Clinical Therapeutics/Volume 40, Number 12, 2018
Review
A Review of the Efficacy and Safety Profiles of the
Novel Oral Anticoagulants in the Treatment and
Prevention of Venous Thromboembolism
Alexis A. Coulis, MS; and William C. Mackey, MD
Tufts University School of Medicine, Boston, MA, USA
ABSTRACT
Purpose: This study aims to review the published
literature concerning the use of novel oral anticoagulants
(NOACs) in the treatment and prevention of venous
thromboembolism (VTE) and to identify the appropriate
niche for each NOAC by comparing their behaviors in
Phase III and Phase IV clinical trial settings.
Methods: The ClinicalTrials.gov database was used to
identify Phase III and postmarketing (Phase IV)
randomized controlled trials concerning the efficacy and
safety profiles of the oral NOACs (apixaban, dabigatran
etexilate, exodaban, and rivaroxaban) for the treatment
or prevention of VTE. Studies of special interest included
those that compared the administration of a NOAC
versus standard anticoagulation therapy with low-
molecular-weight heparin and/or a vitamin K antagonist.
Findings: Overall, the NOACs offer a simplified
anticoagulation regimen that has noninferiority and
similar rates of bleeding when compared with standard
therapy throughout multiple studies. This finding held
true across several VTE conditions that required
anticoagulation, such as the treatment and prophylaxis
of acute VTE, including both deep vein thrombosis and
pulmonary embolism. Absence of dietary restrictions
and fixed oral dosing that does not require monitoring
makes NOACs ideal for the outpatient setting. Apparent
niches for each individual NOAC are discussed in detail;
however, the paucity of trials comparing NOAC
performance in specific clinical settings makes precise
definition of these niches problematic.
Implications: It now seems reasonable for clinicians
to consider NOACs as first-line agents for both the
treatment and prophylaxis of VTE and to attempt to
tailor their particular medication choices for each
patient scenario. More trials comparing NOAC
performance in specific clinical settings are essential to
2140
ensure these medications are being used to their full
potential. (Clin Ther. 2018;40:2140e2167) © 2018
Elsevier Inc. All rights reserved.
Keywords: NOACS, novel oral anticoagulants,
venous thromboembolism, VTE.
INTRODUCTION
Venous thromboembolism (VTE) is the third most
prevalent vascular diagnosis after myocardial infarction
and stroke. It is estimated to affect 300,000 to 600,000
persons in the United States each year.1 Deep vein
thrombosis (DVT) and pulmonary embolism (PE) are
the 2 acute manifestations of VTE. The mainstay of
treatment and prophylaxis of VTEdanticoagulation
therapydworks to inhibit blood clotting, lowering the
risks of DVT or PE. An overview of the coagulation
cascade and the antithrombotic therapy targets are
illustrated in Figure 1.
Conventional anticoagulants include heparin, a
naturally occurring anticoagulant produced by
basophils and mast cells that works by activating
antithrombin, an inhibitor of thrombin formation.
Unfractionated heparin (UFH), the pharmaceutical
version of heparin, contains polysaccharide molecular
chains of varying lengths. Low-molecular-weight
heparin (LMWH), commonly enoxaparin sodium,* is
®
* Trademark: Lovenox (sanofi-aventis U.S., LLC,
Bridgewater, New Jersey).
Accepted for publication October 9, 2018
https://doi.org/10.1016/j.clinthera.2018.10.009
0149-2918/$ - see front matter
© 2018 Elsevier Inc. All rights reserved.
Volume 40 Number 12
December 2018

Figure 1. Coagulation Cascade and Antithrombotic Therapy Targets. Warfarin inhibits the synthesis of Vitamin K-dependent clotting factors

A.A. Coulis and W.C. Mackey

including FII (Prothrombin), FVII, FIX (not pictured), and FX. Direct Thrombin Inhibitors including Dabigatran inhibit FIIa (Thrombin).
Direct Factor Xa Inhibitors including Apixaban, Edoxaban, and Rivaroxaban inhibit FXa. Heparins facilitate the physiological antico-
agulant Antithrombin (AT). Low Molecular Weight Heparin (LMWH) and Fondaparinux preferentially work through AT's inhibition of
FXa while Unfractionated Heparin (UFH) preferentially works through AT's inhibition of FIIa (Thrombin). Working to disrupt platelet
aggregation, Aspirin inhibits the generation of TxA2 while Clipidogrel inhibits the ADP receptor P2Y12.
2141
 Clinical Therapeutics
a further modified version of heparin that has
undergone fractionation to sequester only short-chain
polysaccharides. This helps to increase its
pharmacodynamic predictability. LMWH
preferentially works to activate antithrombin's
inhibition of clotting factor Xa. Fondaparinux
sodiumy is a synthetic pentasaccharide factor Xa
inhibitor that also binds antithrombin but instead
accelerates its inhibition of thrombin. UFH, LMWH,
and fondaparinux must be administered by injection.
The effects of UFH and LMWH can be reversed with
protamine sulfate, a medication that binds to these
agents and inhibits their anticoagulant activity.
A second major class of conventional anticoagulants
includes the vitamin K antagonists (VKAs), most
notably warfarin.z By inhibiting the vitamin
Kedependent synthesis of several clotting factors,
VKAs effectively decrease patients' coagulation
activity. Although given orally, and therefore easily
administered to outpatients, VKAs have a narrow
therapeutic window and require regular blood tests to
monitor their therapeutic effect. Prothrombin time and
the international normalized ratio (INR) are 2 values
obtained to ensure correct dosing. Failure to properly
monitor blood clotting parameters could result in
subtherapeutic anticoagulation, risking thrombus
propagation, or a supratherapeutic effect that
increases the risk of major bleeding. In addition,
because the effectiveness of VKAs is a direct result of
their ability to inhibit a vitamin Kedependent
pathway, this therapy is extremely sensitive to dietary
intake of vitamin K. Patients undergoing anticoagulant
treatment with VKAs must work daily to regulate their
diet to ensure their medication remains in a
therapeutic range. Although this often complicates
patients' daily eating habits, one clinical benefit is
vitamin K's ability to reverse VKA anticoagulation in
the event of major bleeding or VKA overdose.
Although these anticoagulation regimens have been
used in clinical practice for many years, they have
numerous limitations. Characteristics of an ideal
anticoagulant include a simple dosing regimen with a
® ®
y Trademark: Arixtra (GlaxoSmithKline, Brentford,
United Kingdom).
® ®
z Trademark: Coumadin (Bristol-Myers-Squibb, New
York, New York).
2142
wide therapeutic window that eliminates the need for
frequent clinical monitoring, easy oral administration,
minimal food and drug interactions, and the availability
of an antidote that quickly and effectively reverses
anticoagulation. Recently, pharmaceutical companies
developed novel oral anticoagulants (NOACs) with
many of these attributes.
Three of the 4, apixaban,x edoxaban,jj and
rivaroxaban,¶ are direct factor Xa inhibitors. Although
the heparins achieve anticoagulation by increasing
antithrombin's inhibition of factor Xa, these
medications inhibit factor Xa directly. The fourth
NOAC, dabigatran etexilate,# is the prodrug of
dabigatran, which is a direct thrombin inhibitor.
Taken once or twice daily at fixed oral doses, these 4
medications are approved by the US Food and Drug
Administration (FDA) for a variety of anticoagulant
regimens in the treatment and prophylaxis of VTE as
well as in the prevention of stroke and systemic
embolism in adults with nonvalvular atrial fibrillation.
Figure 2 describes the current FDA dosing and
administration recommendations regarding NOAC
anticoagulation therapy for clinical conditions related
to VTE.
Benefits of anticoagulation with the NOACs include
ease of their oral administration, fewer drug and
dietary interactions, and predictable pharmacokinetic
properties that do not require clinical monitoring (see
Table I for a full comparison of anticoagulation
regimens). However, because less is known about
these newer medications and there is limited research
to speak to their behavior in clinical practice, efficacy
and complication rates in comparison with
traditional VKA or heparin therapies are of major
interest. Although these drugs have great promise,
further investigation is needed to firmly establish
their place in clinical practice and define the optimal
role(s) for each of the 4 agents.
®
x Trademark: Eliquis (Bristol-Myers-Squibb, New York,
New York).
®
jj Trademark: Savaysa (Daiichi Sankyo Co, Ltd, Tokyo,
Japan).
¶ Trademark: Xarelto (Janssen Pharmaceuticals Inc,
Raritan, New Jersey) .
# Trademark: Pradaxa (Boehringer Ingelheim Pharma-
ceuticals, Inc, Ingelheim am Rhein, Germany).
Volume 40 Number 12
December 2018

Figure 2. Anticoagulation Regimens in Treatment and/or Prevention of VTE. Regimens are according to the FDA prescribing recommendations in
the United States. Of note, Edoxaban is not currently approved by the FDA for the extended treatment of VTE or prophylactic treatment
following Total Knee or Hip Arthroplasties (TKA/THA). Additionally, Dabigatran Etexilate is not approved by the FDA for prophylactic
treatment following a TKA. *Reduced 30mg dose is intended for patients with CRCL 15-50 mL/min, body weight £60kg, or those
taking concomitant P-gp inhibitors. **Reduced 2.5mg dose is intended for patients with at least 2 of the following characteristics: age
80, body weight £60kg, or serum creatinine 1.5 mg/dL.

A.A. Coulis and W.C. Mackey

2143
 Clinical Therapeutics

Table I. Comparison of anticoagulants.

Variable Heparins Vitamin K Antagonists Novel Oral

Anticoagulants

Administration Parenteral (intravenous or Oral Oral

subcutaneous)
Dosing Dose adjusted to INR 2.0e3.0 Dose adjusted to INR 2.0e3.0 Wide therapeutic
requiring frequent monitoring requiring frequent monitoring window and
because of a narrow therapeutic because of a narrow therapeutic predictable dose
window and varied dose window and varied dose response allows for
response response fixed dosing
Food-drug Fewer drug interactions Many drug interactions and Low potential for drug
interactions directly affected by foods rich interactions and
in vitamin K unaffected by diet
Reversal agent Protamine sulfate Vitamin K Andexanet alfa,*
idarucizumaby
Clinical Reliably used for years in clinical Reliably used for years in clinical Short history of clinical
reliability practice practice use

INR ¼ international normalized ratio.

* Antidote for factor Xa inhibitors, approved by the US Food and Drug Administration in 2018 as a reversal agent for apixaban
and rivaroxaban.
y
Antidote for direct thrombin inhibitors, approved by the US Food and Drug Administration in 2015 as a reversal agent for
dabigatran etexilate.

METHODS for use internationally, it was also excluded from this

The ClinicalTrials.gov database was used to identify
published Phase III and postmarketing (Phase IV)
randomized controlled trials concerning the efficacy
and safety profiles of the oral NOACs (apixaban,
dabigatran etexilate, edoxaban, and rivaroxaban).
Each of these primary sources was subsequently
reviewed for their results concerning the treatment or
prevention of VTE. This process excluded active trials
that were not yet published during or after February
2018 and Phase I or Phase II trials. Particular studies
of interest included those that compared the
administration of a NOAC versus standard
anticoagulation therapy with LMWH and/or a VKA.
Additional exclusions included trials focused on the
prevention of stroke or systemic embolism in adults
with atrial fibrillation because this topic was beyond
the scope of the present review. In addition, although
the oral direct thrombin inhibitor ximelagatran** was
evaluated in Phase III clinical trials and was approved
® companies; however, a formal risk of bias assessment
** Trademark: Exanta (AstraZeneca, Cambridge,
United Kingdom).
review because this medication did not gain approval
from the FDA because of concerns regarding
hepatotoxicity. Electronic searches to supplement the
reported data with additional relevant articles were
conducted as needed.
This review aimed to speak to the practical clinical
applications of each of these medications by
comparing their efficacy and safety profiles in Phase
III and Phase IV trial settings. As such, reported data
include the individual trial designs, study outcomes,
and trial authors’ commentary regarding the studied
drug in clinical practice. Specifically, the measured
efficacy end points included VTE progression or
recurrence in treatment studies and incidence of DVT
and PE in prophylaxis studies, whereas rates of
major bleeding and/or clinically relevant nonmajor
(CRNM) bleeding events were primary safety profile
end points.
The Phase III and Phase IV clinical trials, which
constituted most of the reported results, were funded
by the medications’ respective pharmaceutical
was not performed.

2144 Volume 40 Number 12

 A.A. Coulis and W.C. Mackey

RESULTS inhibiting P-gp. Specifically, strong P-gp inhibitors (eg,

Medication Characteristics
Although the NOACs can be misinterpreted as a
homogeneous group of medications with similar routes
of administration and mechanisms of action, there are
slight variations that could have clinical relevance.
Table II provides an overview of these characteristics,
which are discussed below.
Adverse Effects
In Phase III clinical trials, all 4 NOAC regimens
revealed a relatively low adverse effect profile2e5
Besides bleeding, the only frequently reported significant
adverse effect was dyspepsia associated with dabigatran
etexilate. In clinical study, this affected 3% of patients.2
Drug Interactions
As substrates of the P-glycoprotein (P-gp) transporter,
all 4 NOACs interact with medications, inducing or
antifungals such as ketoconazole as well as the HIV
protease inhibitor ritonavir) increased medication
effect and therefore elevated the risk of bleeding.6e9
For this reason, coadministration of rivaroxaban or
dabigatran etexilate with the aforementioned
medications or other strong P-gp inhibitors is not
recommended.6,8 Conversely, P-gp inducers, such as
the antibiotic rifampicin, or hypericum (commonly
known as St. John's wort, an herb thought to calm
feelings of anxiety or depression), decrease NOAC
effect and could lead to subtherapeutic levels of
anticoagulation.6e9
In addition, because apixaban, edoxaban, and
rivaroxaban are all metabolized by liver oxidative
pathways, including cytochrome P450 3A4 (CYP3A4),
medications that induce or inhibit this enzyme
will affect these anticoagulants. Including the
anticonvulsants carbamazepine and phenytoin as well

Table II. Medication characteristics according to the highlights of prescribing information published by the US
Food and Drug Administration.

Variable Apixaban Dabigatran Etexilate Edoxaban Rivaroxaban

Dosage forms Tablets: 2.5 and Capsules: 75 and Tablets: 15, 30, and Tablets: 10, 15, and
5 mg 150 mg 60 mg 20 mg
Adverse effects Bleeding Dyspepsia, bleeding Rash, abnormal liver Bleeding
function test results,
anemia, bleeding
Drug Strong dual P-gp inducers Anticoagulants, P-gp Strong dual inhibitors
interactions inhibitors or (rifampin), P-gp inducers (rifampin) or inducers of
inducers of inhibitors CYP34A and P-gp,
CYP34A and P- (dronedarone, anticoagulants
gp systemic
ketoconazole)
Contraindicated Breastfeeding Elderly people Breastfeeding mothers, Breastfeeding
patient mothers, renal impairment, mothers, renal
populations pregnancy, moderate-severe impairment,
severe hepatic hepatic impairment hepatic impairment
impairment
Antidote Andexanet alfa Idarucizumab Procoagulant agents Andexanet alfa
(prothrombin
complex,
recombinant factor
VIIa)

CYP34A ¼ cytochrome P450 3A4; P-gp ¼ P-glycoprotein.

December 2018 2145

 Clinical Therapeutics
as many of the same medications mentioned above,
coadministration with apixaban, edoxaban, or
rivaroxaban should be avoided.6,7,9 However, because
of its limited hepatic metabolism and primarily renal
elimination, dabigatran etexilate is not significantly
affected by pharmaceuticals that alter CYP3A4
activity.8
Finally, concomitant use of apixaban or rivaroxaban
with other medications that affect hemostasis is not
recommended.6,7 Because both these medications
are intended to be used as a monotherapeutic, single-
drug approach to anticoagulation, overlapping
administration with an additional anticoagulant
increases the risk of bleeding. With regard to common
antiplatelet agents, such as aspirin or clopidogrel,yy
although coadministration with apixaban or
rivaroxaban is not specifically contraindicated, FDA
prescribing information in the United States includes a
warning regarding the increased risk of bleeding and
recommends that concomitant use be conducted with
caution.6,7
Specific Populations
Systemic anticoagulation effect increases with
decreasing renal function for all 4 NOACs.6e9 For this
reason, patients with severe renal insufficiency
(creatinine clearance [CLCR] <30 mL/min) were
excluded from study during Phase III trials and are not
currently candidates for anticoagulation via a NOAC.
Because of the likelihood of increased anticoagulant
effect, rivaroxaban and apixaban are additionally
contraindicated in patients with hepatic disease
associated with coagulopathy.6,7 Although the effect
of edoxaban does not appear to increase in patients
with mild to moderate hepatic impairment, the FDA
warns against its use in such patients because of the
potential for underlying coagulation abnormalities.9
Again resulting from its renal clearance, the
pharmacokinetic properties of dabigatran etexilate
are not significantly affected by mild to moderate
hepatic impairment.8
Reversal Agents
Since their development and use in clinical practice, a
major concern with NOAC therapy has been the
®
yy Trademark: Plavix (Bristol-Myers-Squibb, New York,
New York).
2146
availability of a reversal agent or antidote in the case of
medication overdose or uncontrolled bleeding.
Although potential reversal strategies, including the
administration of activated charcoal or nonspecific
procoagulant agents (eg, prothrombin complex,
recombinant factor VIIa) may be used, agents that
specifically reverse NOAC anticoagulation are preferred.
Developed as a reversal agent for factor Xa inhibitors
and recently FDA approved, andexanet alfa is a modified
human factor Xa decoy protein that was designed to
sequester factor Xa inhibitors, thus restoring
coagulation by permitting the activity of endogenous
factor Xa. Using this mechanism, the recent Phase III
Randomized, Double-Blind, Placebo-controlled Study
in Older Subjects to Assess Safety and the Reversal of
Apixaban Anticoagulation With Intravenously
Administered Andexanet Alfa (ANNEXA) trials,
ANNEXA-A and ANNEXA-R revealed that within 2
to 5 minutes, andexanet alfa reversed 94% and 92% of
apixaban's and rivaroxaban's antiefactor Xa activity.10
In the subsequent ANNEX-4 study, andexanet alfa
restored hemostasis in 79% of patients with acute
major bleeding associated with these 2 factor Xa
inhibitors.11 Although it is a factor Xa inhibitor as
well, no research currently exists on andexanet alfa's
effect on edoxaban anticoagulation. An additional
reversal agent designed to inhibit antiefactor Xa
activity, ciraparantag, is also under current investigation.
As a direct thrombin inhibitor, dabigatran etexilate
follows a different mechanism of action and is
susceptible to a unique method of inhibition. On the
recent publication of the Phase III Reversal of
Dabigatran Anticoagulant Effect With Idarucizumab
(RE-VERSE AD) trial, idarucizumab, a fully
humanized monoclonal antibody fragment, competed
with dabigatran etexilate for thrombin binding and
completely reversed its anticoagulative effect.
Specifically, researchers reported that idarucizumab
normalized clotting times of 88%e98% of patients
within minutes.12
Treatment for Acute VTE
In the event of acute VTE, including DVT and/or
PE, standard treatment consists of a multiple-phase
anticoagulant regimen. The initial component of
standard therapy lasts for 5 to 10 days and calls for
parenteral LMWH (enoxaparin sodium, UFH, or
fondaparinux sodium). This regimen overlaps with
and is followed by a long-term therapy that consists
Volume 40 Number 12

of a VKA taken for usually 3 to 6 months. Long-term
therapy is not only meant to complete the treatment of
acute VTE but also works to prevent recurrent
thrombotic episodes.
Dosing and Administration
Both apixaban and rivaroxaban were approved as a
single-drug approach for the treatment of acute VTE
and do not require initial parenteral treatment with
LMWH or UFH.4,5 Specifically, apixaban is dosed at
10 mg twice daily for 7 days followed by 5 mg twice
daily for 6 months. Rivaroxaban is administered at
15 mg twice daily for 3 weeks and is followed by 20
mg once daily for 3 to 12 months.
Dabigatran etexilate and edoxaban were both
approved for the treatment of acute VTE after initial
parenteral anticoagulation with heparin.2,3 On the
completion of the initial heparin regimen, dabigatran
etexilate is dosed as 150 mg twice daily for 6
months, and edoxaban can be prescribed at 60 or 30
mg/d for 3 to 12 months. The 30-mg reduced dose of
edoxaban is intended for medically fragile patients
who were defined in the study conditions as those
with a CLCR of 30 50 mL/min, those with a weight
of 60 kg, or those receiving concomitant treatment
with a strong P-gp inhibitor.3
Study Findings
Through Phase III clinical trials investigating the
tolerability and efficacy of the NOACs versus
enoxaparin and warfarin standard therapy, each of
the 4 NOACs were approved by the FDA for short-
term treatment of VTE, including DVT and PE.2e5
Although Hokusai VTE Cancer trial was the only
Phase III trial to speak to the efficacy of edoxaban, the
use of the other 3 NOACs was supported by
secondary studies designed to confirm the initial
results. Specifically, after Apixaban for the Initial
Management of Pulmonary Embolism and Deep-Vein
Thrombosis as First-Line Therapy (AMPLIFY), a
smaller but similarly structured trial in Japanese
patients (AMPLIFY-J) was conducted in Japanese
patients and restated apixaban's noninferiority to
conventional treatment.13 In the case of dabigatran
etexilate, an identical Randomized Trial of Dabigatran
Versus Warfarin in the Treatment of Acute Venous
Thromboembolism (RE-COVER) II trial was run and
confirmed the results of the original RE-COVER
investigation.14 Finally, the EINSTEIN researchers
December 2018
A.A. Coulis and W.C. Mackey
published 2 separate clinical studies individually
revealing rivaroxaban's noninferiority to enoxaparin
and warfarin for the short-term treatments of DVT
and PE.5,15 In each Phase III clinical trial, apixaban,
dabigatran etexilate, edoxaban, and rivaroxaban were
noninferior to conventional therapy for the short-term
treatment of VTE.
Further investigating rivaroxaban's efficacy in the
clinical setting, the noninterventional, prospective XA
Inhibition With Rivaroxaban for Long-term and
Initial Anticoagulation in Venous Thromboembolism
(XALIA) study supported the results of the
EINSTEIN trials, which revealed rates of recurrent
VTE (for rivaroxaban vs LMWH/VKA: 1.4% vs
2.3%; propensity score-adjusted hazard ratio [HR] ¼
0.91; 95% CI, 0.54e1.54; P ¼ 0.72) and major
bleeding (for rivaroxaban vs LMWH/VKA: 0.8% vs
2.1%; HR ¼ 0.77; 95% CI, 0.40e1.50; P ¼ 0.44)
that were consistent with the Phase III findings.16
However, subgroup analysis of the XALIA study,
which investigated the outcomes of early switchers
(patients who received LMWH or fondaparinux and/
or a VKA for >2 to 14 days before switching to
rivaroxaban) revealed that this patient population
experienced higher rates of major bleeding (1.4% vs
0.7%) and recurrent VTE (2.2% vs 1.4%) than the
original rivaroxaban cohort.17
In addition, all 4 NOACs depicted similar or
lowered bleeding profiles.2e5 Apixaban, however,
was the only NOAC to reveal a clinically relevant
reduction in major bleeding events. Specifically, only
0.6% of patients taking apixaban compared with
1.8% of those receiving conventional therapy
experienced major bleeding (relative risk ¼ 0.31;
95% CI, 0.17e0.55; P < 0.001 for superiority).4 The
numerical results from each trial are given in Table III.
In their investigations of NOACs versus standard
anticoagulation therapy, 2 separate Cochrane reviews
spoke to the effectiveness and tolerability of these
oral medications for the treatment of acute DVT and
PE. In the review concerning DVT, 11 randomized
controlled trials in which participants had confirmed
DVT were evaluated. Meta-analysis of the 3 studies
(n ¼ 7596) concerning the oral direct thrombin
inhibitors dabigatran etexilate and ximelagatran
found no difference in the rates of recurrent VTE
(odds ratio [OR] ¼ 1.12; 95% CI 0.80e1.49) and
associated these 2 medications with reduced rates of
bleeding (OR ¼ 0.68; 95% CI 0.47e0.98).18
2147
2148

Clinical Therapeutics
Table III. Trial results for the treatment of acute VTE.*

Variable Apixaban Dabigatran Etexilate Edoxaban Rivaroxaban

AMPLIFY4 AMPLIFY-J13 RE-COVER2 RE-COVER II14 Hokusai VTE Cancer EINSTEIN-DVT5 EINSTEIN-PE15
Trial3

Dosing Apixaban 10 mg Apixaban LMWH or UFH LMWH or UFH for Enoxaparin or UFH Rivaroxaban 15 Rivaroxaban 15 mg
twice daily for 7 10 mg twice for 5e11 days, 5e11 days, then for up to 5 days, mg twice daily twice daily for 7
days, then 5 mg daily for 7 then dabigatran dabigatran then edoxaban for 7 weeks, then weeks, then
twice daily for 6 days, then etexilate etexilate 150 mg 60 mg/d (or 20 mg/d for 3, 6, 20 mg/d for 3, 6,
months vs 5 mg twice 150 mg twice twice daily for 6 30 mg/d) for 3e12 or 12 months vs or 12 months vs
enoxaparin and daily for 6 daily for 6 months vs months vs warfarin enoxaparin and enoxaparin and
warfarin months vs months vs warfarin VKA VKA
UFH and warfarin
warfarin
Patients Apixaban Apixaban Dabigatran Dabigatran Edoxaban (n ¼ Rivaroxaban Rivaroxaban
(n ¼ 2691; (n ¼ 40; 22 etexilate etexilate 4118; 2468 with (n ¼ 1731 with (n ¼ 2419 with
1749 with DVT, with DVT, (n ¼ 1273; 880 (n ¼ 1280; 877 DVT, 1650 with DVT), PE), enoxaparin
678 with PE), 18 with PE), with DVT, 270 with DVT, 298 PE), warfarin enoxaparin or or VKA
enoxaparin and UFH and with PE), with PE), (n ¼ 4122; 2453 VKA (n ¼ 1718 (n ¼ 2413 with
warfarin warfarin warfarin warfarin with DVT, 1669 with DVT) PE)
(n ¼ 2704; 1783 (n ¼ 40; 23 (n ¼ 1266; 869 (n ¼ 1288; 873 with PE)
with DVT, 681 with DVT, with DVT, 271 with DVT, 297
with PE) 17 with PE) with PE) with PE)
Results Recurrent VTE Recurrent VTE Recurrent VTE or Recurrent VTE or Recurrent VTE Recurrent VTE Recurrent VTE
occurred in 2.3% occurred in death occurred death occurred occurred in 3.2% occurred in 2.1% occurred in 2.1%
of patients 0 patients in 2.4% of in 2.3% of of patients taking of patients of patients
taking apixaban taking patients taking patients taking edoxaban and 3.5% taking taking
and 2.7% of apixaban dabigatran dabigatran of those receiving rivaroxaban and rivaroxaban and
those taking subjects and etexilate and etexilate and warfarin 3.0% of those 1.8% of those
Volume 40 Number 12

enoxaparin and 1 patient 2.1% receiving 2.2% of those (HR ¼ 0.89; 95% taking raking
warfarin (−0.4% taking UFH warfarin receiving CI, 0.70e1.13; enoxaparin or enoxaparin or
difference in risk; or warfarin (HR ¼ 1.10; warfarin P < 0.001) VKA (HR ¼ 0.68; VKA (HR ¼ 1.12;
95% CI, −1.3 to 95%, CI 0.65 (HR ¼ 1.08; 95% 95% CI, 0.44 95% CI, 0.75
0.4; P < 0.001) e1.84) CI, 0.64e1.80; e1.04; e1.68;
P < 0.001) P < 0.001) P ¼ 0.003)
December 2018
Table III. (Continued )
Variable Apixaban Dabigatran Etexilate Edoxaban Rivaroxaban
AMPLIFY4 AMPLIFY-J13 RE-COVER2 RE-COVER II14 Hokusai VTE Cancer EINSTEIN-DVT5 EINSTEIN-PE15
Trial3

Major bleeding Major or Major bleeding ¼Major bleeding Major or CRNM Major or CRNM Major bleeding
occurred in 0.6% CRNM occurred in occurred in 1.2% bleeding occurred bleeding or CRNM
of patients bleeding 1.6% of patients of patients in 8.5% of patients occurred in 8.1% bleeding
taking apixaban occurred in taking taking taking edoxaban of patients occurred in
and 1.8% of 7.5% of dabigatran dabigatran and 10.3% of those taking 10.3% of
those patients etexilate and etexilate and receiving warfarin rivaroxaban and patients
undergoing taking 1.9% of those 1.7% of those (HR ¼ 0.81; 95% 8.1% of those taking
enoxaparin and apixaban receiving receiving CI, 0.71e0.94; taking rivaroxaban
warfarin therapy and 28.2% warfarin warfarin P ¼ 0.004) enoxaparin or and 11.4% of
(RR ¼ 0.31; 95% of those (HR ¼ 0.82; (HR ¼ 0.69; 95% VKA those taking
CI, 0.17e0.55; taking UFH 95% CI, 0.45 CI, 0.36e1.32) enoxaparin or
P < 0.001) or warfarin e1.48) VKA
(HR ¼ 0.90;
95% CI, 0.76
e1.07;
P ¼ 0.23)
Pooled analysis revealed HRs of 1.09 Pooled analysis revealed HRs of 0.89
(95% CI, 0.76e1.57) for recurrent for recurrent VTE (95% CI, 0.66
VTE and 0.73 for major bleeding e1.19; P < 0.001) and 0.54 for
(95% CI, 0.48e1.11) major bleeding (95% CI, 0.37e0.79;
P ¼ 0.002)
Outcome Noninferior No clinically Noninferior Noninferior Noninferior efficacy Noninferior Noninferior

A.A. Coulis and W.C. Mackey

efficacy with a important efficacy with a efficacy with a with significantly efficacy with a efficacy with a
clinically relevant difference in similar safety lowered risk of less bleeding potentially potentially
reduction in efficacy with profile bleeding improved improved
major bleeding a favorable benefit-risk benefit-risk
safety profile profile profile

AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; AMPLIFY-J ¼ Japanese AMPLIFY;
CRNM ¼ clinical relevant nonmajor; DVT ¼ deep vein thrombosis; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein
Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HR ¼ hazard ratio;
2149

LMWH ¼ low-molecular-weight heparin; PE ¼ pulmonary embolism; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute
Venous Thromboembolism; RR ¼ relative risk; UFH ¼ unfractionated heparin; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism.
* Major bleeding and clinically relevant nonmajor bleeding were defined according to the International Society on Thrombosis Haemostasis and bleeding scale.
LMWH and VKA were dose adjusted to INR of 2.0e3.0.
 Clinical Therapeutics
Concerning the oral factor Xa inhibitors apixaban,
edoxaban, and rivaroxaban, meta-analysis of 8
studies (n ¼ 16356) found similar rates of recurrent
VTE (OR ¼ 0.89; 95% CI, 0.73e1.07) and reduced
rates bleeding (OR ¼ 0.84; 95% CI, 0.43e0.76).18
In the review concerning PE, 5 randomized controlled
trials in which participants had confirmed PE were
evaluated. For direct thrombin inhibitors, analysis of
2 studies (n ¼ 1602) indicated no difference in the
effectiveness of dabigatran etexilate or ximelagatran
versus standard anticoagulation in the prevention of
recurrent VTE (OR ¼ 0.93; 95% CI, 0.52e1.66) or
in the number of major bleeding events (OR ¼ 0.50;
95% CI, 0.15e1.68).19 In the analysis of direct
factor Xa inhibitors, 3 studies (n ¼ 6295) also
indicated no significant difference in the rates of
recurrent VTE (OR ¼ 0.85; 95% CI, 0.63e1.15) or
major bleeding (OR ¼ 0.97; 95% CI, 0.59e1.62).19
Summarizing their results, the Cochrane review
authors concluded that both oral direct thrombin
inhibitors and oral factor Xa inhibitors may be
tolerable and effective alternatives to conventional
anticoagulation for the treatment of both acute DVT
and PE.18,19
Subgroup Analysis
Subgroup analysis of the Phase III trials investigated
whether the results reported above could be
generalized to vulnerable populations, specifically
patients with active cancer, impaired renal function,
or advanced age.
Active Cancer
Although patients with cancer are at risk for
developing VTE, anticoagulant treatment with VKAs
in this population is associated with an elevated risk
of recurrent VTE and higher rates of bleeding. As
such, current guidelines recommend that patients
with cancer and VTE be treated with a monotherapy
of LMWH for 6 months. However, because a long-
term regimen of this subcutaneous injection is
extremely inconvenient, many patients with cancer
and VTE continue to be treated with VKAs. If
NOACs had noninferiority with respect to VKAs in
the prevention of recurrent VTE while additionally
exhibiting fewer rates of bleeding, these medications
could be convenient options for patients with active
cancer and VTE who decide against LMWH
monotherapy as per current recommendations. On
2150
subgroup analysis for each NOAC regarding its
performance in patients with active cancer, these 4
medications remained noninferior to warfarin in the
prevention of recurrent VTE and continued to be
associated with a lower risk of bleeding
(Table IV).20e23 Edoxaban was the only medication
to undergo further research to investigate its
performance against the recommended long-term
LMWH monotherapy. Evaluating the efficacy and
tolerability of edoxaban 60 mg/d after a 5-day
regimen of LMWH, the Hokusai VTE Cancer trial
established edoxaban's noninferiority to LMWH
monotherapy in the prevention of recurrent VTE in
patients with cancer (12.8% in the edoxaban group
compared with 13.5% in the dalteparin group; HR ¼
0.97; 95% CI, 0.70e1.35; P ¼ 0.006 for
noninferiority and P ¼ 0.87 for superiority).24
However, the rate of major bleeding was significantly
higher with edoxaban (6.9% in the edoxaban group
compared with 4.0% in the dalteparin group; 2.9%
difference in risk; 95% CI, 0.1e5.6).24
Impaired Renal Function
Because renal function directly affects the rate at which
a medication is eliminated from the body, renal
impairment could increase NOAC exposure and
potentially result in more adverse bleeding events.
Acknowledging this, subgroup analyses of renally
impaired patients in the RE-COVER II and the Oral
Direct Factor Xa Inhibitor Rivaroxaban in Patients
With Deep Vein Thrombosis (EINSTEIN-DVT) and in
Patients With Acute Symptomatic Pulmonary Embolism
(EINSTEIN-PE) studies examined the effect of
decreased renal function on dabigatran etexilate's
(primarily renal clearance) and rivaroxaban's (both
hepatic and renal clearance) efficacy and tolerability
compared with the warfarin standard (primarily hepatic
clearance). On subgroup analysis of patients taking
dabigatran etexilate with mild (CRCL 50e80 mL/min)
to moderate (CRCL 30e50 mL/min) renal impairment,
decreasing renal function was associated with lowered
rates of recurrent VTE. This trend was not reflected in
the warfarin group. In both the dabigatran etexilate and
warfarin groups, however, the rates of bleeding
increased with decreased renal function.25 Similar
subgroup analysis of patients taking rivaroxaban
revealed slightly different results because decreased
renal function was associated with increased rates of
recurrent VTE and bleeding for both rivaroxaban and
Volume 40 Number 12
 A.A. Coulis and W.C. Mackey

Table IV. Results of subgroup analysis for patients with active cancer.*

Variable Apixaban Dabigatran Etexilate Edoxaban (Hokusai Rivaroxaban (EINSTEIN-

(AMPLIFY4) (RE-COVER II2,14) VTE Cancer Trial3) DVT and EINSTEIN-
PE5,15)

Patients Apixaban (n ¼ 88), Dabigatran etexilate Edoxaban (n ¼ 378), Rivaroxaban (n ¼ 354),

enoxaparin and (n ¼ 114), warfarin warfarin (n ¼ 393) enoxaparin or VKA
warfarin (n ¼ 81) (n ¼ 107) (n ¼ 301)
Results Recurrent VTE occurred in Recurrent VTE or Recurrent VTE occurred Recurrent VTE occurred in
3.7% of patients taking related death in 4% of patients 5% of patients taking
apixaban and 6.4% of occurred in 5.8% of taking edoxaban and rivaroxaban and 7% of
those taking enoxaparin patients taking 7% of those taking those receiving
or warfarin (RR ¼ 0.56; dabigatran etexilate warfarin (HR ¼ 0.53; enoxaparin or VKA
95% CI, 0.13e2.37) and 7.4% of patients 95% CI, 0.28e1.00; (HR ¼ 0.67; 95% CI,
taking warfarin P ¼ 0.0007) 0.35e1.30)
Major bleeding Major bleeding Major and CRNM Major bleeding occurred
occurred in 2.3% of occurred in 3.8% of bleeding occurred in in 2% of patients taking
patients taking patients taking 12% of patients taking rivaroxaban and 5% of
apixaban patients and dabigatran etexilate edoxaban and 19% of those receiving
5.0% of those taking and 4.6% of those those taking warfarin enoxaparin or VKA
enoxaparin and taking warfarin (HR ¼ 0.64; 95% CI, (HR ¼ 0.42; 95% CI,
warfarin (RR ¼ 0.45; 0.45e0.92; P ¼ 0.017) 0.19e0.99)
95% CI, 0.08e2.46)

AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy;
CRNM ¼ clinically relevant nonmajor; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep
Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic
Pulmonary Embolism; HR ¼ hazard ratio; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment
of Acute Venous Thromboembolism; RR ¼ relative risk; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism.
* Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding
scale. VKA was dose adjusted to international normalized ratio of 2.0e3.0.

warfarin.26 In both subgroup analyses, however, the rates
of recurrent VTE and bleeding were lower in the NOAC
groups than in their warfarin counterparts, maintaining
their noninferiority to standard anticoagulation
treatment in patients with mild-to-moderate renal
impairment (Table V).25,26
Advanced Age
In conjunction with the investigations on the effect of
renal impairment, subgroup analyses regarding elderly
patients (75 years old) were additionally performed
for dabigatran etexilate and rivaroxaban. Analysis of
the RE-COVER II subgroups revealed no increase in
VTE recurrence or bleeding in older (75 years old)
versus younger (<75 years old) patients taking
dabigatran etexilate within equivalent ranges of
CRCL.25 Although the EINSTEIN investigators speak
to the efficacy and safety profile of rivaroxaban in
elderly patients by establishing its noninferiority in the
broader subgroup of medically fragile patients (age >75
years, CLCR <50 mL/min, or weight 50 kg),27 an
independent trial was able to confirm that the
maximum plasma concentration of rivaroxaban is not
increased in elderly people.28 Meanwhile, although the
AMPLIFY investigators state that the efficacy and
tolerability of apixaban remain consistent across a
broad range of subgroups, including those older than
75 years, no in-depth subgroup analysis has been
published on apixaban's efficacy and safety profile this
population.

December 2018 2151

 Clinical Therapeutics

Table V. Results of subgroup analysis for patients with decreased renal function.*

Variable Dabigatran Etexilate (RE-COVER II2,14) Rivaroxaban (EINSTEIN-DVT and EINSTEIN-PE5,15)

Results In patients taking dabigatran etexilate, VTE and In patients taking rivaroxaban and warfarin
associated deaths occurred in 3.1% of those
with normal renal function, 1.9% of those with
mild renal impairment, and 0.0% of those with
moderate renal impairment. In patients taking
warfarin, VTE and associated deaths occurred in renal impairment.
2.6% of those with normal renal function, 1.6%
of those with mild renal impairment, and 4.1%
of moderate renal impairment.
In patients taking dabigatran etexilate, major
bleeding occurred in 0.3% of those with normal
renal function, 1.8% of those with mild renal
impairment, and 5.7% of those with moderate
renal impairment. In patients taking warfarin,
major bleeding occurred in 1.1% of those with
normal renal function, 3.0% of those with mild
renal impairment, and 4.4% of those with
moderate renal impairment.
combined, VTE occurred in 1.8% of those with
normal renal function, 2.8% of those with mild
renal impairment, 3.3% of those with moderate
renal impairment, and 4.8% of those with severe
In patients taking rivaroxaban, major bleeding
occurred in 0.8% of those with normal renal
function, 1.4% of those with mild renal
impairment, 0.9% of those with moderate renal
impairment, and 0% of those with severe renal
impairment. In patients taking warfarin, major
bleeding occurred in 1.0% of those with normal
renal function, 3.0% of those with mild renal
impairment, 3.9% of those with moderate renal
impairment, and 9.1% of those with severe renal
impairment.

EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral
Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; RE-COVER ¼ Randomized
Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; VTE ¼ venous thromboembolism.
* Major bleeding was defined according to the International Society on Thrombosis Haemostasis bleeding scale.

Because edoxaban offers a 30-mg half-dose for the
patient populations described above and other
medically fragile patients (specifically defined as those
with a CLCR of 30e50 mL/min, those with a weight
60 kg, or those receiving concomitant treatment with
strong P-gp inhibitors), an independent study was
conducted to determine the efficacy and safety profile
of this reduced dosage. Published results of this study
exhibited similar rates of recurrent VTE and bleeding
between the fragile patients in the 30-mg group and
those in the 60-mg study group. Specifically, recurrent
VTE occurred in 3.0% of the 30-mg group and 3.2%
of 60-mg group, whereas major or CRNM bleeding
occurred in 7.9% of 30-mg group and 8.6% of the 60-
mg group.29 When comparing this fragile edoxaban
population to fragile patients receiving warfarin, 30
mg of edoxaban resulted in similar rates of recurrent
VTE (3.0% for edoxaban and 4.2% for warfarin) and
a reduced rate of bleeding (7.9% for edoxaban and
12.8% for warfarin).29 These results indicate that not
only did edoxaban 30 mg maintain the efficacy of
edoxaban 60 mg but also it was more tolerable than
warfarin in medically fragile patients.
Extended Treatment of VTE
Although guidelines recommend a 3- to 6-month
regimen of anticoagulant treatment after diagnosed
VTE, patients with a higher risk of VTE recurrence may
be prescribed extended or lifelong anticoagulation
therapy. Extended treatment with a VKA only amplifies
its characteristic drawbacks, prolonging the needed
for dietary restrictions and frequent laboratory
monitoring. To simplify extended anticoagulation
therapy, 3 NOACs (apixaban, dabigatran etexilate, and

2152 Volume 40 Number 12


rivaroxaban) were investigated against placebo in Phase
III clinical trials for the prolonged treatment of VTE.
Study Design
To confirm the clinical benefit of extended
anticoagulation with a NOAC versus the standard 3-
to 6-month regimen, each of these 3 medications
underwent Phase III clinical trials to determine
their superior efficacy compared with placebo in
lower-risk patients for whom there is clinical
equipoise regarding the continuation or cessation of
anticoagulant therapy. For patients who carry an
increased risk of recurrent VTE and would be
explicitly indicated for extended anticoagulation with
a VKA, dabigatran etexilate was further investigated
against warfarin.
Study Findings
The EINSTEIN-Extension and Twice-daily Oral
Direct Thrombin Inhibitor Dabigatran Etexilate in the
Long Term Prevention of Recurrent Symptomatic
VTE (RE-SONATE) studies confirmed rivaroxaban's
and dabigatran etexilate's superiority versus placebo in
the prevention of recurrent VTE.5,30 Similar findings
were evident in the AMPLIFY-EXTENSION trial,
which investigated apixaban at both 2.5 and 5 mg.
Both doses were superior to placebo in reducing the
risk of recurrent VTE.31 Furthermore, trial results
from these 3 studies indicate that apixaban,
dabigatran etexilate, and rivaroxaban were all
associated with similar risks of major bleeding when
compared with placebo. Undergoing further
evaluation in the Phase III, Randomised, Multicenter,
Double-blind, Parallel-group, Active Controlled Study
to Evaluate the Efficacy and Safety of Oral Dabigatran
Etexilate (150 mg Bid) Compared to Warfarin (INR
2.0e3.0) for the Secondary Prevention of Venous
Thromboembolism (RE-MEDY) study, dabigatran
etexilate was found to be noninferior to standard
warfarin therapy for extended anticoagulation and
was associated with a decreased rate of bleeding.30
Results of these trials are given in Table VI.
In comparing NOAC and aspirin treatments for
patients in equipoise regarding the need for continued
anticoagulation, the Reduced-dosed Rivaroxaban in
the Long-term Prevention of Recurrent Symptomatic
VTE (EINSTEIN CHOICE) trial found that
rivaroxaban (at the treatment dose of 20 mg/d and
the prophylactic dose of 10 mg/d) was more effective
December 2018
A.A. Coulis and W.C. Mackey
than aspirin 100 mg in the extended prevention of
recurrent VTE and was associated with a similar rate
of bleeding. Specifically, recurrent VTE occurred in
1.5% of patients taking Rivaroxaban 20 mg, 1.2%
of patients taking rivaroxaban 10 mg, and 4.4% of
patients taking aspirin 100 mg (HR ¼ 0.34; 95% CI,
0.20e0.59 for rivaroxaban 20 mg vs aspirin 100 mg;
HR ¼ 0.26; 95% CI, 0.14e0.47 for rivaroxaban 10
mg vs aspirin 100 mg, P < 0.001 for both
comparisons).32 Rates of major bleeding were 0.5%
in the rivaroxaban 20-mg group, 0.4% in the
rivaroxaban 10-mg group, and 0.3% in the aspirin
100-mg group.32
Prophylactic Treatment After Major Orthopedic
Surgery
VTE is a potentially fatal complication that can occur
in patients after major orthopedic operations, such
as total knee or hip arthroplasties. As such,
thromboprophylaxis for at least 10 days after major
orthopedic joint replacement surgery is now standard
practice. However, as the mean length of stay in the
hospital has decreased to 3 to 4 days, an oral
anticoagulant regimen that is easily administered in an
outpatient setting is ideal. Acknowledging this, all 4
NOACs were investigated for their efficacy regarding
thromboprophylaxis in patients after major orthopedic
joint replacement surgery.
After Total Knee Arthroplasty
The optimal thromboprophylactic strategy for
patients after a total knee arthroplasty (TKA) has not
been established, and different guidelines exist in the
United States, Europe, and Japan. Specifically, the FDA
recommends that in the United States patients receive
30 mg of subcutaneous enoxaparin every 12 hours
(twice daily) beginning 12 to 24 hours before surgery
and continuing until 10 to 14 days after wound
closure. European recommendations state that patients
should have 40 mg of subcutaneous enoxaparin once
daily starting 12 hours before surgery and again until
10 to 14 days after wound closure. Recommendations
in Japan are slightly different and state that patients
should be administered subcutaneous enoxaparin 2000
IU (equivalent to 20 mg) twice daily beginning 24 to 36
hours before surgery and lasting for the next 11 to 14
days. Apixaban, dabigatran etexilate, and rivaroxaban
all underwent 2 separate Phase III clinical trials to
determine their efficacy versus US and European
2153
Clinical Therapeutics

Table VI. Trial results for the extended treatment of acute VTE.

Variable Apixaban (AMPLIFY- Dabigatran Etexilate Rivaroxaban (EINSTEIN-

EXT31) EXT5)
RE-SONATE30 RE-MEDY30

Dosing Apixaban 2.5 mg or 5 mg Dabigatran etexilate Dabigatran etexilate Rivaroxaban 20 mg/d vs

twice daily vs placebo 150 mg twice daily vs 150 mg twice daily vs placebo for 6 or 12
for 12 months placebo for 6 months warfarin for 6e36 months
months
Patients Apixaban (n ¼ 840 at Dabigatran etexilate Dabigatran etexilate Rivaroxaban (n ¼ 602),
2.5 mg, n ¼ 813 at (n ¼ 681), placebo (n ¼ 1430), warfarin placebo (n ¼ 594)
5 mg), placebo (n ¼ 662) (n ¼ 1426)
(n ¼ 829)
Results Recurrent VTE or death Recurrent VTE occurred Recurrent VTE occurred Recurrent VTE occurred
occurred in 1.7% of in 0.4% of patients in 1.8% of patients in 1.3% of patients
patients receiving receiving dabigatran receiving dabigatran receiving rivaroxaban
apixaban 2.5 mg, 1.7% etexilate and 5.6% of etexilate and 1.3% of and 7.1% of patients
of patients receiving patients receiving those receiving warfarin receiving placebo
apixaban 5 mg, and placebo (HR ¼ 0.08; (HR ¼ 1.44; 95% CI, (HR ¼ 0.18; 95% CI,
8.8% of patients 95% CI, 0.02e0.25; 0.78e2.64; P ¼ 0.01) 0.09e0.39; P < 0.001)
receiving placebo P < 0.001)
(−7.2% difference in
risk for 2.5 mg; 95% CI,
5.0e9.3; −7.0%
difference in risk for
5 mg; 95% CI, 4.9e9.1;
P < 0.001 for both
comparisons)
Major bleeding occurred Major bleeding Major bleeding Major bleeding occurred
in 0.2% of patients occurred in 0.3% of occurred in 0.9% of in 0.7% of patients
receiving apixaban patients receiving patients receiving receiving rivaroxaban
2.5 mg, 0.1% of dabigatran etexilate dabigatran etexilate and 0 patients receiving
patients receiving and 0 patients and 1.8% of those placebo (P ¼ 0.11)
apixaban 5 mg, and receiving placebo receiving warfarin
0.5% of patients (HR ¼ 0.52; 95% CI,
receiving placebo 0.27e1.02)
Outcome Superior efficacy with a Superior efficacy with a Noninferior efficacy with Superior efficacy with a
similar safety profile significantly higher fewer major bleeding similar safety profile
risk of major bleeding events

AMPLIFY-EXT ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy
Extension; EINSTEIN-EXT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban Extension; HR ¼ hazard ratio; RE-MEDY ¼ Phase III,
Randomised, Multicenter, Double-blind, Parallel-group, Active Controlled Study to Evaluate the Efficacy and Safety of Oral
Dabigatran Etexilate (150 mg Bid) Compared to Warfarin (INR 2.0e3.0) for the Secondary Prevention of Venous
Thromboembolism; RE-SONATE ¼ Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term
Prevention of Recurrent Symptomatic VTE; VTE ¼ venous thromboembolism.
Major bleeding was defined according to the International Society on Thrombosis Haemostasis bleeding scale.

2154 Volume 40 Number 12


recommendations. The efficacy of edoxaban was
evaluated only against the Japanese guidelines. The
results of each trial are summarized in Table VII.
With respect to US recommendations for
thromboprophylaxis after TKA (subcutaneous
enoxaparin 30 mg twice daily), dabigatran etexilate
at doses of 150 and 220 mg/d, as well as apixaban
2.5 mg twice daily, each failed to find noninferiority
versus the recommended enoxaparin treatment.33,34
Of note, both apixaban and dabigatran etexilate
were noninferior to subcutaneous enoxaparin 40 mg/
d as per European recommendations.35,36 In all Phase
III trials concerning the thromboprophylaxis after
TKAs, these medications exhibited similar rates of
bleeding compared with the enoxaparin regimens for
both US and European guidelines.33e36 In contrast,
rivaroxaban 10 mg/d was superior to standard
enoxaparin treatments recommended in the United
States and Europe.37,38 In addition, prophylactic
therapy with rivaroxaban exhibited similar rates of
bleeding as enoxaparin treatment.37,38
Studied against the Japanese recommendations for
thromboprophylaxis after TKA, edoxaban 30 mg once
daily exhibited superior efficacy versus enoxaparin
2000 IU (20 mg) twice daily in the Phase III Studying
Thrombosis After Replacement Surgery (STARS) E-3
study.39 Rates of bleeding between the edoxaban and
enoxaparin treatment groups were similar.39
After Total Hip Arthroplasty
Recommendations in most countries, including North
America and Europe, regarding thromboprophylaxis
after total hip arthroplasty (THA) include a
subcutaneous injection of enoxaparin 40 mg once daily
beginning the evening before surgery and continuing
for a minimum duration of 10 days. There is also
speculation that an extended prophylactic regimen of
up to 35 days would be beneficial. Of note, although a
subcutaneous regimen of enoxaparin 30 mg twice daily
is alternatively used in some countries and is approved
by the FDA, this dosage is less frequently used and is
not approved for an extended 35-day prophylactic
regimen. Once again, because the typical duration of
hospital stay is only between 3 and 4 days, adherence
to a parenteral anticoagulant regimen is difficult, and
an oral treatment would be preferred in an outpatient
setting.
In Phase III clinical studies, apixaban 2.5 mg twice
daily, dabigatran etexilate 150 and 220 mg/d, and
December 2018
A.A. Coulis and W.C. Mackey
rivaroxaban 10 mg/d were each evaluated against
subcutaneous enoxaparin 40 mg once daily for a period
of 35 days. Study results revealed apixaban and
dabigatran etexilate (at both 150- and 220-mg doses)
were noninferior to the standard enoxaparin
therapy and exhibited similar rates of bleeding.40,41
Rivaroxaban was additionally determined to be
clinically superior to enoxaparin 40 mg/d without an
increase in adverse events or rates of bleeding.42 The
numerical results of these Phase III trials are given in
Table VIII.
Extended anticoagulation with rivaroxaban was
further evaluated against the short-term 10- to 14-
day Enoxaparin therapy recommended by FDA
guidelines. In the Rosiglitazone Evaluated for Cardiac
Outcomes and Regulation of Glycaemia in Diabetes
(RECORD) 2 trial, rivaroxaban 10 mg/d for 40 days
was compared with enoxaparin 40 mg/d for 10 to 14
days. Results of this study indicated the superior
efficacy of long-term rivaroxaban as compared with
short-term enoxaparin therapy.43 Once again, there
were similar rates of bleeding between the study
groups.43
As with the other Phase III trial concerning
edoxaban's efficacy in thromboprophylaxis after
orthopedic surgery, the STARS J-V trial compared
edoxaban 30 mg taken once daily to the Japanese
guideline of enoxaparin 2000 IU (20 mg) twice
daily. Edoxaban 30 mg/d exhibited superior efficacy
with a similar rate of bleeding for patients after
THA.44 Edoxaban additionally underwent further
Phase III testing to determine its efficacy against
enoxaparin in patients undergoing hip fracture
surgery (HFS) for medial or lateral femoral neck
fractures. Revealing a decreased incidence of major
or CRNM bleeding (3.4% of patients taking
edoxaban vs 6.5% of patients taking enoxaparin)
and a slightly increased number of thromboembolic
events (6.5% of patients taking edoxaban patients vs
3.7% of patients taking enoxaparin) Edoxaban
exhibited results comparable to the Japanese
standard of enoxaparin for patients undergoing
HFS.45 However, because the power of the study
was low (n ¼ 92), no official statistical comparison
could be made. Additional research was also
conducted on the safety profile of half-dose
edoxaban 15 mg for thromboprophylaxis in patients
with severe renal impairment (CRCL 15e30 mL/min)
after lower-limb orthopedic operations, including
2155
2156

Clinical Therapeutics
Table VII. Trial results for thromboprophylaxis following total knee arthroplasty.*
Variable Apixaban Dabigatran Etexilate Edoxaban Rivaroxaban
33 35 34 36 (STARS E-339)
ADVANCE 1 ADVANCE 2 RE-MOBILIZE RE-MODEL RECORD 438 RECORD 337
Dosing Apixaban 2.5 mg twice Dabigatran etexilate 150 mg or 220 mg Edoxaban 30 mg/ Rivaroxaban 10 mg/d vs
daily vs twice daily vs d vs
enoxaparin 30 mg enoxaparin 40 mg/ enoxaparin 30 enoxaparin 40 mg/ enoxaparin 2000 enoxaparin 30 mg enoxaparin
twice daily for d for 10e14 days mg twice daily for d for 6e10 days IU twice-daily for 11 40 mg/d for
10e14 days 12e15 days (20 mg) twice e15 days 13e17 days
daily
for 11e14 days
Patients Apixaban (n ¼ 1599), Apixaban Dabigatran etexilate Dabigatran etexilate Edoxaban Rivaroxaban Rivaroxaban
enoxaparin (n ¼ 1596) (n ¼ 1501), (n ¼ 871 at (n ¼ 703 at (n ¼ 360), (n ¼ 1584), (n ¼ 1254),
enoxaparin 150 mg, 150 mg, enoxaparin enoxaparin enoxaparin
(n ¼ 1508) n ¼ 857 at n ¼ 679 at (n ¼ 356) (n ¼ 1564) (n ¼ 1277)
220 mg), 220 mg),
enoxaparin enoxaparin
(n ¼ 868) (n ¼ 694)
Results VTE or death occurred VTE or death VTE or death VTE or death DVT or PE occurred VTE or death VTE or death
in 9.0% of patients occurred in 15% occurred in 33.7% occurred in 40.5% in occurred in 6.9% occurred in
taking apixaban and of patients taking of patients taking of patients taking 7.4% of patients of patients taking 9.6% of
8.8% of patients taking apixaban and dabigatran dabigatran taking rivaroxaban and patients taking
enoxaparin (RR ¼ 24% of patients etexilate 150 mg, etexilate 150 mg, edoxaban and 10.1% of patients rivaroxaban
1.02; 95% CI, 0.78e1.32) taking enoxaparin 31.1% of patients 36.4% of patients 13.9% of taking enoxaparin and 18.9% of
(RR ¼ 0.62; 95% taking dabigatran taking dabigatran patients taking (absolute risk patients taking
CI, 0.51e0.74; etexilate 150 mg, etexilate 220 mg, enoxaparin reduction ¼ enoxaparin
P < 0.0001) and 25.3% of and 37.7% of (RR reduction ¼ 3.19%; 95% (absolute risk
patients taking patients taking 46.8%; CI, 0.71e5.67; reduction ¼
enoxaparin (8.4% enoxaparin P ¼ 0.010) P ¼ 0.0118) 1.6%; 95% CI,
risk difference for (absolute risk 0.4e2.8;
150 mg; 95% CI; 2.8% for 150 mg; P ¼ 0.01)
3.4e13.33; 95% CI, −3.1- to
Volume 40 Number 12

P ¼ 0.0009; 5.8% 8.7; risk

risk difference for difference, −1.3%
220 mg; 95% CI, for 220 mg; 95%
0.8e10.8; CI, −7.3 to 4.6)
P ¼ 0.0234)
December 2018
Table VII. (Continued )

Variable Apixaban Dabigatran Etexilate Edoxaban Rivaroxaban

(STARS E-339)
ADVANCE 133 ADVANCE 235 RE-MOBILIZE34 RE-MODEL36 RECORD 438 RECORD 337
Major or CRNM bleeding Major or CRNM Major bleeding Major bleeding Major bleeding Major bleeding Major
occurred in 2.9% of bleeding occurred occurred in 0.6% occurred in 1.3% occurred in occurred in 0.7% bleeding
patients taking apixaban in 4% of patients of patients taking of patients taking 1.1% of patients of patients taking occurred in
and 4.3% of patients taking apixaban dabigatran dabigatran taking rivaroxaban and 0.6% of
taking enoxaparin and 5% of etexilate 150 mg, etexilate 150 mg, edoxaban and 0.3% of patients patients
(P ¼ 0.03) patients taking 0.6% of patients 1.5% of patients 0.3% of taking enoxaparin taking
enoxaparin taking dabigatran taking dabigatran patients taking (P ¼ 0.1096)
(P ¼ 0.09) etexilate 220 mg, etexilate 220 mg, enoxaparin
and 1.4% of and 1.3% of (P ¼ 0.373)
patients taking patients taking
enoxaparin enoxaparin
Outcome Inferior efficacy with Noninferior efficacy Inferior efficacy with Noninferior efficacy Superior efficacy Superior efficacy Superior efficacy
reduced rates of without increased similar rates of with similar rates with with similar rates with similar
bleeding rates of bleeding bleeding of bleeding similar rates of of bleeding rates of
bleeding bleeding

ADVANCE ¼ Apixaban Versus Enoxaparin For Thromboprophylaxis After Knee Replacement; CRNM ¼ clinically relevant nonmajor; DVT ¼ deep vein thrombosis;
PE ¼ pulmonary embolism; RECORD ¼ Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; RE-MOBILIZE ¼ Prevention of
Venous Thromboembolism After Total Knee Arthroplasty; RE-MODEL ¼ Prevention of Venous Thromboembolism After Total Knee Replacement; RR ¼ relative
risk; STARS ¼ Studying Thrombosis After Replacement Surgery; VTE ¼ venous thromboembolism.
* Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding scale.

A.A. Coulis and W.C. Mackey

2157
2158

Clinical Therapeutics
Table VIII. Trial results for thromboprophylaxis after total hip arthroplasty.*

Variable Apixaban (ADVANCE- Dabigatran Etexilate Edoxaban (STARS J- Rivaroxaban

340) V44)
RE-NOVATE41 RE-NOVATE II51 RECORD 142 RECORD 243

Dosing Apixaban 2.5 mg Dabigatran etexilate Dabigatran etexilate Edoxaban 30 mg/d vs Rivaroxaban 10 mg/ Rivaroxaban 10 mg/
twice daily vs 150 or 220 mg/d vs 220 mg/f vs enoxaparin 2000 IU d vs enoxaparin d for 40 days vs
enoxaparin 40 mg/ enoxaparin 40 mg/ enoxaparin 40 mg/ (20 mg) twice daily 40 mg/d for 35 enoxaparin 40 mg/
d for 35 days d for 35 days d for 35 days for 11e14 days days d for 10e14 days
Patients Apixaban (n ¼ 2708), Dabigatran etexilate Dabigatran etexilate Edoxaban (n ¼ 225), Rivaroxaban Rivaroxaban
enoxaparin (n ¼ 1163 at (n ¼ 1010), enoxaparin (n ¼ 2266), (n ¼ 1252),
(n ¼ 2699) 150 mg, enoxaparin (n ¼ 248) enoxaparin enoxaparin
n ¼ 1146 at (n ¼ 1003) (n ¼ 2275) (n ¼ 1257)
220 mg),
enoxaparin
(n ¼ 1154)
Results DVT, PE, or death VTE or death occurred VTE or death occurred VTE occurred in 2.4% VTE or death occurred VTE or death occurred
occurred in 1.4% of in 8.6% of patients in 7.7% of patients of patients taking in 1.1% of patients in 2.0% of patients
patients taking taking dabigatran taking dabigatran edoxaban and 6.9% taking rivaroxaban taking rivaroxaban
apixaban and 3.9% etexilate 150 mg, etexilate and 8.8% of patients taking and 2.6% of and 9.3% of
of patients taking 6.0% of patients of patients taking enoxaparin patients taking patients taking
enoxaparin taking dabigatran enoxaparin (risk (absolute enoxaparin enoxaparin
(RR ¼ 0.36; 95% etexilate 220 mg, difference, −1.1%; difference, −4.5%; (absolute risk (absolute risk
CI, 0.22e0.54; and 6.7% of 95% CI, −3.8 to 1.6; 95% CI. −8.6 reduction, 2.6%; reduction, 7.3%;
P < 0.001) patients taking P < 0.0001) to −0.09; 95% CI, 1.5e3.7; 95% CI, 2.0e9.4;
patients (1.9% P < 0.001) P < 0.001) P < 0.0001)
difference in risk for
150 mg; 95%
CI, −0.6 to
4.4; −0.7%
Volume 40 Number 12

difference in risk for

220 mg; 95%
CI, −2.9 to 1.6)
December 2018
Table VIII. (Continued )
Variable Apixaban (ADVANCE- Dabigatran Etexilate Edoxaban (STARS J- Rivaroxaban
340) V44)
RE-NOVATE41 RE-NOVATE II51 RECORD 142 RECORD 243

Major or CRNM Major bleeding Major bleeding Major or CRNM Major bleeding Major or CRNM
bleeding occurred occurred in 1.3% of occurred in 1.4% of bleeding occurred occurred in 0.3% of bleeding
in 4.8% of patients patients taking patients taking in 2.6% of patients patients taking occurred in 3.4%
taking apixaban dabigatran etexilate dabigatran etexilate taking edoxaban rivaroxaban and of patients taking
and 5.0% of 150 mg, 2.0% of and 0.9% of and 3.7% of 0.1% of patients rivaroxaban and
patients taking patients taking patients taking patients taking taking enoxaparin 2.8% of patients
enoxaparin (−0.2% dabigatran etexilate enoxaparin enoxaparin (P ¼ 0.18) taking
absolute difference 220 mg, and 1.6% (P ¼ 0.40) (P ¼ 0.475) enoxaparin
in risk; 95% CI, −1.4 of patients taking (P ¼ 0.25)
to 1.0) enoxaparin
(P ¼ 0.60 for
150 mg; P ¼ 0.44
for 220 mg)
Outcome Superior efficacy with Noninferior efficacy Noninferior efficacy Superior efficacy with Superior efficacy with Superior efficacy with
similar rates of with similar rates of with similar rates of similar rates of similar rates of low rates of
bleeding bleeding bleeding bleeding bleeding bleeding

ADVANCE ¼ Apixaban Versus Enoxaparin For Thromboprophylaxis After Knee Replacement; CRNM ¼ clinically relevant nonmajor; DVT ¼ deep vein thrombosis;
PE ¼ pulmonary embolism; RECORD ¼ Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes; RE-MOBILIZE ¼ Prevention of
Venous Thromboembolism After Total Knee Arthroplasty; RE-MODEL ¼ Prevention of Venous Thromboembolism After Total Knee Replacement; RR ¼ relative
risk; STARS ¼ Studying Thrombosis After Replacement Surgery; VTE ¼ venous thromboembolism.
* Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding scale.

A.A. Coulis and W.C. Mackey

2159
 Clinical Therapeutics
TKA, THA, and HFS. Reporting similar rates of
bleeding between patients taking edoxaban 15 mg
with severe renal impairment (20.7%), patients with
severe renal impairment taking fondaparinux 1.5 mg
(40.0%), and patients with mild-to-moderate renal
impairment taking edoxaban 30 mg (33.3%), this
study suggests that edoxaban 15 mg/d is similarly
tolerated in this patient population.46 However,
given these high rates of bleeding, a larger study is
needed to confirm these results and assess the
possible clinical tolerability concerns of these
regimens.
Prophylactic Treatment for Acutely Ill Medical
Patients
Patients hospitalized for acute medical illnesses,
such as pneumonia, stroke, or heart failure, pose an
increased risk of VTE that is often compounded by
additional risk factors, such as prolonged
immobilization, age 75 years, or a history of
previous VTE. Current guidelines regarding such
high-risk patients, hereafter referred to as acutely ill
medical patients, recommends the use of a low-dose
6- to 10-day parenteral anticoagulant regimen
(typically subcutaneous enoxaparin 40 mg/d).
Because this treatment is rarely extended beyond
hospital discharge, the trend toward shorter hospital
stays means that many acutely ill medical patients
receive anticoagulant therapy for a shorter duration
than recommended. Investigating the benefit of
extended thromboprophylaxis in this patient
population, the Extended Prophylaxis for Venous
Thromboembolism in Acutely Ill Medical Patients
With Prolonged Immobilization (EXCLAIM) trial
revealed that enoxaparin 40 mg/d for 40 days
exhibited a reduced incidence of VTE compared with
placebo and was the first study to indicate that
extended anticoagulation for acutely ill medical
patients may be advantageous.47 However, because
daily enoxaparin injections are not ideal in the
outpatient setting, the Apixaban Dosing to Optimize
Protection from Thrombosis (ADOPT) and
Multicenter, Randomized, Parallel Group Efficacy
and Safety Study for the Prevention of Venous
Thromboembolism in Hospitalized Acutely Ill
Medical Patients Comparing Rivaroxaban With
Enoxaparin (MAGELLAN) researchers investigated
whether an extended anticoagulant regimen with oral
apixaban or rivaroxaban could be effective.
2160
Study Design
Phase III clinical trials were conducted to compare
an extended anticoagulation regimen with apixaban
or rivaroxaban to the short-term enoxaparin 40-mg
regimen that is currently recommended. Each NOAC
was administered at their respective doses for 30 to
40 days. Enoxaparin 40 mg was given via
subcutaneous injection for 6 to 14 days.
In its investigation of rivaroxaban, the
MAGELLAN study performed 2 efficacy analyses: a
noninferiority study at day 10 of administration and
a superiority study at day 35. In this way, the
MAGELLAN researchers explored whether
rivaroxaban was as effective as enoxaparin in the
short-term prophylaxis of acutely ill medical patients
as well as whether extended treatment with this
medication exhibited clinical benefit.
Study Findings
In their respective Phase III clinical trials, an
extended regimen of apixaban 2.5 mg twice daily or
rivaroxaban 10 mg/d were each compared to
enoxaparin 40 mg/d for the extended
thromboprophylaxis in acutely ill medical patients. In
their investigations of apixaban, the ADOPT48 trial
revealed that this medication did not exhibit superior
efficacy to enoxaparin therapy. Furthermore,
apixaban was associated with significantly more
bleeding events.48 Although rivaroxaban was also
associated with an increased rate of bleeding in the
MAGELLAN trial, it was determined to be
noninferior to enoxaparin 40 mg/d at the 10-day
efficacy analysis and had superior efficacy at the
conclusion of 35 days.49 Results for these 3 trials are
given in Table IX.
DISCUSSION
Overall, the NOACs offer a simplified anticoagulation
regimen that generally has noninferiority in efficacy
and similar rates of bleeding when compared with
standard therapy throughout multiple studies in the
published literature. In the absence of head-to-head
trials directly comparing each NOAC, patient
preference for certain medication characteristics may
be valuable in determining the anticoagulation
regimen that is most appropriate for an individual.
Although each NOAC treatment was well tolerated
among most patients, because dabigatran etexilate
Volume 40 Number 12
 A.A. Coulis and W.C. Mackey

Table IX. Trial results for thromboprophylaxis in acutely ill medical patients.*

Variable Apixaban (ADOPT48) Rivaroxaban (MAGELLAN49)

Dosing Apixaban 2.5 mg twice daily for 30 days vs
enoxaparin 40 mg/d for 6e14 days
Patients Apixaban (n ¼ 3255), enoxaparin (n ¼ 3273)
Results VTE and associated death occurred in 2.71% of
patients taking apixaban and 3.06% of patients
taking enoxaparin (RR ¼ 0.87; 95% CI, 0.62
e1.23; P ¼ 0.44)
Major bleeding occurred in 0.47% of patients
taking apixaban patients and 0.19% of patients
taking enoxaparin (RR ¼ 2.58; 95% CI, 1.02
e7.24; P ¼ 0.04)
Outcome Did not have superior efficacy with significantly
more bleeding events
Rivaroxaban 10 mg/d for 31e39 days vs
enoxaparin 40 mg/d for 6e14 days
Rivaroxaban (n ¼ 4050), enoxaparin
(n ¼ 4051)
At day 10, VTE occurred in 2.7% of patients
taking rivaroxaban and 2.7% of patients
taking enoxaparin (RR ¼ 0.97; 95% CI, 0.71
e1.31; P ¼ 0.003); at day 35, VTE occurred
in 4.4% of patients taking rivaroxaban and
5.7% of patients taking enoxaparin
(RR ¼ 0.77; 95% CI, 0.62e0.96; P ¼ 0.02)
At day 10, major bleeding occurred in 2.8% of
patients taking rivaroxaban and 1.2% of
patients taking enoxaparin; at day 35, major
bleeding occurred in 4.1% of patients taking
rivaroxaban and 1.7% of patients taking
enoxaparin
At day 10, noninferior efficacy with increased
rates of bleeding; at day 35, superior efficacy
with increased rates of bleeding

ADOPT ¼ Apixaban Dosing to Optimize Protection from Thrombosis; MAGELLAN ¼ Multicenter, Randomized, Parallel Group
Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients
Comparing Rivaroxaban With Enoxaparin; RR ¼ relative risk.
* Major bleeding was defined according to the International Society on Thrombosis Haemostasis bleeding scale.

was associated with an adverse effect of dyspepsia, this
medication may not be the first choice for those
sensitive to gastric upset. In addition, because
apixaban and dabigatran etexilate require twice-daily
dosing, edoxaban or rivaroxaban may be better
suited for patients who prefer a medication with
once-daily administration. Tailoring the prescribed
therapy to fit these patient preferences may promote
medication adherence.
Excluding those with severe hepatic or renal
impairment as well as breastfeeding mothers, the
NOACs can administered to a wide variety of patient
populations and only exhibit serious drug
interactions with strong dual P-gp and CYP3A4
inducers or inhibitors. Owing to its renal clearance
without CYP metabolism, dabigatran etexilate may
be the best NOAC option for patients with impaired
hepatic function or those requiring concomitant
administration with a medication affecting CYP3A4
activity. Offering a variety of dosing options,
edoxaban and apixaban are valuable treatment
alternatives for patients still indicated for NOAC
therapy but who may be highly sensitive to
treatment. However, only half-dosed edoxaban was
explicitly studied and found to be tolerable and
effective in patients with mild-to-moderate renal
impairment, a low weight, or concomitant
administration with strong P-gp inhibitors. Although
apixaban is available in 2.5-, 5-, or 10-mg tablets,
reduced doses were not specifically studied in Phase
III clinical trials. Further research is needed before a
decreased dose of apixaban can confidently be
prescribed for vulnerable patient populations.
Because the ability to quickly reverse the effects of
anticoagulation continues to be of clinical interest,
the approval of andexanet alfa and idarucizumab as

December 2018 2161

 Clinical Therapeutics
antidotes is especially important for patients taking
apixaban, dabigatran etexilate, or rivaroxaban who
are at risk of serious bleeding or who may require
emergency surgery. However, because edoxaban
remains without a specific reversal agent, use of this
medication in high-risk patient populations poses an
increased chance of irreversible bleeding.
Treatment of Acute VTE\
Because apixaban and rivaroxaban were approved
as monotherapies, this opportunity for a simplified
oral regimen would be especially ideal for patients
who do not require hospitalization and are stable for
outpatient management. However, patients who were
initially started on parenteral treatment with LMWH
or UFH are not optimal candidates for subsequent
treatment with apixaban or rivaroxaban. This is
confirmed by the poor outcome of patients taking
rivaroxaban in the subgroup analysis of early
switchers from the XALIA trial. For such patients,
dabigatran etexilate or edoxaban would be superior
choices. This is especially applicable for patients
with pronounced symptoms of VTE who were
initially hospitalized and administered inpatient
anticoagulation. With dabigatran etexilate or
edoxaban, such patients would be able to begin a
NOAC anticoagulation regimen at discharge after
initial heparin treatment.
The efficacy and tolerability of NOAC
anticoagulation for the treatment of acute VTE were
substantially supported with multiple Phase III
trials, 3 of which were able to reproduce and
confirm the initial noninferiority results. Although
only one Phase III trial exists for edoxaban, the
sample size should be noted. With almost twice as
many trial participants as the others, the data
supporting edoxaban's noninferiority to warfarin is
of similar strength to the other NOACs with 2
confirmatory trials. Of additional note, as the
EINSTEIN-PE study sampled the largest number of
individuals with diagnosed PE (n ¼ 4832), almost
twice as many as in other trials, it presents the
strongest supporting data concerning
anticoagulation treatment for acute PE. For this
reason, in the absence of additional preferential
factors affecting a clinician's decision, rivaroxaban
may be the first choice of treatment for patients
with PE. However, head-to-head studies directly
comparing the safety profiles and effectiveness of
2162
the 4 NOACs in the treatment of PE are needed to
more firmly establish this.
When considering tolerability, all 4 NOACs had
similar or reduced major bleeding profiles when
compared with standard therapy. Apixaban was the
only medication that exhibited a clinically relevant
reduction in the risk of major bleeding. While this
indirect comparison should be interpreted with
caution, it is reasonable to postulate that apixaban
may be a logical anticoagulant option for patients for
whom there are bleeding concerns.
In addition, the NOACs maintained their overall
noninferiority and similar tolerability in subgroup
analyses of multiple vulnerable patient populations.
However, only edoxaban offers a reduced dosing
option with published evidence supporting its use for
medically fragile patients. In the event that edoxaban
is not an option for patients with mild-to-moderate
renal impairment or advanced age, subgroup analyses
support the use of dabigatran etexilate and
rivaroxaban. Because individuals with severe renal
function (CRCL <30 mL/min) were excluded from the
original studies, further research is needed before
either of these medications can be confidently
prescribed for this patient population.
Although NOAC anticoagulation in patients with
active cancer may be a valuable alternative to VKAs,
only edoxaban was further investigated against the
recommended long-term LMWH monotherapy. In the
absence of published data establishing the
noninferiority of the other 3 medications, edoxaban
should be the first-choice in NOAC anticoagulation for
patients with active cancer. In addition, patients with
advanced cancer and a life expectancy of <3 months,
many of whom require the recommended long-term
LMWH regimen, were excluded from the original
Phase III trials and subsequent analyses. Therefore,
further research is needed before NOAC
anticoagulation can be recommended for this
population.
NOAC anticoagulation may have the greatest
clinical benefit in patients who require prolonged or
life-long therapy. With no dietary restrictions or need
for routine coagulation monitoring, long-term NOAC
therapy would impose little effect on patients’
activities of daily living. Although long-term therapy
with aspirin also exhibits these lifestyle benefits, it
was inferior to rivaroxaban in the EINSTEIN
CHOICE trial. For these reasons, in patients for
Volume 40 Number 12

whom there is clinical equipoise regarding the
continuation or cessation of anticoagulation,
apixaban, dabigatran etexilate, or rivaroxaban would
be valuable options. Because dabigatran etexilate is
the only medication with published evidence on its
noninferiority to warfarin in the extended treatment
of VTE and additionally was associated with a lower
risk of major bleeding, it is the logical oral
anticoagulant for patients who require extended
anticoagulant therapy.
VTE Prophylaxis
In the case of thromboprophylaxis after a TKA,
rivaroxaban exhibited superiority over both US- and
European-recommended enoxaparin regimens
without increased rates of bleeding. Because
rivaroxaban 10 mg/d was the only medication with
clinically proven superiority over the FDA
recommended enoxaparin 30 mg twice daily in the
United States, it may be the NOAC of choice,
offering a simple and effective treatment alternative.
If solely considering the European standard of care,
apixaban and dabigatran etexilate may also be
valuable options because of their proven
noninferiority compared with enoxaparin 40 mg/d.
Although the Phase III trial of edoxaban seemed
promising, its unique study characteristics must be
taken into consideration. Most obviously, edoxaban's
superiority was established against a 19.4e55.0 ng/mL).50,51 Offering a tolerable and
thromboprophylactic regimen that is not
recommended for patients in the United States or
Europe. Enoxaparin 2000 IU (20 mg) twice daily is a
lower anticoagulant dose than used in the West and
is adjusted for the lower mean weight of Japanese
patients. Of note, the mean weight of studied
participants in the edoxaban trial was 60.2 kg.39 For
reference, mean weights of participants in the
apixaban and rivaroxaban studies were 78 and
80.7 kg, respectively.39 For this reason, although
edoxaban exhibited favorable results in the Japanese
population, these data cannot be extrapolated for US
or European patients and do not indicate superiority
with respect to Western guidelines.
Phase III analyses of apixaban and rivaroxaban
found superior efficacies and similar safety profiles
compared with enoxaparin 40 mg/d after THA.
Although each of these studies investigated their
results for 35 days as recommended by current
guidelines, this lengthy parenteral anticoagulation
December 2018
A.A. Coulis and W.C. Mackey
regimen is rarely administered in clinical practice and
LMWH therapy is often discontinued at hospital
discharge. Because apixaban and rivaroxaban were
superior without increasing the risk of bleeding, these
medications would be ideal for the recommended 35
days. Confirming the benefit of long-term NOAC
anticoagulation over short-term enoxaparin, the
RECORD 2 trial found that rivaroxaban 10 mg/d for
40 days was superior to enoxaparin 40 mg/d for 10
to 14 days with a lower risk of bleeding.
Although unable to prove superiority like apixaban
and rivaroxaban, through its reported noninferiority
and reduced dosing option, dabigatran etexilate
could fill a crucial niche in NOAC
thromboprophylaxis after THA. Further investigation
conducted in an independent study revealed that
when dabigatran etexilate 150 mg was administered
once daily to patients with moderate renal
impairment (CLCR <50 mL/min), the steady-state
drug concentration in this population was in a
similar and therapeutic range to those with mild
renal impairment (CLCR of 50-80 mL/min) receiving
dabigatran etexilate 220 mg in the Oral Dabigatran
Versus Enoxaparin for Thromboprophylaxis After
Primary Total Hip Arthroplasty (RE-NOVATE II)
trial (47.5 ng/mL in patients taking 150 mg;
interquartile range, 29.6e71.2 ng/mL vs 32.0 ng/mL
in patients taking 220 mg; interquartile range,
effective reduced dosing option, dabigatran etexilate
150 mg could be indicated for medically fragile
patients, such as those with moderate renal
impairment or elderly patients. Because this
encompasses a significant portion of patients
receiving a THA, dabigatran etexilate 150 mg is an
important option for thromboprophylaxis.
Although the STARS J-V trial indicated the similar
tolerability and superior efficacy of edoxaban therapy
for thromboprophylaxis after THA, these results
were compared against the Japanese guidelines,
which recommends a lower dose of enoxaparin. In
addition, the mean weight of the STARS J-V study
participants was 57.5 kg, approximately 20 kg lower
than the other Phase III trials (mean weight in the
RECORD 1 trial for patients taking rivaroxaban was
78 kg).44 However, because edoxaban continues to
exhibit favorable results in supplemental avenues of
study, namely in the thromboprophylactic treatment
of patients after HFS and in the successful half-dose
2163
 Clinical Therapeutics
adjustment for patients with severe renal impairment
(CRCL of 15e30 mL/min), further evaluation is
warranted to establish edoxaban's place in Western
medical practice. Furthermore, the potential exhibited
by edoxaban highlights areas of study that are
currently lacking for the other oral anticoagulants.
When considering the clinical role of NOACs in
thromboprophylaxis after major orthopedic surgery,
additional avenues of study should include their
effectiveness compared with aspirin. Offering the
same lifestyle benefits and ease of oral
administration, the relative low-cost and convenience
of over-the-counter aspirin would make it a valuable
anticoagulant option. Investigating this possibility,
the Extended Venous Thromboembolism Prophylaxis
Comparing Rivaroxaban to Aspirin Following Total
Hip and Knee Arthroplasty (EPCAT II) trial
established the noninferiority of aspirin 81 mg/
d versus rivaroxaban 10 mg/d for the prevention of
recurrent VTE after TKA or THA. Numerically, VTE
occurred in 0.64% of the aspirin group and in
0.70% of the rivaroxaban group (0.06 difference in
percentage points; 95% CI, −0.55 to 0.66; P < 0.001
for noninferiority and P ¼ 0.84 for superiority),
whereas major bleeding complications occurred in
0.47% and 0.29% of the aspirin and rivaroxaban
groups, respectively (0.18 difference in percentage
points; 95% CI, −0.65 to 0.29; P ¼ 0.42).52
However, subgroup analysis of patients who were
undergoing long-term aspirin therapy before surgery
revealed higher rates of bleeding for those in the
aspirin group. Specifically, the trial results indicated
that for this subgroup of 885 patients, 0.7% in both
the rivaroxaban and aspirin groups experienced a
recurrent VTE, whereas 0.23% of the rivaroxaban
group and 0.94% of the aspirin group experienced
major bleeding events.52 These results suggest that
for patients already undergoing long-term aspirin
therapy, an additional dose of aspirin 81 mg for VTE
prophylaxis is not recommended. Although it seems
that thromboprophylaxis with rivaroxaban would be
advantageous for such patients, further research is
needed to establish the safety profiles and efficacy of
the NOACs (especially apixaban, dabigatran
etexilate, and edoxaban) compared with aspirin
therapy.
In addition to major orthopedic surgery, apixaban
and rivaroxaban were evaluated for efficacy and
tolerability in the thromboprophylaxis of acutely ill
2164
medical patients with varied results. In Phase III
clinical trials, apixaban failed to establish superiority
with respect to the recommended enoxaparin regimen
of 40 mg once daily for 6e14 days. Speaking to the
potential of apixaban, ADOPT trial researchers state
that their study was underpowered and insist that no
clinically directive conclusion can be drawn from
their results. Specifically, the authors postulate that
the study conditions, namely the required
ultrasonographic screening for VTE even in the
absence of symptoms and continued enoxaparin
treatment for the full recommended 6 to 14 days, do
not accurately portray clinical practice.48
Acknowledging this, although apixaban is not
currently indicated for the extended
thromboprophylaxis in acutely ill medical patients,
further research that better represents clinical
conditions is warranted. In addition to the favorable
results, the study design of the MAGELLAN trial
provides the greatest support for the use of
rivaroxaban in the thromboprophylaxis of acutely ill
medical patients. Establishing its noninferiority at day
10 indicates that oral rivaroxaban is as effective as
subcutaneous enoxaparin, the short-term
anticoagulant regimen recommended by current
guidelines. Because most patients remain in the
hospital for <5 days and it is standard practice to
discontinue enoxaparin injections on hospital
discharge, oral rivaroxaban would be a much simpler
option. Furthermore, it was the only NOAC that has
superiority versus placebo in an extended 35-day
thromboprophylactic regimen. However, because this
medication was associated with increased risks of
bleeding, the benefit to risk ratio must be considered
by the physician.
CONCLUSION
Overall, Phase III and postmarketing VTE treatment
and prophylaxis trials found that NOACs can
effectively simplify anticoagulation therapy for a wide
range of patients. With no restriction on dietary
intake and administered in fixed-oral doses that do
not require routine monitoring, these medications are
ideal for the outpatient setting. Although not
addressed in this review, additional factors, such as
patient satisfaction and overall cost of treatment,
should be considered. Offering a brief insight into
additional benefits that may be associated with
NOAC therapy, subgroup analysis of the EINSTEIN
Volume 40 Number 12

trials indicated that patients taking rivaroxaban
reported greater treatment satisfaction.53 In addition,
researchers investigating financial implications
calculated that during a 5-year period it cost a mean
of $2488 less per patient to treat with rivaroxaban
than with standard enoxaparin or warfarin
therapy.54 Although these results seem promising,
they were not the primary focus of the original study
and should be read with caution. However, these
factors are important aspects of treatment that
should be subject to rigorous study. In light of the
results described above, it now seems reasonable for
clinicians to consider NOACs as first-line agents for
treatment and prophylaxis of venous thromboembolic
disease in most patients and to consider the relative
merits of the available NOACs in tailoring their
choices for individual clinical scenarios. Although
heparins and VKAs may still be recommended for
selected patients, their role is rapidly diminishing,
especially when longer-term therapy is required.
ACKNOWLEDGMENTS
Dr. John Castellot of the Tufts University School of
Medicine provided valuable guidance in the editing
of this manuscript. Author contributions are as
follows: Alexis Coulis: methodology, investigation,
and writing (original draft); William Mackey:
conceptualization, methodology, writing (review and
editing), and supervision.
CONFLICTS OF INTEREST
The authors have indicated that they have no conflicts
of interest regarding the content of this article.
REFERENCES
1. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous
thromboembolism: a public health concern. Am J Prev Med.
2010;38:S495eS501.
2. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus
warfarin in the treatment of acute venous
thromboembolism. N Engl J Med. 2009;361:2342e2352.
3. Buller HR, Decousus H, Grosso MA, et al. Edoxaban
versus warfarin for the treatment of symptomatic
venous thromboembolism. N Engl J Med. 2013;369:
1406e1415.
4. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the
treatment of acute venous thromboembolism. N Engl J Med.
2013;369:799e808.
December 2018
A.A. Coulis and W.C. Mackey
5. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral
rivaroxaban for symptomatic venous thromboembolism.
N Engl J Med. 2010;363:2499e2510.
6. Burness CB, Perry CM. Rivaroxaban: a review of its use in
the treatment of deep vein thrombosis or pulmonary
embolism and the prevention of recurrent venous
thromboembolism. Drugs. 2014;74:243e262.
7. Greig SL, Garnock-Jones KP. Apixaban: a review in venous
thromboembolism. Drugs. 2016;76:1493e1504.
8. Greig SL, McKeage K. Dabigatran etexilate: a review of its
use in the treatment of acute venous thromboembolism
and prevention of venous thromboembolism recurrence.
Drugs. 2014;74:1785e1800.
9. Shirley M, Dhillon S. Edoxaban: a review in deep vein
thrombosis and pulmonary embolism. Drugs. 2015;75:
2025e2034.
10. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa
for the reversal of factor Xa inhibitor activity. N Engl J Med.
2015;373:2413e2424.
11. Connolly SJ, Milling Jr TJ, Eikelboom JW, et al.
Andexanet alfa for acute major bleeding associated with
factor Xa inhibitors. N Engl J Med. 2016;375:1131e1141.
12. Pollack Jr CV, Reilly PA, Eikelboom J, et al. Idarucizumab
for dabigatran reversal. N Engl J Med. 2015;373:511e520.
13. Nakamura M, Nishikawa M, Komuro I, et al. Apixaban for
the treatment of Japanese subjects with acute venous
thromboembolism (AMPLIFY-J Study). Circ J. 2015;79:
1230e1236.
14. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of
acute venous thromboembolism with dabigatran or
warfarin and pooled analysis. Circulation. 2014;129:
764e772.
15. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for
the treatment of symptomatic pulmonary embolism. N Engl
J Med. 2012;366:1287e1297.
16. Ageno W, Mantovani LG, Haas S, et al. Safety and
effectiveness of oral rivaroxaban versus standard
anticoagulation for the treatment of symptomatic deep-
vein thrombosis (XALIA): an international, prospective,
non-interventional study. Lancet Haematol. 2016;3:
e12ee21.
17. Turpie AGG, Mantovani LG, Haas S, et al. Analysis of
patients with deep vein thrombosis switched from standard
therapy to rivaroxaban in the non-interventional XALIA
study. Thromb Res. 2017;155:23e27.
18. Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin
inhibitors or oral factor Xa inhibitors for the treatment of
deep vein thrombosis. Cochrane Database Syst Rev. 2015;6:
CD010956.
19. Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin
inhibitors or oral factor Xa inhibitors for the treatment of
pulmonary embolism. Cochrane Database Syst Rev. 2015;12:
CD010957.
2165
 Clinical Therapeutics
20. Agnelli G, Buller HR, Cohen A, et al.
Oral apixaban for the treatment of
venous thromboembolism in cancer
patients: results from the AMPLIFY
trial. J Thromb Haemost. 2015;13:
2187e2191.
21. Eriksson H, Goldhaber SZ, Kakkar A,
et al. Influence of active cancer on
the efficacy and safety of dabigatran
versus warfarin for the treatment of
acute venous thromboembolism: a
pooled analysis from RE-Cover and
RE-Cover II. Blood. 2013;122:582.
22. Prins MH, Lensing AW, Brighton TA,
et al. Oral rivaroxaban versus
enoxaparin with vitamin K antagonist
for the treatment of symptomatic
venous thromboembolism in patients
with cancer (EINSTEIN-DVT and
EINSTEIN-PE): a pooled subgroup
analysis of two randomised
controlled trials. Lancet Haematol.
2014;1:e37ee46.
23. Raskob GE, van Es N, Segers A, et al.
Edoxaban for venous
thromboembolism in patients with
cancer: results from a non-inferiority
subgroup analysis of the Hokusai-
VTE randomised, double-blind,
double-dummy trial. Lancet Haematol.
2016;3:e379ee387.
24. Raskob GE, van Es N, Verhamme P,
et al. Edoxaban for the treatment of
cancer-associated venous
thromboembolism. N Engl J Med.
2018;378:615e624.
25. Goldhaber SZ, Schulman S,
Eriksson H, et al. Dabigatran versus
warfarin for acute venous
thromboembolism in elderly or
impaired renal function patients:
pooled analysis of RE-COVER and
RE-COVER II. Thromb Haemost.
2017;117:2045e2052.
26. Bauersachs RM, Lensing AW,
Prins MH, et al. Rivaroxaban versus
enoxaparin/vitamin K antagonist
therapy in patients with venous
thromboembolism and renal
impairment. Thromb J. 2014;12:25.
27. Prins MH, Lensing AW,
Bauersachs R, et al. Oral rivaroxaban
2166
versus standard therapy for the
treatment of symptomatic venous
thromboembolism: a pooled analysis
of the EINSTEIN-DVT and PE
randomized studies. Thromb J.
2013;11:21.
28. Kubitza D, Becka M, Roth A,
Mueck W. The influence of age and
gender on the pharmacokinetics and
pharmacodynamics of rivaroxaban:
an oral, direct factor Xa inhibitor.
J Clin Pharmacol. 2013;53:249e255.
29. Verhamme P, Wells PS, Segers A,
et al. Dose reduction of edoxaban
preserves efficacy and safety for the
treatment of venous
thromboembolism: an analysis of the
randomised, double-blind HOKUSAI
VTE trial. Thromb Haemost. 2016;116:
747e753.
30. Schulman S, Kearon C, Kakkar AK,
et al. Extended use of dabigatran,
warfarin, or placebo in venous
thromboembolism. N Engl J Med.
2013;368:709e718.
31. Agnelli G, Buller HR, Cohen A, et al.
Apixaban for extended treatment of
venous thromboembolism. N Engl J
Med. 2013;368:699e708.
32. Weitz JI, Lensing AWA, Prins MH,
et al. Rivaroxaban or aspirin for
extended treatment of venous
thromboembolism. N Engl J Med.
2017;376:1211e1222.
33. Lassen MR, Raskob GE, Gallus A,
Pineo G, Chen D, Portman RJ.
Apixaban or enoxaparin for
thromboprophylaxis after knee
replacement. N Engl J Med. 2009;361:
594e604.
34. Ginsberg JS, Davidson BL, Comp PC,
et al. Oral thrombin inhibitor
dabigatran etexilate vs North
American enoxaparin regimen for
prevention of venous
thromboembolism after knee
arthroplasty surgery. J Arthroplasty.
2009;24:1e9.
35. Lassen MR, Raskob GE, Gallus A,
Pineo G, Chen D, Hornick P.
Apixaban versus enoxaparin for
thromboprophylaxis After knee
replacement (ADVANCE-2): a
randomised double-blind trial.
Lancet. 2010;375:807e815.
36. Eriksson BI, Dahl OE, Rosencher N,
et al. Oral dabigatran etexilate vs.
subcutaneous enoxaparin for the
prevention of venous
thromboembolism after total knee
replacement: the RE-MODEL
randomized trial. J Thromb Haemost.
2007;5:2178e2185.
37. Lassen MR, Ageno W, Borris LC,
et al. Rivaroxaban versus enoxaparin
for thromboprophylaxis after total
knee arthroplasty. N Engl J Med.
2008;358:2776e2786.
38. Turpie AG, Lassen MR, Davidson BL,
et al. Rivaroxaban versus enoxaparin
for thromboprophylaxis after total
knee arthroplasty (RECORD 4): a
randomised trial. Lancet. 2009;373:
1673e1680.
39. Fuji T, Wang CJ, Fujita S, et al. Safety
and efficacy of edoxaban, an oral
factor Xa inhibitor, versus enoxaparin
for thromboprophylaxis after total
knee arthroplasty: the STARS E-3
trial. Thromb Res. 2014;134:1198
e1204.
40. Lassen MR, Gallus A, Raskob GE,
Pineo G, Chen D, Ramirez LM.
Apixaban versus enoxaparin for
thromboprophylaxis after hip
replacement. N Engl J Med. 2010;363:
2487e2498.
41. Eriksson BI, Dahl OE, Rosencher N,
et al. Dabigatran etexilate versus
enoxaparin for prevention of venous
thromboembolism after total hip
replacement: a randomised, double-
blind, non-inferiority trial. Lancet.
2007;370:949e956.
42. Eriksson BI, Borris LC, Friedman RJ,
et al. Rivaroxaban versus enoxaparin
for thromboprophylaxis after hip
arthroplasty. N Engl J Med. 2008;358:
2765e2775.
43. Kakkar AK, Brenner B, Dahl OE, et al.
Extended duration rivaroxaban versus
short-term enoxaparin for the
prevention of venous
thromboembolism after total hip
Volume 40 Number 12
 A.A. Coulis and W.C. Mackey

arthroplasty: a double-blind, II*): a randomised, double-blind,

randomised controlled trial. Lancet. non-inferiority trial. Thromb Haemost.
2008;372:31e39. 2011;105:721e729.
44. Fuji T, Fujita S, Kawai Y, et al. 52. Anderson DR, Dunbar M,
Efficacy and safety of edoxaban Murnaghan J, et al. Aspirin or
versus enoxaparin for the prevention rivaroxaban for VTE prophylaxis after
of venous thromboembolism hip or knee arthroplasty. N Engl J
following total hip arthroplasty: Med. 2018;378:699e707.
STARS J-V. Thromb J. 2015;13:27. 53. Bamber L, Wang MY, Prins MH, et al.
45. Fuji T, Fujita S, Kawai Y, et al. Safety Patient-reported treatment
and efficacy of edoxaban in patients satisfaction with oral rivaroxaban
undergoing hip fracture surgery. versus standard therapy in the
Thromb Res. 2014;133:1016e1022. treatment of acute symptomatic
46. Fuji T, Fujita S, Kawai Y, et al. deep-vein thrombosis. Thromb
A randomized, open-label trial of Haemost. 2013;110:732e741.
edoxaban in Japanese patients with 54. Lefebvre P, Coleman CI,
severe renal impairment undergoing Bookhart BK, et al. Cost-effectiveness
lower-limb orthopedic surgery. of rivaroxaban compared with
Thromb J. 2015;13:6. enoxaparin plus a vitamin K
47. Hull RD, Schellong SM, Tapson VF, antagonist for the treatment of
et al. Extended-duration venous venous thromboembolism. J Med
thromboembolism prophylaxis in Econ. 2014;17:52e64.
acutely ill medical patients with
recently reduced mobility: a
randomized trial. Ann Intern Med.
2010;153:8e18.
48. Goldhaber SZ, Leizorovicz A,
Kakkar AK, et al. Apixaban versus
enoxaparin for thromboprophylaxis
in medically ill patients. N Engl J Med.
2011;365:2167e2177.
49. Cohen AT, Spiro TE, Buller HR, et al.
Rivaroxaban for thromboprophylaxis
in acutely ill medical patients. N Engl J
Med. 2013;368:513e523.
50. Eriksson BI, Mikuska Z, Feuring M,
et al. An open-label study of the
pharmacokinetics and
pharmacodynamics of dabigatran
etexilate 150mg once daily in
Caucasian patients with moderate
renal impairment undergoing
primary unilateral elective total knee
or hip replacement surgery. Thromb
Res. 2016;144:158e164.
51. Eriksson BI, Dahl OE, Huo MH, et al.
Oral dabigatran versus enoxaparin
for thromboprophylaxis after primary
total hip arthroplasty (RE-NOVATE

Address correspondence to: Alexis A. Coulis, MS, Tufts University School

of Medicine, 145 Harrison Ave, Boston, MA 02111, USA. E-mail: Alexis.
Coulis@tufts.edu

December 2018 2167