Anticoagulation in Pulmonary Embolism:

Update in the Age of Direct Oral

Anticoagulants
Rachel Rosovsky, MD, MPH,* and Geno Merli, MD, MACP, FSVM, FHM†

The emergence of direct oral anticoagulants (DOACs) represents a major advancement

and paradigm shift in the treatment of venous thromboembolism. Currently, dabigatran,
rivaroxaban, apixiban, and edoxoban are approved and used routinely for the prevention
and treatment of patients with venous thromboembolism. Because each of the DOACs has
different doses and dosing regimens, clinicians need to become familiar with their use.
This article focuses on the practical considerations of how and when to use the DOACs.
It also aims to explore follow-up monitoring, use in special populations, reversal agents,
periprocedural management, and how to handle bleeding complications with the DOACs.
Tech Vasc Interventional Rad 20:141-151 C 2017 Published by Elsevier Inc.

KEYWORDS Direct Oral Anticoagulants, Dabigatran, Rivaroxaban, Apixaban, Edoxaban,

Anticoagulation, Pulmonary Embolism, Deep Vein Thrombosis

Introduction adjustments place patients at increased risks of either

Venous thromboembolism (VTE) which includes deep
vein thrombosis (DVT) and pulmonary embolism (PE) is
a major cause of morbidity and mortality. Although the
precise number of people affected by VTE is unknown, it is
estimated that 1-2 people per 1000 suffer from a VTE each
year in the United States.1-3 A recent Italian study found
that PE was identified in nearly 1 of every 6 patients
hospitalized for a first episode of syncope.4 Moreover,
population studies show that the incidence of VTE will
continue to rise over time.3,5
Up until this decade, the only Food and Drug Admin-
istration (FDA) approved oral anticoagulant for the treat-
ment and prevention of VTE was the vitamin K antagonist
(VKA), warfarin. However, there are many limitations
with warfarin including delayed onset of action, narrow
therapeutic window, numerous food and drug inter-
actions, and an unpredictable dose response. Patients
require regular monitoring and variable responses to dose
recurrent VTE or bleeding.
The introduction of the direct oral anticoagulants
(DOACS) has offered patients a warfarin alternative. Unlike
warfarin, DOACs inhibit only 1 component in the coagu-
lation cascade; dabigatran inhibits factor II (thrombin), and
rivaroxaban, apixaban, and edoxaban inhibit factor Xa. The
DOACs do not require routine monitoring for safety or
efficacy making them more convenient for patients. They
also have a rapid onset of action, short half-life, predictable
pharmacokinetics and pharmacodynamics, fixed dosing,
and few drug and food interactions. Moreover, DOACs
have fewer bleeding complications when compared to
warfarin in clinical trials.6-10 These qualities make DOACs
attractive anticoagulants and have started to enable pro-
viders to consider treating low-risk VTE patients in an
outpatient setting.11 With the development of these
DOACs, however, it is imperative that clinicians become
familiar with their nuances. The purpose of this article is to
provide critical information and guidance on the practical
management of DOACs for the treatment for VTE.

*Department of Medicine, Division of Hematology and Oncology,

Massachusetts General Hospital, Boston, MA.
†Department of Surgery and Medicine, Jefferson Vascular Center,
Historical Perspective of VTE
Thomas Jefferson University Hospitals, Philadelphia, PA. Treatment
Address reprint requests to Rachel Rosovsky, MD, MPH, Department of
Hematology, Massachusetts General Hospital, 55 Fruit St, Boston, MA Before we begin the review of the DOACs in the manage-
02114. E-mail: rprosovsky@partners.org ment of DVT/PE, let us reflect on the initial discovery of
1089-2516/14/$ - see front matter & 2017 Published by Elsevier Inc. 141
http://dx.doi.org/10.1053/j.tvir.2017.07.003
142
and agents used for the treatment of thromboembolic
disease. The first documented description and treatment
for a DVT dates back to the middle ages, with a young
male named Raoul who developed pain and swelling in his
calf, which eventually progressed to leg ulcers.12,13 The
young man was advised to visit the tomb of Saint Louis in
the church of Saint Denis and instructed to rub dust onto
his ulcers which healed them. Subsequent discoveries and
practice of therapies focused on what was believed to be
the mechanism behind thrombus formation.14,15 The idea
that DVT was caused by the retention of evil humors was
held until the end of the 19th century and led to the
technique of bloodletting, often with leeches.16 The
popularity of bloodletting continued when it was believed
that inflammation of the vein was the likely cause of DVT.
Eventually, in 1856, Rudolph Virchow described the
consequences of a pulmonary embolus that migrated from
the venous circulation, and this later formed what it
known as Virchow’s triad.17 The triad of venous stasis,
endothelial injury, and hypercoagulability was then widely
accepted as a model for understanding the pathophysiol-
ogy of thrombosis. With this acceptance, a number of new
therapies were discovered, mostly by accident. Heparin
was the first parenteral anticoagulant discovered by a
second year medical student, Jay McClean, at Johns
Hopkins University when he isolated a fat-soluble phos-
phatide anticoagulant in canine liver tissue.18 Shortly after
in 1954, warfarin, originally synthesized from spoiled
sweet clover plants that caused spontaneous fatal bleeding
in cattle and initially used as a rodenticide, was adopted to
allow for extended treatment for DVT.19 Notably, when
President Eisenhower suffered a myocardial infarction, he
was treated with warfarin. Low-molecular-weight heparin
(LMWH) was the third agent discovered in 1976 and was
unique in the management of VTE since it was given
subcutaneously, rapidly achieved anticoagulation effect,
did not require monitoring and could be used short term
to bridge to warfarin or used as monotherapy.20 LMWH
not only changed the management of DVT/PE by reducing
the need for hospitalization but also has been effective in
the prevention of thromboembolic events in surgeries,
medically ill hospitalized patients, and the cancer popula-
tion. The synthetic pentasaccharide, Fondaparinux sodium
was then approved in 2001 to treat DVT and PE. It was not
until a decade later that the DOACs followed.
Overview of DOACs
The 4 DOACs that have emerged in the management of
VTE over the past decade gained approval from the FDA
after demonstrating noninferiority to warfarin in regards to
the prevention and treatment of VTE.6-10 Rivaroxaban,
apixaban, and edoxaban are factor Xa inhibitor whereas
dabigatran is a factor II or thrombin inhibitor. Because
these new agents have a number of advantages over the
older anticoagulants and the fact that they do not require
routine monitoring for safety or efficacy make them more
convenient for patients. According to the most recent
R. Rosovsky and G. Merli
CHEST guidelines, in patients with DVT of the leg or PE
and no evidence of cancer, anticoagulation therapy with
dabigatran, rivaroxaban, apixaban, or edoxaban is sug-
gested over VKA therapy as long-term (grade 2B).21
It is often difficult to decide which anticoagulant to use
when treating a patient with DVT or PE. This decision
ultimately depends on a variety of factors including
patient-related factors (comorbidities, bleeding risks,
adherence behaviors, preferences, medications, and
weight) as well as medication-related factors (properties
of the drugs and potential drug-drug interactions) and
procedures available and deemed necessary. An additional
deciding factor and one that is often the most influential is
what medication is covered by the patient’s insurance. The
treatment strategy for VTE is frequently divided into
3 phases as follows: acute (the first 5-10 days), short-term
(3-6 months), and long-term (46 months). During the
acute setting, anticoagulation options include unfractio-
nated heparin (UFH), LMWH, fondaparinux, rivaroxaban,
or apixaban. Dabigatran and edoxaban are effective treat-
ments as well, but both require 5-10 days of an initial
parenteral anticoagulant and are currently not approved
for stand-alone therapy intially.27,28 The length of anti-
coagulation then depends on the presence or resolution of
thrombotic risk factors.21 For patients in whom a transient
risk has resolved, short-term (eg, 3 months) therapy may
be reasonable. Alternatively, for patients with an unpro-
voked VTE, long-term or even lifelong anticoagulation
may be warranted.21,22
A Detailed Look at the DOACs
The DOACs, dabigatran (a direct thrombin inhibitor) and
apixaban, rivaroxaban, and edoxaban (direct factor Xa
inhibitors), are FDA approved in the United States and
elsewhere for prevention of stroke and systemic embolism
in patients with nonvalvular atrial fibrillation, treatment
and secondary prevention of VTE, and prevention of VTE
after major orthopedic surgery. In this section the phar-
macology of DOACs, drug interactions, dosing schedules,
laboratory monitoring, and indication in VTE are
reviewed.
Pharmacology DOACs
The pharmacologic profile of the DOACS is summarized in
Table 1.23-27 These medications share similar properties,
such as rapid onset of action, hepatic metabolism through
interactions with the CYP-450 system and/or P-glycopro-
tein pathway, and renal excretion.
Dabigatran Etexilate (Direct Thrombin Inhibitor)
Dabigatran etexilate is a direct thrombin inhibitor that is
converted to the active form dabigatran by esterase
catalyzed hydrolysis in plasma and is independent of the
cytochrome CYP-450 but is metabolized by P-glycoprotein
system.28 It is administered orally as a fixed dose twice
daily. It is not protein bound and therefore can be
Anticoagulation in PE and use of DOACs 143
Table 1 Pharmacology Direct Oral Anticoagulants
Key Points Dabigatran Apixaban Edoxaban Rivaroxaban
Mechanism Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor
action
Time to peak 1h 3-4 h 1-2 h 2-4 h
Half life 12-17 h 12 h 10-14 h 5-9 h
Bioavailability 3%-7% 50% 62% 66%
Metabolism Hepatic glucouronidation to active CYP 3A4/5 and Minimal CYP 3A4 and CYP 3A4/5 and
metabolites and P-gp substrate P-gp substrate P-gp substrate P-gp substrate
Excretion Renal 80% Renal 27% Renal 50% Renal 36%
P-gp: P-glycoprotein.

removed by hemodialysis. Food and drug interactions are
limited. Dabigatran has a low bioavailability (3%-7%), a
rapid onset of action (1 h), and a half-life of 12-17 hours.
Since dabigatran is 80% renally cleared, a dosage adjust-
ment is recommended based on the patient’s creatinine
clearance.
Apixaban (Factor Xa Inhibitor)
Apixaban is a direct factor Xa inhibitor that is administered
orally twice daily, with an onset of effect in 3- 4 hours, a
bioavailability of 50%, and a half-life of 8-15 hours.29 This
agent selectively and reversibly inhibits Factor Xa, inhibits
free Factor Xa in the prothrombinase complex and
Factor Xa bound to platelets. Apixaban has high plasma
protein binding (87%) and therefore cannot be removed
by hemodialysis. Clearance is 73% hepatic and 27%
renal. Apixaban is metabolized through the CYP
450 system especially CYP3A4/5 and P-glycoprotein
substrates.
Edoxaban (Factor Xa Inhibitor)
Edoxaban is a direct factor Xa inhibitor that is adminis-
tered orally once-daily, has a bioavailability of 62%,
achieves peak plasma concentrations in 1-2 hours and
has a half-life of 10-14 hours. It selectively and reversibly
inhibits both free and clot bound Factor Xa.30 Edoxaban
has high plasma protein binding (55%) and similar to the
other factor Xa inhibitors, it cannot be removed by
hemodialysis. It is 50% metabolized by the liver and
50% renal clearance. Edoxaban is minimal metabolism
through the CYP 34A system with the remainder by
P-glycoprotein substrates.
Rivaroxaban (Factor Xa Inhibitor)
Similar to apixaban, rivaroxaban selectively and reversibly
inhibits Factor Xa, inhibits free Factor Xa in the pro-
thrombinase complex and Factor Xa bound to platelets.31
It is administered orally once-daily with food to ensure
adequate absorption. Rivaroxaban has a relative bioavail-
ability of 66%, achieves peak plasma concentrations within
2-4 hours, and has a half-life ranging from 5-9 hours.
Similar to the other factor Xa inhibitors, this drug has high
plasma protein binding (92%-95%) and cannot be
removed by hemodialysis. It is predominately metabolized
(64%) by the liver but does have 36% renal clearance.
Rivaroxaban is metabolized through the CYP 450 system
especially CYP3A4/5 and P-glycoprotein substrates.
Drug Interactions
Although few in number, drug interactions need
to be considered when prescribing any DOAC
(Tables 2-5).23,25-27,32 Each DOAC is a substrate of the
permeability-glycoprotein (p-gy) and therefore, concom-
itant use of any of the DOACs with P-gp inducer can result
in decreased levels and frequently should be avoided. On
the other hand, P-gp inhibitors can increase the anti-
coagulant effect of a DOAC and should also be avoided,
especially in patients with moderate to severe renal failure.
Another potential drug interaction is with the hepatic
enyzme, cytochrome 3A4. CYP3A4 metabolizes rivarox-
aban and apixaban, and therefore drugs that induce P-gp
and CYP3A4 may decrease the anticoagulant effect, and
concomitant use with these DOACs should be avoided.
Strong P-gp and CYP 3A4 inhibitors may increase the
effect of DOAC and these combinations should also be
avoided. It is recommended in these situations that an
alternative anticoagulant be selected.

Table 2 Dabigatran: Director Oral Anticoagulants Drug Interactions

Dabigatran Interaction DOAC Anticoagulation Recommendation
Effect Treatment DVT/PE
P-gp inducer Rifampin Decreased Avoid use, alternative
anticoagulation
P-gp inhibitor Ketoconazole, dronedarone Increased with CrCl Avoid use, alternative
30-50 mL/min anticoagulation
P-gp inhibitor Ketoconazole, dronedarone, verapamil, Increased with CrCl Avoid use, alternative
amiodarone, quinidine, clarithromycin, ticagrelor 15-30 mL/min anticoagulation
P-gp: P-glycoprotein.
144 R. Rosovsky and G. Merli
Table 3 Apixaban: Director Oral Anticoagulants Drug Interactions
Apixaban Interaction DOAC Anticoagulant Recommendation
Effect Treatment DVT/PE
Strong dual P-gp and Rifampin, carbamazepine, Decreased Avoid use, alternative
CYP3A4 inducers phyenytoin, St. John′s wort anticoagulation
Strong P-gp and CYP3A4 Ketoconazole, itraconazole, Increased Avoid use, alternative
inhibitors ribonavir, clarithromycin anticoagulation
P-gp: P-glycoprotein.

Dosing Schedules for the Treatment

DVT or PE
Each DOAC has a different dosing schedule as detailed in
the following section (Table 6).
Dabigatran
With the use of dabigatran, patients must have a lead-in
parenteral therapy with UFH or LMWH for 5-10 days.10 If
the creatinine clearance is 430 mL/min, dabigatran
150 mg, twice daily is initiated. In patients with a
creatinine clearance o30 mL/min, dabigatran should not
be used. The duration of therapy depends on the etiology
of DVT/PE. For extended VTE prophylaxis following the
initial 12 weeks of therapy, dabigatran 150 mg, twice daily
is used as long as the creatinine clearance remains
430 mL/min.33
Apixaban
For apixaban, patients are started on an initial dose of
10 mg, twice daily for the first 7 days.6 The dose is then
reduced to 5 mg, twice daily thereafter. The duration of
therapy depends on the etiology of DVT/PE. For extended
VTE prophylaxis following the initial 12 weeks of treat-
ment, 2.5 mg, twice daily of apixaban is the recommended
dose.34
Edoxaban
Similar to dabigatran, patients must be treated with a
standard parenteral anticoagulant for at least 5 days (with a
median of 7 days) before starting edoxaban.7 Most patients
are put on 60 mg of edoxaban once daily but if a patient
has a creatinine clearance of 30-50 mL/min or a body
weight o60 kg, 30 mg a day should be used. There are no
studies for extended VTE prevention with edoxaban.
Rivaroxaban
With rivaroxaban, patients are started on an initial dose of
15 mg, twice daily for the first 21 days.8,9 The dose is then
reduced to 20 mg, once daily thereafter. The duration of
therapy as with the other DOACS depends on the etiology
of DVT/PE. For extended VTE prophylaxis following the
initial 12 weeks of treatment, the current FDA approved
dose of rivaroxaban remains 20 mg, once daily. The recent
Einstein CHOICE study demonstrated that either dose of
rivaroxaban (20 or 10 mg daily) was associated with a
lower risk of recurrent events as compared to aspirin in
patients, where there was equipoise regarding the need for
extended anticoagulation.35
Laboratory Monitoring
In the current clinical trials, all the DOACs were admin-
istered in fixed doses and did not require or have
laboratory monitoring. The dosing for each DOAC was
based on renal function for dabigatran, rivaroxaban, and
edoxaban and a combination of renal function, age, and
body weight for apixaban.36,37 If necessary, coagulation
assays most suitable for DOAC quantification of the
anticoagulant effect include the dilute thrombin time
(dTT), ecarin clotting time (ECT), ecarin chromogenic
assay, and chromogenic anti-Xa activity.36,37 However,
these assays are frequently not available on an urgent basis
at most hospitals and their utility has not been rigorously
investigated clinically. In addition, the activated partial
thromboplastin time (aPTT) and prothrombin time (PT)
have insufficient sensitivity and linearity for quantifying
anticoagulation effect of DOACs. In light of these limita-
tions, this section describes the current available data
regarding monitoring for DOACs, which may be indicated
in certain situations such as emergent surgery or proce-
dures, major hemorrhage, major trauma, suspected over-
dose, acute renal failure, or breakthrough thrombotic

Table 4 Edoxaban: Director Oral Anticoagulants Drug Interactions

Edoxaban Interaction DOAC Anticoagulation Recommendation Treatment
Effect DVT/PE
P-gp inducer Rifampin Decreased Avoid use, alternative anticoagulant
Strong P-gp Ritonavir, nelfinavir, saquinavir, indinvir, Increased Avoid use, alternative
inhibitor cyclosporine anticoagulation
P-gp inhibitor Verapamil, quinidine, azithromycin Increased Avoid use, alternative
clarithromycin, itraconazole, anticoagulation or decrease dose
ketoconazole to 30 mg Qd
P-gp: P-glycoprotein; Qd: everyday.
Anticoagulation in PE and use of DOACs
Table 5 Rivaroxaban: Director Oral Anticoagulants Drug Interactions
Rivaroxaban Interaction
Combined P-gp plus Rifampin, carbamazepine, phyentoin,
strong CYP3A4 inducers St. John′s wort
Combined P-gp plus Ketoconazole, itraconazole, ritonavir,
strong CYP3A4 lopinavir/ritonavir, indinavir,
inhibitors conivaptan
Combined P-gp and Diltazem, verapamil, amiodarone,
moderate CYP3A4 dronedarone erythromycin
inhibitors
P-gp: P-glycoprotein.
events.
Dabigatran
For dabigatran, a normal aPTT and dTT excludes clinically
relevant drug levels for anticoagulation. A prolonged aPTT
suggests that the level of dabigatran may be sufficient for
anticoagulation but does not reflect the degree of effect.
The PT and international normalized ratio is insufficiently
sensitive to dabigatran and is not recommended as a
monitoring tool. The dTT and ECT show excellent
linearity across dabigatran concentrations and may be
used for drug quantification, however, the FDA has not
approved these assays for dabigatran management.
Rivaroxaban
Calibrated anti-factor Xa assays provide the best correla-
tion with plasma concentration of rivaroxaban. Some PT
assays correlate well with rivaroxaban concentration, but
many do not. A prolonged PT with no other explanation in
a patient treated with rivaroxaban indicates drug presence;
however, a normal PT does not exclude the possibility of
rivaroxaban presence or greater rivaroxaban concentra-
tions and therefore, is not helpful in these situations.
Apixaban
Similar to rivaroxaban, calibrated anti-factor Xa assays
provide the best correlation with plasma concentration for
apixaban. Most PT and aPTT assays poorly reflect the
anticoagulant effect of apixaban. PT and aPTT are not
useful to assess whether apixaban is present in clinically
important or greater quantities.
Edoxaban
Similar to the other factor Xa inhibitors, calibrated anti-
factor Xa assays provide the best correlation with plasma
concentration for edoxaban. For edoxaban, PT is more
sensitive than aPTT, but there is inter-reagent variability,
and some PT assays are insensitive at trough-like concen-
trations. A prolonged PT with no other explanation in a
patient treated with edoxaban indicates drug presence;
however, a normal PT does not exclude the possibility of
anticoagulant effects of edoxaban concentrations.
145
DOAC Anticoagulation Recommendation
Effect Treatment DVT/
PE
Decreased Avoid use, alternative
anticoagulant
Decreased Avoid use, alternative
anticoagulation
Increased with CrCl Avoid use, alternative
15-30 mL/min anticoagulation
Indication VTE: Acute Treatment
To gain FDA approval, each DOAC was compared to dose-
adjusted warfarin for the treatment and secondary pre-
vention of DVT or PE, and all demonstrated noninferiority
in preventing VTE recurrence. Moreover, in terms of
safety, each DOAC exhibited a better bleeding profile than
warfarin. This section details the specifics of those trials
(Table 6).
Dabigatran
RE-COVER I (2564 patients) and RE-COVER II (2589
patients) were randomized, double-blind, noninferiority
trials comparing dabigatran 150 mg, twice daily with war-
farin for the treatment of VTE.10 Patients were treated with a
parental anticoagulant for a median of 9 days before starting
dabigatran. The primary efficacy outcome was defined as the
composite of symptomatic VTE or VTE-associated death in
the 6 months after randomization. Dabigatran was found to
be as effective and safe as standard therapy in reducing
recurrent VTE. There was a trend toward more gastro-
intestinal hemorrhage in patients treated with dabigatran.
More patients treated with dabigatran stopped therapy due
an adverse event (P ¼ 0.05) and dyspepsia was more
common in the dabigatran group (in RE-COVER I,
P o0.001). Major bleeding occurred equally in both groups,
whereas dabigatran was associated with a statistically sig-
nificant decrease in the composite of major or clinically
relevant nonmajor bleeding compared with VKA. A pooled
analysis of the RE-COVER trial results showed no difference
in recurrent VTE or major bleeding between dabigatran or
warfarin. However, dabigatran was associated with signifi-
cantly less major or clinically relevant nonmajor bleeding.
Apixaban
The apixaban for the Initial Management of Pulmonary
Embolism and Deep Vein Thrombosis as First-Line Ther-
apy (AMPLIFY) trial was a randomized, double-bind study
of 5385 patients comparing apixaban (10 mg twice daily
for the first 7 days followed by 5 mg twice daily) to
standard therapy (LMWH followed by warfarin) for
6 months in patients with a proximal DVT and/or PE.6
The primary efficacy endpoint was the composite of
symptomatic recurrent VTE or VTE-related death, whereas
the main safety outcome was major bleeding. Apixaban
146 R. Rosovsky and G. Merli

Do not use CrCl o 30 mL/

Do not use CrCl o 30 mL/

was found to be as effective as standard therapy with

CrCl 4 30 mL/min then

15 mg, BID × 21 d then
significantly less major bleeding. In fact, major bleeding
was reduced by almost 70% in the apixaban group

min or on dialysis
CrCl 4 30 mL/min
compared to conventional therapy.
Rivaroxaban

10 mg, daily*
20 mg, daily

20 mg, daily
Edoxaban
The Hokusai-VTE trial was a randomized, double-blind,
min
noninferiority study of 8292 patients comparing the effects
of edoxaban 60 mg once daily (or 30 mg once daily in
patients with a creatinine clearance 30-50 mL/min or
bodyweight o60 kg) with warfarin for treatment of acute
VTE.7 The principal efficacy outcome was the incidence of
CrCl 15-50 mL/min or weight o60 kg or
on P-gp inhibitors, use 30 mg, daily

symptomatic, recurrent VTE, whereas the principal safety

measure was the composite of major or clinically relevant
nonmajor bleeding. Furthermore, 40% of patients were
diagnosed with a PE (with or without a DVT). As in the
5-10 d LMWH or UFH then

RE-COVER trials, patients were treated with a standard

anticoagulant for at least 5 days before being exposed to
CrCl 4 30 mL/min and

the study drug. A medium time of 7 days elapsed before

the patients assigned to the edoxaban group received the
oral, anti-Xa inhibitor. Edoxaban was found to be non-
inferior to warfarin in preventing the primary efficacy
60 mg, daily

Not studied
Edoxaban

outcome, whereas it was superior to warfarin in reducing

the risk of clinically relevant bleeding.

Rivaroxaban
Two trials investigated the use of rivaroxaban for the
Do not use CrCl o 30 mL/

treatment of VTE. The Einstein-Acute DVT study was an

CrCl 4 30 mL/min then

open-label, randomized, event-driven, noninferiority trial

10 mg, BID × 7 d then

comparing rivaroxaban (15 mg twice daily for the first

min or on dialysis
CrCl 4 30 mL/min

3 weeks followed by 20 mg once daily) to conventional

anticoagulation therapy, which consisted of a LMWH
2.5 mg, BID
Table 6 Recommended Dosing: Treatment and Extended Prevention of DVT/PE
Apixaban

followed by warfarin, in 3449 patients with a proximal

5 mg, BID

DVT without PE.8 The primary efficacy outcome was

symptomatic, recurrent VTE (including fatal PE), whereas
the main safety measure was the combination of major or
clinically relevant nonmajor bleeding. Rivaroxaban was as
effective as standard therapy in preventing recurrent VTE
with a similar safety profile. Patients with a creatinine
clearance o30 mL/min were excluded and all subjects
Do not use CrCl o 30 mL/min

Do not use CrCl o 30 mL/min

received the 20 mg daily dose regardless of kidney

5-10 d- LMWH or UFH then

function.
The Einstein-PE trial was an open-label, event-driven,
CrCl 4 30 mL/min and

noninferiority study with a similar design to the Einstein-

CrCl 4 30 mL/min

acute DVT trial comparing rivaroxaban with standard

or on dialysis

or on dialysis

therapy in 4832 patients with a PE (with or without a

Dabigatran

150 mg, BID

150 mg, BID

DVT). The principal efficacy outcome and safety measure

P-gp: P-glycoprotein; BID: twice a day.

were the same as in the Einstein-DVT trial.9 A dose

confirmation phase was performed in which the first 400
patients underwent repeat lung imaging at the end of the
first 3 weeks of treatment to exclude asymptomatic
Not yet approved by FDA.

deterioration. There was no difference in the efficacy

Secondary Prevention

outcome at the end of the first 21 days of therapy.

Rivaroxaban was found to be as effective and safe as
standard therapy in preventing recurrent VTE. Signifi-
Indication

cantly less major bleeding occurred in patients treated with

DVT/PE
DVT/PE

rivaroxaban. There were no differences in the efficacy

outcome according to thrombus burden or type of index
event. A pooled analysis of the Einstein trials was recently
⁎
Anticoagulation in PE and use of DOACs 147
2866 patients) or placebo (RE-SONATE, placebo control,
Rivaroxaban
15 mg twice daily 1353 patients) in patients who completed at least 3 months
20 mg once daily
for 21 days
of treatment for VTE with an approved anticoagulant or
dabigatran in the RE-COVER trials.33 The primary efficacy
10 mg twice outcome was symptomatic, recurrent VTE in both trials.
Apixaban daily
for 7 days
5 mg twice daily Unexplained death was also included in the primary
efficacy outcome in the placebo control study. Dabigatran
was found to be as effective as warfarin and superior to
Parenteral agent 60 mg once daily placebo for the efficacy outcomes. However, numerically
Edoxaban with UFH or (30 mg once daily if CrCl 15-50
LMWH for 5-10 cc/min or weight < 60 kg or on P-gp more patients experienced recurrent VTE in the active
days inhibitors) control study and the upper limit of the CI for the hazard
ratio approached the prespecified noninferiority margin.
Parenteral agent
Dabigatran with UFH or
150 mg twice daily There was a trend toward less major bleeding with
LMWH for 5-10 dabigatran compared with warfarin; moreover, signifi-
days
cantly fewer patients treated with dabigatran experienced
Legend the composite of major or clinically relevant bleeding
UFH= unfractionated heparin; LWMH = low molecular weight heparin events. Compared with placebo, significantly more clin-
Red: need for higher dose initially ically relevant bleeding events occurred in patients
Purple: need for parenteral agent initially exposed to dabigatran with no significant difference in
Green: once daily dosing
Blue: twice daily dosing major bleeding observed between these 2 groups.

Figure 1 Key differences between DOACs dosing in treatment of Apixaban

acute VTE.
published that verified the noninferiority of rivaroxaban
compared with VKA.38 That analysis also revealed a
statistically significant reduction in major bleeding in
patients exposed rivaroxaban.
Key Differences Between the DOACs in Treatment
for Acute VTE
Currently, there are no head-to-head trials comparing the
4 DOACs to each other. However, there are a few differ-
ences that may help guide the optimal choice of treatment
(Fig. 1). Rivaroxaban and edoxaban are once daily med-
ications, whereas apixaban and dabigatran are twice daily
medications.7-9 Edoxaban and dabigatran require an initial
5-10 day course of parenteral anticoagulation whereas
rivaroxaban and apixaban are approved for initiation
therapy.7,10 Rivaroxaban must be taken with food.8,9
Dabigatran should be avoided in patients with dyspepsia
and coronary heart disease. Dabigatran has an approved
reversal agent, idarucizumab, while andexanet, the reversal
agent for factor Xa inhibitors is currently in clinical trials.
Clinical Trial Results for Extended Treatment
of VTE
Trials investigating the secondary prevention of VTE have
been performed with each DOAC except for edoxaban and
all demonstrated superiority in preventing their primary
efficacy endpoints as compared to placebo, warfarin or
aspirin. Each agent also had an increase in clinically
relevant nonmajor bleeding but no significant increase in
major bleeding was found (Table 6).
Dabigatran
Two double-blind studies compared dabigatran 150 mg
twice daily with either warfarin (RE-MEDY, active control,
In the AMPLIFY–Extended Treatment (AMPLIFY-Exten-
sion) trial, 2 doses of apixaban (2.5 and 5 mg, twice daily)
were compared with placebo in 2486 patients who
completed at least 6 months of anticoagulation for either
a DVT or PE.34 The main efficacy outcome was defined as
the composite of symptomatic recurrent VTE or death
from any cause, whereas the primary safety measure was
major bleeding. The exclusion criteria were similar
to those of the AMPLIFY study. However, patients
with thrombophilia, multiple episodes of unprovoked
DVT or PE, or those taking potent P-glycoprotein inhib-
itors were excluded from the extended treatment trial.
Both doses of apixaban were found to be superior to
placebo in reducing the main efficacy outcome. The rates
of major bleeding as well as the composite of major or
clinically relevant nonmajor bleeding were not statistically
different.
Rivaroxaban
The Einstein Extension trial was a double-blind trial in
which 1197 patients with either a DVT or PE who were
treated for at least 6 months with either standard therapy
or rivaroxaban were randomly assigned to continue treat-
ment with rivaroxaban 20 mg daily or placebo.8 The
exclusion criteria were the same as in the Einstein acute
DVT trial. Most of the patients were treated for at least
6 months. The primary efficacy outcome was sympto-
matic, recurrent VTE, and the main safety measure was
major bleeding (as opposed to the Einstein DVT and PE
trials, which investigated the composite of major and
clinically relevant non major bleeding as the main safety
outcome). Rivaroxaban reduced the rate of recurrent VTE
by 82% (P o 0.001 for superiority) with a nonsignificant
increase in major bleeding. However, more patients
exposed to rivaroxaban experienced the composite
of major or clinically relevant nonmajor bleeding
(P o 0.001). There were no major differences in
148
premature discontinuation of drug, vascular events, or
changes in liver function between study drug and placebo.
More recently, the EINSTEIN Choice study investigated
the use of full or lower intensity anticoagulation for the
extended treatment of VTE.35 In this double-blind trial,
3396 patients who had completed 6-12 months of anti-
coagulation therapy for their DVT or PE and who had
equipoise with respect for needing ongoing anticoagula-
tion therapy were randomized to receive once daily
rivaroxaban (10 or 20 mg dose) or 100 mg aspirin. The
risk of recurrent VTE was significantly lower with rivar-
oxaban (1.2% with 10 mg dose and 1.5% with 20 mg
dose) than with aspirin (4.4%) and there were no major
differences in bleeding rates.35
Special Populations
Although the DOACs have many attractive qualities,
when contemplating their use, one must determine if a
patient has comorbidities that preclude their application.
Data and guidance remain scant on the use of these
agents in patients with extreme body weights, cancer-
associated VTE, antiphospholipid syndrome, unusual
sites of VTE, extensive DVT or massive PE, hepatic
disease, inherited thrombophilia, and concomitant use
with antiplatelet agents or thrombolytic therapies.
Obese Patients
The uncertainty about the use of DOACs in extreme
weights stems from the lack of data in this patient
population.39-41 The mean weight in the DOAC trials
was 84 kg with most of the patients weighing between 60
and 100 kg.6-10 Less than 15% of patients weighed
o60 kg and less than 20% of patients weighed
4100 kg.6-10 Although there is limited pharmacokinetic
and pharmacodynamic information on these patients,
available data suggest that decreased drug exposures,
reduced peak concentration, and shorter half-lives occur
with increasing weights.39-41 These findings raise concerns
that obese patients may be under dosed. As such, a recent
guidance statement from the Scientific and Standardiza-
tion Committee of the International Society of Thrombosis
and Hemostasis suggests that DOACs not be used in
patients with a BMI 4 40 kg/m2 or weight 4 120 kg.42
If an obese patient has no other alternative than a DOAC,
checking a drug-specific peak and trough level may be
helpful and if levels are within range, the DOAC can be
continued but if not, an alternative anticoagulant should
be considered.42
Cancer Associated VTE
For patients with cancer associated VTE, the preferred first-
line therapy is presently LMWH.21,22 This recommendation
is based on a number of studies that compared LMWH to
warfarin and found LMWH to be superior.43 Although there
are meta-analyses of cancer patients that demonstrated
similar efficacy and safety for the DAOCS as compared to
R. Rosovsky and G. Merli
warfarin, it is unknown if DOACs are as safe and efficacious
as compared to LMWH.44,45 A recent prospective study of
200 cancer patients with VTE who were treated with
6 months of rivaroxaban showed 4.4% with new or
recurrent VTE, 2.2% with major bleeding, and all cause
mortality of 17.6%. These results are promising; however,
randomized controlled trials of LMWH vs DOAC are needed
to verify their findings and several are currently underway.
Other Populations and Concerns
Patients with hepatic cirrhosis (Child-Pugh class B and C),
abnormal liver function tests or coagulopathy owing to
liver disease should avoid DOACs as these patients were
excluded in the seminal trials. Similarly, most DOACs are
contraindicated in patients with severe renal failure and
dose modifications are necessary in patients with moderate
renal failure (Table 6). There are ongoing trials investigat-
ing the safety and efficacy of DOACs in patients with
antiphospholipid syndrome. Pregnant patients should
avoid DOACs as they may cross the placenta and have
not been adequately investigated for efficacy or fetal
safety.21,22 Similarly, these agents have not been evaluated
in conjunction with thrombolytic therapies.
In addition to patient comorbidities, owing to lack of
well-established monitoring guidelines, adherence and
compliance issues must be taken into account when
considering DOAC therapy. Unlike warfarin, there is no
international normalized ratio to test if a patient is taking
their medication appropriately. Lastly, cost and reimburse-
ment issues related to DOACs may affect patient access to
their use. However, many of the companies have patient
assistant programs. Understanding these limitations and
contraindications is important for practitioners who are
contemplating using these new agents.
Reversal Agents
All anticoagulants are associated with risk of bleeding,
reduced hemostatic response, and in rare cases severe or
life-threatening bleeding. As such, reversal agents are
necessary for use in these situations as well as for urgent
procedures. Presently, idarucizumab is the only FDA-
approved DOAC specific reversal agent and is indicated
for the reversal of dabiagtran in appropriate situations. It is
a humanized monoclonal antibody fragment that binds to
dabigatran with 350-fold higher affinity than that of
dabigatran for thrombin and does so without a procoagu-
lant effect. The phase III trial, REVERSE-AD, enrolled
dabigatran-treated patients who presented with serious
bleeding (Group A) or required urgent procedures (Group
B).46 Patients received 5 g of idarucizumab (2 doses of
2.5 g) administered within 15 minutes. The primary
endpoint was maximum percentage of reversal of dabiga-
tran measured by ECT or dTT.46 In an interim analysis, 90
patients had complete reversal of the anticoagulant effect
of dabigatran within minutes with no safety concerns. As a
result, idarucizumab (Praxbind) received approval by US
Anticoagulation in PE and use of DOACs
FDA in October 2015 for the reversal of dabigatran in
emergency situations.
Currently there are 2 reversal agents, andexanet alfa and
ciraparantag, in late-phase clinical development for the
reversal of factor Xa inhibitors. Andexanet alfa is a
recombinant human factor Xa variant that serves as a
decoy for the oral factor Xa inhibitors because it binds with
similar affinity to native factor Xa. In phase II studies,
andexanet alfa transiently reversed the anti-FXa activity of
apixaban and rivaroxaban in healthy older volunteers
without any adverse events.47 Another reversal agent,
ciraparantag, is a synthetic molecule that binds to DOACs
through noncovalent hydrogen bonding and charge-
charge interactions. In a phase I trial of healthy patients
who took a single dose of edoxaban 60 mg, ciraparantag
produced a decrease in whole blood clotting time
within 10 minutes and demonstrated return to baseline
hemostasis within 10-30 minutes which continued for
24 hours.48 In addition to reversing the anticoagulant
effects of DOACs, ciraparantag can bind to other anti-
coagulants including LMWHs, UFH, and fondaparinux,
and thus, has the potential to be a universal reversal agent.
Presently, there are ongoing trials evaluating both of these
agents.
149
Periprocedural Management
When clinicians are faced with how to manage patients on
DOACs perioperatively, there are 6 factors to consider:
bleeding risk of the procedure, bleeding risk of the patient,
thromboembolic risk of the patient, renal function of the
patient, half-life of the DOAC, and urgency of the
procedure. Because the recurrent rate of VTE is highest
in the first 3 months after the initial event, any elective
procedure should be delayed until after that time if
possible. If a delay is not possible, the clinician must
weigh the risks of bleeding during and after the procedure
if the DOAC is to be continued vs the thrombotic risk if the
DOAC is to be suspended.49 Any interruption in therapy is
generally warranted unless the surgery or procedure is
considered very low bleeding risk. As a guide, for a low
bleeding risk surgery in a patient with normal renal
function, the DOAC should be held for 2-3 half-lives.
For a high bleeding risk surgery in a patient with normal
renal function, the DOAC should be held for 4-5 half-lives.
Earlier cessation is warranted in patients with either renal
insufficiency or any concerning bleeding risk. Although a
detailed description of how to manage the DOACs for each
procedure is beyond the scope of this article, a number of

Initial Questions
Is the patient actively bleeding?
Where is the location and what is the severity of the bleed?
Can local hemostatic measures be applied or is a surgical invention or procedure required?
What DOAC is the patient taking and when was the last dose?
Does the patient have renal failure or liver disease which may affect metabolism or clearance of DOAC?
Is the patient on an antiplatelet or alternative medication that may further increase risk of bleeding?
Does the patient have comorbidities that may increase the risk of bleeding?
Is the patient hemodynamically stable?
Initial Testing
Complete Blood Count
Comprehensive Metabolic Panel to assess kidney and liver function
Coagulation tests: PT, PTT, INR
dTT (if on dabigatran) or anti-factor Xa (if on apixaban, rivaroxaban edoxaban)
Intervention: based on severity of bleed

Minor Moderate ♦ Severe

• Local hemostatic • Local hemostatic

• Place in ICU and monitor closely
measures measures
• Hemodynamic support if necessary
• Consider • Monitor closely
• Blood transfusion support if necessary ♦ ♦
discontinuation • Discontinue DOAC
• Discontinue DOAC
of DOAC • Surgical or
• Surgical or • Activated charcoal if last dose <6 hours
procedural
procedural intervention if
intervention if Consider additional medications/interventions if life
necessary
threatening bleed
necessary • Blood transfusion
• Idarucizumab if on dabigatran
support if
necessary • Hemodialysis if on dabigatran
• Adnexanet if on apixaban, rivaroxaban, or
edoxaban and if available (only on trial currently)
In some circumstances, may need to employ severe
bleeding strategies • 3 or 4 factor PCC if on apixaban, rivaroxaban, or
edoxaban (although limited data available and may
Blood transfusion support: RBC, platelets, FFP, cryoprecipitate be prothrombotic)
Adapted from Burnett et al.
• Antifibrinolytic therapies if appropriate
RBC = Red Blood Cells; FFP = Fresh Frozen Plasma • DDAVP in patients with impaired platelet function
DDAVP = desmopressin; ICU = Intensive Care Unit

Figure 2 Management of bleeding on a DOAC.

150
guidelines are available for review on this topic.49-52
Practitioners should also refer to the package insert for each
drug. Most importantly, the clinician performing the
procedure should engage in discussions with the patient
and the prescriber of the DOAC to determine the optimal
timing of the cessation and resumption of the drug.
Management of Bleeding on a
DOAC
Bleeding is a serious risk for patients on anticoagulation
and when it occurs, an immediate evaluation is necessary
(Fig. 2, adapted from Burnett et al.50). The first step when
managing a bleeding patient on a DOAC is to determine
the severity of the bleed (mild, moderate, or severe) and
the need for life saving measures such as hemodynamic
support, blood product transfusions, and volume resusci-
tation. The next step is to identify the source of bleeding
and if possible, apply local hemostatic measures. For
moderate and severe bleeds, the DOAC should be held.
Surgical or procedural interventions to identify and man-
age the source of bleeding may be necessary in severe
bleeds. Verifying when the last dose of the DOAC was
ingested is also helpful because if less than 6 hours,
activated charcoal may be used. Clarifying the renal
function of the patient will help determine how quickly
the DOAC will be eliminated. Dabigatran is the only
DOAC that is not protein bound and therefore can be
dialyzed; it is also the only drug for which there is an
FDA-approved reversal agent, idarucizumab. This drug
should be considered in patients on dabigatran who have
uncontrolled or life-threatening bleeding or require emer-
gent surgery.46 For patients on rivaroxaban, apixaban, or
edoxaban, the reversal agents, andexanet alpha and cir-
aparantag are currently in clinical trials and should be used
if appropriate and available.47,53 Other reversal strategies,
such as prothrombin complex concentrates (3 factor PCC,
4 factor PCC) and recombinant FVIIa have meager and
low-quality evidence supporting their use. The data is
limited to in vitro experiments, animal models, and studies
in healthy volunteers without relevant clinical outcomes.54
Furthermore, these agents may cause an increased risk of
thrombosis. Despite this limited data, for patients refrac-
tory to general measures, nonspecific reversal approaches
for factor Xa inhibitor reversal have been reported includ-
ing off-label use of clotting factor concentrates using
activated and nonactivated PCCs, antifibrinolytics and
desmopressin.55 Importantly, the safety and efficacy of
these approaches remain unknown. Perhaps the strongest
advice for clinicians to give to their patients is to avoid
high bleeding situations while on a DOAC.
Conclusion
DOACs are the most recent development in the prevention
and treatment for VTE, and offer several significant
advantages over older and parenteral therapies.
R. Rosovsky and G. Merli
Understanding the characteristics of each DOAC is impor-
tant for those prescribing them. As providers become more
familiar with their individual dosing regimens, benefits,
limitations, and associated challenges, their use will likely
continue to grow.
Acknowledgment
The authors wish to acknowledge the interest and help
from George Davis, PharmD, BCPS.
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