REVIEWS

Oral anticoagulants in the management

of venous thromboembolism
John N. Makaryus, Jonathan L. Halperin and Joe F. Lau
Abstract | Despite advances in diagnosis, prevention, and management, venous thromboembolism (VTE) remains
a common cause of morbidity and mortality. For decades, antithrombotic therapy for prevention and treatment of
VTE was limited to parenteral agents related to heparin and oral vitamin K antagonists (VKAs). Both classes
of anticoagulants are effective, but have limitations, including considerable variability in dose–response, narrow
therapeutic margins between the risks of thrombosis and bleeding, and the need to monitor anticoagulation
intensity. Over the past decade, the introduction of new oral anticoagulants that specifically inhibit coagulation
factors IIa (thrombin) or Xa has changed practice in a variety of clinical situations, including VTE prophylaxis
and treatment. In this Review, we outline the use of the novel oral anticoagulants apixaban, dabigatran,
edoxaban, and rivaroxaban in the prevention and treatment of VTE, and discuss practical considerations
for choosing the appropriate drug for each patient. Although the introduction of novel anticoagulant drugs is
promising, selecting the optimum strategy for an individual patient requires an understanding of the specific
circumstances associated with thrombus formation and the pharmacological properties of each agent.
Makaryus, J. N. et al. Nat. Rev. Cardiol. 10, 397–409 (2013); published online 21 May 2013; doi:10.1038/nrcardio.2013.73

Introduction
Venous thromboembolism (VTE) can be difficult to
prevent and manage because of the diversity of patient-
specific and disease-specific risk factors. Patients at
risk of VTE include those with atrial fibrillation (AF),
valvular heart disease, or malignancy, and those under­
going major orthopaedic surgery of the hip or knee,
all of whom are managed differently. Nevertheless, for
over half a century, long-term anticoagulant therapy has
been limited to vitamin K antagonists (VKAs), such as
warfarin, which is the most-commonly used VKA in
the world.1 Although the clinical effectiveness of dose-
adjusted VKA therapy for prevention and treatment
of thromboembolic disease is not disputed, long-term
use of VKAs is difficult, and anticoagulation intensity,
measured using the international normalized ratio, can
be outside the intended therapeutic range for much of
the treatment time. VKAs have a number of limitations,
including a narrow therapeutic window between the
risks of thrombosis and haemorrhage, which necessi-
tates frequent blood-coagulation monitoring; pharmaco­
kinetics that are subject to variation owing to genetic
and physiological factors; and frequent interactions
with other drugs and foods.2,3 The ageing patient popu-
lation, among whom anticoagulation is required for a
variety of indications, has increased the need for oral
Competing interests
J. L. Halperin declares associations with the following
companies: AstraZeneca, Bayer AG HealthCare, Biotronic,
Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson,
Ortho–McNeil–Janssen Pharmaceuticals, and Sanofi–Aventis.
See the article online for full details of the relationships.
J. N. Makaryus and J. F. Lau declare no competing interests.
anticoagulants that offer the effectiveness of VKAs with
fewer logistical limitations.
Other anticoagulant agents for the management
of  VTE include unfractionated heparin, the low-
molecula­r-weight heparins (LMWHs, for example
dalteparin or enoxaparin), and indirect-acting
factor Xa inhibitors (such as fondaparinux). Although
these drugs can be viable alternatives to VKAs in
most clinical situations, the routes of administration
(subcutaneous­ and parental) make these drugs time-
consuming to use and less convenient than oral medica-
tions. Furthermore, the pharmacokinetic properties of
these anticoagulants have limited their use. For example,
unfractionated heparin requires continuous intravenous
infusion or daily dosing, and the LMWHs have unpre-
dictable bioavailability in some patient populations, such Department of
as those with obesity or renal failure. Cardiology, Hofstra
These issues have stimulated the development of North Shore-Long
Island Jewish School of
altern­ative agents with practical advantages over VKAs Medicine, Long Island
and the intravenous anticoagulant drugs. 4 A large Jewish Medical Center,
270‑05 76th Avenue,
number of clinical trials of novel oral anticoagulant Suite O‑4000, New
drugs have been completed for indications such as atrial Hyde Park, NY 11040,
fibrillation and acute coronary syndrome (ACS) as well USA (J. N. Makaryus,
J. F. Lau). Zena and
as VTE. In this Review, we evaluate clinical trial data Michael A. Wiener
for the use of novel oral anticoagulants in comparison Cardiovascular
Institute, Mount Sinai
with conventional anticoagulation strategies for VTE, School of Medicine,
and discuss the use of these agents in the prevention and One Gustave L. Levy
Place, Box 1030, New
treatment of this condition.5
York, NY 10029, USA
(J. L. Halperin).
Novel oral anticoagulants
Correspondence to:
VKAs inhibit γ‑glutamyl carboxylation of coagulation J. F. Lau
factors II, VII, IX, X, and the coagulation inhibitor jlau@nshs.edu

NATURE REVIEWS | CARDIOLOGY VOLUME 10  |  JULY 2013  |  397

© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
■■ Vitamin K antagonists (VKAs), such as warfarin, are the mainstay of the
management of venous thromboembolism (VTE)
■■ The logistical difficulties associated with the use of VKAs include a narrow
therapeutic window, unpredictable pharmacodynamics, and the need for routine
monitoring; novel oral anticoagulants address some of these concerns
■■ Novel anticoagulants include direct thrombin inhibitors, such as dabigatran,
and factor Xa inhibitors such as apixaban, edoxaban, and rivaroxaban
■■ Novel anticoagulants are in various stages of approval in the USA and Europe
for several indications, including stroke prevention in atrial fibrillation, and the
prophylaxis and treatment of VTE
■■ The inability to quickly reverse or properly monitor the effects of the novel
anticoagulants must be considered in the clinician’s decision-making algorithm
■■ The results of randomized trials will continue to clarify the role of these new
agents in the management and prevention of VTE events
XII XIIa
Vitamin K
antagonists
XI XIa
Vitamin K
IX IXa VIIa
antagonists
VIIIa TF
Factor Xa inhibitors:
■ Apixaban
■ Betrixaban
■ Edoxaban X Xa X
■ Rivaroxaban
Vitamin K Va
antagonists
Prothrombin Thrombin
II IIa
Fibrinogen Fibrin
I Ia
Figure 1 | Coagulation cascade and point of effect of the common oral
anticoagulants. Vitamin K antagonists, such as warfarin, inhibit factors II, VII,
IX, and X. Dabigatran directly inhibits factor IIa (thrombin). Apixaban, betrixaban,
edoxaban, and rivaroxaban inhibit factor Xa. Abbreviation: TF, tissue factor.
proteins C and S. By contrast, novel oral anti­coagulants
target specific proteins in the coagulation cascade
(Figure 1), and have predictable pharmacokinetic pro-
files that simplify dosing and render routine coagulation
monitoring unnecessary. However, the benefits of the
newer agents come at a cost. Strategies to rapidly quan-
tify or reverse the anticoagulant effects of these drugs
are lacking.6,7 The current indications and data from
trials on VTE prophylaxis and treatment of the novel
anticoagulant­s are discussed below for each drug.
Dabigatran
Dabigatran, a direct thrombin inhibitor, is administered
orally as dabigatran etexilate, a prodrug with an overall
bioavailability of about 3–7% (Table 1).8 The half-life is
approximately 12–17 h. Dabigatran is not dependent on
the cytochrome P450 system for conversion to the active
drug or for its metabolism, which avoids drug–drug
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© 2013 Macmillan Publishers Limited. All rights reserved
interactions with commonly prescribed medications
such as atorvastatin and digoxin. Transport of a substan-
tial proportion of the active drug to the intestinal lumen
is, however, mediated by P‑glycoprotein, and inhibitors
and activators of the P‑glycoprotein efflux mechanism
can alter the plasma level of dabigatran. Care should also
be taken, and the dose adjusted, in patients with renal
insuff­iciency, because approximately 80% of dabigatran
is cleared by the kidneys.9 The therapeutic effect of dabi-
gatran does not require routine blood-test monitor­ing.
Thrombin time correlates most closely with the blood level
and anticoagulant effect of dabigatran, but measurement
requires a diluted assay methodology.10,11 Prolongation of
the activated partial thromboplastin time correlates more-
closely with blood levels and the anti­coagulant effect of
dabigatran than the prothromb­in time, and is used where
the assay for thrombin time is u­navailable. Activated
partial thromboplastin times between 1.5 and 2.0 times
the control value are typically observed during therapeutic
dosing. Monitoring of dabigatran is not routine; there-
fore, clinicians are underexperience­d in monitoring its
VII effects, if indicated.
On the basis of the VTE prophylaxis trials described
below, dabigatran was approved in Europe and Canada
in 2008 for prevention of VTE in patients undergoing
total hip or knee replacement surgery, but the FDA has
not yet granted approval for these indications (Table 2).
In countries where dabigatran has been approved, this
agent is initiated at a dose of 110 mg within 1–4 h of
the operation, and continued at a daily dose of 220 mg.
A lower dose of 75 mg twice daily is recommended for
Direct thrombin patients with moderate or severe renal insufficiency
inhibitor: (creatinine clearance 30–50 ml/min and 15–30 ml/min,
• Dabigatran
respectively), those aged >75 years, or patients taking
Cross-
linked medications such as amiodarone, quinidine, or vera-
fibrin pamil, which inhibit P‑glycoproteins (Table  2).
clot
Dabigatran should be prescribed for a minimum of
10 days after knee or hip arthroplasty, with recom-
mendations to extend therapy for least 28–35 days if
possible in patients who have undergone hip arthro-
plasty. Dabigatran is not approved for use in the treat-
ment of acute VTE. Filing with the FDA to approve
the use of dabigatran for this indication is likely to take
an important step forward with the completion of the
RE‑COVER II trial12 in 2012.
VTE prophylaxis
The efficacy of dabigatran for the prevention of VTE has
been examined in four large-scale clinical trials. In the
RE‑MODEL trial,13 dabigatran (150 mg or 220 mg daily)
was compared with enoxaparin (40 mg subcutaneously
daily) in patients undergoing knee replacement surgery
(Table 3). Dabigatran was noninferior to enoxaparin
with respect to the primary end point—a composite of
VTE events and all-cause mortality. However, the results
of the RE‑MOBILIZE trial,14 in which two daily doses of
dabigatran were compared with enoxaparin (30 mg sub-
cutaneously twice daily) in knee replacement surgery,
did not show the noninferiority of dabigatran in prevent-
ing the same end point (34% with dabigatran 150 mg;
 REVIEWS

Table 1 | Novel oral anticoagulants in VTE prophylaxis and treatment

Characteristic Apixaban Dabigatran Edoxaban Rivaroxaban
Mechanism of Direct factor Xa inhibitor Direct thrombin (IIa) inhibitor Direct factor Xa Direct factor Xa inhibitor
action inhibitor
Oral bioavailability 50% 3–7% Approximately 60% 10 mg: 80–100%; 20 mg: 66%
Half-life 8–15 h 12–17 h 8–10 h 5–9 h
Metabolism and 27% renal, 73% faecal 80% renal, 20% faecal 33% renal 66% renal, 33% faecal
excretion or biliary
Protein binding 87% 35% 40–59% 92–95%
Time to peak effect 1–3 h 1–3 h 1–2 h 1–3 h
Dosing for VTE *Initiate at 2.5 mg twice *Normal renal function: initiate ‡
5, 15, 30 and 60 mg §
Initiate at 10 mg (6–10 h after surgery);
prophylaxis daily (12‑–24 h after at 110 mg (1–4 h after surgery); daily have been continue at 10 mg daily for 12 days
surgery); continue at 2.5 mg continue at 220 mg for 28–35 days evaluated, optimal (knee surgery) or 25 days (hip surgery)
twice daily for 10–14 days Abnormal renal function (creatinine dose is unknown
(knee surgery) or clearance <50 ml/min): initiate at 75 mg;
32–38 days (hip surgery) continue at 150 mg daily for 28–35 days
Dosing for VTE Not currently approved Not currently approved Not currently Acute VTE: initiate at 15 mg twice daily
treatment approved for 3 weeks, then 20 mg daily for
treatment period
Extended therapy: after an initial 6 months
of anticoagulation, initiate at 20 mg daily
Antidote None None None None
Coagulation No No No No
monitoring
Drug interactions CYP3A4, P‑glycoprotein P-glycoprotein CYP3A4, P‑glycoprotein CYP3A4, P‑glycoprotein
*Canada and Europe. Japan. Canada, Europe, and USA. Abbreviations: CYP3A4, cytochrome P450 3A4; VTE, venous thromboembolism.
‡ §

31% with dabigatran 220 mg; 25% with enoxaparin).
In the RE‑NOVATE15 and RE‑NOVATE II16 trials, dabi-
gatran (220 mg daily) was noninferior to enoxaparin
(40 mg subcutaneously daily) in reducing the risk of
the composite end point of VTE or all-cause mortality
in patients undergoing hip replacement surgery. Safety
profiles for dabigatran and enoxaparin were similar in
all four studies (Table 3). On the basis of the results of
the RE‑MODEL,13 RE‑MOBILIZE,14 RE‑NOVATE,15
and RE‑NOVATE II16 trials, dabigatran seems to be a
safe and effective agent for VTE prophylaxis in patients
undergoing orthopaedic surgery, with a similar safety
profile to traditional therapy with enoxaparin.
VTE treatment
Dabigatran has also been studied for the treat-
ment of VTE. The RE‑COVER trial17 was a phase III,
­d ouble-blind, randomized, noninferiority study, in
which 2,539 patients with acute pulmonary embolism
(PE) or proximal deep vein thrombosis (DVT) were
enrolled. In this study, long-term (6 months) therapy
with war­farin was compared with dabigatran (150 mg
twice daily), after initial therapy with LMWH for a
median of 9 days (Table 4). The primary outcome was
the incidence of recurrent VTE or VTE-related deaths
at 6 months (2.4% in the dabigatran group, 2.1% in the
warfarin group; HR 1.10, 95% CI 0.65–1.84, P <0.001
for non­inferiority).17 Although the incidence of major
bleeding was similar in both groups, the overall rate
of bleeding was higher in the warfarin cohort than in
the dabigatran cohort (21.9% and 16.1%, respectively;
HR 0.71, 95% CI 0.59–0.85, P <0.001).17 The similarly
designed, phase III RE‑COVER II study, 12 in which
6 months of treatment with dabigatran or war­farin for the
treatment of acute VTE was compared in 2,589 patients,
has just been completed and the results are forthcom-
ing. 18 The main difference betweenRE‑COVER and
RE‑COVER II is that participants in RE‑COVER II
were deemed to be at high risk of recurrent VTE on the
basis of the site investigator’s evaluation. Otherwise,
the f­ollow-up study was designed to replicate the initial
study with a larger patient cohort.12
Two parallel trials, RE‑MEDY19 and RE‑SONATE,19
were motivated by the uncertainty over the optimal
d­uration of anticoagulation treatment in patients with
idiopathic or unprovoked VTE. In these two studies,
the efficacy and safety of dabigatran were examined
in the secondary prevention of VTE (‘extended’ VTE
therapy). Patients enrolled in these two studies of
extended VTE therapy were deemed to have at least a
moderate risk of VTE recurrence. In the RE‑MEDY
study,19 almost 3,000 patients were randomly assigned to
receive either dabigatran (150 mg twice daily) or warfarin
for an additional period of 6–36 months after an initial
3‑month treatment course with anticoagulation (Table 4).
The primary outcome measures were fatal and non­fatal
PE and DVT, and VTE-related deaths. The hazard ratio
for the composite primary end point for dabigatran
compared with warfarin was 1.44 (95% CI 0.78–2.64,
P = 0.01 for noninferiority) over the 6–36 month follow-
up period.19 Of note, significantly fewer major or clini-
cally relevant bleeding events occurred in the dabigatran
arm than in the warfarin arm (HR 0.54, 95% CI 0.41–
0.71, P <0.001).19 In the RE‑SONATE study,19 a similarly

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Table 2 | Approved clinical use, contraindications, and warnings for novel oral anticoagulants
Drug Approved indications Approved indications Contraindications Warnings/precautions
in Canada and Europe in the USA
Apixaban Nonvalvular AF Nonvalvular AF Bleeding Concomitant use of P‑glycoprotein inducers
VTE prophylaxis after Hypersensitivity or inhibitors
orthopaedic surgery Concomitant use of strong CYP3A4 inhibitors
Renal insufficiency
Hepatic impairment
Prosthetic heart valves
Pregnancy (FDA category B*)
Dabigatran Nonvalvular AF Nonvalvular AF Bleeding Concomitant use of P‑glycoprotein inducers
VTE prophylaxis after Hypersensitivity or inhibitors
orthopaedic surgery Renal insufficiency (creatinine clearance
15–30 ml/min: use 75 mg twice daily,
avoid if creatinine clearance <15 ml/min
or in end-stage renal disease)
Prosthetic heart valves
Pregnancy (FDA category C‡)
Rivaroxaban Nonvalvular AF Nonvalvular AF Bleeding Concomitant use of P‑glycoprotein inducers
VTE prophylaxis after VTE prophylaxis after Hypersensitivity or inhibitors
orthopaedic surgery orthopaedic surgery Concomitant use of strong CYP3A4 inhibitors
Acute VTE treatment Acute VTE treatment Renal insufficiency
Extended VTE therapy Extended VTE therapy Hepatic impairment
Prosthetic heart valves
Pregnancy (FDA category C‡)
*FDA Pregnancy category B: either animal reproduction studies have not shown a risk to the foetus and no adequate and well-controlled studies in pregnant
women exist; or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have not shown a risk to the foetus
in any trimester. ‡FDA Pregnancy category C: animal reproduction studies have shown an adverse effect on the foetus and no adequate and well-controlled
studies in humans exist, but potential benefits might warrant the use of the drug in pregnant women despite potential risks. Abbreviations: AF, atrial fibrillation;
CYP3A4, cytochrome P450 3A4; VTE, venous thromboembolism.

designed trial comparing dabigatran to placebo in Rivaroxaban

extended VTE therapy, the hazard ratio for the primary
end point was 0.08 (95% CI 0.02–0.25, P <0.001), and the
hazard ratio for major or clinically relevant bleeding was
2.92 (95% CI 1.52–5.60, P = 0.001).
Importantly, in the RE‑MEDY trial, 19 a significant
increase in the incidence of ACS events was noted with
dabigatran compared with warfarin (0.9% versus 0.2%;
P <0.02). A similarly significant increase in the rate of
ACS events was previously noted in the RE‑LY trial,20
in which the role of dabigatran in nonvalvular atrial
fibrillation was evaluated. The increase in ACS events
observed in the RE‑MEDY and RE‑LY trials might
have been driven by the increased prevalence of comor­
bidities, such as coronary artery disease, hypertension,
and type 2 diabetes mellitus, in the dabigatran arm. This
difference in the rate of ACS events was also described
in a meta-analysis, in which an increased risk of ACS,
but decreased mortality, was reported with dabigatran
compared with warfarin.21 However, the results from the
meta-analysis were driven mostly by data from the RE‑LY
trial.20 Notably, despite the significant difference in the
rate of ACS events, the overall number of patients with
ACS remains low in all the dabigatran trials. Long-term
follow-up and further multivariate analyses are needed to
investigate the relationship between dabigatran and the
rate of ACS events.
In summary, dabigatran has been found to be equally
as effective as warfarin for the secondary prevention
of VTE. Dabigatran seems to have a similar, if not
s­uperior, safety profile for the treatment of patients with
established DVT or PE, as measured by the incidence
of recurren­t VTE and VTE-related deaths.
Rivaroxaban, the first commercially available oral
factor Xa inhibitor, has a half-life of 5–9 h (Table 1).
Approximately one-third of the drug is cleared by the
kidneys and the remainder is eliminated by the hepato-
biliary route. Care should be taken when the drug is used
in patients with hepatic or renal impairment; the dose
should be reduced if creatinine clearance is 30–50 ml/min,
and rivaroxaban should be avoided if the creatinine clear-
ance is <30 ml/min.22 Similarly to dabigatran, riva­roxaban
has no documented clinically important drug–drug
interactions with commonly used medications, such as
a­torvastatin, clopidogrel, or naproxen. However, rivar-
oxaban is partly metabolized via cytochrome P450 3A4,
and interactions have been observed with strong inducers
(such as ketoconazole) or inhibitors (such as rifampicin)
of the cytochrome P450 system.22,23
The recommended dose of rivaroxaban for the
prophylaxis of DVT in patients undergoing hip or knee
replacement surgery is 10 mg daily, with the initial dose
given 6–10 h after surgery (once haemostasis has been
achieved). The recommended treatment duration is
12 days for patients undergoing knee replacement surgery,
and 25 days for those undergoing hip replacement
surgery (Table 2). The FDA announced in November 2012
that rivaroxaban had been approved for the treatment of
patients with acute DVT or PE at a dose of 15 mg twice
daily for 3 weeks, followed by 20 mg daily for the remain-
ing treatment period. The drug has also been approved to
reduce the risk of recurrent DVT and PE at a daily dose of
20 mg, after an initial 6‑month treatment course for acute
VTE. In 2008, rivaroxaban was approved for use in the
prevention and treatment of VTE in Europe and Canada.

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Table 3 | Phase III clinical trials of dabigatran for VTE prophylaxis

Trial Patient population Dose and Enoxaparin dose DVT, PE, or death Major bleeding
and cohort size duration of and duration (dabigatran vs (dabigatran vs
dabigatran enoxaparin) enoxaparin)
RE‑MODEL13* Total knee replacement 150 mg or 40 mg daily 40.5% (150 mg), 36.4% 1.3% (150 mg), 1.5%
n = 2,101 220 mg daily 6–10 days (220 mg) vs 37.7% (220 mg) vs 1.3%
6–10 days P = 0.82 (150 mg), P = 1.00 (150 mg),
P = 0.38 (220 mg) P = 0.82 (220 mg)
Dabigatran did not
achieve noninferiority
RE‑MOBILIZE14* Total knee replacement 150 mg or 30 mg twice daily 33.7% (150 mg), 31.1% 0.6% (150 mg), 0.6%
n = 2,615 220 mg daily 12–15 days (220 mg) vs 25.3% (220 mg) vs 1.4%
12–15 days P = 0.0009 (150 mg),
P = 0.0234 (220 mg)
RE‑NOVATE15* Total hip replacement 150 mg or 40 mg daily 8.6% (150 mg), 6.0% 1.3% (150 mg), 2.0%
n = 3,493 220 mg daily 28‑­35 days (220 mg) vs 6.7% (220 mg) vs 1.6%
28–35 days P <0.0001 (150 mg), P = 0.60 (150 mg),
P <0.0001 (220 mg) P = 0.44 (220 mg)
RE‑NOVATE II16* Total hip replacement 220 mg daily 40 mg daily 7.7% vs 8.8% 1.4% vs 0.9%
n = 2,055 28–35 days 28‑­35 days P <0.0001 P = 0.40
*Randomized, double-blind, noninferiority trial. Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

VTE prophylaxis VTE therapy

On the basis of pooled results from the four RECORD
trials,24–27 rivaroxaban (10 mg once daily) compared favour-
ably with enoxaparin regimens administered over various
intervals after hip or knee surgery, with a relative risk of
VTE of 0.38 when compared with subcutaneous enoxa-
parin 40 mg daily (P <0.0001) and 0.77 when compared
with subcutaneous enoxaparin 30 mg twice daily (P = 0.05;
Table 5). Rivaroxaban therapy was continued for an average
of 12 days after knee surgery and 35 days after hip surgery.
Consistently with safety profiles for dabigatran, the rate
of major bleeding did not differ significantly between
r­ivaroxaban and enoxaparin in the RECORD trials.28
In the MAGELLAN trial,29 extended oral rivaroxaban
therapy (10 mg daily for 35 ± 4 days) was compared with
short-term prophylaxis with enoxaparin (40 mg sub­
cutaneously daily for 10 ± 4 days) followed by placebo in
medically ill patients aged ≥40 years with a life expectancy
≥6 months, reduced mobility for ≤3 days before enrol-
ment, and who were likely to have reduced mobility for
≥3 days after enrolment.30 Enrolled patients suffered from
a wide variety of medical illnesses, including infectious
diseases, heart failure, respiratory disease, and various
malignancies. Rivaroxaban was found to be noninferior to
enoxaparin in preventing the primary end point—a com-
posite of asymptomatic proximal or symptomatic VTE—
after both 10 days and 35 days of follow-up.29 After10 days,
the relative risk with rivaroxaban treatment was 0.97
(95% CI 0.71–1.31, P = 0.003) when compared with enoxa-
parin plus placebo. The relative risk was 0.77 (95% CI
0.62–0.96, P = 0.02 for noninferiority) after 35 days. In
this study, however, rivaroxaban was associated with a sig-
nificantly increased risk of bleeding at both day 10 (2.8%
with rivaroxaban versus 1.2% with enoxaparin; P <0.001)
and day 35 (4.1% and 1.7%, respectively; P <0.001).29 The
four RECORD trials24–27 and the MAGELLAN trial29 have
shown rivaroxaban to be at least as effective as enoxaparin
in VTE prophylaxis in patients undergoing orthopaedic
surgery, with a similar, if not superior, safety profile.
Rivaroxaban has been compared with either a placebo
or a LMWH and a VKA for treatment of patients with
established VTE in two trials. In EINSTEIN‑DVT,31 a ran-
domized, noninferiority trial, rivaroxaban (15 mg twice
daily for 3 weeks followed by 20 mg once daily for 3, 6,
or 12 months) was compared with LMWH followed by
VKA in 3,449 patients who had DVT without sympto­
matic PE  (Table  4). 31 The incidence of recurrent,
s­ymptomatic VTE was 3.0% in the conventional-therap­y
arm compared with 2.1% in the rivaroxaban arm (HR 0.68,
95% CI 0.44–1.04, P <0.0001 for noninferiorit­y). The rate
of major and nonmajor clinically relevant bleeding was
similar in both groups.31 EINSTEIN‑PE32 was of a similar
study design to EINSTEIN‑DVT, but in EINSTEIN‑PE,
4,832 patients with symptomatic, acute PE, with or
without DVT were enrolled. Rivaroxaban was deemed
to be noninferior to the standard therapy of LMWH
and VKA (noninferiority margin 2.0, P = 0.003) for the
primary efficacy outcome of symptomatic recurrent VTE,
with 50 events (2.1%) recorded in the rivaroxaban arm and
44 events (1.8%) in the standard-therapy arm (HR 1.12,
95% CI 0.75–1.68, P = 0.003). Of note, fewer major bleed-
ing events occurred in the rivaroxaban group than in
the standard-therapy group (1.1% versus 2.2%; HR 0.49,
95% CI 0.31–0.79; P = 0.003), suggesting that a fixed-dose
regimen of rivaroxaban might have a better safety profile
than standard therapy.32,33
In the EINSTEIN-Extension trial,31 rivaroxaban 20 mg
daily for 6–12 months was compared with placebo for
secondary prevention of VTE in 1,197 patients who had
completed a prescribed 6–12 month course of therapy.
Rivaroxaban was found to be more effective than placebo,
with 1.3% of patients in the rivaroxaban group and 7.1%
of patients in the placebo group developing symptomatic,
recurrent VTE (82% relative risk reduction; P = 0.001),
with a major bleeding incidence of 0.7% in the rivaroxa-
ban group and 0.0% in the placebo group (Table 4).31,34 On
the basis of these trial data, rivaroxaban seems to be a safe

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Table 4 | Phase III clinical trials of novel OACs for VTE therapy

Trial Study design Patient population and Recurrent VTE Major bleeding
cohort size (OAC vs control) (OAC vs control)
Apixaban
AMPLIFY-EXT40 Randomized, double-blind, Patients with VTE who 1.7% (2.5 mg) and 0.2% (2.5 mg) and 0.1%
superiority, intention to treat completed 6–12 months 1.7% (5.0 mg) vs 8.8% (5.0 mg) vs 0.5%
analysis* of anticoagulation therapy P <0.001 (superiority) RR (2.5 mg vs control)
n = 2,482 0.49, 95% CI 0.09–2.64
RR (5.0 mg vs control)
0.25, 95% CI 0.03–2.24
Dabigatran
RE-COVER17 Randomized, double-blind, Acute VTE treated with 2.4% vs 2.1% 1.6% vs 1.9%
noninferiority‡ parenteral anticoagulation P <0.001 HR with dabigatran,
(median 9 days) (noninferiority) 0.82; 95% CI 0.45–1.48)
n = 2,539
RE-MEDY19 Randomized, double-blind, VTE, already completed 1.8% vs 1.3% 0.9% vs 1.8%
active-controlled, 3 months of therapy P = 0.03 P = 0.06
noninferiority‡ n = 2,856
RE-SONATE19 Randomized, double-blind, VTE, already completed 0.4% vs 5.6% 0.3% vs 0.0%
placebo-controlled, 3 months of therapy
noninferiority‡ n = 1,343
Rivaroxaban
EINSTEIN‑DVT31 Randomized, open-label Acute, symptomatic DVT 2.1% vs 3.0% 8.0% vs 8.0%
noninferiority§ n = 3,449 P <0.001
(noninferiority)
EINSTEIN‑PE32 Randomized, double-blind Acute, symptomatic PE 2.1% vs 1.8% 10.3% vs 11.4%
noninferiority§ with or without DVT P = 0.003 P = 0.23
n = 4,832 (noninferiority)
EINSTEIN‑EXT31,34 Randomized, double-blind Patients with VTE who 1.3% vs 7.1% 0.7% vs 0.0%
superiority§ completed 6–12 months P <0.001 (superiority) P = 0.11
of anticoagulation therapy
n = 1,196
*Apixaban (2.5 mg or 5.0 mg twice daily) vs placebo. ‡Dabigatran (150 mg twice daily) vs warfarin. §Rivaroxaban alone (15 mg twice daily for 3 weeks, followed by
20 mg daily) vs enoxaparin (1 mg/kg), followed by a vitamin K antagonist for 3, 6, or 12 months. Abbreviations: DVT, deep vein thrombosis; HR, hazard ratio;
OAC, oral anticoagulant; PE, pulmonary embolism; RR, relative risk; VTE, venous thromboembolism.

and effective option for the secondary prevention of VTE,
with a similar adverse event rate to standard therapy.
Apixaban
Apixaban, a potent, oral, direct factor Xa inhibitor,
is eliminated primarily via the faecal route (approxi-
mately 50%) with smaller portions metabolized via the
cytochrome P450 3A4-dependent pathway in the liver
(approximately 25%) and via the urine (approximately
25%). Apixaban might, therefore, be the preferred agent
for patients with renal insufficiency. This possibility
remains unsubstantiated by evidence as there have been
no direct comparative studies to date. The peak plasma
level is achieved 1–3 h after oral intake, and apixaban has
a h­alf‑life of 8–15 h (Table 1).34
Apixaban was approved in Canada and Europe in 2011
for the primary prevention of VTE in patients under­
going knee or hip replacement surgery (Table 2). The
recommended dosage is 2.5 mg twice daily, to be initiated
12–24 h after orthopaedic surgery. The recommended
treatment duration is 10–14 days for patients who have
had knee replacement surgery, and 32–38 days for
patients who have had hip replacement surgery. The drug
is not approved for the prophylaxis or treatment of VTE
in the USA (Table 2). The FDA is expected to review the
use of apixaban for this indication in early 2013.
VTE prophylaxis
In the ADVANCE trials,35–37 the efficacy and safety of
apixaban was evaluated for the prevention of VTE in
approximately 6,000 patients undergoing knee replace-
ment surgery. The primary end point was a composite
of nonfatal PE, symptomatic and asymptomatic DVT,
and all-cause mortality (Table 6). In the ADVANCE‑1
trial,35 apixaban 2.5 mg twice daily did not meet the pre-
specified criteria for noninferiority when compared with
enoxaparin 30 mg twice daily, with event rates of 9.0%
and 8.9%, respectively (relative risk 1.02, 95% CI 0.78–
1.32). However, the noninferiority criteria were met in
the ADVANCE‑2 trial,36 in which apixaban 2.5 mg twice
daily (started the day after surgery) compared favour-
ably with enoxaparin 40 mg once daily in a randomized,
double-blind, phase III study involving 3,057 patients. In
both studies, the rate of major bleeding was similar in the
two treatment arms. The ADVANCE‑3 trial37 involved
3,866 patients undergoing hip surgery treated with
apixaban or enoxaparin (40 mg daily). The primary end
point occurred in 1.4% of patients in the apixaban group
compared with 3.9% in the enoxaparin group (relative
risk 0.36, 95% CI 0.22–0.54, P <0.001 for s­uperiority;
absolute risk reduction 2.5%, 95% CI 1.5–3.5).37 Again,
safety data were similar in each group.37 Although apixa-
ban has not been approved by the FDA, and despite

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Table 5 | Phase III clinical trials of rivaroxaban for VTE prophylaxis

Trial Patient population Dose and Enoxaparin DVT, PE, or death Major bleeding
and cohort size duration of dose and (rivaroxaban vs (rivaroxaban vs
rivaroxaban duration enoxaparin) enoxaparin)
RECORD 124* Total hip replacement 10 mg daily 40 mg daily 1.1% vs 3.7% 0.3% vs 0.1%
n = 4,501 35 days 35 days P <0.001 P = 0.18
RECORD 225* Total hip replacement 10 mg daily 40 mg daily 2.0% vs 9.3% <0.1% vs <0.1%
n = 2,509 31–39 days 14 days P <0.001
RECORD 326* Total knee replacement 10 mg daily 40 mg daily 9.6% vs 18.9% 0.6% vs 0.5%
n = 2,615 10‑­14 days 10–14 days P <0.001 P = 0.77
RECORD 427* Total knee replacement 10 mg daily 30 mg twice daily 6.9% vs 10.1% 0.7% vs 0.3%
n = 2,055 10‑­14 days 10–14 days P = 0.0118 P = 0.11
MAGELLAN29‡ Acute medical illness 10 mg daily 40 mg daily 2.7% vs 2.7% (day 10) 2.8% vs 1.2% (day 10)
n = 8,101 35 ± 4 days 10 ± 4 days 4.4% vs 5.7% (day 35) 4.1% vs 1.7% (day 35)
(Oral placebo: P = 0.003 (noninferiority), P = 0.001 for both
35 ± 4 days) P = 0.02 (superiority) time points
*Randomized, double-blind, noninferiority trial. ‡Randomized, double-blind noninferiority (day 10) and superiority (day 35) trial. Abbreviations: DVT, deep vein
thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

failure to meet noninferiority criteria in the ADVANCE‑1
trial, 35 apixaban seems to be at least as effective (in
the ADVANCE‑2 trial36) and potentially superior (in the
ADVANCE‑3 trial37) to enoxaparin in preventing VTE
in patients undergoing orthopaedic surgery.
In the ADOPT trial, 38 the safety and efficacy of
extended prophylaxis with apixaban (2.5 mg twice daily
for 30 days) was compared with short-term prophy-
laxis with enoxaparin (40 mg once daily for 6–14 days)
in an initial cohort of 6,528 acutely ill medical patients
(Table 6). The most-common medical indications for
admission were heart failure, acute respiratory failure,
infection, and acute rheumatic disorders. No significant
difference in the incidence of VTE events was observed
between the two groups. However, at 30 days, a signifi-
cant increase in the risk of major bleeding occurred in
the apixaban group compared with the enoxaparin group
(0.47% versus 0.19%, respectively; relative risk 2.58,
95% CI 1.02–7.24, P = 0.04). Notably, the bleeding rates
between the cohorts seemed to diverge primarily when
patients in the enoxaparin arm were taking placebo (the
short-term prophylaxis with enoxaparin was only 6–14
days) while the patients in the apixaban arm were still
taking the study drug.38 On the basis of the ADOPT trial
results, not enough evidence exists to support the use of
apixaban for extended VTE prophylaxis (after hospital
discharge) in patients admitted with an acute medical
illness, particularly because of the increased bleeding rate
in the apixaban cohort. Further studies are needed to
determine the potential utility of extended prophylaxis
with apixaban.
VTE treatment
Two trials have focused specifically on the use of
a­pixaban for the treatment of VTE. The AMPLIFY
trial39 is an ongoing safety and efficacy study, in which
a­pixaban (plus placebo) is being compared with enoxa-
parin and warfarin (plus placebo) in patients with symp-
tomatic PE or DVT. In the double-blind companion
trial, AMPLIFY‑EXT (Extension),40 apixaban was eval-
uated for the prevention of death or recurrent VTE in
patients who had completed treatment for DVT or PE.
In this trial, patients were randomly assigned to receive
2.5 mg apixaban twice daily (n = 840), 5 mg apixaban
(n = 813), or placebo (n = 829) for 12 months (Table 4).40
All 2,486 patients enrolled in the AMPLIFY‑EXT trial
had pre­viously finished 6–12 months of anticoagulation
therapy. The primary efficacy outcome was the composite
of symptomatic recurrent VTE or death from any cause.
The primary safety outcome was major bleeding, and the
secondary safety outcome was the composite of signifi-
cant, nonmajor bleeding. The AMPLIFY‑EXT data were
analysed on the basis of intention-to-treat. The investi­
gators found that each dose of apixaban reduced the risk
of recurrent VTE compared with placebo, without an
increased risk of bleeding. Approximately 8.8% of the
placebo group had a symptomatic recurrent VTE or died
of a VTE-related cause (suggesting that these patients
had a high baseline risk of recurrent VTE), compared
with 1.7% of patients taking 2.5 mg of apixaban and
1.7% of patients taking 5 mg of apixaban.40 The rate of
major bleeding was unexpectedly low in the treatment
groups, but this difference might be attributable to chance
because of the small number of overall events. The rate
of nonmajor bleeding was similar in all three arms. In an
appropriate population with high risk of VTE recurrence,
apixaban can, therefore, be a safe and effective treat-
ment option over a long-term period (1 year). However,
r­egulatory approval for this indication is pending.
Edoxaban
Edoxaban is a reversible direct factor Xa inhibitor with
good oral bioavailability (about 50%), and a half-life
of approximately 8–10 h. The peak plasma concen­
tration is reached 1–2 h after oral intake. Approximately
one-third of edoxaban is renally cleared. Accordingly,
patients with renal insufficiency (creatinine clearance
30–50 ml/min) should take a reduced dose. Similarly
to the other factor Xa inhibitors, edoxaban does not
require regular monitoring and no antidote is readily
available. Edoxaban is a substrate for P‑glycoprotein and,
as a result, the concurrent use of strong P‑glycoprotein

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Table 6 | Phase III clinical trials of apixaban for VTE prophylaxis

Trial Patient population Dose and Enoxaparin DVT, PE, or death Major bleeding
and cohort size duration dose and (apixaban vs (apixaban vs
of apixaban duration enoxaparin) enoxaparin)
ADVANCE‑135* Total knee replacement 2.5 mg twice daily 30 mg twice daily 9.0% vs 8.8% 0.7% vs 1.4%
n = 3,195 10–14 days 12 days P = 0.06 P = 0.05
Apixaban did not achieve
noninferiority
ADVANCE‑236* Total knee replacement 2.5 mg twice daily 40 mg daily 15.1% vs 24.4% 0.6% vs 0.9%
n = 3,057 10–14 days 10–14 days P <0.0001 (superiority) P = 0.30
ADVANCE‑337‡ Total hip replacement 2.5 mg twice daily 40 mg daily 1.4% vs 3.9% 0.8% vs 0.7%
n = 5,407 35 days 35 days P <0.001 (superiority) P = 0.54
ADOPT38‡ Medical illness 2.5 mg twice daily 40 mg twice daily 2.71% vs 3.06% 0.46% vs 0.19%
n = 4,495 30 days 6–14 days P = 0.44 P = 0.04
Apixaban did not achieve
superiority
*Randomized, double-blind, noninferiority trial. ‡Randomized, double-blind, superiority trial. Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism;
VTE, venous thromboembolism.

inhibitors, such as amiodarone, dronederone, quinidine,
and verapamil, could increase the half-life and serum
drug level of edoxaban.
Edoxaban is approved in Japan for VTE prevention
after lower limb orthopaedic surgery. This agent has not
received approval for any indication outside of Japan,
although several international trials are currently under-
way, such as ENGAGE AF TIMI 48,41 in which the use
of edoxaban for stroke prevention in patients with atrial
fibrillation will be evaluated, and HOKUSAI VTE42 in
which the use of edoxaban in the treatment of VTE or
PE will be evaluate. Nevertheless, partly as a result of the
low prophylactic dose of enoxaparin (2,000 inter­national
units or 20 mg) used in the Japanese trials in which
edoxaban was compared with standard therapy, the data
outlined below do not seem to warrant w­idespread use
of this agent.43
VTE prophylaxis
In an analysis of data pooled from two phase III trials,
STARS E‑344 and STARS J‑V,44 in which a total of 1,326
Japanese patients undergoing orthopaedic surgery were
evaluated, edoxaban 30 mg once daily significantly
reduced the risk of VTE compared with enoxaparin
(5.1% and 10.7%, respectively; P <0.001). No signifi-
cant difference in bleeding risk between the groups was
reported.45 Edoxaban was also evaluated in a random­
ized, double-blind, dose-response study in the USA.
Edoxaban (15 mg, 30 mg, 60 mg, or 90 mg once daily) was
compared with dalteparin (5,000 units subcutaneously
daily) for 7–10 days after hip surgery. The incidence of
VTE in each edoxaban dose cohort was significantly less
than in the dalteparin group (28.2%, 21.2%, 15.2%, and
10.6% in the edoxaban groups, respectively, and 43.8% in
the dalteparin group; P <0.005).46 In another trial, various
doses of edoxaban (5, 15, 30, and 60 mg daily) were eval-
uated for the prevention of VTE in patients undergoing
total knee arthroplasty.47 A total of 523 Japanese patients
were randomly assigned to receive edoxaban or placebo
once daily for 11–14 days after total knee arthroplasty.
A dose-dependent decrease in the incidence of VTE was
noted across all doses of edoxaban (29.5%, 26.1%, 12.5%,
and 9.1% in the groups treated with 5, 15, 30, or 60 mg,
respectively, compared with 48.3% in the placebo group).
Of note, the incidence of major and clinically-relevant
nonmajor bleeding was not significantly different across
all doses of edoxaban, or between edoxaban and placebo.
VTE treatment
Edoxaban is also currently under investigation for the
prevention of recurrent VTE in patients with previously
diagnosed DVT, PE, or both, in the large-scale, multi-
national, double-blind, randomized HOKUSAI VTE
phase III noninferiority trial. 42 In this trial, several
anticoagulant protocols are being investigated. Patients
will initially be treated with heparin (either unfrac-
tionated heparin or LMWH), and will then trans­ition
to either warfarin or edoxaban (60 mg once daily or
30 mg in patients with body mass <60 kg, creatinine
clearance 30–50 ml/min, or concomitant use of potent
P‑glycoprotein inhibitors) for varying treatment periods
of 3, 6, or 12 months. The treatment duration is at
the discretion of the clinician, with consideration of the
patients’ preferences and their risk of recurrent VTE
and bleeding. The variable length of treatment is meant
to provide flexibility to clinicians and simulate actual
clinical practice, as duration of anticoagulant therapy
in patients with unprovoked VTE remains unclear, but
treatment beyond 3 months is likely to provide a benefit.
The primary efficacy outcome is symptomatic, recur-
rent VTE during the 12‑month study. The enrolment
phase of this study, involving >8,250 patients, was com-
pleted in late 2012, and the study should be the largest
clinical trial to date for the treatment and secondary
preventio­n of VTE.
Combination with antiplatelet agents
Patients with atherosclerosis and associated risk factors
for coronary artery disease, such as type 2 diabetes, have
an increased risk of VTE.48–52 In the appropriate clinical
context, using antiplatelet agents together with VKAs
might, therefore, become necessary. For example, the

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2013 ACC Foundation/AHA guidelines for the manage-
ment of ST‑segment elevation myocardial infarction53
outline class 1A recommendations for the combined use
of warfarin and aspirin, clopidogrel, or both for patients
with an indication for anticoagulant therapy, such as the
presence of paroxysmal or chronic atrial fibrillation or
atrial flutter, or left ventricular thrombus. This recom-
mendation, however, is specific to patients with ACS and
does not apply to patients with stable coronary artery
disease or VTE. Furthermore, current guidelines indi-
cate that the duration of triple antithrombotic therapy
with aspirin, a P2Y12 receptor inhibitor, such as clopi-
dogrel or ticagrelor, and a VKA must be limited because
of the increased risk of associated bleeding.53 Additional
data for the optimal duration of therapy, as well as target
values of the international normalized ratio, are needed
to clarify therapeutic regimens for these patients. The use
of the novel oral anticoagulants has not been evaluated in
the context of concurrent ACS and VTE, and no specific
recommendations regarding their use in such a clinical
scenario have been published.
The extent of atherothrombotic protection afforded
by the novel oral anticoagulants needs further investi­
gation. First, in some clinical trials, an increased inci-
dence of ACS among patients taking direct thrombin
inhibitors, such as dabigatran (for example, the RE‑LY20
and RE‑MEDY19 trials) or ximelagatran (for example, the
THRIVE,54 SPORTIF III,55 and SPORTIF V56 trials) alone
has been observed, but not in those taking anti-factor Xa
medications. This finding could suggest that the range
of atheroembolic protection using these agents does not
approach the degree provided by traditional antiplatelet
agents, such as aspirin, clopidogrel, or warfarin, although
this hypothesis is debated.21,57 Second, the risk:benefit
ratio for the combined use of novel oral anticoagulants
and antiplatelet medications remains to be determined.
In a meta-analysis, the use of novel anticoagulants in
patients receiving antiplatelet therapy after ACS did not
improve overall clinical outcome, but increased the risk
of major bleeding.58 Antiplatelet agents should, there-
fore, continue to be used as directed in current guide-
lines, along with oral anticoagulation if appropriate, in
patients with concomitant risk of atheroembolic events
(for example, patients with coronary or peripheral artery
disease) and VTE.
Practical concerns
Bleeding and lack of antidotes
In the large, randomized safety and efficacy trials, the
major bleeding rate associated with novel anticoagulants
has been similar to, or even lower than, those associ-
ated with LMWH or VKAs (Tables 3, 4, 5, and 6). For
patients undergoing surgery who have normal renal
function and a nonelevated risk of bleeding, dabigatran
(half-life 12–17 h) or rivaroxaban (half-life 5–9 h) should
be discontinued at least 24 h before surgery. An addi-
tional 1–3 days could be necessary to allow for sufficient
clearance in patients of advanced age (≥75 years), with
moderate or severe renal insufficiency, or at high risk
of bleeding.
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One of the major, frequently cited potential draw-
backs of the novel oral anticoagulant agents is the lack
of reversibility of their anticoagulant effect. Bleeding
is of particular concern for the large percentage of the
patients receiving these agents who tend to be >65
years of age. Media reports and litigation have raised
questions as to the safety of these agents as a result of
anecdotal cases of irreversible bleeding, with one report
citing that 542 deaths attributable to dabigatran (the
most-commonl­y prescribed novel anticoagulant) were
reported to the FDA in 2011 alone.59
Outside of clinical trials, the lack of options when
treating a patient who is bleeding is a concern for
patients and physicians. Proponents of the novel oral
anti­c oagulant agents argue that the shorter half-life
and predictable pharmacokinetics of these drugs
renders the need for reversal less likely than for VKAs.8
Nevertheless, the lack of readily available reversal agents
has resulted in some physician trepidation to use novel
oral a­nticoagulants, particularly for elderly patients.
Prothrombin complex concentrate (PCC) is a poten-
tial, but unproven, means of reversing the anticoagulant
effects of apixaban, dabigatran, and rivaroxaban.60–62
PCCs are concentrated, pooled plasma products con-
taining inactivated clotting factors and usually a small
amount of protein C and protein S. In April 2013,
the FDA approved the first nonactivated, four-factor
PCC (which includes Factors II, VII, IX, and X) to
treat patients who are taking warfarin or other VKAs.
However, there are minimal data from clinical trials
supporting the use of PCCs to reverse bleeding asso-
ciated with the novel oral anti­coagulants. In a small,
randomized, double-blind, placebo-controlled study,
12 healthy male volunteers received rivaroxaban 20 mg
twice daily (n = 6) or dabigatran 150 mg twice daily
(n = 6) for 2.5 days, followed by either a bolus of saline
or a bolus of PCC of 50 international units per kg. The
PCC successfully reversed the laboratory effect of rivar-
oxaban (reduced partial thromboplastin time), but not
the effect of dabigatran.60 In an animal study, an acti-
vated PCC did not correct the prolonged activated partial
thromboplastin time caused by dabigatran treatment, but
substantially reduced bleeding time.63 Ex vivo analysis
has provided evidence for the potential utility of PCCs in
reversing nearly all aspects of the laboratory effects of the
novel oral anticoagulants,62 but their potential use in clin-
ical settings remains understudied. Furthermore, PCCs
might pose a high risk for thrombosis, and co­nsultation
with a haematologist is recommended before use.64
Recombinant factor VIIa could also potentially be used
to reverse the effects of apixaban.60–62 In animal models of
rivaroxaban overdose, recombinant factor VIIa improved
the coagulopathic profile (including bleeding time, clot-
ting time, and thrombin generation), but was ineffective
at reversing rivaroxaban-associated bleeding.65 Minimal
data on the use of recombinant factor VIIa in humans
exist, and thus its use is primarily on the basis of anec­
dotal evidence. Regular use is, therefore, not recom-
mended and any use in the management of bleeding
related to the use of oral anticoagulants is off-label.65
REVIEWS
Plasma-derived and recombinant factor Xa are also
being investigated as potential reversal agents for the
factor Xa inhibitors.66 Urgent haemodialysis could also be
considered for patients with bleeding associated with dabi­
gatran or for patients with underlying renal insuf­ficiency.
In patients with end-stage renal disease, haemodialysis
has been shown to remove 62–68% of circulating, active
dabigatran.9 Insufficient data exist to determine whether
haemodialysis is useful in patients taking ­apixaban or
rivaroxaban, although the high percentage of the drug that
is bound to proteins in the blood renders effective dialy-
sis unlikely (~66% of rivaroxaban is cleared via the renal
route compared with ~80% of dabigatran).67 Despite some
promising data, the results of trials in which ‘antidotes’
to these agents have been assessed have been mixed, and
the lack of availability of reversal agents continues to be
a c­hallenge in the use of new oral anticoagulants.
Lack of monitoring
No standardized monitoring tests are currently available
for the novel oral anticoagulants. Although these agents
do affect various coagulation parameters, the correlation
between these effects and the associated risks of bleeding
and thrombosis have not been measured and standard-
ized. Low doses of the novel oral anticoagulants are avail-
able to reduce the risk of bleeding in certain subgroups of
patients. For most patients, routine monitoring to gauge
the precise anticoagulant effect of these agents is prob-
ably unnecessary, as shown by randomized efficacy and
safety trials. Nevertheless, some clinical scenarios, such
as the management of a patient during the preoperative
period, or with active bleeding, might require knowledge
of the precise degree of anticoagulation.68
The lack of monitoring that is required for these novel
agents has other potentially deleterious effects. The need
to monitor the international normalized ratio in patients
taking VKAs is also a compliance tool, enabling health-
care providers to assess patient progress and adherence
to prescribed regimens. Furthermore, the need for daily
dosing of the novel oral anticoagulants and their relatively
short half-lives (compared with VKAs) could be prob-
lematic for some patients—missing a few doses of these
drugs might result in an abrupt decline in anti­coagulant
effect, whereas a reduction of VKA dose usually leads to a
more-gradual decrease. Thus, although the lack of moni-
toring required for the novel oral anticoagulants might be
a benefit for most patients, the potentially negative impact
of reduced monitoring must be kept in mind.
Contraindications
The use of novel oral anticoagulants is relatively or abso-
lutely contraindicated in a number of clinical scenarios
(Table 2). Patients at risk of bleeding or with a hyper-
sensitivity to the drug should not take any of the novel
oral anticoagulants.
Renal failure
Agents such as dabigatran and rivaroxaban should be
avoided in patients with severe renal failure (c­reatinine
clearance <30 ml/min).9 The risk of bleeding complications
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in patients with renal dysfunction might be lower for
apixaban and edoxaban, because these drugs are excreted
by the kidney to a lesser degree than dabigatran and rivar-
oxaban.69 Using unfractionated heparin and VKAs for
patients with severe renal dysfunction is probably still
the most-prudent option.
Mechanical heart valves
Currently, VKAs are the only agents approved for
thrombo­prophylaxis in patients with mechanical heart
valves.70 None of the novel oral anticoagulants is likely
to receive approval for use in these patients. In fact, the
FDA has listed dabigatran as an absolute contra­indication
in these instances, after a case report of blood-clot for-
mation on mechanical prosthetic heart valves. 71 The
phase II RE‑ALIGN72 trial was designed to test the use of
dabigatran in this patient population, but was abruptly
terminated in December 2012 when excessive blood-
clot formation was again found on prosthetic valves.
Furthermore, patients taking dabigatran experienced
more bleeding after surgery than patients taking warfarin,
and had an increased propensity for t­hromboembolism
leading to stroke and myocardial infarction.72
Pregnancy
VTE during pregnancy and in the peripartum period is
an important cause of maternal morbidity and mor­tality.
VTE is estimated to occur in approximately 0.5–2.2 per
1,000 pregnancies.73,74 Negatively charged heparin particles
cannot cross the placenta, so this class of anticoagulants
is associated with a very low risk to the foetus.75,76 The
LMWHs are, therefore, currently the preferred means
of prophylaxis and therapy for VTE during pregnancy.77
No substantial published data currently exist for the use
of the novel oral anticoagulants in patients who are preg-
nant. These agents are expected to cross the placental
barrier and could lead to undesired foetal anticoagulation.
Furthermore, the protease inhib­itory capacity of these
drugs might actually hinder foetal development.78 As
a result, the novel oral anticoagulants are currently contra­
indicated for use in patients who are pregnant. Heparin,
LMWH, and warfarin have not been found in high enough
concentrations to be clinically relevant in breast milk and,
therefore, are likely to pose minimal risk to newborns.79
Further studies, however, are necessary to determine the
concentrations of the novel oral anticoagulants secreted
by lactating women and the potential risks posed to new-
borns. As a result, the use of the novel anticoagulants
in breastfeeding mothers in not recommended.
Patients with cancer
Malignancy is associated with a high rate of VTE events.
Patients with cancer are estimated to be at a fourfold to
sevenfold increased risk of VTE, and 15–20% of patients
with cancer experience at least one VTE episode during
the course of their disease.80–82 The annual incidence of
VTE in patients with cancer is estimated to be in the range
of 0.5–20.0%, depending on clinical parameters, such as
the type of cancer and baseline risk factors.83 VTE is the
second most-common cause of death in patients with
 REVIEWS

cancer.84 For hospitalized patients with cancer, current
guidelines generally recommend thrombo­prophylaxis
with LMWH (enoxaparin 40 mg daily or dalteparin
5,000 units daily), fondaparinux (75 international units
per kg, subcutaneous daily), or low-dose unfractionated
heparin (5,000 units every 8–12 h).85 Patients under­
going surgery for cancer are at particularly high risk
of the development of VTE. Therapy must be tailored
s­pecifically to each clinical scenario and risk-factor profile.
Unfractionated heparin, LMWH, and the VKAs remain
the mainstays of anticoagulant treatment in patients with
cancer, with data from the CLOT trial86 favouring the use
of LMWHs (specifically dalteparin) over warfarin in pre-
venting recurrent VTE.87 This finding is reflected in the
current guidelines.88 The benefits of the novel oral anti-
coagulants in patients without cancer are also likely to be
applicable to patients with cancer,89 although this remains
to be tested in large-scale, randomized trials.
Conclusions
During the past decade, new oral anticoagulants for the
prevention and treatment of VTE have become available.
Apixaban, dabigatran, edoxaban, and rivaroxaban are
at various stages of approval for VTE indications. These
agents are easy to administer without the need for routine
monitoring, and have several other advantages, including
predictable pharmacokinetics, infrequent drug and food
interactions, and rapid onset of action. One important
limitation is the lack of proven reversal strategies for use in
the event of bleeding or when urgent surgery is necessary.
Dabigatran and rivaroxaban have been approved for
VTE prophylaxis in Europe and Canada, but in the USA,
only rivaroxaban is approved for prophylaxis against VTE
in patients undergoing major orthopaedic surgery of the
hip or knee, or for treatment of patients with established
DVT or PE. Despite promising results in several trials of
the novel oral anticoagulants, these drugs should be used
cautiously in patients with substantial renal or hepatic
impairment, elderly patients, or those prone to bleeding,
because of the relative paucity of information on the man-
agement of bleeding complications that could arise during
treatment. In addition, given the rising cost of health care,
the widespread use of such agents might or might not be
cost-effective in the long-term.
The novel oral anticoagulants are an important leap
forward in the clinical approach to the prophylaxis and
management of venous thromboembolic disease. The
success and comparative safety of the currently available
agents, such as apixaban, dabigatran, and rivaroxaban, are
likely to spur further research on these and other poten-
tial new drugs. With the completion of the HOKUSAI
trial,42 further information is expected on the efficacy and
safety of edoxaban in the prevention of VTE recurrence.
The utility of other factor Xa inhibitors, such as betrixa-
ban, the subject of the EXPERT trial,90 will continue to be
defined in ongoing studies. Otamixaban, another factor Xa
inhibitor, is currently in late-stage clinical development for
the management of ACS, and might also eventually be used
for VTE prophylaxis or therapy. These and other agents are
at various stages of development and await phase III cl­inical
trials to clarify their role in the management of VTE.
Review criteria
The NCBI PubMed database was searched for full-
text, English language papers published since 1980.
Search terms included “venous thromboembolism”,
“deep venous thrombosis”, “pulmonary embolism”,
“anticoagulation”, “novel oral anticoagulants”, “vitamin K
antagonists”, “dabigatran”, “apixaban”, “rivaroxaban”,
and “edoxaban”. The search was performed most
recently in March 2013.

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Author contributions
All authors contributed substantially to researching
data for the article, discussion of content, wrote the
article, and reviewed and edited the manuscript
before submission.