DOI 10.1378/chest.11-2292
2012;141;e44S-e88SChest
Elaine M. Hylek and Gualtiero Palareti
Walter Ageno, Alexander S. Gallus, Ann Wittkowsky, Mark Crowther,
Evidence-Based Clinical Practice Guidelines
ed: American College of Chest Physicians
Therapy and Prevention of Thrombosis, 9th
Oral Anticoagulant Therapy : Antithrombotic
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e44S
CHEST Supplement
Oral Anticoagulant Therapy
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES
on laboratory and clinical monitoring and on rever-
sal strategies.
More recently, new oral anticoagulant drugs, namely
the direct thrombin inhibitor dabigatran etexilate and
the direct factor Xa inhibitor rivaroxaban, have been
approved for clinical use in several countries. A growing
body of laboratory and clinical data is becoming avail-
able to better understand the mechanisms of action and
the optimal management of these new compounds. In
this article we summarize the published literature con-
cerning the pharmacokinetics and pharmacodynamics
of all oral anticoagulant drugs that are currently avail-
able for clinical use and other aspects related to their
management.
For many decades, the vitamin K antagonists (VKAs) have been the only oral anticoagulant
drugs available for clinical use for the primary and
secondary prevention of venous and arterial throm-
boembolic events. VKAs have been consistently
shown to be highly effective in many settings and
are now used by millions of patients worldwide.
Laboratory and clinical studies have contributed to
understanding of the complex pharmacokinetics
and pharmacodynamics of VKAs, their interac-
tions, antithrombotic effects, and the risks associ-
ated with their use. Several studies have addressed
the practical issues related to the management of
patients on VKAs treatment, with particular focus
Background: The objective of this article is to summarize the published literature concerning the
pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available
for clinical use and other aspects related to their management.
Methods: We carried out a standard review of published articles focusing on the laboratory and
clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran
etexilate; and the direct factor Xa inhibitor, rivaroxaban.
Results: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the mon-
itoring of anticoagulation intensity are described in detail and discussed without providing spe-
cifi c recommendations. Moreover, we describe and discuss the clinical applications and optimal
dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring,
adverse events such as bleeding and other potential side effects, and available strategies for
reversal.
Conclusions: There is a large amount of evidence on laboratory and clinical characteristics of
vitamin K antagonists. A growing body of evidence is becoming available on the fi rst new oral
anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.
CHEST 2012; 141(2)(Suppl):e44S–e88S
Abbreviations: AC 5 anticoagulation clinic; AMS 5 anticoagulation management service; aPTT 5 activated partial
thromboplastin time; AUC 5 area under the curve; Cmax 5 peak plasma concentration; ECT 5 ecarin clotting time;
HR 5 hazard ratio; INR 5 international normalized ratio; ISI 5 international sensitivity index; PCC 5 prothrombin
complex concentrate; PE 5 pulmonary embolism; POC 5 point of care; PSM 5 patient self-management; PST 5 patient
self testing; PT 5 prothrombin time; TCT 5 thrombin clotting time; TTR 5 time in therapeutic range; UC 5 usual care;
VKA 5 vitamin K antagonist; VKOR 5 vitamin K oxide reductase; WHO 5 World Health Organization
Oral Anticoagulant Therapy
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines
Walter Ageno , MD ; Alexander S. Gallus , MBBS ; Ann Wittkowsky , PharmD , FCCP ;
Mark Crowther , MD ; Elaine M. Hylek , MD , MPH ; and Gualtiero Palareti , MD
© 2012 American College of Chest Physicians
at ZheJiang University on March 1, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e45S
effect of the VKAs can be overcome by low doses of
phytonadione (vitamin K) ( Fig 1 ).
1.2 Pharmacokinetics and Pharmacodynamics
Warfarin is a racemic mixture of two optically
active isomers, the R and S enantiomers. Warfarin is
highly water soluble, is rapidly absorbed from the
gastrointestinal tract, has high bioavailability, 15,16 and
reaches maximal blood concentrations about 90 min
after oral administration. 15,17 Racemic warfarin has a
half-life of 36 to 42 h 18 (R-warfarin 45 h, S-warfarin
29 h), circulates bound to plasma proteins (mainly
albumin), and accumulates in the liver where the two
enantiomers are metabolically transformed by dif-
ferent pathways ( Fig 1 ). 18 The S enantiomer of warfa-
rin (2.7-3.8 times more potent than the R enantiomer)
undergoes approximately 90% oxidative metabolism,
primarily by the CYP2C9 enzyme of the cytochrome
P450 system and to a lesser extent by CYP3A4. 19 The
less potent R enantiomer undergoes approximately
60% oxidative metabolism, primarily by two cyto-
chrome P450 enzymes, CYP1A2 and CYP3A4, and to
a lesser extent by CYP2C19. The remainder of the
metabolism of both enantiomers involves reduction
to diastereomeric alcohols. The relationship between
the dose of warfarin and the response is modifi ed by
genetic and environmental factors that can infl uence
the absorption of warfarin, its pharmacokinetics, and
its pharmacodynamics.
Other available VKAs include acenocoumarol, phen-
procoumon, and fl uindione. Like warfarin, aceno-
coumarol and phenprocoumon also exist as optical
isomers, but with different stereochemical character-
istics. R-acenocoumarol has an elimination half-life
of 9 h, is primarily metabolized by CYP2C9 and
CYP2C19, and is more potent than S-acenocoumarol
because of faster clearance of S-acenocoumarol,
which has an elimination half-life of 0.5 h and is pri-
marily metabolized by CYP2C9. 20 Phenprocoumon is
a much longer-acting agent, with both the R- and
S-isomers having elimination half-lives of 5.5 days. Both
are metabolized by CYP2C9, and S-phenprocoumon
is 1.5 to 2.5 times more potent than R-phenprocou-
mon. 21 Finally, fl uindione is an indandione VKA with
a mean half-life of 31 h. 22 Unlike warfarin, fl uindione
is not a chiral compound. 22
1.3 Interactions
1.3.1 Genetic Factors: A number of point muta-
tions in the gene coding for the CYP2C9 have been
identifi ed. 23 These polymorphisms, the most common
of which are CYP2C9*2 and CYP2C9*3, are associ-
ated with an impaired ability to metabolize S-warfarin,
resulting in a reduction in S-warfarin clearance and,
1.0 Vitamin K Antagonists
1.1 Pharmacology
VKAs produce their anticoagulant effect by inter-
fering with the cyclic interconversion of vitamin K
and its 2,3 epoxide (vitamin K epoxide), thereby
modulating the g -carboxylation of glutamate residues
(Gla) on the N-terminal regions of vitamin K-dependent
proteins ( Fig 1 ). 1-8 The vitamin K-dependent coagula-
tion factors II, VII, IX, and X require g -carboxylation
for their procoagulant activity, and treatment with
VKAs results in the hepatic production of partially
carboxylated and decarboxylated proteins with reduced
coagulant activity. 9,10 Carboxylation is required for a
calcium-dependent conformational change in coagu-
lation proteins 11-13 that promotes binding to cofactors
on phospholipid surfaces. In addition, the VKAs
inhibit carboxylation of the regulatory anticoagulant
proteins C, S, and Z and thereby have the potential to
be procoagulant. 14 Although the anticoagulant effect
of VKAs is dominant, a transient procoagulant effect
may occur when baseline protein C and protein S
levels are reduced due to the start of VKA therapy
and the acute phase of a thrombotic event and before
the balanced decrease of vitamin K-dependent clot-
ting factor levels is achieved. Carboxylation requires
the reduced form of vitamin K (vitamin KH 2 ), a
g -glutamyl carboxylase, molecular oxygen, and CO 2 . 1
Vitamin K epoxide can be reused by reduction to
VKH 2 . The oxidation-reduction reaction involves a
reductase pair. The fi rst, vitamin K epoxide reduc-
tase, is sensitive to VKA, whereas vitamin K reduc-
tase is less sensitive. 1-3 Therefore, the anticoagulant
Revision accepted August 31, 2011 .
Affi liations: From the University of Insubria (Dr Ageno), Varese,
Italy; Flinders University (Dr Gallus), Adelaide, SA, Australia; the
University of Washington (Dr Wittkowsky), Seattle, WA; McMas-
ter University (Dr Crowther), St. Joseph’s Hospital, Hamilton,
ON, Canada; the Boston University School of Medicine (Dr Hylek),
Boston, MA; and the University Hospital S. Orsola-Malpighi
(Dr Palareti), Bologna, Italy .
Funding/Support: The Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines received support from
the National Heart, Lung, and Blood Institute [R13 HL104758]
and Bayer Schering Pharma AG. Support in the form of educa-
tional grants was also provided by Bristol-Myers Squibb; Pfi zer,
Inc; Canyon Pharmaceuticals; and sanofi -aventis US.
Disclaimer: American College of Chest Physician guidelines are
intended for general information only, are not medical advice, and
do not replace professional medical care and physician advice,
which always should be sought for any medical condition. The
complete disclaimer for this guideline can be accessed at http://
chestjournal.chestpubs.org/content/141/2_suppl/1S.
Correspondence to: Walter Ageno, MD, Department of Clinical
Medicine, Ospedale di Circolo, Viale Borri 57, 21100 Varese,
Italy; e-mail: walter.ageno@uninsubria.it
© 2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians ( http://www.chestpubs.org/
site/misc/reprints.xhtml ).
DOI: 10.1378/chest.11-2292
© 2012 American College of Chest Physicians
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e46S Oral Anticoagulant Therapy
(VKOR) enzyme fi rst described in 1974. 36 The gene
coding for the VKOR protein is located on the short
arm of chromosome 16. 37,38 The gene encodes for
several isoforms of a protein that are collectively
termed the vitamin K oxide reductase complex 1
(VKORC1). Subsequently, mutations in this gene
have been identifi ed leading to enzymes with vary-
ing sensitivities to inhibition by warfarin, 38-43 thereby
affecting the pharmacodynamics of warfarin. The
mutations occur with differing frequencies in various
ethnic populations and account, in part, for the dif-
ference in warfarin doses required to maintain a ther-
apeutic international normalized ratio (INR) (Table
S1) (tables that contain an “S” before the number
denote supplementary tables not contained in the
body of the article and available instead in an online
data supplement; see the “Acknowledgments” for
more information). 39-41,44,45
Genetic mutations in the gene coding for the
VKORC1often involve several mutations leading to
various haplotypes that cause greater resistance to
warfarin therapy. Harrington et al 43 found a warfarin-
resistant individual who had high serum warfarin
as a result, an increased S-warfarin elimination half-
life. 24 Mutations in this gene occur with different
frequencies in various ethnic groups (Table S1). 25,26
In comparison with patients who are homozygous
for the wild-type allele (CYP2C9*1*1), patients
with heterozygous (CYP2C9*1*2, CYP2C9*1*3,
CYP2C9*2*3) or homozygous (CYP2C9*2*2,
CYP2C9*3*3) expression of a variant allele require
lower doses of warfarin, as determined by a systematic
review of the literature and meta-analysis of studies
that assessed the infl uence of CYP2C9 polymor-
phisms on warfarin dose requirements (Table S2). 27
Several investigations 25,28,29 have shown that these
mutations, as well as others, 30-32 are also associated
with an increase in bleeding complications associated
with warfarin therapy. Mutations in CYP2C9 also
affect acenocoumarol, although to a lesser degree
because the anticoagulation potencies of the R and S
enantiomers are comparable. 33,34 The effects of CYP2C9
polymorphisms are least pronounced with the use of
phenprocoumon. 33,35
The target for warfarin’s inhibitory effect on the
vitamin K cycle is the vitamin K oxide reductase
Figure 1. [Section 1.1] Vitamin K 1 is reduced to vitamin KH2. The major warfarin-sensitive enzyme in
this reaction is the vitamin K oxide reductase mainly inhibited by the S-enantiomer of warfarin. S-warfarin
is metabolized by the p450 cytochrome enzyme, CYP2C9. Reprinted with permission from Ansell et al. 8
© 2012 American College of Chest Physicians
at ZheJiang University on March 1, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e47S
tive metabolism of either the S-enantiomer or
R-enantiomer of warfarin). The inhibition of S-warfarin
metabolism is more important clinically, because this
enantiomer is more potent than the R-enantiomer as
a VKA. 50,51 Phenylbutazone, 52 sulfi npyrazone, 53 metro-
nidazole, 54 and trimethoprimsulfamethoxazole 55 inhibit
the clearance of S-warfarin, and each potentiates the
effect of warfarin on the prothrombin time (PT). In
contrast, drugs such as cimetidine and omeprazole,
which inhibit the clearance of the R-isomer, poten-
tiate the PT only modestly in patients who are treated
with warfarin. 51,54,56 Amiodarone is a potent inhibitor
of the metabolic clearance of both the S-enantiomer
and the R-enantiomer and potentiates warfarin anti-
coagulation. 57 The anticoagulant effect of warfarin is
inhibited by drugs like barbiturates, rifampin, azathi-
oprine, and carbamazepine, which increase its clear-
ance by inducing hepatic metabolism. 58 Azathioprine
also reduces the anticoagulant effect of warfarin, pre-
sumably through a potentiating effect on hepatic
clearance. 59 Long-term alcohol consumption has a
similar potential to increase the clearance of warfarin,
but ingestion of even relatively large amounts of wine
had little infl uence on the PT in normal volunteers
who were given warfarin. 60 The effect of enzyme
induction on warfarin therapy has been analyzed in
a critical review. 58 Ten hepatic microsomal enzyme
agents were assessed. Enzyme induction of warfarin
metabolism by rifampin and barbiturates was consid-
ered likely, and an interaction with carbamazepine,
griseofulvin, aminoglutethimide, nafcillin, and diclox-
acillin was considered probable.
Drugs may also infl uence the pharmacodynamics
of warfarin by inhibiting the synthesis of or increas-
ing the clearance of vitamin K-dependent coagula-
tion factors or by interfering with other pathways of
hemostasis. The anticoagulant effect of warfarin is aug-
mented by second-generation and third-generation
cephalosporins, which inhibit the cyclic interconver-
sion of vitamin K; 61,62 by thyroxine, which increases the
metabolism of coagulation factors; 63 and by clofi brate
through an unknown mechanism. 64 Doses of salicylates
of . 1.5 g per day 65 may augment the anticoagulant
effect of warfarin. Acetaminophen potentiates the
effect of warfarin when used over prolonged periods
of time, as demonstrated in a recent randomized,
blinded trial. 66-68 Acetaminophen possibly potentiates
the anticoagulant effect of warfarin through inhibi-
tion of VKOR by a toxic metabolite of the drug, 69
although the accumulation of this metabolite may
vary among individuals, thus accounting for a variable
potentiating effect. 70 Heparin potentiates the anti-
coagulant effect of warfarin, but in therapeutic doses
produces only a slight prolongation of the PT. The
mechanisms by which erythromycin 71 and some ana-
bolic steroids 72 potentiate the anticoagulant effect of
concentrations and a 196G . A transition, predicting
a Val66Met substitution in VKORC1. D’Andrea et al, 39
studying 147 patients, found that those with a 1173CC
genotype required a higher mean maintenance dose
compared with those with a CT or TT genotype, as did
Quiteineh et al, 46 who found that a 1173 C . T poly-
morphism was signifi cantly associated with the risk
of anticoagulant overdose. By identifying a number
of noncoding single nucleotide polymorphisms,
Rieder et al 40 were able to infer that there are fi ve
major haplotypes associated with different dose
requirements for maintaining a therapeutic INR.
The maintenance dose ranged from a low of 2.7 mg
warfarin per day for the sensitive haplotypes up to
a high of 6.2 mg per day for the resistant haplo-
types. Asian Americans had the highest proportion
of sensitive haplotypes, whereas African Americans
more frequently exhibited the resistant haplotypes
(Table S1).
1.3.2 Drugs: VKAs are highly susceptible to
drug-drug interactions. For warfarin, for example,
manufacturer-provided product information lists . 200
specifi c agents that may interfere with this agent. 47
Unfortunately, there seems to be little concordance
among commonly used drug compendia and product
labels with respect to interactions involving warfarin.
Indeed, a major problem with the literature on this
topic is that many reports are single-case reports and
are not well documented. Anthony et al 44 recently
reviewed three drug information compendia, Clinical
Pharmacology, ePocrates, and Micromedex, and the
warfarin sodium (Coumadin) product label approved
by the US Food and Drug Administration, for listings
of interactions between warfarin and drugs, biologics,
foods, and dietary supplements and found that of
a total of 648 entries from the four sources, only 50
were common to all the sources. 44 As in the previous
edition of this article, 8 Table 1 summarizes a compre-
hensive list of drugs that potentiate, inhibit, or have
no effect on the anticoagulant effect of warfarin based
on the results of a systematic review of available evi-
dence completed in 2005, which rated warfarin drug
interaction reports according to interaction direc-
tion, clinical severity, and quality of evidence, and
developed lists of warfarin drug interactions consid-
ered highly prob