(Chest. 2001;119:8S-21S.)
© 2001
American College of Chest Physicians
Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range
Jack Hirsh, MD, FCCP, Chair;
James E. Dalen, MD, Master FCCP;
David R. Anderson, MD;
Leon Poller, MD;
Henry Bussey, PharmD;
Jack Ansell, MD and
Daniel Deykin, MD
Correspondence to: Jack Hirsh, MD, FCCP, Director, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, Ontario L8V 1C3, Canada
 |
Introduction
|
|---|
The
optimal therapeutic range for oral anticoagulant therapy was reviewed
by the Committee on Antithrombotic Therapy of the American College of
Chest Physicians and the National Heart, Lung, and Blood Institute in
1986, 1989, 1992, 1995, and again in 1998. The validity of the
recommendation made at the earlier conferences, that the intensity of
warfarin treatment should be reduced for many indications, continues to
be upheld. Thus, whenever a more intense international normalized ratio
(INR) is compared directly in a randomized trial, with an INR of 2.0 to
3.0, the less intense INR is as effective and safer. The
recommendations for the optimal therapeutic range for the various
indications remains unchanged (Table 1
).
A recommendation of an INR of 2.0 to 3.0 is made for most indications.
The exceptions are some types of mechanical prosthetic heart valves
(see chapter on Antithrombotic Therapy in Patients With Mechanical and
Biological Prosthetic Heart Valves). In addition, certain patients with
thrombosis and the antiphospholipid syndrome may require a higher
targeted INR than 2.0 to 3.0. Results of studies in atrial
fibrillation (AF) support the earlier findings that the effectiveness
of warfarin is reduced when the INR falls to < 2.0 and is essentially
lost when the INR falls to < 1.5.145
145a
The Coumadin
Aspirin Reinfarction Study (CARS)144
and recently
reported CHAMP (combined hemotherapy and
mortalitly prevention) study144a
also showed that the addition of low-dose warfarin (mean INR 1.3 and
1.9, respectively) did not improve the efficacy of aspirin in the
secondary prevention of acute myocardial infarction (AMI). In contrast,
the Thrombosis Prevention Trial,119
a primary
prevention study in men free of ischemic heart disease at entry,
reported that warfarin is effective in reducing myocardial ischemic
events (including fatal events) when used at a targeted INR of 1.3 to
1.8 (mean warfarin dose of 4.1 mg). The addition of low-dose aspirin to
warfarin therapy resulted in a further small benefit but at a risk of
increased bleeding.
In summary, the results of studies (1) do not support the use of
fixed low-dose warfarin therapy for the treatment of patients with AMI
or AF144
145
; (2) indicate that the effectiveness of
warfarin is reduced when the INR is < 2.0144
145
145a
;
(3) indicate that adjusted-dose warfarin therapy produces some benefit
at an INR of 1.3 to 2.0 when used for primary prevention, and that an
INR of > 1.5 confers some benefit in patients with AF, although the
benefit is clearly less than that which occurs with an INR of
> 2.0145a
; and (4) two studies evaluating the
long-term treatment of deep vein thrombosis (DVT) reported that
recurrences are prevented completely at an INR of 2.0 to
3.0137
138
; the small number of events in the warfarin
group occurred when the patients discontinued treatment. These findings
suggest that it might be possible to lower the INR range to < 2.0, a
hypothesis that is being tested in a number of randomized trials.
|
Mechanism of Action of Coumarin Anticoagulant Drugs
|
|---|
Coumarins are vitamin K antagonists that produce their
anticoagulant effect by interfering with the cyclic interconversion of
vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a
cofactor for the posttranslational carboxylation of glutamate residues
to 
-carboxyglutamates on the N-terminal regions of vitamin
K-dependent proteins (Fig 1
).1
2
3
4
5
6
These coagulation factors (factors II, VII, IX, and
X) require -carboxylation for their biological activity. Coumarins
produce their anticoagulant effect by inhibiting the vitamin K
conversion cycle, thereby causing hepatic production of partially
carboxylated and decarboxylated proteins with reduced procoagulant
activity.7
8
In addition to their anticoagulant effect,
the vitamin K antagonists inhibit carboxylation of the regulatory
anticoagulant proteins C and S and therefore have the potential to
exert a procoagulant effect.
In the presence of calcium ions, carboxylation causes a conformational
change in coagulation proteins9
10
11
that promotes binding
to cofactors on phospholipid surfaces. The carboxylation reaction
requires the reduced form of vitamin K (vitamin
KH2), molecular oxygen, and carbon dioxide, and
is linked to the oxidation of vitamin KH2 to
vitamin K epoxide. Vitamin K epoxide is then recycled to vitamin
KH2 through two reductase steps. The first, which
is sensitive to vitamin K antagonists,1
2
3
reduces vitamin
K epoxide to vitamin K1 (the natural food form of vitamin
K1), while the second, which is relatively insensitive to
vitamin K antagonists, reduces vitamin K1 to vitamin
KH2. Treatment with vitamin K antagonists leads
to the depletion of vitamin KH2, thereby limiting
the -carboxylation of the vitamin K-dependent coagulant proteins.
The effect of coumarins can be counteracted by vitamin K1
(either ingested in food or administered therapeutically) because the
second reductase step is relatively insensitive to vitamin K
antagonists (Fig 1)
. Patients treated with a large dose of vitamin
K1 can also become warfarin resistant for up to a
week because vitamin K1 accumulates in the liver
and is available to the coumarin-insensitive reductase.
Warfarin also interferes with the carboxylation of -carboxyglutamate
proteins synthesized in bone.12
13
14
15
Although these effects
contribute to fetal bone abnormalities in mothers treated with warfarin
during pregnancy,16
17
there is no evidence that warfarin
affects bone metabolism when administered to children or
adults.18
|
Pharmacokinetics and Pharmacodynamics of Warfarin
|
|---|
Warfarin is a racemic mixture of two optically active isomers, the
R and S forms in roughly equal proportion. It has high
bioavailability,19
20
is rapidly absorbed from the GI
tract, and reaches maximal blood concentrations in healthy volunteers
in 90 min after oral administration.19
21
Racemic warfarin
has a half-life of 36 to 42 h, circulates bound to plasma proteins
(mainly albumin), and accumulates in the liver where the two isomers
are metabolically transformed by different pathways.22
The
dose-response relationship of warfarin is influenced by genetic and
environmental factors, including a recently identified common mutation
in the gene coding for one of the common cytochrome P450 enzymes (2C9),
the hepatic enzyme responsible for oxidative metabolism of the warfarin
S-isomer.23
24
This mutation likely contributes to the
variability in dose response to warfarin among healthy
subjects.25
In addition to known and unknown genetic
factors, various disease states, drugs, and dietary factors can
interfere with the response to warfarin.
The anticoagulant response to warfarin is influenced by pharmacokinetic
factors, including drug interactions that affect the absorption or
metabolic clearance of warfarin, and pharmacodynamic factors that alter
the hemostatic response to given concentrations of the drug.
Variability in anticoagulant response also occurs as a result of
inaccuracies in laboratory testing, patient noncompliance, and
miscommunication between patient and physician. Other drugs may
influence the pharmacokinetics of warfarin by reducing GI absorption or
by disrupting its metabolic clearance. For example, the anticoagulant
effect of warfarin is reduced by cholestyramine, which impairs its
absorption, and is potentiated by drugs that inhibit warfarin clearance
through stereoselective or nonselective pathways.25
26
27
Stereoselective interactions affect oxidative metabolism of either the
S-isoner or R-isomer of warfarin.26
27
Inhibition of
S-warfarin metabolism is more important clinically because this isomer
is five times more potent as a vitamin K antagonist than the
R-isomer.26
27
Clearance of S-isomer warfarin is inhibited
by phenylbutazone,28
29
sulfinpyrazone,30
metronidazole,31
and
trimethoprim- sulfamethoxazole,32
each of which
potentiates the effect of warfarin on the prothrombin time (PT). In
contrast, drugs such as cimetidine and omeprazole that inhibit
clearance of the R-isomer have only moderate potentiating effects on
the PT in patients treated with warfarin.27
28
33
Amiodarone inhibits the metabolic clearance of both the S-isomer and
R-isomer and potentiates the anticoagulant effect of
warfarin.34
The anticoagulant effect is inhibited by
barbiturates,32
rifampicin,34
and
carbamazepine,32
which increase its metabolic clearance by
inducing hepatic mixed oxidase activity. Although long-term alcohol use
has a potential to increase the clearance of warfarin through a similar
mechanism, consumption of even relatively large amounts of wine was
shown in one study29
to have little influence on PT in
subjects treated with warfarin. For a more thorough discussion of the
effect of enzyme induction on warfarin therapy, the reader is referred
to a critical review (Table 2 ).35
The pharmacodynamics of warfarin are subject to genetic and
environmental variability. Hereditary resistance to warfarin occurs in
rats36
as well as in human beings.37
38
Patients with genetic warfarin resistance require doses fivefold to
20-fold higher than average to achieve an anticoagulant effect. This
disorder is attributed to altered affinity of the receptor for warfarin
since the plasma warfarin levels required to achieve an anticoagulant
effect are increased.
Two mis-sense mutations in the factor IX propeptide have been
described39
40
41
that cause bleeding without excessive
prolongation of PT. When affected individuals are treated with coumarin
drugs, factor IX activity decreases to about 1 to 3%, while levels of
other vitamin K-dependent coagulation factors decrease to 30 to 40% of
normal. These mutations are uncommon and have been estimated to occur
in < 1.5% of the population. A plausible mechanism for the selective
increase in coumarin sensitivity of the mutant factor IX proposed by
Chu et al39
reconciles the following observations: (1)
normal factor IX activity in the absence of coumarin despite reduced
binding of the variant propeptide to -carboxylase, and (2) marked
suppression of factor IX activity by coumarin despite only modest
suppression of the other three vitamin K-dependent coagulation factors.
Subjects receiving long-term warfarin therapy are sensitive to
fluctuating levels of dietary vitamin K,42
43
which is
provided predominantly by phylloquinone in plant
material.43
The phylloquinone content of a wide range of
foodstuffs has been listed by Sadowski and associates.44
Phylloquinone acts through the warfarin-insensitive reductase
reaction.45
Important fluctuations in vitamin K intake
occur in both apparently healthy and sick subjects.46
Increased intake of dietary vitamin K sufficient to reduce the
anticoagulant response to warfarin42
occurs in patients on
weight-reduction diets consuming green vegetables or receiving vitamin
K-containing supplements, and in patients treated with IV supplements
containing vitamin K. Reduced dietary vitamin K1
intake potentiates the effect of warfarin in sick patients treated with
antibiotics and IV fluids without vitamin K supplementation and in
states of fat malabsorption. Hepatic dysfunction potentiates the
response to warfarin through impaired synthesis of coagulation factors.
Hypermetabolic states produced by fever or hyperthyroidism increase
warfarin responsiveness, probably by increasing the catabolism of
vitamin K-dependent coagulation factors.47
48
Drugs may
influence the pharmacodynamics of warfarin by inhibiting synthesis or
increasing clearance of vitamin K-dependent coagulation factors or by
interfering with other pathways of hemostasis (Table 3
). The anticoagulant effect of warfarin is augmented by the
second-generation and third-generation cephalosporins, which inhibit
the cyclic interconversion of vitamin K,49
50
by
thyroxine, which increases the metabolism of coagulation
factors,48
and by clofibrate, through an unknown
mechanism.51
Doses52
53
of salicylates
> 1.5 g/d also augment the anticoagulant effect of
warfarin,54
possibly because these drugs have
warfarin-like activity. Acetaminophen has also been reported to augment
the anticoagulant effect of warfarin,52
although this
contention has been challenged (see below). Although heparin
potentiates the anticoagulant effect of warfarin, in therapeutic doses,
it produces only slight prolongation of the PT.
Drugs such as aspirin,55
nonsteroidal
anti-inflammatory drugs,56
high doses of
penicillins,57
58
and moxolactam50
increase
the risk of warfarin-associated bleeding by inhibiting platelet
function. Of these, aspirin is the most important because of its
widespread use and prolonged effect.59
Aspirin and
nonsteroidal anti-inflammatory drugs can also produce gastric erosions
that increase the risk of upper-GI bleeding.58
The risk of
clinically important bleeding is heightened when high doses of aspirin
are taken in combination with high-intensity warfarin therapy (INR, 3.0
to 4.5).55
60
In two studies, one study61
in
patients with prosthetic heart valves and the other
study62
in asymptomatic individuals at high risk of
coronary artery disease, low doses of aspirin (100 mg/d and 75 mg/d,
respectively) were also associated with increased rates of minor
bleeding when combined with moderate-intensity and low-intensity
warfarin anticoagulation.
The mechanisms by which erythromycin63
and some anabolic
steroids64
potentiate the anticoagulant effect of warfarin
are unknown. Sulfonamides and several broad-spectrum antibiotic
compounds may augment the anticoagulant effect of warfarin by
eliminating bacterial flora and aggravating vitamin K deficiency in
patients whose diet is deficient of vitamin K.65
Wells and associates66
performed a critical analysis of
articles reporting possible interaction between drugs or foods and
warfarin. Studies were assigned to one category if the interaction was
considered highly probable, to a second category if interaction was
probable, to a third level if judged possible, and to a fourth level if
doubtful. Of 751 citations retrieved, pertinent results from 172
original articles are summarized in Table 3
. Strong evidence of
interaction was found for 39 of the 81 different drugs and foods
appraised; 17 potentiate warfarin effect, 10 inhibit, and 12 produce no
effect. Many other drugs have been reported to either interact with
oral anticoagulants or alter the PT response to
warfarin,67
68
but convincing evidence of a causal
association is lacking. In a case-control study,52
low to
moderate doses of acetaminophen (nine or more tablets per week) were
reported to be associated with excessively prolonged INR values. The
presence of a causal association between acetaminophen use and
potentiation of a warfarin effect is uncertain. The
article52
was supported by an editorial,53
but has been challenged by personal experiences (case series) cited in
two letters69
70
and by the results of a prospective
study71
in normal volunteers. However, until more
information is presented, it would be prudent to monitor the INR more
frequently when acetaminophen is used in this quantity by patients
during warfarin therapy. Indeed, it would be reasonable to monitor the
PT more frequently when any drug therapy is added or withdrawn from the
regimen of a patient treated with an oral anticoagulant.
|
The Antithrombotic Effect of Warfarin
|
|---|
The antithrombotic effect of warfarin is conventionally viewed as
being a consequence of the reduction of all four vitamin K-dependent
coagulation factors. However, there is evidence that the anticoagulant
effect and the antithrombotic effect of warfarin is dissociated during
the induction phase of treatment. Using a stasis model of thrombosis in
rabbits, Wessler and Gitel72
reported that the
antithrombotic effect of warfarin requires 6 days of treatment, whereas
an anticoagulant effect was observed after 2 days. This finding
suggests that during the induction phase of warfarin treatment, the
reduction of clotting factor(s) responsible for prolonging the PT in
the first 2 days are less important for the antithrombotic effect of
warfarin than those that are reduced after 4 days or 5 days. More
recent evidence supports this notion and suggests that reduction
of prothrombin (a zymogen with a relatively long half-life of about
96 h) is more important for the antithrombotic effect of warfarin
than reduction of factors VII and IX zymogens with half-lives of 6 to
24 h, respectively.73
Thus, experiments in a rabbit
model of tissue factor-induced intravascular coagulation73
demonstrated that the protective effect of warfarin was overcome with
the infusion of factor II, and to a lesser extent factor X, while
infusion of factors VII or IX had no effect. Support for the importance
of reduction of prothrombin (factor II) for the antithrombotic effect
of warfarin also comes from the studies of Patel and
associates.74
Using fibrinopeptide A as an index of
clot-associated thrombin activity, they demonstrated that clots formed
from plasma with reduced prothrombin concentrations generated
significantly less fibrinopeptide A than clots formed in the presence
of normal concentrations of prothrombin, presumably because reduction
in prothrombin levels decreases the amount of thrombin generated and
bound to fibrin, thereby reducing the thrombogenicity of the
clot.74
75
The concept that the antithrombotic effect of warfarin reflects its
ability to lower prothrombin levels is important clinically. This is
the basis for overlapping heparin with warfarin during treatment of
patients with thrombosis, until the PT INR has been prolonged into the
therapeutic range for at least 4 days. Further, the levels of native
prothrombin antigen during warfarin therapy have been reported to more
closely reflect antithrombotic activity than the PT.76
These considerations also support the use of a maintenance dose of
warfarin (approximately 5 mg), rather than a loading dose, during
initiation of therapy, since the rate of reduction of prothrombin
levels is similar with either a 5-mg or a 10-mg initial warfarin
dose.77
In contrast, the anticoagulant protein C is
reduced more rapidly and more patients have excessive anticoagulation
(INR > 3.0) with the 10-mg loading dose.
|
Monitoring Oral Anticoagulant Therapy
|
|---|
The PT test is the most common method for monitoring oral
anticoagulant therapy.78
The PT responds to reduction of
three of the four vitamin K-dependent procoagulant clotting factors
(II, VII, and X). During the first few days of warfarin therapy, the
prolongation of the PT reflects mainly a reduction of factor VII, while
subsequently it also reflects a reduction of factors X and II. The PT
assay is performed by adding calcium and thromboplastin to citrated
plasma. The term thromboplastin traditionally refers to a
phospholipid-protein extract of tissue, usually lung, brain, or
placenta, containing both the tissue factor and phospholipid necessary
to promote the activation of factor X by factor VII. Thromboplastins
vary in their responsiveness to the anticoagulant effects of warfarin,
depending on their source, phospholipid content, and
preparation.79
80
81
82
The responsiveness of a given
thromboplastin to warfarin-induced changes in clotting factors reflects
the intensity of activation of factor X by the factor VIIa/tissue
factor complex. An unresponsive thromboplastin produces less
prolongation of the PT for a given reduction in vitamin K-dependent
clotting factors than a responsive thromboplastin. The responsiveness
of a thromboplastin can be measured by assessing its International
Sensitivity Index (ISI; see below). Highly sensitive thromboplastins
(ISI approximately 1.0) composed of human tissue factor and defined
phospholipid preparations are now available.
In the past, PT monitoring of warfarin treatment was imprecise because
the PT was expressed in seconds or as a simple ratio of the patient
over the normal control value. During the 1980s, most laboratories in
the United States used insensitive thromboplastins with ISI values
between 1.8 and 2.8, while many in Europe used more responsive reagents
with ISI values of 1.0 to 1.4. Difference in thromboplastin
responsiveness was the main reason for clinically important differences
in oral anticoagulant dosing in different countries shown by Poller and
Taberner.82
Recognition of the clinical importance of
these differences led to the wide adoption of the INR standard for
monitoring oral anticoagulant therapy.
The history of standardization of the PT has been reviewed by
Poller80
and by Kirkwood.83
In 1992, the ISI
of thromboplastins used in the United States varied between 1.4 and
2.8.84
Subsequently, more responsive thromboplastins with
lower ISI values came into use in the United States and Canada. The
recombinant human preparations consisting of relipidated synthetic
tissue factor, for example, have ISI values of 0.9 to
1.0.85
The World Health Organization (WHO) designated a
batch of human brain thromboplastin as the first International
Reference Preparation (IRP) for thromboplastin in
1977.80
83
Subsequently, this first IRP was replaced with
primary- and secondary-reference thromboplastins. Calibration was based
on a linear relationship between the logarithm of the PT measured by
the reference and test thromboplastin reagents.80
83
86
This calibration model, adopted in 1982, is now used to standardize
reporting by converting the PT ratio measured with the local
thromboplastin into an INR, calculated as follows:
 |
or
 |
where ISI denotes the ISI of the thromboplastin used to perform
the PT measurement at the local laboratory. The ISI reflects the
responsiveness of a given thromboplastin to reduction of the vitamin
K-dependent coagulation factors compared to the primary WHO IRP; the
more responsive the reagent, the lower the ISI value. Viewed another
way, the INR is the PT ratio that would be obtained if the WHO IRP had
been used to perform the PT test on the same sample with the manual PT
technique.80
83
An up-to-date classification of the current thromboplastin IRP and
details of their application in ISI calibration have been described in
the recent revision of the WHO guidelines.87
Recommended
procedures for ISI calibration of reference and commercial batches of
thromboplastin are provided.
The revised WHO guidelines87
describe three levels of ISI
calibration. The most accurate is the international multicentre
calibration of thromboplastin IRP by at least 10 centers against the
three species of WHO IRP (human, rabbit, and bovine). The ISI assigned
is the mean of these, as the three different routes of calibration give
different INRs. The second is the calibration of secondary standards
against the relevant species of IRP by at least two laboratories. The
third level, where the least precision is needed, is
calibration of individual reagents and batch-to-batch testing by a
manufacturer. For this step, pooled coumarin or artificially depleted
plasmas are also allowed. With each successive step, there is a serial
error so that the chain of calibrant reagents should be as short as
possible.
Most commercial manufacturers now provide ISI values for thromboplastin
reagents, and the INR standard has been widely adopted by hospitals in
North America. Recently, thromboplastins with recombinant tissue factor
have been introduced with ISI values close to 1.0 that yield PT ratios
virtually equivalent to the INR. According to the College of American
Pathologists Comprehensive Coagulation Survey, implementation of the
INR standard in the United States increased between 1991 and 1997 from
21 to 97%.88
Although the adoption of the INR standard of
reporting has markedly increased the reliability of warfarin
monitoring, the system is not perfect. Problems identified with the INR
system are listed in Table 4
. They were discussed in detail in the last supplement, and the most
clinically relevant are reviewed below.
The INR is based on ISI values derived from plasma of patients
receiving stable doses of anticoagulant for at least 6
weeks.89
As a result, the INR is less reliable early in
the course of warfarin therapy, particularly when results are obtained
from different laboratories. Even under these conditions, however, the
INR is more reliable than the unconverted PT ratio90
and
is thus recommended during both initiation and maintenance of warfarin
treatment. Although its accuracy in patients with liver disease has
been questioned, the reliability of the INR exceeds alternatives such
as the PT ratio or the PT itself and is valid in this situation as
well.91
Although, from a theoretic viewpoint, the precision of the INR could be
improved by using reagents with low ISI values, laboratory proficiency
studies indicate that this produces only modest improvement in
precision,88
92
93
94
but use of reagents with higher ISI
values results in higher coefficients of interlaboratory variation for
the INR measurement.95
96
The precision of INR measurement
is also influenced by instrumentation. The INR is based on a
mathematical relationship between the PT ratio obtained with test
thromboplastin and the IRP using a manual method of clot detection.
Thus the automated clot detectors now used in most laboratories
introduces another variable that affects the accuracy of the
INR.97
98
99
100
101
102
A system ISI for an instrument/thromboplastin
combination may reduce the error but is not dependable. Variability of
ISI determination is reduced by calibrating the instrument with
lyophilized plasma depleted of vitamin K-dependent clotting
factors.96
103
104
Based on these observations, the
College of American Pathologists has recommended that laboratories use
reagent/instrument combinations for which the ISI has been
established.105
For reliable INR, local ISI calibration is
required. As conventional WHO-type ISI calibration is not usually
feasible at local centers due to the requirement for parallel PT
testing and the need for a thromboplastin IRP, a simpler method of ISI
determination is required. The use of certified lyophilized plasmas
with manual PT values with the thromboplastin IRP to derive ISI has
been shown to give good correction for coagulometer effects in several
recent national and international field studies. Some such procedure
for verifying local INR is also desirable in clinical trials of
anticoagulation to validate the stated values.
The mean normal plasma PT is not interchangeable with a laboratory
control PT.106
The mean normal PT is determined with fresh
plasma samples from at least 20 healthy individuals of both genders
over a range of ages and should be checked with each new batch of
thromboplastin with the same instrument used to assay the
PT.106
Several investigators have noted incorrect ISI
values provided by manufacturers of thromboplastin
reagents.107
108
109
Although local calibrations can be
performed with plasma samples with certified PT values to determine the
instrument-specific ISI, the process is tedious and beyond the scope of
many laboratories.
A simple ISI calibration procedure using lyophilized plasma calibrants
with certified manual PT with reference IRP has been
developed,96
110
111
112
and one type recently has received
US Food and Drug Administration approval as showing substantial
equivalence to the WHO method. The ISI calculation has also been
simplified by the use of a computer calibration disk available at token
cost from the Health Technology Unit, WHO 1211, Geneva 27, Switzerland.
The lupus anticoagulants prolong the activated partial
thromboplastin time, but usually cause only slight prolongation of the
PT depending on the reagent.113
114
The optimum method for
monitoring anticoagulation in patients with lupus anticoagulants is
uncertain, but the prothrombin and proconvertin
tests115
116
and measurements of prothrombin activity or
native prothrombin concentration have been
proposed.76
113
117
118
Clinical Applications of Oral Anticoagulant Therapy
The clinical effectiveness of oral anticoagulants has been
established in a variety of conditions, based on well-designed clinical
trials. Oral anticoagulants are effective for primary and secondary
prevention of venous thromboembolism, for prevention of systemic
embolism in patients with tissue or mechanical prosthetic heart valves
or AF, for prevention of AMI in patients with peripheral arterial
disease, for prevention of stroke, recurrent infarction, or death in
patients with AMI, and for prevention of myocardial infarction (MI) in
men at high risk.119
Although effectiveness has not been
proven by a randomized trial, oral anticoagulants are indicated for
prevention of systemic embolism in high-risk patients with mitral
stenosis. For most indications, a moderate anticoagulant effect (INR,
2.0 to 3.0) is appropriate (Table 5
).
Although anticoagulants are sometimes used for secondary prevention of
cerebral ischemia of presumed arterial origin when antiplatelet agents
have failed, this practice has never been shown to be effective and the
Stroke Prevention in Reversible Ischemia Trial120
found
high- intensity oral anticoagulation (INR, 3.0 to 4.5) dangerous in
such cases.120
Patients in that study who had experienced
transient ischemic attack or minor ischemic stroke were randomly
assigned to treatment with oral anticoagulation (INR, 3.0 to 4.5) or
aspirin, 30 mg/d. The primary measure of outcome was the constellation
of death from vascular causes, stroke, MI, or major bleeding. The trial
was stopped at the first interim analysis of 1,316 patients with a mean
follow-up of 14 months because of excess primary outcome events in the
anticoagulated group (hazard ratio, 2.3; 95% confidence interval
[CI], 1.6 to 3.5). There were 53 major bleeding complications (27
intracranial, 17 fatal) during anticoagulant therapy vs 6 during
aspirin therapy (3 intracranial, 1 fatal).
|
Prevention of Venous Thromboembolism
|
|---|
Oral anticoagulants are effective for prevention of venous
thrombosis after hip surgery121
122
123
and major gynecologic
surgery124
125
when given at a dose sufficient to maintain
INR between 2.0 and 3.0. The risk of clinically important bleeding at
this intensity is small. A very low fixed dose of warfarin (1 mg/d) was
effective in a study in which subclavian vein thrombosis was prevented
in patients with malignancy with indwelling catheters.126
In contrast, four randomized trials127
128
129
130
found this
dose of warfarin ineffective for preventing postoperative venous
thrombosis in patients undergoing major orthopedic surgery. Levine and
associates131
reported that warfarin, 1 mg/d for 6 weeks,
followed by adjustment to a targeted INR of 1.5, prevented thrombosis
in patients with stage IV breast cancer receiving chemotherapy.
|
Treatment of DVT
|
|---|
The optimum duration of oral anticoagulant therapy is influenced
by whether thrombosis is unprovoked (idiopathic), associated with
ongoing risk factors (such as malignancy), or is secondary to a
reversible cause; a longer course of therapy should be given for
idiopathic thrombosis132
and when there is an ongoing risk
factor. Treatment should also be longer in patients with proximal vein
thrombosis than in those with distal thrombosis and in patients with
recurrent thrombosis vs those with a single episode. Laboratory
evidence of thrombophilia may warrant a longer duration of
anticoagulant therapy. Oral anticoagulant therapy is indicated for at
least 3 months in patients with proximal DVT,133
134
or in
patients with acute pulmonary embolism (PE) for at least 6 months in
those with idiopathic proximal vein thrombosis or recurrent venous
thrombosis, and for 6 to 12 weeks in patients with symptomatic calf
vein thrombosis.135
136
137
138
Indefinite anticoagulant therapy
is indicated in patients with more than one episode of idiopathic
proximal vein thrombosis or PE, thrombosis complicating malignancy, or
idiopathic venous thrombosis associated with homozygous factor V Leiden
genotype, the antiphospholipid antibody syndrome, or deficiencies of
antithrombin, protein C, or protein S.138
139
140
141
Prospective
cohort studies138
139
142
indicate that in patients with
idiopathic venous thrombosis, neither heterozygous factor V Leiden nor
the G20210A prothrombin gene mutation increases the risk of recurrence.
Moderate-intensity anticoagulation (INR, 2.0 to 3.0) is as effective as
a more intense regimen (INR, 3.0 to 4.5) but associated with less
bleeding (Table 5)
.143
Randomized
trials138
139
evaluating short vs long courses of warfarin
therapy have demonstrated that oral anticoagulants effectively prevent
recurrent venous thrombosis (risk reduction > 90%), that treatment
for 6 months is more effective than for 6 weeks,136
and
that treatment for 2 years is more effective than for 3
months.138
|
Primary Prevention of Ischemic Coronary Events
|
|---|
The Thrombosis Prevention Trial119
evaluated warfarin
(target INR, 1.3 to 1.8), aspirin (75 mg/d), both, or neither in 5,499
men aged 45 to 69 years at risk of a first MI. The primary outcome
consisted of acute ischemic coronary events defined as coronary death
or nonfatal MI. Although the anticoagulant intensity was low, the mean
warfarin dose was 4.1 mg/d. The annual incidence of coronary events was
1.4%/yr in the placebo group. The combination of warfarin and aspirin
reduced the relative risk by 34% (p = 0.006); however, when
administered separately, neither warfarin nor aspirin produced a
significant reduction in acute ischemic events (although they
both showed a similar trend), and the efficacy of these treatments was
similar to one another (relative risk reductions of 22% and 23%,
respectively). The combined treatment, though most effective, was
associated with a small but significant increase in hemorrhagic stroke.
The importance of these results is that in the primary prevention
setting, they show that targeting an INR of 1.3 to 1.8 is about as
effective as aspirin for prevention of acute ischemic events, and that
the combination of low-intensity warfarin plus aspirin is more
effective than either agent alone at the price of a small increase in
bleeding.
The effectiveness of the combination of low-intensity warfarin plus
aspirin in the Thrombosis Prevention Trial119
contrasts
with the results of the CARS144
and Stroke Prevention in
Atrial Fibrillation (SPAF)-III studies,145
in which this
type of combination therapy (for different indications) was
ineffective. In the Thrombosis Prevention Trial,119
the
dose of warfarin was adjusted between 0.5 mg/d and 12.5 mg/d, whereas
in the CARS and SPAF-III studies, warfarin was given in fixed doses.
Thus, if low-intensity warfarin is to be evaluated further for any
indication, the marked dose-response variability mandates that dose be
adjusted to the required INR (1.5).
|
AMI
|
|---|
The role of coumarins in AMI has been the subject of intense
controversy almost from the time that they were introduced into
clinical practice. Coumarins have been evaluated in AMI using different
levels of intensity and either used alone or in combination with
aspirin. The results have been summarized in a recent
meta-analysis146
that stratified the studies by intensity
of anticoagulation and use of aspirin to yield five categories (Tables 6
,
7
): (1) high-intensity INR (approximately 2.8 to 4.8) vs control
treatment; (2) moderate-intensity INR (approximately 2.0 to 3.0) vs
control treatment; (3) moderate-intensity INR plus aspirin vs aspirin;
(4) moderate- to high-intensity INR vs aspirin; and (5) low-intensity
(low fixed dose) plus aspirin vs aspirin.
There were a total of 44 trials on 24,115 patients identified. The
largest number of patients (n = 10,056) were enrolled in studies
comparing high-intensity oral anticoagulants with control treatment.
Substantial numbers (n = 8,435) were also enrolled in studies of
low-fixed-dose warfarin plus aspirin vs aspirin and in studies of
moderate- to high-intensity oral anticoagulants vs aspirin. Conclusions
from these trials are as follows: (1) high-intensity oral
anticoagulants are more effective than control treatment, but at a
substantially increased risk of major bleeding; (2) low-fixed-dose
unmonitored warfarin plus aspirin is no more effective than aspirin,
but produces a small increase in major bleeding; and (3) treatment with
moderate- to high-intensity oral anticoagulants is only moderately (not
significantly) more effective than aspirin but causes more bleeding.
Although the number of patients studied is small (n = 480),
moderate-intensity warfarin plus aspirin appears to be substantially
better than aspirin alone, with only a marginal (nonsignificant)
increase in major bleeding. These promising results with the
combination of moderate-intensity warfarin and aspirin should be
confirmed in a much larger sample of patients with AMI.
|
Prosthetic Heart Valves
|
|---|
The most convincing evidence that oral anticoagulants are
effective in patients with prosthetic heart valves comes from a study
of patients treated with warfarin for 6 months who were randomized to
receive warfarin of uncertain intensity vs either of two
aspirin-containing platelet-inhibitor drug regimens.147
The incidence of thromboembolic complications in the group who
continued warfarin therapy was significantly lower than in the groups
that received either of the two antiplatelet drug regimens (relative
risk reduction, 60 to 79%). The incidence of bleeding was highest in
the warfarin group. Three studies addressed the minimum effective
intensity of anticoagulant therapy. One included only patients with
bioprosthetic heart valves and showed that a moderate-dose regimen
(INR, 2.0 to 2.25) was as effective, but produced less bleeding than a
more intense regimen (INR, 2.5 to 4.0).148
The second
study,149
which included patients with mechanical
prosthetic heart valves, compared a very high-intensity regimen
(estimated INR, 7.4 to 10.8) with a lower-intensity regimen (estimated
INR, 1.9 to 3.6) and found no difference in effectiveness but
significantly more bleeding with the higher-intensity regimen. A third
study150
of patients with mechanical prosthetic valves
treated with aspirin and dipyridamole compared moderate-intensity (INR,
2.0 to 3.0) and high-intensity (INR, 3.0 to 4.5) warfarin regimens and
found no difference in efficacy but significantly more bleeding with
the high-intensity regimen. A more recent randomized
trial61
showed that addition of aspirin, 100 mg/d, to
warfarin (INR, 3.0 to 4.5) improved efficacy compared to warfarin (INR,
3.0 to 4.5) plus placebo. This combination of low-dose aspirin and
high-intensity warfarin therapy was associated with a statistically and
clinically significant reduction in all-cause mortality, cardiovascular
mortality, and stroke. This benefit occurred at the expense of
increased minor bleeding and a nonsignificant trend for an increase in
major bleeding.
In a retrospective study of 16,081 patients with mechanical heart
valves attending four regional anticoagulation clinics in The
Netherlands with a target range of 3.6 to 4.8, Cannegieter and
associates151
reported that the incidence of embolic
events rose sharply when INR fell to < 2.5, while bleeding increased
when INR rose to > 5.0.
Guidelines developed by the European Society of
Cardiology152
called for anticoagulant intensity in
proportion to the thromboembolic risk associated with specific types of
prosthetic heart valves. For first-generation valves, an INR of 3.0 to
4.5 was recommended, an INR of 3.0 to 3.5 was considered sensible for
second-generation valves in the mitral position, and an INR of 2.5 to
3.0 was deemed sufficient for second-generation valves in the aortic
position. The American College of Chest Physicians 1998 guidelines
recommended an INR of 2.5 to 3.5 for most patients with mechanical
prosthetic valves, and 2.0 to 3.0 for those with bioprosthetic valves
and low-risk patients with bileaflet mechanical valves (such as the St.
Jude Medical device) in the aortic position.
|
Atrial Fibrillation
|
|---|
Five trials with relatively similar study designs have addressed
anticoagulant therapy for primary prevention of ischemic stroke in
patients with nonvalvular (nonrheumatic) AF. The SPAF
study,153
the Boston Area Anticoagulation Trial for Atrial
Fibrillation,154
and the Stroke Prevention in Nonrheumatic
Atrial Fibrillation Trial155
were carried out in the
United States; the Atrial Fibrillation, Aspirin, Anticoagulation
(AFASAK) study was carried out in Denmark156
; the Canadian
Atrial Fibrillation Anticoagulation study157
was stopped
before completion because of convincing results in three of the other
trials.158
In the AFASAK and SPAF trials, patients were
also randomized to aspirin therapy. Eligibility required that patients
be acceptable candidates for anticoagulant therapy. The results of all
five studies were similar; pooled analysis on an intention-to-treat
basis showed a 69% risk reduction and > 80% risk reduction in
patients who remained on treatment with warfarin (efficacy
analysis).159
There was little difference between rates of
major or intracranial hemorrhage in the warfarin and control groups,
but minor bleeding was approximately 3%/yr more frequent in the
warfarin-assigned groups.160
Pooled results from two
studies were consistent with a smaller benefit from aspirin. In the
AFASAK study, 75 mg/d did not significantly reduce thromboembolism,
while in the SPAF trial, 325 mg/d was associated with a 44% stroke
risk reduction in younger patients.
A secondary prevention trial in Europe161
compared
anticoagulant therapy, aspirin, and placebo in patients with AF who had
sustained nondisabling stroke or transient ischemic attack within 3
months. Compared to placebo, there was a 68% reduction in stroke with
warfarin and an insignificant 16% stroke risk reduction with aspirin.
None of the patients in the anticoagulant group suffered intracranial
hemorrhage.
The SPAF-II162
trial compared the efficacy and safety of
warfarin with aspirin in patients with AF. Warfarin was more effective
than aspirin for preventing ischemic stroke, but this difference was
almost entirely offset by a higher rate of intracranial hemorrhage with
warfarin, particularly among patients > 75 years old, in whom the
rate of intracranial hemorrhage was 1.8%/yr. The intensity of
anticoagulation was greater in the SPAF trials than in most of the
other primary prevention studies; in addition, the majority of
intracranial hemorrhages during these trials occurred when estimated
INR was > 3.0. In the SPAF III study,145
warfarin (INR,
2.0 to 3.0) was much more effective than a fixed-dose combination of
warfarin (1 to 3 mg/d; INR, 1.2 to 1.5) plus aspirin (325 mg/d) in
high-risk patients with AF, while aspirin alone was sufficient for
patients at low intrinsic risk of thromboembolism.
|
Other Indications for Oral Anticoagulant Therapy
|
|---|
There are other widely accepted indications for oral anticoagulant
therapy that have not been evaluated in properly designed clinical
trials. These indications include patients with valvular heart disease
associated with AF and certain patients with mitral stenosis, and
patients who have sustained one or more episodes of systemic
thromboembolism of unknown etiology. For both of these indications, a
moderate-dose regimen (INR, 2.0 to 3.0) is recommended. Anticoagulants
are not presently indicated in patients with ischemic cerebrovascular
disease, but this issue is presently under
investigation.163
|
Footnotes
|
|---|
Abbreviations: AFASAK = Atrial Fibrillation,
Aspirin, Anticoagulation; AMI = acute myocardial infarction; AF =
atrial fibrillation; CARS = Coumadin Aspirin Reinfarction Study; CI =
confidence interval; DVT = deep vein thrombosis; INR =
international normalized ratio; IRP = international reference
preparation; ISI = international sensitivity index; MI = myocardial
infarction; PE = pulmonary embolism; PT = prothrombin time; SPAF =
Stroke Prevention in Atrial Fibrillation; WHO = World Health
Organization
|
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Introduction
Mechanism of Action of...
