteins and to cells is nonspecific and occurs independently of the AT-III binding site. Reprinted with permission from Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 suppl):64S–94S.
Heparin is cleared through a combination of a rapid
saturable mechanism and much slower first-order
mechanisms54 55 56
(Figure 6). The saturable phase of heparin clearance is
attributed to binding to endothelial cell
receptors57 58
and macrophages,59
where it is
depolymerized60 61
(Figure 5). The slower, unsaturable mechanism of clearance is
largely renal. At therapeutic doses, a considerable proportion of
heparin is cleared through the rapid saturable, dose-dependent
mechanism
(Figure 6). These kinetics make the anticoagulant response to
heparin nonlinear at therapeutic doses, with both the intensity and
duration of effect rising disproportionately with increasing dose.
Thus, the apparent biological half-life of heparin increases from 30
minutes after an IV bolus of 25 U/kg to 60 minutes with an IV bolus of
100 U/kg and 150 minutes with a bolus of 400
U/kg.54 55 56
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The plasma recovery of heparin is reduced62 when the drug is administered by SC injection in low doses (eg, 5000 U/12 h) or moderate doses of 12 500 U every 12 hours63 or 15 000 U every 12 hours.49 However, at high therapeutic doses (>35 000 U/24 hours), plasma recovery is almost complete.64 The difference between the bioavailability of heparin administered by SC or IV injection was demonstrated strikingly in a study of patients with venous thrombosis49 randomized to receive either 15 000 U of heparin every 12 hours by SC injection or 30 000 U by continuous IV infusion; both regimens were preceded by an IV bolus dose of 5000 U. Therapeutic heparin levels and aPTT ratios were achieved at 24 hours in only 37% of patients given SC heparin compared with 71% of those given the same total dose by continuous IV infusion.
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Dose-Response Relationships and Laboratory Monitoring |
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The risk of heparin-associated bleeding increases with dose65 66 and with concomitant thrombolytic67 68 69 70 or abciximab71 72 therapy. The risk of bleeding is also increased by recent surgery, trauma, invasive procedures, or concomitant hemostatic defects.73 Randomized trials show a relationship between the dose of heparin administered and both its efficacy49 63 74 and its safety.71 72 Because the anticoagulant response to heparin varies among patients with thromboembolic disorders,75 76 77 78 it is standard practice to adjust the dose of heparin and monitor its effect, usually by measurement of the aPTT. This test is sensitive to the inhibitory effects of heparin on thrombin, factor Xa, and factor IXa. Because there is a relationship between heparin dose and both anticoagulant effect and antithrombotic efficacy, it follows that there should be a relationship between anticoagulant effect and antithrombotic efficacy.
In the past, we were secure in the contention that a strong
relationship existed between the ex vivo effect of heparin on the aPTT
and its clinical effectiveness, but several lines of evidence have
challenged the strength of such a relationship. First, the initial
findings supporting a tight relationship between the effect of heparin
on aPTT and its clinical efficacy were based on retrospective subgroup
analysis of cohort studies and are therefore subject to
potential
bias49 63 75 76 77 78 79
(Table 3). Second, the results of a randomized
trial80 and 2 recent
meta-analyses of contemporary cohort
studies81 82 call
into question the value of the aPTT as a useful predictor of heparin
efficacy in patients with venous thrombosis. Third, no direct
relationship between aPTT and efficacy was observed in the subgroup
analysis of the GUSTO-I study (Global Utilization of
Streptokinase and Tissue plasminogen activator
for Occluded coronary arteries) in patients with acute MI who
were treated with thrombolytic therapy followed by
heparin.83 Fourth, even if
the aPTT results were predictive of clinical efficacy, the value of
this test would be limited by the fact that commercial aPTT reagents
vary considerably in responsiveness to
heparin.84 Although
standardization can be achieved by calibration against plasma heparin
concentration (the therapeutic range is 0.2 to 0.4 U/mL based on
protamine titration or 0.3 to 0.7 U/mL based on
anti-factor Xa chromogenic assay), this is beyond the scope
of many clinical laboratories. Heparin monitoring is likely to become
less problematic in the future as LMWH replaces UFH for
most
indications.85
|
Despite its limitations for monitoring heparin, aPTT remains
the most convenient and most frequently used method for monitoring the
anticoagulant response. aPTT should be measured 6 hours after the
bolus dose of heparin, and the continuous IV dose should be adjusted
according to the result. Various heparin dose-adjustment nomograms have
been developed86
(Tables 4 and 5), but none are
applicable to all aPTT
reagents,84 and the
therapeutic range must be adapted to the responsiveness of the reagent
used. In addition, the dosage regimen should be modified when heparin
is combined with thrombolytic
therapy87 or platelet GP
IIb/IIIa
antagonists.72
When heparin is given by SC injection in a dose of 35 000 U/24 hours
in 2 divided doses,64 the
anticoagulant effect is delayed 1 hour, and peak plasma levels occur
after 3 hours.
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Limitations of Heparin |
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The limitations of heparin are based on its pharmacokinetic, biophysical, and nonanticoagulant biological properties.88 All are caused by the AT-independent, charge-dependent binding properties of heparin to proteins and surfaces. Pharmacokinetic limitations are caused by AT-independent binding of heparin to plasma proteins,89 proteins released from platelets,90 and possibly endothelial cells, resulting in the variable anticoagulant response to heparin and the phenomenon of heparin resistance.80 AT-independent binding to macrophages and endothelial cells also results in a dose-dependent mechanism of heparin 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 binding of heparin to osteoblasts,46 which then release factors that activate osteoclasts, whereas HIT results from heparin binding to platelet factor 4 (PF4), forming an epitope to which the HIT antibody binds.91 92 The pharmacokinetic and nonanticoagulant biological limitations of heparin are less evident with LMWH,93 whereas the limited ability of the heparin-AT complex to inactivate fibrin-bound thrombin and factor Xa is overcome by several new classes of AT-independent thrombin and factor Xa inhibitors.94
Platelets, fibrin, vascular surfaces, and plasma proteins modify the anticoagulant effect of heparin. Platelets limit the anticoagulant effect of heparin by protecting surface factor Xa from inhibition by the heparin-AT complex95 96 and by secreting PF4, a heparin-neutralizing protein.97 Fibrin limits the anticoagulant effect of heparin by protecting fibrin-bound thrombin from inhibition by heparin AT.98 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, it protects fibrin-bound thrombin from inactivation by the heparin-AT complex.99 100 Thrombin also binds to subendothelial matrix proteins, where it is protected from inhibition by heparin.101 These observations explain why heparin is less effective than the AT-independent thrombin and factor Xa inhibitors94 for preventing thrombosis at sites of deep arterial injury in experimental animals102 103 and may explain why hirudin is more effective than heparin in patients with unstable angina or non–Q-wave MI.104
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Clinical Use of Heparin |
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Heparin is effective for the prevention and treatment of venous thrombosis and PE, for prevention of mural thrombosis after MI, and for treatment of patients with unstable angina and MI. Although heparin is used to prevent acute thrombosis after coronary thrombolysis, recent reports question the benefits of heparin in this setting when patients are also treated with aspirin (see below).
In patients with venous thromboembolism or unstable angina,
the dose of heparin is usually adjusted to maintain aPTT at an
intensity equivalent to a heparin level of 0.2 to 0.4 U/mL as measured
by protamine titration or an anti-factor Xa
level of 0.30 to 0.7 U/mL. For many aPTT reagents, this is equivalent
to a ratio (patient/control aPTT) of 1.5 to 2.5. The recommended
therapeutic
range49 79 is
based on evidence from animal
studies105 and supported by
subgroup analysis of prospective cohort studies involving
treatment of deep vein thrombosis
(DVT),49 prevention of mural
thrombosis after MI,63 and
prevention of recurrent ischemia after coronary
thrombolysis.75 76
Recommended heparin regimens for venous and arterial
thrombosis are summarized in
Table 6.
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Treatment of Venous Thromboembolism
Use of heparin for the treatment of venous thrombosis
and PE is based on results of randomized
studies.106 107
The effectiveness and safety of heparin administered by continuous IV
infusion have been compared with intermittent IV injection in 6
studies108 109 110 111 112 113
and with high-dose SC heparin in 6
studies.64 114 115 116 117 118
It is difficult to determine the optimal route of heparin
administration because different doses were used in these studies, most
of the studies were small and underpowered, and different criteria were
used to assess efficacy and safety. Nevertheless, the results indicate
that heparin is safe and effective when appropriate doses are given.
Thus, in a recent pooled analysis of 11 clinical trials in
which 15 000 patients were treated with either heparin
(administered as an initial bolus of 5000 U followed by 30 000 to
35 000 U/24 hours with aPTT monitoring) or SC
LMWH,119 the mean incidence
of recurrent venous thromboembolism among patients assigned heparin was
5.4%. The rate of major bleeding was 1.9%, fatal recurrent venous
thromboembolism occurred in 0.7%, and bleeding was fatal in 0.2% of
heparin-treated patients. The initial dose of heparin is particularly
critical when heparin is administered by SC injection, because an
adequate anticoagulant response is not achieved in the first 24 hours
unless a high starting dose is used (17 500 U
SC).64
Audits of heparin monitoring practices indicate that dosage
adjustments are frequently inadequate, and dosing practices can be
improved by use of a simple and effective weight-adjusted dosage
regimen.74 There is evidence
that a 5-day course of heparin is as effective as a 10-day
course120 121
(Table 7). The short-course regimen has obvious appeal,
reducing hospital stay and the risk of HIT. Although the shorter course
of treatment can be recommended for most patients with venous
thromboembolism, this may not be appropriate in cases of extensive
iliofemoral vein thrombosis or major PE, because such patients were
underrepresented in these
studies.120 121
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Prophylaxis of Venous Thromboembolism
Heparin in a fixed low dose of 5000 U SC every 8 or 12
hours is an effective and safe form of prophylaxis in medical and
surgical patients at risk of venous thromboembolism. Low-dose heparin
reduces the risk of venous thrombosis and fatal PE by 60% to
70%.122 123
Among general surgical patients, the incidence of fatal PE was reduced
from 0.7% in controls to 0.2% in one study
(P<0.001)120
and from 0.8% to 0.3%
(P<0.001) in a larger
analysis that included orthopedic surgical
patients.123 There was also
a small but statistically significant decrease in mortality from 3.3%
to 2.4% with low-dose heparin prophylaxis
(P<0.02).123
The use of low-dose heparin is associated with a small excess incidence
of wound
hematoma122 123 124
and a minimal, statistically insignificant increase in major bleeding
but no increase in fatal bleeding. Low-dose heparin also effectively
prevents venous thromboembolism in patients with MI and in those with
other serious medical
disorders,125 and it
reduced in-hospital mortality by 31%
(P<0.05) in a study of 1358
general medical patients aged >40
years.126 Although low-dose
heparin is also effective in reducing DVT after hip
surgery,123 the incidence
of thrombosis remains substantial (20% to 30%) and can be reduced
further with either adjusted low-dose
heparin127 or fixed-dose
LMWH.93 Moderate-dose
warfarin is effective in patients undergoing major orthopedic surgical
procedures,128 129
but direct comparisons of low-dose heparin and warfarin have not been
performed in major orthopedic surgery.
Coronary Artery Disease
Coronary thrombosis is important in the
pathogenesis of unstable angina, acute MI, and sudden cardiac death. It
is also important in the pathogenesis of reinfarction and death in
patients with acute MI treated with thrombolytic agents
or percutaneous transluminal coronary
angioplasty. In most patients, heparin ameliorates the thrombotic
manifestations of acute coronary syndromes, but it is no longer
used as the sole antithrombotic drug in these settings. Today, heparin
is always used in combination with aspirin in potentially eligible
patient groups with acute myocardial
ischemia,130 in
those receiving thrombolytic therapy for evolving MI,
in those treated with platelet GP IIb/IIIa antagonists
for unstable
angina,131 132
and in those undergoing high-risk coronary
angioplasty.71 72 132
When combined with
aspirin,130 133
thrombolytic agents, or GP IIb/IIIa
antagonists, however, heparin in full doses increases the
risk of bleeding, and the dose is usually reduced in these
settings.72
Unstable Angina and Non–Q-Wave MI
Heparin has been evaluated in a number of randomized,
double-blind, placebo-controlled clinical trials for the short-term
treatment of unstable angina or non–Q-wave
MI.134 135 136 137
When given alone to patients with unstable angina, heparin is effective
in preventing acute MI and recurrent
angina,135 136 137
and when used in combination with aspirin, the results of a
meta-analysis of 6 small trials suggest that the combination
also reduces short-term rates of cardiovascular death
and MI by 30% over those achieved with aspirin
alone.134
Theroux et al135
compared the relative efficacy and safety of heparin, aspirin, and
their combination in 479 patients with unstable angina. Heparin was
administered as an initial 5000-U IV bolus, followed by IV infusion of
1000 U/h, adjusted to maintain the aPTT at 1.5 to 2.0 times the control
value. Treatment was initiated within 24 hours after the onset of chest
pain and continued for 6 days. The incidence of MI during the acute
period was 11.9% in the placebo group and was reduced to 3.3% in the
aspirin groups
(P=0.012), 0.8% in the heparin
group (P<0.0001), and 1.6% in
the group given the combination of aspirin and heparin
(P=0.001). The incidence of
refractory angina (22.9% in the placebo group) was significantly
reduced to 8.5% (P=0.002) in
the heparin group and 10.7% in the heparin-plus-aspirin group
(P=0.11) but was 16.5% in the
aspirin group. In a second
study,138 these
investigators compared the efficacy and safety of heparin and aspirin.
This was a continuation of the previous study in which the placebo and
combination groups were discontinued and an additional 245 patients
were randomized to receive either continuous IV heparin or oral aspirin
twice daily during the in-hospital phase (6 days). Fatal or nonfatal
MI occurred during the acute period in 4 of 362 heparin-treated
patients compared with 23 of 362 patients who did not receive heparin
(odds ratio [OR] 0.16,
P<0.005).
In contrast, the RISC (Research group in InStability in Coronary artery disease) investigators134 did not show that heparin was more effective than aspirin. They compared low-dose aspirin (75 mg/d) with intermittent IV heparin (10 000 U bolus every 6 hours during the initial 24 hours followed by 7500 U every 6 hours for 5 days) in 796 men with unstable angina or non–Q-wave MI. Patients were randomized on the basis of a factorial design to treatment with heparin, aspirin, heparin plus aspirin, or placebo. The main outcome was a composite of MI or death evaluated 5 days after enrollment. The rate of this end point was 6.0% in the placebo group, 5.6% in the heparin group, 3.7% in the aspirin group, and 1.4% in the combined treatment group and was significantly reduced only with the combination (P=0.027). At 30 and 90 days, both the aspirin and aspirin-plus-heparin groups showed significantly better results than the placebo group, but the outcome with heparin alone was no better than with placebo.
Cohen et al139 performed a randomized, open-label study of 214 patients with unstable angina or non–Q-wave MI assigned to either aspirin (162.5 mg/d) or aspirin plus heparin for 3 to 4 days and warfarin for up to 12 weeks after enrollment. The main outcome measure was a composite of recurrent angina, MI, or death. After 12 weeks, the incidence of the main outcome was 28% for the aspirin group and 19% for the aspirin-plus-anticoagulation group (P=0.09).
A meta-analysis of published data from 6 small
randomized trials (n=1353 subjects), including the 3 described above,
reported a risk reduction of 33% (95% confidence interval [CI]
-2% to 56%) in cardiovascular death and MI with the
combination of UFH and aspirin, which was of borderline significance
(Figure 7).130
|
Acute MI
Information on the benefit of heparin in patients with
acute MI not given thrombolytic therapy is limited to
those who were not treated with aspirin either, so the results may not
be applicable to current clinical practice. An overview of randomized
clinical trials performed before the reperfusion era reported a 17%
reduction in mortality and a 22% reduction in reinfarction in patients
assigned heparin.140 The
control groups in these trials were not treated with aspirin, which is
now considered routine.
The effect of heparin on the incidence of mural thrombosis has been evaluated in 2 randomized trials.141 142 One compared heparin in a fixed dose of 12 500 U SC every 12 hours with an untreated control group, and the other used low-dose heparin (5000 U SC every 12 hours) for comparison. In both studies, moderate-dose heparin (12 500 U SC every 12 hours) reduced the incidence of mural thrombosis detected by 2-dimensional echocardiography by 72% and 58%, respectively (P<0.05 for each study).
Coronary
Thrombolysis
Although in the past it was generally accepted that
heparin was effective after coronary
thrombolysis, the results of recent studies cast doubt
on this view. In 3 studies that used angiographic patency as a usually
surrogate end point, the combination of heparin and aspirin was not
compared with aspirin alone. Topol et
al143 reported that a
single IV bolus of 10 000 U of heparin did not improve
coronary artery patency at 90 minutes. In another trial, in
which heparin alone was compared with no
treatment,144 patency of
the infarct-related artery at 2 days was 71% in the heparin group and
44% in the control group
(P<0.023). In the
Heparin-Aspirin Reperfusion
Trial,145 coronary
artery patency at 18 hours was 82% in patients treated with heparin
and 52% in a group given aspirin 80 mg/d
(P<0.0002). The conclusion
that heparin is more effective than aspirin in maintaining patency has
been criticized because the aspirin dose was too low to completely
suppress platelet thromboxane A2
production. The results were less impressive when the
combination of heparin and aspirin was compared with aspirin in a dose
of 325 mg/d. In the sixth European Cooperative Study Group (ECSG-6)
trial,77 687 patients
receiving aspirin were randomized to heparin or no heparin. Patency at
a mean of 81 hours was 80% in the heparin group and 75% in the
comparison group (P<0.01). In
the Australian National Heart Study
Trial,146 202 patients
received heparin for 24 hours before randomization to either continuous
IV heparin or a combination of aspirin (300 mg/d) and
dipyridamole (300 mg/d). Patency after 1 week was 80%
in both groups. Col et
al147 treated 128 patients
with streptokinase and aspirin and randomized the patients to either an
IV bolus of heparin or no heparin; the study reported no difference in
coronary patency at 24 hours (86% versus
87%).147 The DUCCS-1 (Duke
University Clinical Cardiology Studies) investigators
treated 250 patients with anisoylated
plasminogen–streptokinase activator complex
(APSAC) and aspirin and randomized patients to heparin or no heparin.
There was a small difference in coronary artery patency (80%
in the heparin group versus 74% in the control
group).148
Two large trials, the International Study Group149 and the ISIS-3150 (International Study of Infarct Survival) studies, assessed the value of adjunctive heparin in patients receiving thrombolytic therapy and aspirin. In both, heparin was given (12 500 U SC every 12 hours). In the International Study Group trial, heparin was begun 12 hours after randomization to fibrinolytic therapy; in the ISIS-3 trial, heparin began 4 hours after randomization.
The International Study Group study149 of 20 891 patients reported no difference in mortality between the heparin (8.5%) and no-heparin (8.9%) groups, whereas the risk of major bleeding was significantly increased by 0.5% in the heparin-treated group. The ISIS-3 study150 of 41 299 patients reported a vascular mortality rate of 10.3% in the heparin group and 10.0% in the no-heparin control group at 35 days. During the 7-day treatment period, mortality was 7.4% in the heparin group and 7.9% in the control group (P=0.06). In-hospital rates of reinfarction with heparin were 3.2% compared with 3.5% in the no-heparin group (P=0.09); stroke rates were not different. Major bleeding requiring transfusion was slightly more frequent in the heparin group (1.0% versus 0.8%, P<0.01).
In both studies, moderate doses of heparin produced marginal benefits at the cost of increased bleeding. The issue of whether IV heparin would prove more effective and at least as safe as the SC regimen used in the ISIS-3 study was addressed in the GUSTO trial,151 in which patients receiving streptokinase were given either a high-dose heparin regimen (5000 U initial IV bolus, followed by an infusion of 1000 to 1200 U/h to maintain aPTT at 60 to 85 seconds) or the delayed SC heparin regimen used in the ISIS-3 trial. IV heparin was not superior to SC heparin among patients receiving streptokinase either in terms of mortality, reinfarction, major hemorrhage, cerebral hemorrhage, infarct-related artery patency, or arterial reocclusion.
In a much smaller study, O’Connor et
al152 randomized 250
patients who had received APSAC to either aspirin alone or aspirin plus
weight-adjusted IV heparin beginning 4 hours after APSAC infusion.
There were no differences in ischemic outcomes, but bleeding
was significantly greater with heparin (32% versus 17.2%;
P=0.006). From a
meta-analysis composed largely of the International Study Group
and ISIS-3 studies, Collins and
associates133 reported that
in the presence of aspirin, heparin produced a relative risk reduction
of mortality of only 6% (95% CI 0% to 10%;
P=0.03),
representing just 5 fewer deaths per 1000 patients treated
(Table 8). There were 3 fewer reinfarctions per 1000
(P=0.04) and 1 fewer PE per
1000 patients (P=0.01). This
small beneficial effect was associated with an insignificant excess
incidence of stroke but a definite excess of 3 major bleeding incidents
per 1000 patients (P<0.0001).
In trials using high-dose heparin, there was an 2-fold increase in
the absolute risk of major extracranial bleeding (31 per 1322 [2.3%]
versus 14 per 1321 [1.1%];
P=0.01).153
|
Data on the role of adjunctive heparin in patients treated with tissue plasminogen activator are limited. From contemporary studies, Kruse and associates154 concluded that the role of heparin as adjunctive treatment to accelerated tissue plasminogen activator is still an open issue. A pooled analysis by Mahaffey et al155 of 6 randomized trials exposed a trend toward reduced in-hospital mortality with heparin (9% reduction; OR 0.91, 95% CI 0.59 to 1.39) but a significantly higher rate of hemorrhagic complications when adjunctive heparin was used in tissue plasminogen activator–treated patients.156
Recommendations for use of heparin in patients with acute MI are provided in the American College of Cardiology/American Heart Association guidelines.87 156 The intensity of the suggested heparin regimen is influenced by whether thrombolytic therapy is given, the type of thrombolytic agent used, and the presence or absence of risk factors for systemic embolism.
Coronary Angioplasty
Percutaneous transluminal
coronary angioplasty can be complicated by early thrombotic
occlusion in the instrumented artery. It is standard practice to give
heparin, commencing with either an IV bolus of 10 000 U with repeated
smaller bolus injections as required or as a weight-adjusted-dose
regimen of 100 to 175 U/kg followed by 10 to 15 U/kg per hour. The dose
is adjusted to maintain the activated clotting time (ACT)
greater than 300 to 350 seconds, because there is some evidence that
the complication rate is higher with lower ACT
values.157 When these
high-dose regimens are used in combination with abciximab and aspirin,
however, heparin increases the risk of major
bleeding.77 78
The risk can be reduced without compromising efficacy by lowering the
bolus dose of heparin to 70 U/kg and giving bolus doses as needed to
achieve an ACT of >200 seconds and by removing arterial
sheaths when the ACT falls below 150 to 180
seconds.78 After
coronary angioplasty, postprocedural heparin infusions are not
needed for most patients who are treated with a combination of aspirin
and ticlopidine.
A beneficial role for heparin has not been established when unstable angina develops within the first 6 months after coronary angioplasty. In a recent randomized trial, 200 patients who had undergone angioplasty without intracoronary stenting were randomized to IV nitroglycerin, heparin, the combination of both agents, or placebo for 63±30 hours. Recurrent angina developed in 75% of patients in the placebo and heparin-alone groups compared with 42.6% of patients in the nitroglycerin-alone group and 42% of patients in the nitroglycerin-plus-heparin group (P<0.003). Refractory angina occurred in 23%, 29%, 4%, and 4% of patients, respectively (P<0.002). The OR for being event free was 0.98 (95% CI -0.55 to 1.73, P=NS) for heparin versus no heparin in this study.158
Atrial Fibrillation
The role of heparin for prevention of ischemic
stroke and systemic embolism in high-risk patients with
nonvalvular AF has been less thoroughly investigated than oral
anticoagulation with warfarin. It is likely that heparin
represents an effective alternative to warfarin for
antithrombotic prophylaxis, because both anticoagulants decrease
hemostatic activation associated with atrial stasis in patients with
this cardiac rhythm
disturbance.159
Heparin is sometimes given as an alternative to oral anticoagulation
perioperatively in patients with chronic AF who are
undergoing elective surgery, but no consensus has emerged regarding
when and how to substitute heparin in this
situation.160
Patients with AF who have sustained recent cerebral
ischemic events are among those at highest risk of
thromboembolism (12% per year). Oral anticoagulation reduces the
risk by two thirds, similar to the benefit achieved in primary
prevention. When oral anticoagulation is contraindicated, aspirin is a
much less effective
alternative.161 How rapidly
and intensively to initiate anticoagulation after a cerebral
ischemic event is controversial, however, considering that
hemorrhagic transformation might worsen the neurological
deficit.162 163
In a study of 231 patients with nonvalvular AF and acute stroke, heparin was administered IV or SC in doses adjusted to an aPTT 1.5 to 2.0 times control values.164 Delay before the initiation of heparin therapy was <6 hours from the onset of symptoms in 74 patients and 6 to 48 hours in 157 patients. In-hospital mortality was 9%, hemorrhagic worsening occurred in 3% of patients, and stroke recurred early in 2% of patients. Neurological recovery was associated with age younger than 70 years (OR 0.2), normal baseline computed tomography (CT)-scan findings (OR 8.9), and early heparin treatment (OR 1.7, 95% CI 1.1 to 2.5), even though targeted aPTT ratios were achieved at 24 hours in fewer than 50% of patients. Stroke recurrence was associated with lower mean aPTT ratios, but higher ratios were observed in patients with symptomatic bleeding, especially on the day bleeding occurred. Neither age, initial stroke severity, blood pressure, or baseline CT findings predicted hemorrhagic worsening. Functional recovery was improved sooner when heparin was administered early, but close monitoring of aPTT was necessary to lessen the risk of hemorrhagic complications.
Hemorrhagic transformation after acute ischemic stroke is compounded by thrombolytic therapy, but the impact of heparin can only be inferred. The Multicenter Acute Stroke Trial-Europe (MAST-E) study165 evaluated the safety and efficacy of streptokinase administered IV within 6 hours of stroke onset. Among 310 patients, 159 (51%) had evidence of hemorrhagic transformation on CT scan, but only 23% of these were symptomatic. The relative risk of hemorrhagic transformation after streptokinase in this trial was in the same range as in other trials of thrombolytic therapy for acute stroke. Multivariate secondary analysis found that patients with symptomatic hemorrhagic transformation were more likely to have AF and less likely to have received heparin treatment.165
To minimize the risk of thromboembolism after electrical cardioversion of AF or flutter, therapeutic anticoagulation should be established for at least 3 weeks before and for 4 weeks after cardioversion when the dysrhythmia has persisted longer than 2 days or when the duration is unknown. Warfarin is usually used during the outpatient phase.166 167 A more recent approach uses transesophageal echocardiography to demonstrate the absence of thrombi in the left atrium and left atrial appendage. If no thrombus is evident, heparin anticoagulation may be initiated before pharmacological or electrical cardioversion, followed by warfarin therapy for 1 month after cardioversion. This treatment algorithm has a safety profile similar to that of conventional therapy and minimizes both the period of anticoagulation and the duration of AF before cardioversion, but no outcome superiority has been established.168
A similar rationale underlies the use of heparin in conjunction with radiofrequency catheter ablation of cardiac tachyarrhythmias. A review of the literature over the last 10 years found an overall incidence of reported thromboembolic complications of 0.6% associated with radiofrequency catheter ablation. The risk is increased (to 1.8% to 2%) when ablation is performed in the left heart, but this increase is less than when the indication is ventricular tachycardia (2.8%).169 For the ablation of AF, creation of extensive left atrial lesions has been associated with a high rate of thromboembolic stroke, despite administration of IV heparin and modulated electromagnetic energy. Adjuvant platelet inhibitor therapy to reduce the risk of thromboembolism in this specialized situation is under investigation.170
|
Heparin-Induced Thrombocytopenia |
|---|
HIT is an antibody-mediated adverse reaction to heparin that can result in venous or arterial thrombosis. Diagnosis of HIT is based on both clinical and serological features.171 172 Manifestations of the HIT syndrome include an otherwise unexplained fall in platelet count
50%, even if the nadir remains above
150x109/L, or skin lesions at heparin
injection
sites173 174
accompanied by HIT antibody formation. The fall in platelet count
almost always occurs between day 5 and day 15 after introduction of
heparin but can develop earlier in patients exposed to heparin during
the previous 3 months. The frequency of HIT varies in different
clinical
settings175 176
such that the risk of venous thrombosis from HIT is higher in high-risk
surgical patients175 than
in medical
patients.176
The HIT antigen is a multimolecular complex between PF4 and
heparin.91 92 177 178 179
HIT antibodies bind to regions of the PF4 molecule that have been
conformationally modified by its interaction with heparin. The
increased propensity to thrombosis in HIT is probably mediated by
thrombin generated as a result of in vivo platelet
activation,180 181
as a consequence of interaction between heparin/PF4/IgG immune
complexes with Fc receptors on
platelets.182 A minimum
of 12 to 14 saccharides are required to form the antigenic
complex with
PF4,178 179 so
heparin molecules with a molecular weight greater than 4000 Da have
the potential to cause HIT, and HIT occurs less commonly with LMWH than
with
UFH.183 184
Diagnosis
Two main classes of laboratory assays have been
developed to detect HIT
antibodies,185 186
activation assays and antigen assays. The use of washed platelets
rather than platelet-rich plasma derived from normal donors
increases the reliability of activation assays. Of the various
activation assays available, those that use washed platelets and
platelet serotonin
release187 or
heparin-induced platelet
activation188 189
are most accurate.173
Antigen assays, now commercially available, that are based on detecting
antibodies against PF4 bound to
heparin188 or
polyvinylsulfonate190
respond to clinically insignificant antibodies more often than do
activation
assays.175</