An To Coagulant Es

Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse
effects
Author: Lawrence LK Leung, MD
Section Editor: Pier Mannuccio Mannucci, MD
Deputy Editor: Jennifer S Tirnauer, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Sep 2018. | This topic last updated: Aug 03, 2018.
INTRODUCTION — Options for anticoagulation have been expanding steadily over the past
few decades, providing a greater number of agents for prevention and management of
thromboembolic disease. In addition to heparins and vitamin K antagonists, anticoagulants
that directly target the enzymatic activity of thrombin and factor Xa have been developed.
Appropriate use of these agents requires knowledge of their individual characteristics, risks,
and benefits.
This topic review discusses practical aspects of the use of direct thrombin inhibitors (oral
and parenteral) and oral direct factor Xa inhibitors, along with a brief mention of other
anticoagulants in development. Indications and efficacy of these agents in specific clinical
settings are presented in separate topic reviews on the relevant conditions. (See
'Indications' below.)
Management of bleeding and perioperative management of patients receiving direct

thrombin inhibitors or direct factor Xa inhibitors is also discussed in detail separately. (See
"Management of bleeding in patients receiving direct oral anticoagulants" and
"Perioperative management of patients receiving anticoagulants".)
The following topic reviews discuss other anticoagulants in clinical use:
● Heparins – (See "Heparin and LMW heparin: Dosing and adverse effects".)
● Vitamin K antagonists – (See "Warfarin and other VKAs: Dosing and adverse effects"
and "Biology of warfarin and modulators of INR control".)
● Fondaparinux – (See "Fondaparinux: Dosing and adverse effects".)
MECHANISMS OF ACTION AND TERMINOLOGY
Sites of action — Hemostasis involves several processes. These include platelet activation,

generation of fibrin by activated coagulation factors, inhibition of procoagulant factors to
prevent excessive clot propagation, and fibrinolysis to dissolve the fibrin clot as the
endothelial surface is repaired (figure 1 and figure 2).
Although these processes are often described separately, there are multiple points of
overlap and crosstalk between platelets, procoagulant factors, endogenous anticoagulant
and fibrinolytic factors, and the endothelium, to promote an appropriate level of hemostasis
and limit clot formation to sites of vessel injury. (See "Overview of hemostasis".)
The direct thrombin inhibitors and direct factor Xa inhibitors block major procoagulant
activities involved in the generation of a fibrin clot (figure 3).
● Thrombin – Thrombin (factor IIa) is the final enzyme of the clotting cascade that
produces fibrin; it is formed by the proteolytic cleavage of prothrombin by factor Xa.
Thrombin has a central role in coagulation: it cleaves fibrinogen to fibrin; activates
other procoagulant factors including factors V, VIII, XI, and XIII; and activates platelets
[1]. The active site of the thrombin enzyme is buried deep in a groove on one side of the
molecule (figure 4); this deep groove and surrounding amino acids enhance the
specificity of the enzyme [2,3]. (See "Overview of hemostasis", section on 'Thrombin
generation'.)
Direct thrombin inhibitors (DTIs) can bind to the active site of the thrombin enzyme
(univalent DTIs) or to two sites: the active site and "exosite I," a positively charged
region of the thrombin molecule that is physically separated from the active site
(divalent DTIs) [1,4]. Exosite I is also the site of interaction of many physiologic
thrombin substrates, including fibrinogen, factor V, protein C, thrombomodulin (a
thrombin receptor on endothelial cells), and thrombin receptors (PAR1 and PAR4) on
platelets [2-6].
Thrombin is active in both circulating and clot-bound forms. Direct thrombin inhibitors
are able to block the action of both forms of thrombin because their site of binding to
thrombin is not masked by fibrin (or binding is not obstructed). In contrast, heparins are
only able to inactivate thrombin in the fluid phase, via antithrombin (previously called
antithrombin III) [7-10].
● Factor Xa – Factor Xa acts immediately upstream of thrombin in the clotting cascade,

at the convergence point of the intrinsic and extrinsic coagulation pathways (figure 1);
it is formed by the proteolytic cleavage of factor X by one of two X-ase (ten-ase)
complexes, which are made up of other procoagulant factors. Inhibition of factor Xa
can prevent amplified thrombin generation because one molecule of factor Xa can
cleave over 1000 molecules of prothrombin to thrombin [11]. Direct factor Xa inhibitors
bind to the active site of factor Xa and inhibit factor Xa activity without a requirement
for cofactors [12,13]. (See "Overview of hemostasis", section on 'Multicomponent
complexes'.)
Similarly to thrombin, factor Xa is active in circulating and clot-bound forms. Direct

factor Xa inhibitors are able to block the action of both forms of factor Xa, whereas
indirect factor Xa inhibitors such as heparin and fondaparinux (the antithrombin-
binding pentasaccharide) are only able to inactivate factor Xa in the fluid phase, via
antithrombin.
Terminology — Terminology for anticoagulants continues to evolve as new agents become

available. The following terminology describes agents in clinical use:
● Antithrombotic agent – Antithrombotic agents generally include both antiplatelet

agents (eg, aspirin, clopidogrel) as well as anticoagulants.
● Anticoagulant – Anticoagulants include a variety of agents that inhibit one or more

steps in the coagulation cascade. Their mechanisms vary, including direct enzymatic
inhibition, indirect inhibition by binding to antithrombin, and antagonism of vitamin K-
dependent factors by preventing their synthesis in the liver and/or modification of their
calcium-binding properties. Available agents include unfractionated heparin, low
molecular weight heparins, fondaparinux, vitamin K antagonists, direct thrombin
inhibitors, direct factor Xa inhibitors, and other agents at various stages of
development. (See 'Anticoagulants in development' below.)
● Direct thrombin inhibitor – Direct thrombin inhibitors (DTIs) prevent thrombin from
cleaving fibrinogen to fibrin. They bind to thrombin directly, rather than by enhancing
the activity of antithrombin, as is done by heparin.
• Parenteral DTIs include bivalirudin (Angiomax), argatroban (Argatra, Novastan,

Arganova, Exembol), and desirudin (Iprivask, Revasc).
• The only oral DTI available for clinical use is dabigatran etexilate (Pradaxa);
another oral agent, ximelagatran (Exanta), was withdrawn from the market in 2006
due to hepatotoxicity and cardiovascular events [11].
● Direct factor Xa inhibitor – Direct factor Xa inhibitors prevent factor Xa from cleaving
prothrombin to thrombin. They bind directly to factor Xa, rather than enhancing the
activity of antithrombin, as is done by heparin.
• There are no parenteral direct factor Xa inhibitors in clinical use.
• Several oral agents are available, including rivaroxaban (Xarelto), apixaban

(Eliquis), edoxaban (Lixiana, Savaysa), and betrixaban (Bevyxxa). Of note, the
generic names for these agents all end in "Xa-ban" (eg, rivaroxaban, apixaban,
edoxaban, betrixaban).
Other acronyms that have been created to refer to the orally acting direct thrombin
inhibitors and direct factor Xa inhibitors together include direct oral anticoagulants
(DOACs), target-specific oral anticoagulants (TSOACs), oral direct inhibitors (ODIs), and
NOACs, which stands for "novel oral anticoagulants," "new(er) oral anticoagulants," and
"non-vitamin K antagonist oral anticoagulants" [14-17].
COMPARISON WITH HEPARIN AND WARFARIN — Anticoagulants differ in efficacy

depending on the clinical setting; there are also differences in dosing, monitoring, cost, and
risks. Thus, advantages and disadvantages of each agent must be individualized to the
patient and clinical setting (table 1). Recommendations for each agent are based largely on
the efficacy and safety in the specific patient population and clinical indications.
However, there are settings in which efficacy and safety of long-term oral administration are
similar for vitamin K antagonists and DOACs. In such cases it may be worth considering
some additional advantages and disadvantages of each class of drugs in decision making
[18].
Clinician familiarity with dosing — Dabigatran was the first of the DOACs to become
clinically available (approved in 2010 in the United States). The direct factor Xa inhibitors
became available in subsequent years. However, many clinicians remain unfamiliar with the
appropriate dosing of these drugs.
The lack of clinician familiarity with recommended dosing was illustrated in a 2017 report
involving over 1500 patients with venous thromboembolism (VTE) who were treated with a
DOAC [19]. For initial therapy, use of a dose or dosing frequency that differed from the
product labeling was common (rivaroxaban: 287 of 1591 patients [18 percent]; apixaban: 22
of 44 patients [50 percent]). There were similar degrees of deviation from the
recommended doses in patients receiving long-term DOAC therapy (rivaroxaban: 14
percent; apixaban: 36 percent; dabigatran: 46 percent). Deviations from recommended
dosing typically involved a dose or dosing frequency that was lower than recommended (eg,
once-daily dosing instead of twice-daily dosing), and these deviations from recommended
dosing correlated with higher rates of VTE recurrence (adjusted hazard ratio [HR] 10.5).
Rates of bleeding and death were not different from patients who received the correct dose.
It is often stated that clinicians should become familiar with one of the DOACs and use that
drug when a DOAC is indicated. However, differences among these drugs, as described
below, as well as institutional or pharmacy preferences, may make a different drug a better
choice for a given patient. Thus, it is important to develop familiarity with key aspects of
prescribing different agents.
Drug adherence — Drug adherence appears to be relatively similar in large populations,
although these may differ in some individuals or clinical settings. A set of strategies to
maximize drug adherence and minimize bleeding have been published [20]. These
emphasize useful ways to ask about compliance, reminders about medication storage,
counseling about missed doses, planning for surgical procedures, avoidance of prescribed
and nonprescription medications that interfere with platelet function (unless medially
indicated), monitoring of renal function, aggressive management of hypertension, and
approaches to minimizing the risk of falls.
The similar adherence to DOACs versus warfarin was demonstrated in a meta-analysis of

randomized trials (18 trials, 101,801 patients) that evaluated drug discontinuation rates in
patients with VTE or atrial fibrillation (AF), who were treated for more than 12 weeks with a
DOAC or a pharmacologically active comparator [21]. Individuals receiving a DOAC had
similar rates of drug discontinuation to those receiving a vitamin K antagonist, both for VTE
(13 versus 14 percent; relative risk [RR] 0.91; 95% CI 0.74-1.13) and for AF (22 percent for
both types of agent; RR 1.01; 95% CI 0.87-1.17).
A review of 4863 patients who were prescribed dabigatran for atrial fibrillation found a
median adherence rate of 74 percent (interquartile range, 66 to 80 percent) [22]. Adherence
was higher at institutions that preselected patients for the ability to adhere to twice-daily
medication and at those that provided pharmacist-based patient education and greater
communication regarding medication use. Lower adherence rates could be improved by
instituting these measures.
Importantly, patients prescribed a DOAC who do not or cannot take the medication as
prescribed may have a greater amount of time during which they are not therapeutically
anticoagulated compared with patients who miss occasional doses of warfarin. The ability
to monitor the degree of nonadherence is lost when a DOAC is substituted for warfarin. As
noted below, a single missed dose of a DOAC has greater potential to result in inadequate
anticoagulation than a single missed dose of warfarin. (See 'Settings in which a heparin or
vitamin K antagonist may be preferable' below.)
Advantages over heparin and warfarin — The DOACs differ significantly from vitamin K
antagonists in their onset of action, half-life, drug-drug interactions, need for monitoring,
ability to monitor should this be called into question, as well as availability of antidotes in
the case of excessive bleeding (table 1). In some cases, these differences may translate
into similar efficacy with greater ease of administration and lower bleeding risk. However,
as noted above, the efficacy and bleeding risk depend on patient variables such as
compliance and interacting medications, and all decisions must be individualized to take
these factors into account.
● Lower bleeding risk – Overall, all-cause mortality from DOACs appears to be lower than
that from warfarin, driven primarily by a decrease in fatal intracranial bleeding risks
[23]. However, direct comparison of bleeding risk with different agents is challenging
because risks appear to vary in different patient populations and clinical settings, and
meta-analysis often combines different doses of the same anticoagulant [24]. This
issue is discussed in detail separately. (See "Management of bleeding in patients
receiving direct oral anticoagulants", section on 'Bleeding risks from DOACs'.)
● Laboratory monitoring – Heparin and warfarin both have a relatively narrow therapeutic
window and more variable dose-response relationship that depends on a variety of
factors; these features lead to a requirement for frequent monitoring of clotting times
to optimize the therapeutic dose range and prevent bleeding [25,26]. Dose may be
affected by differing bioavailability, diet, and acute medical illnesses. In contrast, the
DOACs are generally used without a requirement for monitoring of drug levels or
coagulation (clotting) times. This may be an advantage for patients for whom frequent
monitoring is a greater burden. It remains to be determined whether laboratory
monitoring of any of the DOACs can further improve their efficacy or safety. (See
'Laboratory testing and monitoring (dabigatran)' below.)
● Pharmacokinetics – Warfarin pharmacokinetics is affected by the level of vitamin K

intake and production in the gastrointestinal tract, as well as induction of hepatic
cytochromes. Thus, warfarin effect can be altered by changes in diet, administration of
other medications, gastrointestinal disorders, and reduced oral intake. Patients with
difficulty controlling the prothrombin time/international normalized ratio (PT/INR) may
benefit from a DOAC because these agents have less variability in drug effect for a
given dose than vitamin K antagonists. Affected patients may include those with
unavoidable drug-drug interactions (such as frequent need for antibiotics or a large
number of concomitant and variable medications) or unexplained poor warfarin
control. However, it is important to determine that the INR instability with a vitamin K
antagonist is not due to poor compliance, which may be easier to monitor for vitamin K
antagonists than for the target-specific agents.
● Biology – The biology of the parenteral direct thrombin inhibitors (eg, bivalirudin,
argatroban) may give them advantages over heparins in certain clinical settings such
as percutaneous cardiac interventions, where inhibition of clot-bound thrombin might
be important; and heparin-induced thrombocytopenia (HIT), where induction of an
aggressive hypercoagulable state (due to anti-heparin-PF4 antibodies) must be avoided
(see 'Indications' below). Dabigatran was associated with a lower risk of osteoporotic
fractures than warfarin (0.7 versus 1.1 per 100 person-years) in a retrospective study of
individuals with new-onset atrial fibrillation; it is not clear whether this reflects a
difference in the biology of these anticoagulants or other patient factors [27-29].
Settings in which a heparin or vitamin K antagonist may be preferable — There are several
settings in which warfarin may be preferable to one of the DOACs, or in which a DOAC is
contraindicated (eg, prosthetic heart valve, pregnancy). In addition, patients who are
receiving warfarin with excellent stable INR control and minimal bleeding side effects may
have little to gain by switching to a different agent. In many inpatient settings, heparins are
preferable because of similar efficacy to parenteral direct thrombin inhibitors, availability of
an antidote, and substantially lower costs.
● Prosthetic heart valves – The direct thrombin inhibitors and direct factor Xa inhibitors
are not used in patients with prosthetic heart valves, due to greater risk of valve
thrombosis, which may be fatal. (See "Antithrombotic therapy for prosthetic heart
valves: Indications", section on 'Direct oral anticoagulants'.)
● Pregnancy – Direct thrombin inhibitors and direct factor Xa inhibitors are not used
during pregnancy, due to lack of clinical experience in this setting; LMW heparin is
preferred in most pregnant women who require an anticoagulant. If a patient taking one
of these agents becomes pregnant, she should be switched to LMW heparin
immediately. This issue is discussed in detail separately. (See "Use of anticoagulants
during pregnancy and postpartum".)
● Renal impairment – Renal insufficiency is a common setting in which heparin or

warfarin may be preferable to the DOACs. Creatinine clearance can be estimated from
the patient's sex, age, weight, and serum creatinine (calculator 1 and calculator 2).
Direct thrombin inhibitors and direct factor Xa inhibitors are renally excreted to variable
degrees.
• In hospitalized patients with renal insufficiency, heparin is generally used.
• For outpatients with moderate renal impairment (creatinine clearance 30-50

mL/minute), the DOACs appear to be at least as safe as warfarin [30]. Of the
DOACs, apixaban is the least dependent on renal clearance. Dose adjustments
may be appropriate, as discussed below under the specific agents. (See 'Dosing
(dabigatran)' below and 'Dosing, monitoring, risks (rivaroxaban)' below and 'Dosing,
monitoring, risks (apixaban)' below and 'Edoxaban' below.)
• For outpatients with severe renal impairment (creatinine clearance <30

mL/minute), there is insufficient evidence to predict how DOACs may compare
with warfarin. Warfarin or dose-adjusted low molecular weight (LMW) heparin
(table 2) is generally preferred over a DOAC in those with a creatinine clearance
<30 mL/minute who require long-term anticoagulation. Product labeling for
dabigatran and the direct factor Xa inhibitors state that the agents are not to be
used in individuals with a creatinine clearance <15 mL/minute [31-34]. (See
"Anticoagulation for continuous renal replacement therapy".)
● Severe liver disease – DOACs are hepatically metabolized to varying degrees, and
most clinicians do not use DOACs in individuals with severe hepatic impairment, as
shown in the table (table 3).
● Antiphospholipid syndrome – In patients with the antiphospholipid syndrome (APS)

who require anticoagulation, there are very few data on the efficacy of DOACs. Heparin
followed by warfarin is generally the preferred therapy. A randomized trial is in progress
comparing rivaroxaban with warfarin in individuals with high-risk APS [35]. (See
"Treatment of antiphospholipid syndrome".)
● Compliance – Use of DOACs may be challenging in patients who are unable to take
their medication as prescribed. The lack of routine monitoring and short half-lives of
these agents make it more difficult to determine if a patient is taking them
appropriately. In addition, missing one or two doses can leave the patient inadequately
anticoagulated; in contrast, missing a couple of doses of warfarin is unlikely to
substantially increase the time outside the therapeutic range.
● Gastrointestinal disease – Patients with gastrointestinal diseases, especially those

with a history of bleeding, may prefer to avoid the direct factor Xa inhibitors because of
an increased bleeding risk. Individuals with severe dyspepsia may not tolerate
dabigatran. (See 'Risks (dabigatran)' below.)
● Dosing convenience – Dabigatran and apixaban require twice daily dosing, which may
cause an increased burden for patients who place a higher value on taking a single
daily dose of an anticoagulant. European labeling for dabigatran includes once daily
dosing. Rivaroxaban and edoxaban have a once daily dosing schedule, as does
warfarin.
● Cost – Vitamin K antagonists are typically much less expensive than DOACs.
INDICATIONS — Clinical indications for direct thrombin inhibitors and direct factor Xa

inhibitors in various settings are discussed in separate topic reviews:
● Venous thromboembolism (VTE) prophylaxis (nonorthopedic) – (See "Prevention of

venous thromboembolic disease in adult nonorthopedic surgical patients".)
● VTE prophylaxis (orthopedic) – (See "Prevention of venous thromboembolism in adult

orthopedic surgical patients".)
● VTE treatment (individuals without cancer, initial anticoagulation) – (See "Venous

thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Direct factor
Xa and thrombin inhibitors'.)
● VTE treatment (individuals without cancer, long-term anticoagulation) – (See "Venous

thromboembolism: Anticoagulation after initial management", section on 'Direct
thrombin and factor Xa inhibitors'.)
● VTE treatment (individuals with cancer) – (See "Treatment of venous

thromboembolism in patients with malignancy".)
● Atrial fibrillation (AF) – (See "Atrial fibrillation: Anticoagulant therapy to prevent

embolization", section on 'Select an anticoagulant'.)
● Acute coronary syndromes (ACS) – (See "Anticoagulant therapy in non-ST elevation

acute coronary syndromes" and "Anticoagulant therapy in acute ST elevation
myocardial infarction" and "Antithrombotic therapy for elective percutaneous coronary
intervention: Clinical studies", section on 'Bivalirudin' and "Chronic anticoagulation after
acute coronary syndromes".)
● Heparin-induced thrombocytopenia (HIT) – (See "Management of heparin-induced

thrombocytopenia", section on 'Direct oral anticoagulants'.)
These agents are not used in individuals with prosthetic heart valves, severe renal
insufficiency, or pregnancy; and data are too preliminary to support their use in
antiphospholipid syndrome (APS). (See "Antithrombotic therapy for prosthetic heart valves:
Indications" and "Treatment of antiphospholipid syndrome".)
Possible contraindications to anticoagulation are listed in the table (table 4); however, this
list is not intended to substitute for the judgment of the treating clinician who is able to
weigh the risks and benefits for the individual patient.
DIRECT THROMBIN INHIBITORS — Direct thrombin inhibitors inactivate circulating and clot-

bound thrombin (factor IIa) (figure 3). This may be especially important in individuals with
coronary thrombosis. (See "Anticoagulant therapy in non-ST elevation acute coronary
syndromes", section on 'UFH compared with bivalirudin'.)
Unlike heparin, the direct thrombin inhibitors do not bind to platelet factor 4 (PF4) and thus
are not able to induce or react with the anti-heparin/PF4 antibodies that cause heparin-
induced thrombocytopenia (HIT). Thus, the parenteral direct thrombin inhibitors are options
for anticoagulation in patients with HIT. (See "Management of heparin-induced
thrombocytopenia", section on 'Anticoagulation'.)
Parenteral direct thrombin inhibitors — Parenteral direct thrombin inhibitors include

bivalirudin, argatroban, and desirudin (figure 3). Lepirudin is a recombinant hirudin that has
been unavailable since May 2012, when the manufacturer discontinued marketing
(unrelated to safety concerns) [36-38]. (See 'Bivalirudin' below and 'Argatroban' below.)
Bivalirudin — Bivalirudin (Angiomax, previously called Hirulog) is a synthetic 20 amino

acid peptide that binds to the thrombin catalytic site and exosite I, reversibly inhibiting
thrombin enzymatic activity [39]. The peptide sequence is an analog of hirudin, a protein
extracted from the salivary gland of the medicinal leech. (See 'Sites of action' above.)
The indications and use of bivalirudin in patients undergoing percutaneous coronary

interventions (PCI) and heparin induced thrombocytopenia (HIT) are discussed separately:
● PCI – (See "Antithrombotic therapy for elective percutaneous coronary intervention:

Clinical studies", section on 'Bivalirudin' and "Anticoagulant therapy in non-ST elevation
acute coronary syndromes" and "Anticoagulant therapy in acute ST elevation
myocardial infarction".)
● HIT – (See "Management of heparin-induced thrombocytopenia".)
Bivalirudin is administered at a dose of 0.75 mg/kg intravenously as a bolus followed by

1.75 mg/kg per hour during a procedure. Patients with renal failure do not require a change
in the bolus dose; those with CrCl <30 mL/minute may use a lower infusion rate (eg, 1
mg/kg per hour) [39]. Intravenous administration produces an immediate anticoagulant
effect. The half-life of bivalirudin is approximately 25 minutes; prolonged coagulation times
return to normal approximately one hour after discontinuation [40]. The drug is metabolized
in kidney, liver, and other sites [1]. Bivalirudin can be hemodialyzed.
Bivalirudin can be monitored by the activated clotting time (ACT); action is rapid and the
effect can be tested within minutes of administration. Monitoring can also be performed
using the activated partial thromboplastin time (aPTT), with a target of 1.5 to 2.5 times the
normal range. Patients with renal impairment should be monitored with an activated
clotting time; the therapeutic range varies with the device used.
Argatroban — Argatroban (Arganova, Argaron, Argatra, Da Bei, Exembol, Gartban,

Novastan, Slonon) is a synthetic peptide-based direct thrombin inhibitor that interacts with
the active site of thrombin [41]. It has a short in vivo plasma half-life (terminal elimination
half-life approximately 40 to 50 minutes) [42]. (See 'Sites of action' above.)
Dosing and monitoring of argatroban differs depending on the indication:
● Heparin-induced thrombocytopenia (HIT) – For patients with HIT who have normal
hepatic function, argatroban is administered at an initial dose of 2 mcg/kg per minute
intravenously as a continuous infusion [42]. Monitoring is done by the aPTT; a baseline
aPTT should be obtained prior to administration, and the aPTT should be repeated two
hours after starting therapy, and after any dose changes. The dose is adjusted to
achieve a target aPTT of 1.5 to 3 times the initial baseline value, not to exceed 100
seconds [42]. Further details of the use of argatroban in HIT are presented separately.
(See "Management of heparin-induced thrombocytopenia", section on 'Argatroban'.)
● Percutaneous coronary intervention (PCI) – For PCI in patients with HIT or at high risk
for HIT, argatroban is given as a bolus of 350 mcg/kg over three to five minutes, with an
infusion of 25 mcg/kg per minute. Monitoring is done by the activated clotting time.
Parameters are discussed in detail separately. (See "Antithrombotic therapy for elective
percutaneous coronary intervention: General use", section on 'Heparin-induced
thrombocytopenia'.)
Argatroban is hepatically metabolized, and dosing adjustment is advised in patients with

hepatic impairment [1]. Dose adjustment is not required in patients with renal impairment
[42,43].
Argatroban prolongs the prothrombin time/international normalized ratio (PT/INR). Thus,

when patients receiving argatroban are transitioned to warfarin, it is necessary to use an
adjusted INR target during overlap, and repeat the INR upon discontinuation of argatroban.
Institutional guidelines regarding the appropriate INR target should be followed.
Desirudin — Desirudin (Iprivask, Revasc) is a recombinant hirudin derivative that inhibits

free and clot-bound thrombin [44]. The half-life is approximately two hours; this is increased
in patients with renal insufficiency. A typical dose in patients with normal renal function is
15 mg subcutaneously every 12 hours, with the first dose administered 30 minutes before
hip arthroplasty or postoperatively [45,46]. There is a Boxed Warning regarding the risk of
spinal/epidural hematoma in patients anticoagulated with desirudin when neuraxial
anesthesia is used.
Oral direct thrombin inhibitor — Dabigatran is the only oral direct thrombin inhibitor
available for clinical use. Additional agents are under development (eg, AZD-0837) [47].
Dabigatran
Overview (dabigatran) — Dabigatran etexilate (Pradaxa) is an orally administered

prodrug that is converted in the liver to dabigatran, an active direct thrombin inhibitor that
inhibits clot-bound and circulating thrombin [48]. The half-life is approximately 12 to 17
hours in individuals with normal renal function. Absorption is unaffected by food.
Importantly, dabigatran capsules should only be dispensed and stored in the original bottle
(with desiccant) or blister package in which they came, due to the potential for product
breakdown from moisture and resulting loss of potency. Patients should not store or place
this agent in any other container, such as pill boxes or pill organizers. Once the bottle is
opened, the pills inside must be used within four months [49]. The capsules should not be
crushed or opened before administration, as removal of the capsule shell results in
dramatic increases in oral bioavailability [50].
Dabigatran is used in the prevention and management of venous thromboembolic (VTE)

disease, and in stroke prevention in patients with atrial fibrillation (AF). These indications
are discussed in detail separately:
● VTE prophylaxis – (See "Prevention of venous thromboembolic disease in adult

nonorthopedic surgical patients".)
● VTE overview of treatment – (See "Overview of the treatment of lower extremity deep
vein thrombosis (DVT)".)
● VTE initial treatment – (See "Venous thromboembolism: Initiation of anticoagulation

(first 10 days)".)
● VTE extended treatment – (See "Venous thromboembolism: Anticoagulation after

initial management".)
● AF – (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization".)
Dabigatran should not be used in patients with prosthetic heart valves or during pregnancy.
(See "Antithrombotic therapy for prosthetic heart valves: Indications" and "Use of
anticoagulants during pregnancy and postpartum".)
Dosing (dabigatran) — Dabigatran is generally given at a fixed dose without

monitoring (table 5). Maximum anticoagulant effects are achieved within two to three hours
of ingestion [51]. Renal excretion of unchanged drug is the predominant elimination
pathway, with approximately 80 percent of an intravenous dose being excreted unchanged
in the urine [52,53]. The dosing differs according to the clinical indication and the patient's
renal function [50]:
● Venous thromboembolism (VTE) primary prophylaxis in surgical patients: 110 mg one

to four hours after surgery, followed by 220 mg once daily for 28 to 35 days (hip
replacement) or 10 days (knee replacement).
● Treatment and secondary prevention of VTE: 150 mg orally twice daily after 5 to 10
days of parenteral anticoagulation (CrCl >30 mL/minute).
● Stroke prevention in atrial fibrillation (AF): 110 mg orally twice daily or 150 mg orally
twice daily (CrCl >30 mL/minute). European labeling suggests dose reduction in
patients older than 75 years (eg, 150 mg orally once per day or 110 mg orally twice per
day) [24,54]. This is discussed in more detail separately. (See "Atrial fibrillation:
Anticoagulant therapy to prevent embolization", section on 'Dosing of non-vitamin K
antagonist oral anticoagulants'.)
Clinical settings in which dose modification or drug avoidance may be indicated include the
following:
● Renal insufficiency – Dabigatran is metabolized in the kidney, and the half-life is

extended in patients with renal insufficiency. As an example, a study in volunteers with
mild, moderate, and severe chronic kidney disease and renal failure receiving dialysis
found half-lives of approximately 14, 17, 19, 28, and 34 hours, respectively [52]. Dose
reduction has been recommended for those with a creatinine clearance in the range of
15 to 30 mL/minute, since such patients otherwise have had marked increases in
bleeding events when taking full doses [55]. We reduce the dose in patients with CrCl
15 to 30 mL/minute (eg, 75 mg orally twice daily instead of doses listed above).
Product labeling in the United States recommends avoidance of dabigatran in
individuals with creatinine clearance <15 mL/minute or in those who are hemodialysis
dependent; the Canadian, United Kingdom, and European Medicines Agency labeling
recommend avoidance in patients with a creatinine clearance <30 mL/minute [56-58]
(table 6). Creatinine clearance can be estimated from the patient's sex, age, weight, and
serum creatinine (calculator 1 and calculator 2).
● P-glycoprotein inhibitors or inducers – Dabigatran is a substrate for P-glycoprotein.

Concomitant use of dabigatran with P-glycoprotein inducers (eg, rifampin) reduces the
anticoagulant effect of dabigatran and generally should be avoided. Concomitant use
of dabigatran with P-glycoprotein inhibitors (eg, ketoconazole, verapamil) in patients
with renal failure may increase the anticoagulant effect of dabigatran (table 6 and table
7) [50]. Official prescribing information and/or a drug interactions resource should be
consulted for any questions.
By contrast, dabigatran is not metabolized by the cytochrome p450 system (CYP); dose
changes are not generally required with concomitant administration of CYP inducers or
inhibitors.
● Obesity – Data are limited on the efficacy and toxicity of dabigatran in obese
individuals. Based on a 2016 review of available literature, the International Society of
Hemostasis and Thrombosis (ISTH) recommends avoidance of dabigatran in
individuals with a body mass index (BMI) >40 kg/m2, or weight ≥120 kg [59]. They
recommend use of dabigatran (and other direct oral anticoagulants) at standard dose
for patients with a BMI ≤40 kg/m2 or weight <120 kg. This reflects our general practice,
although it should not replace clinical judgment regarding avoidance in individuals with
a lower BMI or use in those with a higher BMI.
Support for the approach of tailoring dosage according to patient variables such as age or
renal function comes from a study of 100 patients with atrial fibrillation, which found that a
lower dose of dabigatran (110 mg twice daily) in patients who were older, of lower body
weight, or had lower creatinine clearance, resulted in trough levels that were comparable to
the higher dose (150 mg twice daily) in patients who lacked these characteristics [60].
Laboratory testing and monitoring (dabigatran) — Laboratory testing prior to initiating

dabigatran should include platelet count, prothrombin time (PT), and activated partial
thromboplastin time (aPTT), to assess and document coagulation status before
anticoagulation; and measurement of serum creatinine, as a baseline and for potential dose
adjustment in the event of renal insufficiency.
Routine laboratory monitoring of coagulation times is not required for patients taking
dabigatran, because drug levels are relatively predictable for a given dose. However,
possible improvements in efficacy and/or safety with monitoring of dabigatran plasma
concentrations have been suggested, and monitoring recommendations may change [61-
66].
Settings in which coagulation testing for dabigatran effect may be helpful include the
following:
● Bleeding in a patient receiving dabigatran, or with suspected dabigatran overdose –

(See "Management of bleeding in patients receiving direct oral anticoagulants", section
on 'Assessment of anticoagulation status'.)
● Need for emergent or urgent surgery in a patient receiving dabigatran – (See

"Perioperative management of patients receiving anticoagulants", section on
'Dabigatran'.)
In such cases, the ecarin clotting time is the best method to assess bleeding risk, but this
test is not widely available. Other coagulation tests that are prolonged in the presence of
therapeutic doses of dabigatran include the dilute thrombin time (dilute TT), activated
partial thromboplastin time (aPTT), and the activated clotting time (ACT). In contrast, the
prothrombin time (PT) cannot be used as a reliable measure of dabigatran activity. A study
that compared the PT, aPTT, and TT in plasma to which dabigatran had been added found
that the TT was the most sensitive test for detecting low levels of dabigatran [67]. There
was test-kit variability for all of these assays, emphasizing the need for caution when
comparing tests from different studies and/or manufacturers. Some clinicians find the TT
too sensitive and prefer to use the aPTT to assess the presence of dabigatran. Point-of-care
devices for measuring the prothrombin time/international normalized ratio (PT/INR) should
not be used [68]. (See "Clinical use of coagulation tests".)
Risks (dabigatran) — As with all anticoagulants, dabigatran increases bleeding risk.
However, an antidote has been developed (see "Management of bleeding in patients
receiving direct oral anticoagulants", section on 'Dabigatran reversal'). Product labeling for
dabigatran has a Boxed Warning regarding the risk of spinal/epidural hematoma in patients
undergoing neuraxial anesthesia or spinal puncture [69].
Bleeding risks of dabigatran compared with other oral anticoagulants have been evaluated
in several meta-analyses and large observational series. In general, these have shown that
overall bleeding rates are similar with dabigatran compared with warfarin. Dabigatran may
be associated with a slightly lower rate of intracranial hemorrhage and death, and a slightly
higher risk of gastrointestinal bleeding at the 150 mg twice daily dose (but not 110 mg
twice daily) [24,70-73]. A discussion of bleeding risks and comparison with other oral
anticoagulants, such as vitamin K antagonists, in various clinical settings is presented
separately. (See "Management of bleeding in patients receiving direct oral anticoagulants",
section on 'Bleeding risks from DOACs'.)
The management of bleeding and perioperative management in patients receiving

dabigatran is also discussed in detail separately. (See "Management of bleeding in patients
receiving direct oral anticoagulants" and "Perioperative management of patients receiving
anticoagulants".)
As with all anticoagulants, dabigatran is administered in the setting of increased

thromboembolic risk. Dabigatran has a Boxed Warning regarding the risk of thrombotic
events following premature discontinuation [69].
Dyspepsia is a common side effect of dabigatran, with an incidence from 12 to 33 percent

in some studies [74-76]. In the RE-LY trial, which randomized 18,113 individuals with AF to
dabigatran or warfarin, non-bleeding gastrointestinal events (eg, dyspepsia, dysmotility,
gastrointestinal reflux) were twice as common in those who received dabigatran (16.9
versus 9.4 percent; relative risk [RR] 1.81; 95% CI 1.66-1.97 percent) [77]. This may limit
dabigatran use in some patients. (See "Approach to the adult with dyspepsia".)
There does not appear to be an increased risk of serious liver injury with dabigatran, despite
concerns with an earlier direct thrombin inhibitor that was not approved (ximelagatran). In a
cohort study involving 51,887 patients receiving a DOAC (3778 of whom [7 percent] had
prior liver disease), the adjusted hazard ratio (HR) for serious liver injury was 0.99 (95% CI
0.68-1.45), and there was a trend towards a lower risk of serious liver injury in the
individuals with prior liver injury that did not reach statistical significance (adjusted HR 0.68;
95% CI 0.33-1.37) [78].
DIRECT FACTOR Xa INHIBITORS

General issues for direct factor Xa inhibitors — Direct factor Xa inhibitors inactivate
circulating and clot-bound factor Xa (figure 3). Several orally acting direct factor Xa
inhibitors are clinically available. (See 'Rivaroxaban' below and 'Apixaban' below and
'Edoxaban' below and 'Betrixaban' below.)
There are no parenteral direct factor Xa inhibitors available for clinical use. Otamixaban was
developed as an intravenous factor Xa inhibitor, but development was discontinued due to
an increased risk of bleeding compared with unfractionated heparin in patients with acute
coronary syndromes [79,80].
Direct factor Xa inhibitors are metabolized in the kidney (approximately 25 to 35 percent)

and liver, and severe hepatic impairment could result in accumulation of these agents.
However, direct factor Xa inhibitors do not appear to cause hepatotoxicity. In a cohort study
involving 51,887 patients receiving a DOAC (3778 of whom [7 percent] had prior liver
disease), there was not an increased risk of serious liver injury (adjusted hazard ratio [HR]
0.99; 95% CI 0.68-1.45) [78]. In the individuals with prior liver disease, there was a trend
towards a lower risk of serious liver injury with the DOACs that did not reach statistical
significance (adjusted HR 0.68; 95% CI 0.33-1.37).
Data are limited on the efficacy and toxicity of direct factor Xa inhibitors in obese
individuals. Based on a 2016 review of available literature, the International Society of
Hemostasis and Thrombosis (ISTH) recommends avoidance of these agents in individuals
with a body mass index (BMI) >40 kg/m2, or weight ≥120 kg [59]. They recommend use of
these agents at standard dose for patients with a BMI ≤40 kg/m2. This reflects our general
practice, although it should not replace clinical judgment regarding avoidance in individuals
with a lower BMI or use in those with a higher BMI. A 2017 review specific to rivaroxaban
concluded that it could be administered to individuals with a BMI >40 kg/m2 (or weight
>120 kg) without dose adjustment, although data were limited [81]. (See 'Dosing,
monitoring, risks (rivaroxaban)' below.)
A reversal agent for the direct factor Xa inhibitors, andexanet alfa, was approved for the
management of life-threatening bleeding associated with direct factor Xa inhibitor
anticoagulation, although experience is limited. The use of this and other agents in the
management of bleeding and perioperative management in patients receiving direct factor
Xa inhibitors are discussed in detail separately. (See "Management of bleeding in patients
receiving direct oral anticoagulants" and "Perioperative management of patients receiving
anticoagulants".)
Rivaroxaban
Overview (rivaroxaban) — Rivaroxaban (Xarelto) is an orally available direct factor Xa

inhibitor with a half-life of 5 to 9 hours (may be longer in older individuals [eg, 11 to 13
hours]).
Rivaroxaban is used in the prevention and treatment of venous thromboembolic (VTE)

disease, and in stroke prevention in patients with atrial fibrillation (AF). These indications
are discussed in detail separately:


(first 10 days)".)

Rivaroxaban should not be used during pregnancy. (See "Use of anticoagulants during
pregnancy and postpartum".)
Dosing, monitoring, risks (rivaroxaban) — Rivaroxaban is generally given at a fixed dose

without monitoring (table 5). The 15 and 20 mg tablets are to be taken with food [82,83].
The dosing differs according to the clinical indication and the patient's renal function.
● Venous thromboembolism (VTE) prophylaxis in surgical patients: 10 mg daily; duration

(12 days versus extended to 35 days) depends on the type of surgery, as discussed
separately. (See "Prevention of venous thromboembolism in adult orthopedic surgical
patients" and "Prevention of venous thromboembolic disease in adult nonorthopedic
surgical patients".)
● Treatment and secondary prevention of VTE: 15 mg twice daily (with food) for 21 days,
followed by 20 mg once daily (with food). If therapy is continued after six months, the
dose can be reduced to 10 mg once daily for selected individuals. However, for those
with an increased risk for VTE beyond six months of anticoagulation (eg, two or more
episodes of VTE), the 20 mg once-daily dose should be used [84]. (See "Rationale and
indications for indefinite anticoagulation in patients with venous thromboembolism",
section on 'Factor Xa and direct thrombin inhibitors'.)
● Stroke prevention in atrial fibrillation (AF): 20 mg once daily with the evening meal (CrCl
>50 mL/minute); or 15 mg once daily with the evening meal (CrCl ≤50 mL/minute).
Rivaroxaban is not recommended for VTE prophylaxis, treatment, or secondary prevention
in individuals with a creatinine clearance <30 mL/minute. The drug should not be used in
individuals with a creatinine clearance <15 mL/minute, as well as in those with significant
hepatic impairment (Child-Pugh Class B and C with coagulopathy) [85]. Creatinine clearance
can be estimated from the patient's sex, age, weight, and serum creatinine (calculator 1 and
calculator 2). Rivaroxaban has not been tested in children younger than 18 years [86].
Recommendations for obese individuals are listed above. (See 'General issues for direct
factor Xa inhibitors' above.)
Rivaroxaban interacts with drugs that are potent dual inhibitors of CYP-3A4 and P-
glycoprotein (eg, systemic ketoconazole, itraconazole, voriconazole, posaconazole or
ritonavir), and concurrent use is contraindicated by Canadian product information (table 6
and table 8 and table 7) [56]. Drugs that inhibit either CYP-3A4 or P-glycoprotein, as
opposed to both, do not seem to significantly alter rivaroxaban [87]. Potent inducers of CYP-
3A4 (eg, rifamycins, carbamazepine, St. John's wort) may reduce rivaroxaban's effects
(table 8) [87-89].
Laboratory testing prior to initiating rivaroxaban should include platelet count, prothrombin
time (PT), and activated partial thromboplastin time (aPTT), to assess and document
coagulation status before anticoagulation; and measurement of serum creatinine and liver
function tests, as a baseline and for potential dose adjustment in the event of renal or
hepatic insufficiency.
Routine monitoring of coagulation times is not required for patients taking rivaroxaban,
because drug levels are relatively predictable for a given dose. However, possible
improvements in efficacy and/or safety with monitoring have been suggested [65,66].
Settings in which coagulation testing for rivaroxaban effect may be helpful include the
following:
● Bleeding in a patient receiving rivaroxaban, or with suspected rivaroxaban overdose –

(See "Management of bleeding in patients receiving direct oral anticoagulants", section
on 'Assessment of anticoagulation status'.)
● Need for emergent or urgent surgery in a patient receiving rivaroxaban – (See

'Rivaroxaban'.)
In such cases, monitoring is best done by measuring anti-factor Xa activity using an assay
specifically calibrated for rivaroxaban. If an anti-factor Xa assay calibrated to rivaroxaban is
not available, it may be possible to use an anti-factor Xa assay calibrated to another
anticoagulant such as low molecular weight (LMW) heparin. Other assays such as the PT
and aPTT are not very reliable [90].
Cases of liver injury following rivaroxaban administration have been reported, although this
was not seen in larger trials [91,92]. The incidence of this complication is unknown.
As with all anticoagulants, rivaroxaban increases bleeding risk and is administered in the
setting of increased thrombotic risk. Product labeling for rivaroxaban has Boxed Warnings
regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia
or spinal puncture and the risk of thrombotic events following premature discontinuation
[93]. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant
or antiplatelet medication".)
Apixaban
Overview (apixaban) — Apixaban (Eliquis) is an orally active factor Xa inhibitor with a

half-life of approximately 12 hours.
Apixaban is used in the prevention and treatment of VTE and in stroke prevention in
patients with AF. These indications are discussed in detail separately:


(first 10 days)".)

Apixaban should not be used in patients with prosthetic heart valves or during pregnancy.
Dosing, monitoring, risks (apixaban) — Apixaban is generally given at a fixed dose

without monitoring (table 5).
The dosing of apixaban differs according to the clinical indication and the patient's age,
weight, and renal function [94].
● Venous thromboembolism (VTE) prophylaxis in surgical patients: 2.5 mg twice daily;

duration (12 days versus extended to 35 days) depends on the type of surgery, as
discussed separately. (See "Prevention of venous thromboembolism in adult
orthopedic surgical patients" and "Prevention of venous thromboembolic disease in
adult nonorthopedic surgical patients".)
● Treatment and secondary prevention of VTE: 10 mg twice daily for seven days,
followed by 5 mg twice daily. If therapy continues beyond six months, the dose is
reduced to 2.5 mg twice daily [95].
● Stroke prevention in atrial fibrillation (AF): 5 mg twice daily (CrCl >50 mL/minute); or
2.5 mg twice daily for those with any two of the following: age ≥80 years, body weight
≤60 kg, or serum creatinine ≥1.5 mg/dL.
Apixaban dose reduction is recommended for patients who are also receiving strong dual
inhibitors of CYP-3A4 and P-glycoprotein (table 6 and table 8 and table 7) [94].
Recommendations for obese individuals are listed above. (See 'General issues for direct
Apixaban has the least dependence on renal clearance of the direct factor Xa inhibitors.
Canadian product information states that apixaban is not recommended in individuals with
creatinine clearance <15 mL/minute; United States product information recommends dose
adjustments based on creatinine clearance, body weight, and age [33,96]. Creatinine
clearance can be estimated from the patient's sex, age, weight, and serum creatinine
(calculator 1 and calculator 2).
Laboratory testing prior to initiating apixaban should include platelet count, prothrombin
time (PT), and activated partial thromboplastin time (aPTT), to assess and document
coagulation status before anticoagulation; and measurement of serum creatinine and liver
function tests, as a baseline and for potential dose adjustment in the event of renal or
hepatic insufficiency.
Routine monitoring of coagulation times is not required for patients taking apixaban,
because drug levels are relatively predictable for a given dose. However, possible
improvements in efficacy and/or safety with monitoring have been suggested [65,66].
Settings in which coagulation testing for apixaban effect may be helpful include the
following:
● Bleeding in a patient receiving apixaban, or with suspected apixaban overdose – (See

"Management of bleeding in patients receiving direct oral anticoagulants", section on
'Assessment of anticoagulation status'.)
● Need for emergent or urgent surgery in a patient receiving apixaban – (See

'Apixaban'.)
In such cases, monitoring can be accomplished through the measurement of anti-factor Xa
activity [97].
As with all anticoagulants, apixaban increases bleeding risk and is administered in the
setting of increased thromboembolic risk. Product labeling for apixaban has Boxed
Warnings regarding the risk of spinal/epidural hematoma in patients undergoing neuraxial
anesthesia or spinal puncture and the risk of thrombotic events following premature
discontinuation [94].
Edoxaban — Edoxaban (Lixiana, Savaysa) is an orally active factor Xa inhibitor with a half-

life in the range of 10 to 14 hours.
Edoxaban is used in the prevention and treatment of VTE and in stroke prevention in
patients with AF. These indications are discussed in detail separately:


(first 10 days)".)

Edoxaban should not be used in patients with prosthetic heart valves or during pregnancy.
Edoxaban is generally given at a fixed dose without monitoring (table 5). For patients being
treated for VTE, edoxaban is given after 5 to 10 days of parenteral anticoagulation. Typical
dosing is 30 or 60 mg orally once daily [98-101]. Possible improvements in efficacy and/or
safety with monitoring have been suggested [65]. Recommendations for obese individuals
are listed above (see 'General issues for direct factor Xa inhibitors' above). Absorption is
unaffected by food.
Edoxaban is renally excreted and is a substrate for P-glycoprotein. Product information

advises dose reduction for people with creatinine clearance of 15 to 50 mL/minute, and
edoxaban is not to be used in those with creatinine clearance >95 mL/minute or <15
mL/minute (table 6) [34]. Creatinine clearance can be estimated from the patient's sex, age,
weight, and serum creatinine (calculator 1 and calculator 2).
As with all anticoagulants, edoxaban increases bleeding risk and is administered in the
setting of increased thrombotic risk. Product labeling for edoxaban has Boxed Warnings
or spinal puncture, the risk of thrombotic events following premature discontinuation, and
reduced efficacy in nonvalvular atrial fibrillation in patients with a high CrCl (>95
mL/minute) [102].
Betrixaban — Betrixaban (Bevyxxa) is an orally active direct factor Xa inhibitor with a half-

life in the range of 19 to 27 hours [103].
Betrixaban is used in the prevention of VTE in hospitalized adult medical patients, as

discussed separately. (See "Prevention of venous thromboembolic disease in acutely ill
hospitalized medical adults".)
Betrixaban should not be used in patients with prosthetic heart valves or during pregnancy.
Betrixaban is given at a fixed dose without monitoring (table 5). Typical dosing is 160 mg on
the first day followed by 80 mg once daily. Doses are given at the same time each day with
food [104,105]. Betrixaban is renally excreted and is a substrate for P-glycoprotein. For
individuals with CrCl <30 mL/minute or those taking concomitant P-glycoprotein inhibitors,
product information advises a dose of 80 mg on the first day followed by 40 mg daily [103].
For VTE prophylaxis in medical patients, the duration of therapy is 35 to 42 days [104].
Routine monitoring of coagulation times is not required for patients taking betrixaban
because drug levels are relatively predictable for a given dose.
As with all anticoagulants, betrixaban increases bleeding risk and is administered in the
setting of increased thrombotic risk. Product labeling for betrixaban has a boxed warning
or spinal puncture [103].
TRANSITIONING BETWEEN ANTICOAGULANTS — The goal when transitioning between

anticoagulants is to maintain stable anticoagulation. Thus, when transitioning from a DOAC
to a vitamin K antagonist (VKA), it is important to keep in mind that the full effect of the
VKA does not occur for the first few days, despite prolongation of the prothrombin
time/international normalized ratio (PT/INR) [106,107] (see "Warfarin and other VKAs:
Dosing and adverse effects", section on 'Initial dosing'). Likewise, when transitioning from
warfarin to a DOAC, the resolution of warfarin effect may take several days.
The following approaches are reasonable when transitioning from a DOAC to warfarin but
do not substitute for clinical judgment regarding individual patient factors.
● Dabigatran to warfarin – The two agents are overlapped [108]. The number of days of
overlap depends on the patient's renal function:
• Creatinine clearance (CrCl) ≥50 mL/minute – Start VKA three days before
discontinuing dabigatran.
• CrCl 30 to 50 mL/minute – Start VKA two days before discontinuing dabigatran.
• CrCl 15 to 30 mL/minute – Start VKA one day before discontinuing dabigatran.
● Rivaroxaban to warfarin – Prescribing information suggests stopping rivaroxaban and

providing a parenteral agent during warfarin initiation because the INR cannot be
monitored adequately during administration of a direct factor Xa inhibitor [82]. The
warfarin can be started at the same time as the parenteral agent or afterwards,
whichever is more appropriate for the patient's final warfarin schedule.
● Apixaban to warfarin – Prescribing information suggests stopping apixaban and

providing a parenteral agent during warfarin initiation because the INR cannot be
monitored adequately during administration of a direct factor Xa inhibitor [109].
● Edoxaban to warfarin – For patients taking 60 mg of edoxaban, reduce the dose to 30

mg and begin the VKA concomitantly [110]. For patients receiving 30 mg of edoxaban,
reduce the dose to 15 mg and begin the VKA concomitantly. The INR must be
measured at least weekly and just prior to the daily dose of edoxaban to minimize the
effect of edoxaban on INR measurements. Discontinue edoxaban once a stable
increased INR (ie, INR ≥2.0 for at least two days) is reached.
● Betrixaban to warfarin – Transition from betrixaban to warfarin has not been described
because betrixaban is only used for VTE prophylaxis.
Alternative approaches for transitioning from a direct factor Xa inhibitor to warfarin based
on the pharmacodynamics of warfarin and the anticoagulant might be reasonable.
However, the directions from the prescribing information mirror those that were used in the
landmark clinical trials.
The direct factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) also prolong the
PT/INR, which may make monitoring during the transition more challenging.
When switching from a VKA to a DOAC, the product-specific package inserts differ slightly,
but in general, we think it is reasonable to discontinue the VKA and initiate the DOAC when
the INR is ≤2.0:
● Warfarin to argatroban – Start argatroban when the INR is <2.0. (See "Perioperative
management of patients receiving anticoagulants", section on 'Bridging
anticoagulation'.)
● Warfarin to dabigatran – Discontinue the VKA, monitor the PT/INR, and start
dabigatran when the PT/INR is <2.0 [108].
● Warfarin to rivaroxaban – Discontinue the VKA, monitor the PT/INR, and start
rivaroxaban when the PT/INR is <3.0 [111].
● Warfarin to apixaban – Discontinue the VKA, monitor the PT/INR, and start apixaban
when the PT/INR is <2.0 [112].
● Warfarin to edoxaban – Discontinue the VKA, monitor the PT/INR, and start edoxaban
when the PT/INR is ≤2.5 [110].
Switching from a parenteral direct thrombin inhibitor to an oral anticoagulant is discussed

separately:
● Argatroban to warfarin – (See "Management of heparin-induced thrombocytopenia",

section on 'Transition to warfarin or other outpatient anticoagulant'.)
● Bivalirudin to warfarin – (See "Anticoagulant therapy in acute ST elevation myocardial

infarction" and "Anticoagulant therapy in non-ST elevation acute coronary syndromes",
section on 'UFH compared with bivalirudin'.)
Aspects of anticoagulant transitioning specific to individual clinical settings are discussed

in detail separately:
● Atrial fibrillation – (See "Atrial fibrillation: Anticoagulant therapy to prevent

embolization", section on 'Transition from NOAC to warfarin' and "Atrial fibrillation:
Anticoagulant therapy to prevent embolization", section on 'Transition to NOAC from
warfarin'.)
● Prosthetic heart valve – (See "Antithrombotic therapy for prosthetic heart valves:
Management of bleeding and invasive procedures", section on 'Management of
antithrombotic therapy for invasive procedures'.)
● Venous thromboembolism – (See "Venous thromboembolism: Anticoagulation after

initial management", section on 'Switching anticoagulants during therapy'.)
● Perioperative management – (See "Perioperative management of patients receiving

anticoagulants".)
● Gastrointestinal procedures – (See "Management of anticoagulants in patients

undergoing endoscopic procedures".)
ANTICOAGULANTS IN DEVELOPMENT — A variety of anticoagulant strategies targeting
other steps in coagulation are in development:
● Tissue factor pathway inhibitors – The recombinant form of tissue factor pathway
inhibitor (TFPI), the physiologic inhibitor of the TF/FVIIa complex, is being tested;
specific TF/FVIIa and factor VIIa inhibitors (eg, nematode anticoagulant protein) are
also in development [113-116].
● Factor VIII inhibitor – TB-402 is a human IgG4 monoclonal antibody that is a partial
inhibitor of factor VIII. As a result of its long half-life (approximately three weeks), this
agent may provide a prolonged antithrombotic effect after a single dose. This was
demonstrated in a randomized phase II trial in patients following total knee
replacement, in which a single postoperative intravenous injection of TB-402 was found
to be as effective and safe as 10 days of the LMW heparin enoxaparin (40 mg/day for
at least 10 days) in preventing postoperative VTE [117].
● Thrombomodulin – When thrombin binds to thrombomodulin on the endothelial cell

surface, it is converted from a procoagulant enzyme into an anticoagulant enzyme by
its ability to activate protein C [118]. The recombinant form of the extracellular domain
of thrombomodulin was developed as a novel anticoagulant (ART-123), and has been
approved in Japan for treatment of DIC. It has a long plasma half-life of two to three
days after a subcutaneous injection, such that it can be given once every five to six
days with maintenance of anticoagulant activity [119]. In a phase II trial, ART-123 was
shown to be efficacious for VTE prophylaxis following total hip replacement surgery
[120].
● Factor IXa inhibitor – REG1 consists of pegnivacogin (RB006), an injectable RNA

aptamer that specifically binds and inhibits factor IXa, and anivamersen (RB007), the
complementary oligonucleotide that neutralizes its anti-IXa activity if and when needed
(ie, as an antidote). Initial tests of this agent combined with antiplatelet therapy in
patients with coronary artery disease appeared promising [121,122]. However, a
randomized trial comparing REG1 with bivalirudin in patients undergoing percutaneous
coronary intervention (PCI) was terminated early, after enrollment of 3232 patients, due
to severe allergic reactions with REG1 in 10 of 1616 patients (1 percent), compared
with 1 of 1616 patients (0.1 percent) given bivalirudin [123]. REG1 was associated with
reduced stent thrombosis and increased bleeding relative to bivalirudin, but a primary
composite endpoint of death, myocardial infarction, stroke, and unplanned
revascularization was similar between the two groups.
● Factor XI inhibitor – A factor XI antisense oligonucleotide (FXI-ASO) that reduces

factor XI to undetectable levels has been developed [124]. In an open-label trial, 300
patients undergoing elective knee replacement were randomly assigned to receive FXI-
ASO at one of two doses (200 or 300 mg) or the low molecular weight heparin
enoxaparin (40 mg) once daily [125]. The rate of venous thromboembolism, assessed
by venography in all patients, was dramatically reduced in those receiving the higher
dose of FXI-ASO (3 of 71 patients; 3 percent), compared with the lower dose of FXI-
ASO or enoxaparin (27 and 30 percent, respectively). Bleeding was not increased with
the higher FXI-ASO dose (3 percent, versus 3 and 8 percent for FXI-ASO 200 mg and
enoxaparin, respectively). These results raise the interesting hypothesis that
antithrombotic activity might be uncoupled from normal hemostasis, by targeting FXIa
and inhibiting the tertiary amplification pathway in the clotting cascade (figure 2),
allowing maximal anticoagulation without incurring more bleeding risk. Many caveats
for this strategy remain, however, including a long duration of anticoagulation due to
the extended half-life of the antisense therapy (up to three months), injection site
reactions, and potential cost [126].
● Factor XIIa inhibitor – The selective factor XIIa inhibitor rHA-Infestin-4 (recombinant
human albumin fused to the factor XIIa inhibitor Infestin-4) is highly active in human
plasma and profoundly protects mice and rats from pathologic thrombus formation
while not affecting hemostasis [127]. This agent is being considered for the prevention
and treatment of acute ischemic cardiovascular and cerebrovascular events in
humans.
● Protein disulfide isomerase inhibitors – Protein disulfide isomerase (PDI) is an

oxidoreductase enzyme that catalyzes redox protein folding in newly synthesized
proteins in the endoplasmic reticulum, including coagulation factor XI and tissue factor.
PDI is also found on the surface of several types of cells, including platelets, where it
promotes platelet aggregation via integrin activation [128]. Inhibition of PDI is emerging
as a possible target for antithrombotic therapy that blocks the contributions of both
fibrin generation and platelet activation. A number of molecules inhibit PDI, including
quercetins, which are found in certain plant-based foods. Preclinical studies using a
peptide inhibitor of PDI have demonstrated antiplatelet activity in vitro [129]. Clinical
trials with PDI inhibitors are planned.
● Polyphosphate inhibitors – Polyphosphate (released from platelets upon their

activation or from a microbial source) may initiate and/or accelerate coagulation via
intrinsic pathway clotting factors. A variety of compounds that inhibit polyphosphate
and reduce thrombosis in preclinical models are under investigation [130].
Additional details of the hemostatic processes targeted by these anticoagulant strategies

are discussed separately. (See "Overview of hemostasis".)
ANTIDOTES/BLEEDING/INVASIVE PROCEDURES — Separate topic reviews discuss the

bleeding risk in patients receiving one of these medications, antidotes available or under
development, management of bleeding, and management of individuals who require an
invasive procedure:
● Bleeding risk – (See "Management of bleeding in patients receiving direct oral

anticoagulants", section on 'Bleeding risks from DOACs'.)
● Antidotes – (See "Management of bleeding in patients receiving direct oral

anticoagulants", section on 'Dabigatran reversal' and "Management of bleeding in
patients receiving direct oral anticoagulants", section on 'Rivaroxaban, apixaban,
edoxaban, betrixaban (reversal)' and "Management of bleeding in patients receiving
direct oral anticoagulants", section on 'Antidotes under development'.)
● Management of bleeding – (See "Management of bleeding in patients receiving direct

oral anticoagulants".)
● Management of invasive procedure/surgery – (See "Perioperative management of

patients receiving anticoagulants".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society
guideline links: Anticoagulation".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in
plain language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for patients
who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Anti-clotting medicines: Direct oral anticoagulants
(The Basics)")
SUMMARY AND RECOMMENDATIONS
● The direct thrombin inhibitors and direct factor Xa inhibitors act at major points in the
coagulation cascade that appear to be rate-limiting in clot formation (figure 3). These
drugs inactivate both circulating and clot-bound activated coagulation factors, and they
do not induce antiplatelet antibodies, features that may have advantages in specific
clinical settings. A major advantage of these agents is the lack of a requirement for
monitoring, due to less variability in drug effect for a given dose. While the overall risks
of bleeding are similar to vitamin K antagonists, the risks for intracranial bleeding are
less with the direct oral anticoagulants (DOACs). However, the DOACs are expensive,
they are not recommended in severe liver disease (table 3), and compliance is more
difficult to monitor than vitamin K antagonists. (See 'Mechanisms of action and
terminology' above and 'Comparison with heparin and warfarin' above.)
● Clinical indications for these agents are discussed in detail in separate topic reviews,
which are listed above. Their use is not appropriate in patients with severe renal
insufficiency, pregnancy, or prosthetic heart valves. (See 'Indications' above.)
● Parenteral direct thrombin inhibitors (DTIs) include bivalirudin (Angiomax) and

argatroban (Argatra, Novastan, Arganova, Exembol). These agents have very short half-
lives and specific clinical indications such as percutaneous coronary intervention (PCI)
and heparin-induced thrombocytopenia (HIT). There are no parenteral direct factor Xa
inhibitors. (See 'Parenteral direct thrombin inhibitors' above.)
● The oral direct thrombin inhibitor or oral direct factor Xa inhibitors are generally
administered at fixed doses without laboratory monitoring (table 5). Dose adjustments
for liver disease are presented in the table (table 3). Laboratory testing prior to
administration of these agents should include prothrombin time (PT) and activated
partial thromboplastin time (aPTT), to assess and document coagulation status before
anticoagulation; and measurement of serum creatinine, as a baseline and for potential
dose adjustment in the event of renal insufficiency. Patients with impaired renal
function should have appropriate dose reduction or drug avoidance depending on the
creatinine clearance. These agents generally should be avoided in individuals with a
body mass index (BMI) >40 kg/m2 or weight >120 kg. (See 'Dabigatran' above and
'Direct factor Xa inhibitors' above.)
• Dabigatran (Pradaxa) is the only orally active DTI available for clinical use. It must
be stored in the original blister pack with desiccant and not crushed. Dosing
differs in the United States versus Europe. Dose reductions are used in renal
insufficiency and with concomitant P-glycoprotein inducers or inhibitors (table 6
and table 7). Risks include bleeding, thrombosis upon discontinuation, and
dyspepsia. (See 'Dabigatran' above.)
• Several orally active direct factor Xa inhibitors are available, including rivaroxaban
(Xarelto), apixaban (Eliquis), edoxaban (Lixiana, Savaysa), and betrixaban
(Bevyxxa). Rivaroxaban is administered once daily and apixaban twice daily; they
interact with drugs that are potent inhibitors of both CYP-3A4 and P-glycoprotein
(table 6 and table 8 and table 7). Edoxaban and betrixaban are administered once
daily; these are renally excreted and are substrates for P-glycoprotein. Risks of
these agents include bleeding and thrombosis upon discontinuation. (See 'Direct
● The goal when transitioning between anticoagulants is to maintain stable

anticoagulation. When transitioning between DOACs and a vitamin K antagonist (VKA;
eg, warfarin), it is important to keep in mind that the full effect of the VKA does not
occur for the first few days, and when transitioning from a VKA to a DOAC, it is
important to keep in mind that the resolution of VKA effect may take several days.
Specific combinations of anticoagulants are discussed above. (See 'Transitioning
between anticoagulants' above.)
● Anticoagulants that inhibit other procoagulant factors are in development. (See

'Anticoagulants in development' above.)
● All anticoagulants increase bleeding risk. The agents discussed herein generally do not
appear to increase bleeding risk more than heparins or vitamin K antagonists; their
bleeding risk may be lower. In many cases, the short half-lives of these anticoagulants
allow relatively rapid reversal after drug discontinuation. For emergency situations,
specific antidotes are available to reverse the effects of dabigatran (idarucizumab;
Praxbind) and the factor Xa inhibitors (andexanet alfa; AndexXa). Bleeding risks,
antidotes under development, management of bleeding, and perioperative
management of patients receiving these agents are presented in detail separately. (See
"Management of bleeding in patients receiving direct oral anticoagulants" and
"Perioperative management of patients receiving anticoagulants".)
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Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse

Management of bleeding and perioperative management of patients receiving direct

The following topic reviews discuss other anticoagulants in clinical use:

● Fondaparinux – (See "Fondaparinux: Dosing and adverse effects".)

MECHANISMS OF ACTION AND TERMINOLOGY

Sites of action — Hemostasis involves several processes. These include platelet activation,

● Factor Xa – Factor Xa acts immediately upstream of thrombin in the clotting cascade,

Similarly to thrombin, factor Xa is active in circulating and clot-bound forms. Direct

Terminology — Terminology for anticoagulants continues to evolve as new agents become

● Antithrombotic agent – Antithrombotic agents generally include both antiplatelet

● Anticoagulant – Anticoagulants include a variety of agents that inhibit one or more

• Parenteral DTIs include bivalirudin (Angiomax), argatroban (Argatra, Novastan,

• There are no parenteral direct factor Xa inhibitors in clinical use.

• Several oral agents are available, including rivaroxaban (Xarelto), apixaban

COMPARISON WITH HEPARIN AND WARFARIN — Anticoagulants differ in efﬁcacy

The similar adherence to DOACs versus warfarin was demonstrated in a meta-analysis of

● Pharmacokinetics – Warfarin pharmacokinetics is affected by the level of vitamin K

● Renal impairment – Renal insufﬁciency is a common setting in which heparin or

• In hospitalized patients with renal insufﬁciency, heparin is generally used.

• For outpatients with moderate renal impairment (creatinine clearance 30-50

• For outpatients with severe renal impairment (creatinine clearance <30

● Antiphospholipid syndrome – In patients with the antiphospholipid syndrome (APS)

● Gastrointestinal disease – Patients with gastrointestinal diseases, especially those

INDICATIONS — Clinical indications for direct thrombin inhibitors and direct factor Xa

● Venous thromboembolism (VTE) prophylaxis (nonorthopedic) – (See "Prevention of

● VTE prophylaxis (orthopedic) – (See "Prevention of venous thromboembolism in adult

● VTE treatment (individuals without cancer, initial anticoagulation) – (See "Venous

● VTE treatment (individuals without cancer, long-term anticoagulation) – (See "Venous

● VTE treatment (individuals with cancer) – (See "Treatment of venous

● Atrial ﬁbrillation (AF) – (See "Atrial ﬁbrillation: Anticoagulant therapy to prevent

● Acute coronary syndromes (ACS) – (See "Anticoagulant therapy in non-ST elevation

● Heparin-induced thrombocytopenia (HIT) – (See "Management of heparin-induced

DIRECT THROMBIN INHIBITORS — Direct thrombin inhibitors inactivate circulating and clot-

Parenteral direct thrombin inhibitors — Parenteral direct thrombin inhibitors include

Bivalirudin — Bivalirudin (Angiomax, previously called Hirulog) is a synthetic 20 amino

The indications and use of bivalirudin in patients undergoing percutaneous coronary

● PCI – (See "Antithrombotic therapy for elective percutaneous coronary intervention:

● HIT – (See "Management of heparin-induced thrombocytopenia".)

Bivalirudin is administered at a dose of 0.75 mg/kg intravenously as a bolus followed by

Argatroban — Argatroban (Arganova, Argaron, Argatra, Da Bei, Exembol, Gartban,

Dosing and monitoring of argatroban differs depending on the indication:

Argatroban is hepatically metabolized, and dosing adjustment is advised in patients with

Argatroban prolongs the prothrombin time/international normalized ratio (PT/INR). Thus,

Desirudin — Desirudin (Iprivask, Revasc) is a recombinant hirudin derivative that inhibits

Overview (dabigatran) — Dabigatran etexilate (Pradaxa) is an orally administered

Dabigatran is used in the prevention and management of venous thromboembolic (VTE)

● VTE prophylaxis – (See "Prevention of venous thromboembolic disease in adult

● VTE initial treatment – (See "Venous thromboembolism: Initiation of anticoagulation

● VTE extended treatment – (See "Venous thromboembolism: Anticoagulation after

● AF – (See "Atrial ﬁbrillation: Anticoagulant therapy to prevent embolization".)

Dosing (dabigatran) — Dabigatran is generally given at a ﬁxed dose without

● Venous thromboembolism (VTE) primary prophylaxis in surgical patients: 110 mg one

● Renal insufﬁciency – Dabigatran is metabolized in the kidney, and the half-life is

● P-glycoprotein inhibitors or inducers – Dabigatran is a substrate for P-glycoprotein.

Laboratory testing and monitoring (dabigatran) — Laboratory testing prior to initiating

● Bleeding in a patient receiving dabigatran, or with suspected dabigatran overdose –

● Need for emergent or urgent surgery in a patient receiving dabigatran – (See

The management of bleeding and perioperative management in patients receiving

As with all anticoagulants, dabigatran is administered in the setting of increased

Dyspepsia is a common side effect of dabigatran, with an incidence from 12 to 33 percent

DIRECT FACTOR Xa INHIBITORS

Direct factor Xa inhibitors are metabolized in the kidney (approximately 25 to 35 percent)

Overview (rivaroxaban) — Rivaroxaban (Xarelto) is an orally available direct factor Xa