U p d a t e o n D i rec t O r a l

A n t i c o a g u l a n t s a n d Th e i r
Uses
Vigyan Bang, MDa,b,*, Russell S. Zide, MD
a,b
,
Chi-Cheng Huang, MDb,c,d,e,f,g

KEYWORDS
 Direct oral anticoagulants  Warfarin  Atrial fibrillation  Venous thromboembolism

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Anticoagulants are beneficial for treatment of venous thromboembolism and

prevention of stroke in atrial fibrillation.
2. Direct oral anticoagulants (DOACs) are a growing alternative to warfarin
because of their predictable pharmacokinetics and ease of use.
3. There is an advent of rapid and safe reversal agents for DOACs for use
in situations of major bleeding and preprocedurally.

INTRODUCTION

Direct oral anticoagulants (DOACs) are rapidly gaining traction as the preferred
method of oral anticoagulation for patients with nonvalvular atrial fibrillation (NVAF)
and venous thromboembolism (VTE), and for prophylaxis of deep vein thrombosis
(DVT). Their predictable pharmacokinetic properties allow easy dosing regimens
that avoid many of the difficulties and challenges associated with vitamin K antagonist
(VKA) therapy. However, the DOAC agents pose unique challenges for health care pro-
viders, who have previously developed comfortable strategies to manage VKAs and
must now adapt to a new class of medications. This article reviews the indications

a
General Internal Medicine, Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA
01805, USA; b Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02110,
USA; c Department of Hospital Medicine, Lahey Health System, 41 Mall Road, Burlington,
MA 01805, USA; d Lahey Hospital and Medical Center, 41 Mall Road, Burlington, MA 01805,
USA; e Lahey Medical Center, 1 Essex Center Dr, Peabody, MA 01960, USA; f Beverly Hospital,
85 Herrick Street, Beverly, MA 01915, USA; g Addison Gilbert Hospital, 298 Washington Street,
Gloucester, MA 01930, USA
* Corresponding author.
E-mail address: Vigyan.bang@lahey.org

Hosp Med Clin - (2016) -–-

http://dx.doi.org/10.1016/j.ehmc.2016.11.004
2211-5943/16/ª 2016 Elsevier Inc. All rights reserved.
2 Bang et al

and dosing considerations, clinical efficacy and safety, laboratory monitoring, and
reversibility considerations of DOACs.
DOACs include oral direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxa-
ban) and direct thrombin inhibitors such as dabigatran.

MECHANISM OF ACTION AND PHARMACOLOGY

Direct Thrombin Inhibitors
Dabigatran etexilate, a prodrug of dabigatran, is the only commercially available oral
direct thrombin inhibitor, or inhibitor of factor IIa. Dabigatran is a small, synthetic mole-
cule that specifically and reversibly inhibits free and clot-bound thrombin by binding to
the active site of thrombin.1 Inhibition of thrombin attenuates formation of fibrin, re-
duces thrombin generation, and may limit platelet aggregation.
Oral Activated Factor X Inhibitors
Factor Xa inhibitors bind directly to the active site of factor Xa, located at the conver-
gence of the intrinsic and extrinsic pathways in the coagulation cascade. Inhibition at
this site blocks thrombin generation from both pathways, and prevents subsequent
amplification of thrombin generation, and thrombin-mediated activation of coagula-
tion and platelets.2
The DOAC plasma concentration reaches their peak at 1 to 4 hours. Therefore, the
therapeutic effect of DOACs occurs more rapidly and the risk of bleeding increases
proportionately. The bioavailability of most of the DOACs is between 60% and
100%. The exception is dabigatran, which has low bioavailability, therefore requiring
a higher dosage. The high bioavailability of DOACs contributes to a more predictable
anticoagulant response, eliminating the need for routine monitoring.
The metabolism of DOACs is mainly performed by the liver. There may be interpa-
tient variability when these drugs are given to patients with moderate hepatic disease,3
and they must therefore be used with caution in such patients. Most of the DOACs are
excreted renally, with primary excretion rates ranging from 60% to 85%, except for
apixaban and edoxaban, which have a much lower excretion rates. Therefore, patients
with impaired renal function can have increased plasma drug concentrations.

LABORATORY MONITORING OF DIRECT ORAL ANTICOAGULANTS

With the use of VKA for anticoagulation, clinicians have become accustomed to
checking International Normalized Ratio (INR) values to assess how well patients
are being anticoagulated and adjust VKA dosing. The DOACs challenge this paradigm
by offering predictable pharmacokinetics, thus eliminating the need for routine labora-
tory monitoring. However, there are certain clinical scenarios when laboratory moni-
toring is clinically warranted, such as before urgent or emergent surgery, when
assessing medication compliance, and for ensuring adequate anticoagulation in pa-
tients at the extremes of weight. A few routine laboratory tests are available that,
when properly calibrated, can offer insight into the degree of anticoagulation for pa-
tients taking DOACs. For patients taking dabigatran, a normal thrombin time can be
used to rule out any clinically relevant anticoagulation.4 The dilute thrombin time is
the best option for assessing whether patients are appropriately or overly anticoagu-
lated, but this test is not universally available. A normal activated partial thrombo-
plastin time likely excludes supratherapeutic levels of dabigatran.
For patients taking rivaroxaban, apixaban, or edoxaban, use of the anti-Xa activity
can reliably assess the degree of anticoagulation across a wide range of drug concen-
trations, including subtherapeutic, therapeutic, and supratherapeutic levels.5 This
 Direct Oral Anticoagulants and Their Uses 3

assessment is best done using a calibrated anti-Xa activity for each individual factor
Xa inhibitor. However, when calibrated anti-Xa activity levels are not available, a
generic chromogenic anti-Xa activity at a normal level is likely to rule out meaningful
levels of any factor Xa inhibitor. A normal prothrombin time is likely to exclude supra-
therapeutic levels of the anti-Xa inhibitors.
Perhaps more relevant to most patients is the need for regular, ongoing renal func-
tion monitoring. Each of the DOACs is, at least in part, cleared by the kidneys. There-
fore, patients require periodic assessment of renal function to determine when dose
adjustments are necessary or whether their use is contraindicated. The American Col-
lege of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society
(HRS) guidelines on the use of DOACs outlines that renal function should be evaluated
before initiation of DOACs and reassessed when clinically indicated (at least annu-
ally).6 Note that all major trials of DOACs versus warfarin for stroke prevention in AF
used the Cockcroft-Gault equation to estimate renal function. Although many elec-
tronic medical records automatically calculate estimated creatinine clearance (CrCl)
or glomerular filtration rates, these are often done using the Modification of Diet in
Renal Disease or Chronic Kidney Disease Epidemiology Collaboration equations
and can have significantly disparate values from the Cockcroft-Gault estimate. There-
fore, clinicians should calculate the CrCl and clearly document this value at appro-
priate intervals and when assessing DOAC dosing.

REVERSIBILITY OF DIRECT ORAL ANTICOAGULANTS

The meta-analysis of primary studies in AF showed lower rates of major bleeding with
the DOACs compared with warfarin in Randomized Evaluation of Long-Term Antico-
agulation Therapy (RE-LY)7 with dabigatran and Apixaban for Reduction in Stroke and
Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)8 with apixaban. Rate
of major bleeding was neutral in the Rivaroxaban Once daily Oral Direct Factor Xa In-
hibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism
Trial in Atrial Fibrillation (ROCKET-AF)9 with rivaroxaban. The DOACs reduced the rela-
tive risk of intracranial bleeding compared with warfarin. However, they showed higher
rates of major gastrointestinal (GI) bleeding with the DOACs compared with warfarin in
the same studies.10 Although several meta-analyses and major published clinical trials
suggested that DOACs do not increase the risk of significant bleeding, a lack of anti-
dote always concerned clinicians because, in emergency situations, the bleeding
might need to be reversed. Bleeding associated with warfarin can be predictably
managed with close monitoring of INR and reversal with fresh frozen plasma (FFP)
and vitamin K. Neither FFP nor vitamin K is effective to reverse the effects of DOACs.11
Activated charcoal has been shown, in vitro, to absorb 99.9% of dabigatran sus-
pended in acidic water. This treatment option could be useful in cases of acute intox-
ication. However, the efficacy of activated charcoal has not been tested in clinical
practice. Desmopressin (D-arginine-deamino-vasopressin) increases the coagulation
activity by stimulating the release of factor VIII and von Willebrand factor from the
vascular endothelium. However, no clinical trials have evaluated the efficacy in
bleeding patients on DOACs. Prothrombin complex concentrate (PCC) is a mixture
of inactive factors II, IX, X, and VII. Studies on the efficacy of PCC in the reversal of
the anticoagulant effect have shown inconsistent results. The activated PCC has
been the most reasonable alternative for reversing dabigatran effect until recently.
Clinical trials with a humanized antibody fragment directed against dabigatran (idar-
ucizumab) and recombinant, modified factor Xa (andexanet alfa) have recently been
completed.
4 Bang et al

IDARUCIZUMAB

Idarucizumab, which is a humanized monoclonal antibody fragment (Fab), binds both

free and thrombin-bound dabigatran. A prospective cohort study was performed to
determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse
the anticoagulant effects of dabigatran in patients who had serious bleeding (group
A) or required an urgent procedure (group B).12 The primary end point was the per-
centage reversal of the anticoagulant effect of dabigatran within 4 hours after the
administration of idarucizumab, by the determination at a central laboratory of the
dilute thrombin time or ecarin clotting time. A key secondary end point was the resto-
ration of hemostasis. Idarucizumab normalized the test results in 88% to 98% of the
patients, an effect that was evident within minutes. Among 35 patients in group A who
could be assessed, hemostasis, as determined by local investigators, was restored at
a median of 11.4 hours. Among 36 patients in group B who underwent a procedure,
normal intraoperative hemostasis was reported in 33 patients, and mildly or moder-
ately abnormal hemostasis was reported in 2 patients and 1 patient, respectively.
One thrombotic event occurred within 72 hours after idarucizumab administration in
a patient in whom anticoagulants had not been reinitiated.

ANDEXANET ALFA

Andexanet is a reversal agent that is designed to neutralize the anticoagulant effects of

both direct and indirect factor Xa inhibitors. Andexanet binds and removes factor Xa
inhibitors, thereby enhancing the activity of endogenous factor Xa and attenuating
levels of anticoagulant activity. This activity is assessed by measurement of thrombin
generation and anti–factor Xa activity.13 For each factor Xa inhibitor (apixaban and
rivaroxaban), a 2-part randomized placebo-controlled study was conducted to eval-
uate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The pri-
mary outcome was the mean percentage change in anti–factor Xa activity, which is a
measure of factor Xa inhibition by the anticoagulant. Andexanet alfa reversed the anti-
coagulant activity of apixaban and rivaroxaban in older healthy participants within mi-
nutes after administration and for the duration of infusion, without serious adverse or
thrombotic events.14 Subsequently, a multicenter, prospective, open-label, single-
group study evaluated 67 patients who had acute major bleeding within 18 hours after
the administration of a factor Xa inhibitor.15 The patients all received a bolus of andex-
anet followed by a 2-hour infusion of the drug. Among the apixaban-treated partici-
pants, anti–factor Xa activity was reduced by 94% among those who received an
andexanet bolus (24 participants), compared with 21% among those who received
placebo (9 participants) (P<.001). Among the rivaroxaban-treated participants, anti–
factor Xa activity was reduced by 92% among those who received an andexanet bolus
(27 participants), compared with 18% among those who received placebo (14 partic-
ipants) (P<.001). No serious adverse or thrombotic events were reported. In conclu-
sion, andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in
older, healthy participants within minutes after administration and for the duration of
infusion, without evidence of clinical toxic effects.

CIRAPARANTAG (PER977)

Ciraparantag, is an intravenously administered synthetic small molecule for use as a

broad-spectrum reversal agent for anticoagulants, including low-molecular-weight
heparin (LMWH), unfractionated heparin (UFH), and the DOACs that is currently being
studied in phase II clinical trials.
 Direct Oral Anticoagulants and Their Uses 5

DIRECT ORAL ANTICOAGULANTS IN ATRIAL FIBRILLATION

Anticoagulation is important in stroke prevention in patients with atrial fibrillation (AF).

There are multiple factors that contribute to the risk of thromboembolism in patients
with AF. Several scoring systems are used for risk stratification. The 2014 ACC/
AHA/HRS guidelines recommend using CHA2DS2-VASc score.6 When using this
score, 1 point is assigned for the presence of each of the following: congestive heart
failure, hypertension, age (65–74 years, 1 point; 75 years, 2 points), diabetes, prior
stroke or transient ischemic attack (TIA) (2 points), vascular disease (myocardial
infarction [MI], peripheral arterial disease [PAD], and carotid disease), and sex (female)
with a maximum of 9 points. The anticoagulation/antiplatelet therapy recommended
for the groups of patients is as follows: 1 point, no therapy, acetylsalicylic acid (75
or 325 mg daily), or oral anticoagulation (OAC); and 2 points or more, OAC (VKA or
DOACs).
The currently US Food and Drug Administration (FDA)–approved DOACs include 1
direct thrombin inhibitor (dabigatran) and several factor Xa inhibitors (rivaroxaban,
apixaban, and edoxaban). In the 2014 ACC/AHA guidelines (published before edoxa-
ban approval), dabigatran, apixaban, and rivaroxaban are recommended for use in pa-
tients with NVAF who have had prior stroke or TIA, or are at risk by virtue of a
CHA2DS2-VASc score of 2 or more. In addition, DOACS are recommended if it is
not possible to maintain therapeutic INR with VKA. It must be remembered that
DOACs have not been studied in patients with valvular AF, which includes mitral ste-
nosis, mechanical or bioprosthetic valves, and mitral valve repair.

DABIGATRAN

The RE-LY trial compared different dosages of dabigatran with warfarin in patients
with AF.7 Enrolled patients received fixed dosages of dabigatran (110 or 150 mg twice
daily) or warfarin. The primary outcome was stroke or systemic embolism. In patients
with AF, dabigatran administered at a dose of 150 mg, compared with warfarin, was
associated with lower rates of stroke and systemic embolism but similar rates of major
hemorrhage. Dabigatran given at a dose of 110 mg was associated with similar rates
of stroke and systemic embolism to those associated with warfarin, but lower rates of
major hemorrhage. At present, dabigatran is available in 2 FDA-approved dosages:
150 mg twice a day or 75 mg twice a day (for patients with CrCl 15–30 mL/min). Sub-
group analysis showed a higher risk of intracranial hemorrhage in patients greater than
75 years of age and on the higher 150 mg twice daily dose. Thus, caution should be
used in patients with renal impairment or those who are greater than 75 years of age.16

DIRECT FACTOR XA INHIBITORS

At present, there are 3 factor Xa inhibitors available in the United States: rivaroxaban,
apixaban, and edoxaban.

RIVAROXABAN

The ROCKET AF trial randomized patients to rivaroxaban versus warfarin with the pri-
mary end point of stroke or systemic embolism.9 The primary end point occurred in
188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group
(2.2% per year) (hazard ratio [HR] in the rivaroxaban group, 0.79; 95% confidence in-
terval [CI], 0.66–0.96; P<.001 for noninferiority). The risk of major bleeding was not
different between the two groups (14.9% in rivaroxaban vs 14.5% in warfarin groups);
however, intracranial bleeding occurred less often in the rivaroxaban group compared
6 Bang et al

with warfarin (0.5% vs 0.7%; P 5 .02). Risk of GI bleeding was higher in the rivarox-
aban group (3.2% vs 2.2%; P<.001). In patients with AF, rivaroxaban was noninferior
to warfarin for the prevention of stroke or systemic embolism. There was no significant
between-group difference in the risk of major bleeding, although intracranial and fatal
bleeding occurred less frequently in the rivaroxaban group. At present, rivaroxaban is
available in 2 FDA-approved dosages: 20 mg daily or 15 mg daily for patients with CrCl
of 15 to 49 mL/min.

APIXABAN

ARISTOTLE was a large noninferiority trial comparing apixaban with warfarin, with
stroke or systemic embolism as the primary outcome.8 The trial was also designed
for secondary objectives of testing for superiority with respect to the primary outcome
and to the rates of major bleeding and death from any cause. The rate of the primary
outcome was 1.27% per year in the apixaban group versus 1.60% per year in the
warfarin group (HR with apixaban, 0.79; 95% CI, 0.66–0.95; P<.001 for noninferiority;
P 5 .01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban
group, compared with 3.09% per year in the warfarin group (HR, 0.69; 95% CI, 0.60–
0.80; P<.001), and the rates of death from any cause were 3.52% and 3.94%, respec-
tively (HR, 0.89; 95% CI, 0.80–0.99; P 5 .047). It concluded that, in patients with AF,
apixaban was superior to warfarin in preventing stroke or systemic embolism, caused
less bleeding, and resulted in lower mortality.

EDOXABAN

Edoxaban is the newest approved direct factor Xa inhibitor. ENGAGE AF-TIMI 48 trial
(Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-
Thrombolysis in Myocardial Infarction Study 48) compared the use of edoxaban
with warfarin with regard to stroke and systemic embolism.17 Compared with warfarin,
the high-dose (60 mg) edoxaban showed superiority in preventing stroke or systemic
emboli (HR, 0.79; P<.001), and low-dose (30 mg) edoxaban was noninferior (HR, 1.07;
P 5 .005). The rate of major bleeding, including intracranial bleeding, was lower with
edoxaban compared with warfarin, regardless of the dose. However, the rate of GI
bleeding was higher in the high-dose edoxaban group compared with warfarin (HR,
1.23; P 5 .03).

DIRECT ORAL ANTICOAGULANTS IN VENOUS THROMBOEMBOLISM

Clinical trials have been designed to study the efficacy of DOACs in VTE for short-
term, long-term, and extended-term treatment. Short-term treatment is defined as
the therapy initiated at the time of diagnosis and continued for 5 to 7 days, which
is the necessary time for overlap for VKA to become sufficiently therapeutic. Long-
term therapy is defined as treatment extending 3 to 12 months from the initiation of
anticoagulation, and is thought to be the proper duration of anticoagulation for
most patients with an initial thromboembolic event. Extended treatment is recom-
mended for patients who have had recurrent VTE and are at low or moderate risk
of bleeding.

DABIGATRAN

The RE-COVER18 and RE-COVER II19 studies had similar trial designs evaluating pa-
tients with acute VTE. Both were designed as noninferiority trials comparing the same
initial therapy, consisting of parenteral anticoagulation (UFH or LMWH, or
 Direct Oral Anticoagulants and Their Uses 7

fondaparinux) followed by randomization for long-term treatment to either dabigatran

150 mg twice daily or warfarin. The primary outcome was the 6-month incidence of
recurrent symptomatic, objectively confirmed VTE and related deaths for both studies.
In the RE-COVER trial, the primary outcome of recurrent VTE at 6 months was 2.4%
in the dabigatran-treated patients versus 2.1% in the warfarin group (P<.001 for non-
inferiority). Major bleeding occurred in 1.6% versus 1.9% of the dabigatran-treated
and warfarin-treated patients, respectively (P 5 .38). As might be anticipated, the re-
sults from RE-COVER II were virtually identical to those observed in RE-COVER. The
primary efficacy outcome of recurrent VTE was 2.3% and 2.2% in the dabigatran and
warfarin groups, respectively (P<.001 for noninferiority). Major bleeding occurred in
1.2% and 1.7% of patients in the dabigatran and warfarin groups. Any bleeding
occurred in 15.6% of the patients on dabigatran versus 22.1% of the patients on
warfarin. Deaths, adverse events, and acute coronary syndromes were similar in
both groups.
Dabigatran was the first DOAC studied to assess the risks and benefits of extended
therapy and compared an active control (VKA) with placebo for prevention of VTE
recurrence. The active-controlled study was RE-MEDY20 and the placebo-
controlled study was RE-SONATE.20 The active-controlled study was designed to
evaluate whether dabigatran was noninferior to warfarin in preventing recurrent VTE.
The placebo-controlled study was designed to evaluate whether extended treatment
with dabigatran was superior to placebo in preventing recurrent VTE.
In the active-controlled RE-MEDY study, the primary efficacy outcome was recur-
rent VTE, which occurred in 1.8% of the patients on dabigatran and 1.3% of the pa-
tients on VKA. Dabigatran met the noninferiority margin for prevention of recurrent
VTE (P 5 .01). Major bleeding occurred in 0.9% of the dabigatran group and
1.8% of the warfarin group (P 5 .06). Major or clinically relevant nonmajor
(CRNM) bleeding occurred in 5.6% of the patients on dabigatran and 10.2% of
warfarin-treated patients (P 5 .001). Of the patients on dabigatran, 0.9% had acute
ischemic coronary events during treatment, compared with 0.2% of warfarin-treated
patients (P 5 .02).
In the placebo-controlled RE-SONATE trial, the primary efficacy outcome for recur-
rence during the first 6 months occurred in 0.4% of the dabigatran group and 5.6% of
the placebo group (HR, 0.08; P 5 .001). After the extended 12-month follow-up, the
recurrence rate was 6.9% in the dabigatran group compared with 10.7% in the pla-
cebo group (HR, 0.61; P 5 .03). Protection from recurrent VTE was provided during
administration of dabigatran; however, once active drug was terminated, the rate of
recurrence in the dabigatran group was similar to the rate of recurrence in the match-
ing placebo group. There was no difference in major bleeding between the dabigatran
and placebo groups. Major or CRNM bleeding occurred in 5.3% of patients in the
dabigatran group compared with 1.8% in the placebo group (P 5 .001). Only 1 acute
coronary event occurred in each treatment group.

RIVAROXABAN

The EINSTEIN investigators21 studied oral rivaroxaban for symptomatic VTE and
symptomatic pulmonary embolism (PE).22 In their first study, patients with symptom-
atic proximal DVT with or without PE were randomized to rivaroxaban or enoxaparin
followed by warfarin, targeting an INR of 2.0 to 3.0. During initial therapy with rivarox-
aban, patients received 15 mg twice daily for 3 weeks, then were converted to 20 mg
daily for 3 to 12 months. The primary efficacy outcome of symptomatic recurrent VTE
occurring during the 3-month to 12-month treatment period, occurred in 3.0% of the
8 Bang et al

enoxaparin-VKA group and 2.1% of the rivaroxaban-treated group (HR<0.68; P 5 .001

for noninferiority and P<.08 for superiority). The primary safety outcome of major and
CRNM bleeding was 8.1% for both the treatment groups (HR<0.97; P<.77).
The EINSTEIN-PE study22 was similarly designed, and it randomized 4833 patients
with confirmed symptomatic PE, with or without DVT. Patients were similarly treated
after randomization with either rivaroxaban 15 mg twice daily for 3 weeks and con-
verted to 20 mg daily for 3 to 12 months or with open-label enoxaparin 1 mg/kg twice
daily and converted to warfarin with a target INR of 2.0 to 3.0. The primary efficacy
outcome was symptomatic recurrent VTE occurring during the 3-month to 12-month
treatment period. The primary safety outcome was major and CRNM bleeding. Results
revealed a 2.1% recurrence rate in the rivaroxaban-treated patients versus a 1.8%
recurrence rate in patients receiving conventional therapy (HR<1.12; P<.003 for non-
inferiority). Major and CRNM bleeding occurred in 10.3% of the rivaroxaban-treated
patients versus 11.4% of the warfarin group (HR<0.90; P<.23). The EINSTEIN investi-
gators21 additionally performed a double-blind extended-treatment study in patients
with confirmed VTE who were treated for 6 to 12 months with therapeutic anticoagu-
lation. This study was an event-driven superiority trial assuming a primary outcome of
3.5% in the placebo group and a 70% risk reduction with rivaroxaban. Patients were
then randomized and assigned to receive continued treatment with rivaroxaban 20 mg
daily for 6 to 12 months or with placebo. The primary efficacy outcome was symptom-
atic recurrent VTE and the primary safety outcome was major bleeding. The net clinical
benefit was calculated for both the groups and was defined as the composite of symp-
tomatic recurrent VTE or major bleeding. The primary efficacy outcome occurred in
1.3% of the rivaroxaban group compared with 7.1% of the placebo group
(P 5 .001), resulting in a relative risk reduction of 82%. The principal safety outcome
of major bleeding occurred in 0.7% of the rivaroxaban-treated patients and in no pa-
tients in the placebo group (P 5 .11). Net clinical benefit occurred in 2% of patients
receiving rivaroxaban and 7.1% receiving placebo (P<.001). Efficacy and safety out-
comes were consistent across the prespecified subgroups.

APIXABAN

The AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and
Deep-Vein Thrombosis as First-Line Therapy) investigators23 studied apixaban versus
conventional therapy for patients with acute VTE. Patients (N 5 5400) with symptom-
atic proximal DVT or PE were randomized to apixaban 10 mg twice daily for 7 days and
converted to 5 mg twice daily for a period of 6 months versus conventional anticoagu-
lation with enoxaparin 1 mg/kg twice daily and warfarin targeting an INR of 2.0 to 3.0.
The primary efficacy outcome was a composite of recurrent symptomatic VTE or
death related to VTE. The primary safety outcome was major bleeding. The primary
efficacy outcome occurred in 2.3% of the apixaban-treated patients versus 2.7% of
those treated with conventional anticoagulation (P<.001 for noninferiority). Major
bleeding occurred in 0.6% of apixaban-treated patients versus 1.8% of those given
warfarin (P<.0001 for superiority). There was no difference observed in the outcomes
in patients presenting with acute symptomatic DVT versus those presenting with acute
PE.
The AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism
and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment) investiga-
tors evaluated 2 doses of apixaban (5 mg twice daily and 2.5 mg twice daily) versus
placebo in a randomized, double-blind study of 2486 patients who had completed 6
to 12 months of anticoagulation for symptomatic VTE.24 The study drugs and placebo
 Direct Oral Anticoagulants and Their Uses 9

drugs were assigned in a 1:1:1 ratio and given for a period of 12 months. Outcome
analysis was observed during the 12-month treatment period. The primary efficacy
end point was symptomatic recurrent VTE or death from any cause. The secondary
efficacy end point was a composite of symptomatic recurrent VTE, death related to
VTE, MI, stroke, or death secondary to any cardiovascular disease. The primary safety
outcome was major bleeding. The secondary safety outcome was the composite of
major or CRNM bleeding.
Symptomatic recurrent VTE or death from any cause occurred in 11.6% of patients
receiving placebo, 3.8% receiving the 2.5-mg dose of apixaban, and 4.2% receiving
the 5-mg dose of apixaban (P<.001). Major bleeding occurred in 0.5% of the placebo
group and 0.2% and 0.1% of the 2.5-mg and 5-mg apixaban dose groups, respec-
tively, resulting in no significant difference.
The composite outcome of symptomatic recurrent VTE, death caused by VTE, MI
and stroke, cardiovascular death, or major bleeding occurred in 10.4% of patients tak-
ing placebo versus 2.4% of those receiving 2.5 mg and 2.5% of those receiving 5 mg
of apixaban. During the 30-day follow-up after active drug was discontinued, symp-
tomatic recurrent VTE occurred in 0.2% of patients in the placebo group, 0.4% in
the 2.5-mg apixaban group, and 0.6% in the 5-mg apixaban group. The composite
outcome of MI, stroke, or cardiovascular death occurred once each in the 2.5-mg
and 5-mg apixaban groups and did not occur in the placebo group. The 2.5-mg twice
daily dose is currently approved by the UFDA for extended therapy.

EDOXABAN

The Hokusai VTE study25 design was similar to the RE-COVER study design in that all
patients had initial therapy with parenteral anticoagulation (enoxaparin or UFH). After a
minimum of 5 days of parenteral anticoagulation, patients were treated with oral edox-
aban 60 mg daily or VKA targeting an INR of 2.0 to 3.0. The primary efficacy outcome
of symptomatic VTE within 12 months from randomization occurred in 3.5% of pa-
tients receiving warfarin and 3.2% of patients receiving edoxaban (P 5 .001 for non-
inferiority). The primary safety outcome of a first major or CRNM event occurred in
8.5% of patients receiving edoxaban versus 10.3% of those receiving warfarin
(P<.004). The Hokusai study showed that after at least 5 days of treatment with paren-
teral heparin, edoxaban at 60 mg daily was as effective as warfarin in reducing recur-
rent VTE, but was associated with fewer major or CRNM bleeding events.

DIRECT ORAL ANTICOAGULANTS IN PREGNANCY

Because warfarin is a category X drug in pregnancy (contraindicated: animal or human

studies showed fetal abnormalities), heparin and LMWH have been the only choices
for anticoagulation during pregnancy. Although dabigatran, rivaroxaban, and edoxa-
ban are category C in pregnancy (risk not ruled out: animal studies showed adverse
effect and no human studies done), apixaban is category B (no risk in other studies:
animal studies showed no risk or adverse fetal effects during all 3 trimesters, no hu-
man studies done).

SUMMARY

The DOACs offer an exciting alternative to warfarin for a variety of thrombotic condi-
tions, including nonvalvular AF and VTE. Their unique properties allow more predict-
able dosing and ease of use, avoid the need for perioperative bridging
anticoagulation, and have similar or improved efficacy and reduced side effect risk
10 Bang et al

compared with warfarin. Although they have now become the first-line choice for
treatment of VTE and AF, there is still an important role for warfarin. For example, pa-
tients with mechanical valve replacement should not be treated with any DOAC. In
addition, many patients are unable to afford these medications and warfarin remains
a more attractive option. In addition, in patients with severe renal dysfunction, the
DOACs should be avoided because a lack of renal clearance may lead to bleeding
complications. Engaging patients in a shared decision-making process to identify
the most appropriate anticoagulant and ensuring safe long-term management are
essential for high-quality, patient-centered care. The nuances of anticoagulation
with DOACs will continue to evolve with their increased use and the incumbency of
additional information, providing a challenging aspect to this innovative nemesis to
warfarin.

REFERENCES

1. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharma-
cokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin
Pharmacokinet 2009;48(1):1–22.
2. Alexander JH, Singh KP. Inhibition of factor Xa: a potential target for the develop-
ment of new anticoagulants. Am J Cardiovasc Drugs 2005;5(5):279–90.
3. DeWald TA, Becker RC. The pharmacology of novel oral anticoagulants.
J Thromb Thrombolysis 2014;37:217–33.
4. Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the antico-
agulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;
64(11):1128–39.
5. Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of
the oral Xa inhibitors. Clin Lab Med 2014;34(3):503–17.
6. January CT, Wann LS, Alpert JS, et al, ACC/AHA Task Force Members. 2014 AHA/
ACC/HRS guideline for the management of patients with atrial fibrillation: execu-
tive summary: a report of the American College of Cardiology/American Heart As-
sociation Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation 2014;130(23):2071–104.
7. Connolly SJ, Ezekowitz MD, Yusuf S, et al, RE-LY Steering Committee and Inves-
tigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J
Med 2009;361:1139–51.
8. Granger CB, Alexander JH, McMurray JJ, et al, ARISTOTLE Committees and In-
vestigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J
Med 2011;365:981–92.
9. Patel MR, Mahaffey KW, Garg J, et al, ROCKET AF Investigators. Rivaroxaban
versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
10. Sardar P, Chatterjee S, Lavie CJ, et al. Risk of major bleeding in different indica-
tions for new oral anticoagulants: insights from a metaanalysis of approved dos-
ages from50 randomized trials. Int J Cardiol 2015;179:279–87.
11. Bouillon K, Bertrand M, Maura G, et al. Risk of bleeding and arterial thromboem-
bolism in patients with non-valvular atrial fibrillation either maintained on a vitamin
K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retro-
spective, matched-cohort study. Lancet Haematol 2015;2:e150–9.
12. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal.
REVERSE AD trial. N Engl J Med 2015;373:511–20.
 Direct Oral Anticoagulants and Their Uses 11

13. Lu G, DeGuzman FR, Hollenbach SJ. A specific antidote for reversal of anticoa-
gulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;
19:446–51.
14. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of fac-
tor Xa inhibitor activity. N Engl J Med 2015;373(25):2413–24.
15. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al, ANNEXA-4 Investigators.
Andexanet alfa for acute major bleeding associated with factor Xa inhibitors.
N Engl J Med 2016;375(12):1131–41.
16. Hart RG, Diener HC, Yang S, et al. Intracranial hemorrhage in atrial fibrillation pa-
tients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke
2012;43(6):1511–7.
17. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients
with atrial fibrillation. N Engl J Med 2013;369(22):2093–104.
18. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treat-
ment of acute venous thromboembolism. N Engl J Med 2009;361:2342–52.
19. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous throm-
boembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;
129:764–72.
20. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or
placebo in venous thromboembolism. N Engl J Med 2013;368:709–18.
21. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic
venous thromboembolism. N Engl J Med 2010;363:2499–510.
22. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symp-
tomatic pulmonary embolism. N Engl J Med 2012;366:1287–97.
23. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute
venous thromboembolism. N Engl J Med 2013;369:799–808.
24. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous
thromboembolism. N Engl J Med 2013;368:699–708.
25. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of
symptomatic venous thromboembolism. N Engl J Med 2013;369:1406–15.