REVIEW

The New Oral Anticoagulants in Clinical Practice

Wilson I. Gonsalves, MD; Rajiv K. Pruthi, MBBS; and Mrinal M. Patnaik, MBBS

Abstract

Vitamin K antagonists were the only class of oral anticoagulants available to clinicians for decades. However,
with the US Food and Drug Administration approval of new oral anticoagulants, such as dabigatran,
rivaroxaban, and apixaban, clinicians now have a broader choice. Given the recent approval and availability
of these medications, several questions arise while deciding which of them would be best suited for a
particular patient. This article provides a concise review for clinicians entailing the main studies that
evaluated the efcacy and safety of these drugs, their pharmacokinetic and pharmacodynamic properties,
and a practical approach to their clinical use. For this review, we conducted searches of PubMed and
MEDLINE for articles published between January 1, 2000, and January 30, 2013, using the following search
terms: oral anticoagulants, dabigatran, apixaban, rivaroxaban, novel anticoagulants, bleeding complications,
management of bleeding complications, pharmacodynamics, and pharmacokinetics. Studies published in English
were selected for inclusion in this review, as were additional articles identied from bibliographies.
2013 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2013;88(5):495-511

F
or more than half a century, warfarin, a
vitamin K antagonist (VKA), had been
the only available oral anticoagulant. Its
narrow therapeutic index and multiple drug
and diet interactions affected its safety, compli-
ance, and efcacy. A meta-analysis revealed that
44% of bleeding complications with warfarin
were associated with supratherapeutic interna-
tional normalized ratios (INRs) and that 48%
of thromboembolic events occurred with sub-
therapeutic readings.1 Difculties in achieving
optimal anticoagulation with warfarin therapy
are attributed to its slow onset of action, variable
pharmacologic effects, and numerous food and
drug interactions.2 These shortcomings have
prompted the development of new oral antico-
agulants (NOAs) that target key coagulation fac-
tors, such as factors Xa and IIa (thrombin)
(Supplemental Figure, available online at http://
www.mayoclinicproceedings.org). The NOAs
approved in the United States are dabigatran
(Pradaxa; Boehringer Ingelheim), rivaroxaban
(Xarelto; Bayer HealthCare AG and Janssen
Research & Development LLC, a Johnson &
Johnson Company), and apixaban (Eliquis;
Pzer and Bristol-Myers Squibb).
For this review, we conducted searches of
PubMed and MEDLINE for articles published
between January 1, 2000, and January 30,
2013, using the following search terms: oral
anticoagulants, dabigatran, apixaban, rivaroxa-
ban, novel anticoagulants, bleeding complica-
tions, management of bleeding complications,
pharmacodynamics, and pharmacokinetics. Stud-
ies published in English were selected for in-
clusion in this review, as were additional From the Division of
Hematology (W.I.G.,
articles identied from bibliographies. R.K.P., M.M.P.) and
Division of Hematopa-
DABIGATRAN thology (R.K.P., M.M.P.),
Dabigatran etexilate (Pradaxa) is the rst oral Mayo Clinic, Rochester,
MN.
direct thrombin inhibitor to be approved by
the US Food and Drug Administration (FDA).
Mechanism of Action
Dabigatran etexilate is a prodrug that is rapidly
converted to its active compound, dabigatran,
by nonspecic esterases in the plasma and liver.
This active compound competitively and revers-
ibly binds to the active site of free and clot-bound
thrombin, thereby blocking its procoagulant
activity (Supplemental Figure; available online
at http://www.mayoclinicproceedings.org).3 Its
pharmacokinetic and pharmacodynamic prole
is detailed in Table 1.
Approved Indications
Dabigatran is approved for use in the preven-
tion of stroke and systemic embolism in adult
patients with nonvalvular atrial brillation
(AF) (FDA, European Medicines Agency [EMA],
and Canadas Health Products and Food
Branch [HPFB]) and in the primary prevention
of venous thromboembolic events (VTEs) in
adult patients who have undergone elective
total hip (THA) or knee (TKA) arthroplasty
(EMA and HPFB).

Mayo Clin Proc. n May 2013;88(5):495-511 n http://dx.doi.org/10.1016/j.mayocp.2013.03.006 495

www.mayoclinicproceedings.org n 2013 Mayo Foundation for Medical Education and Research

ARTICLE HIGHLIGHTS
n Warfarin, an oral vitamin K antagonist, is an effective, time-
tested anticoagulant option for most patients, especially in the
setting of minimal food-drug interactions, reliable monitoring,
and good patient compliance.
n The new oral anticoagulants (NOAs) have increased thera-
peutic options and work independent of the vitamin K pathway.
Dabigatran inhibits coagulation factor IIa, and rivaroxaban and
apixaban inhibit coagulation factor Xa.
n The NOAs are able to overcome some of the shortcomings of
warfarin, such as its slow onset of action, variable pharmaco-
logic effects, food-drug interactions, and the need for close
monitoring.
n At the same time, the NOAs are limited by their high cost, lack
of specic antidotes, and lack of long-term safety data.
n Until further data are available, the NOAs should be avoided in
pregnancy, patients with mechanical heart valves, and those
with severe renal insufciency.
Clinical Trials
Dabigatran has been evaluated in several phase
3 clinical trials to assess its safety and efcacy
in different clinical situations, which are sum-
marized as follows and in Table 2.
Prevention of Stroke and Systemic Embo-
lism in Nonvalvular AF. The RE-LY (Ran-
domized Evaluation of Long-term Anticoagulant
Therapy, Warfarin, compared with Dabigatran)
study4 was a noninferiority trial that evaluated
the efcacy and safety of dabigatran at 110 or 150
mg twice daily compared with dose-adjusted
warfarin targeting an INR of 2 to 3 in patients
with nonvalvular AF and an intermediate risk of
thromboembolism.
Efcacy. The stroke (including hemorrhagic
stroke) or systemic embolism rate per year
was lower with the 150-mg dabigatran dose
(1.11%; P<.001 for superiority) and equiva-
lent with the 110-mg dabigatran dose (1.53%;
P<.001 for noninferiority) compared with
warfarin (1.69%). The superiority of the 150-
mg dose was seen only when compared with
patients taking warfarin with moderate/poor
regulation of their INRs (dened as the INR
being in the target range <65% of the time).5
n n
496 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
Safety. The annual rate of major bleeding with
the 150-mg dabigatran dose was not different
(3.11%; P.31) compared with warfarin
(3.36%) but was lower with the 110-mg dose
(2.71%; P.003). The rates of hemorrhagic
stroke with the 110- and 150-mg dabigatran
doses were lower than with warfarin (0.12%
and 0.10% vs 0.38%; P<.001), as were the
rates of intracranial hemorrhage (0.23% and
0.30% vs 0.74%; P<.001).
Treatment of Acute VTE. The RE-COVER
study6 evaluated patients with acute VTE and
compared 6 months of treatment with either
dabigatran, 150 mg twice daily, or dose-adjusted
warfarin after initial unfractionated heparin
or low-molecular-weight heparin (LMWH)
anticoagulation.
Efcacy. The 6-month incidence of recurrent
symptomatic VTE and related deaths was
2.4% (2.3% VTE; 0.1% deaths) in patients
treated with dabigatran vs 2.1% (1.9% VTE;
0.2% deaths) in those treated with warfarin
(P<.001 for noninferiority).
Safety. The rates of major bleeding episodes
were similar in the dabigatran and warfarin
groups (1.6% vs 1.9%). However, the inci-
dence of all bleeding events was lower with
dabigatran use (16.1% vs 21.9%).
Postoperative VTE Prophylaxis for TKA.
Dabigatran dosed at 220 or 150 mg/d starting
with half a dose 1 to 4 hours after surgery
was evaluated for the prevention of VTE after
TKA compared with enoxaparin, 40 mg/d, start-
ing the evening before surgery for 6 to 10 days
in the European RE-MODEL study7 and
enoxaparin, 30 mg twice daily, starting the
morning after surgery for 13 days in the North
American RE-MOBILIZE study.8
Efcacy. There were conicting results between
the 2 trials. In RE-MODEL, the incidence of VTE
or mortality was 37.7% (37.5% VTE; 0.2%
deaths) in the enoxaparin arm compared with
36.4% (36.2% VTE; 0.2% deaths) in the dabi-
gatran, 220-mg, arm (P.0003 for non-
inferiority) and 40.5% (40.3% VTE; 0.2%
deaths) in the dabigatran, 150-mg, arm (P.017
for noninferiority). However, in RE-MOBILIZE,
the composite of VTE and death occurred in
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NEW ORAL ANTICOAGULANTS

TABLE 1. Comparative Properties of Warfarin, Dabigatran, Rivaroxaban, and Apixaban

Characteristic Warfarin Dabigatran Rivaroxaban Apixaban
Target Vitamin K epoxide reductase Factor IIa (free and Factor Xa Factor Xa
clot-bound thrombin)
Prodrug No Yes No No
Bioavailability (%) >95 6.5 >80 50
Metabolism Hepatic, mainly via CYP2C9, Hepatic Hepatic, mainly via Hepatic, mainly via CYP3A4
CYP1A2, CYP3A4, CYP2C8, CYP3A4, CYP3A5, with minor contributions from
CYP2C18, and CYP2C19 and CYP2J2 CYP1A2, CYP2C8, CYP2C9,
CYP2C19, and CYP2J2
Plasma protein 97 34-35 w92-95 (primarily 87
binding (%) albumin)
Half-life (h) 40 14-17 5-9 10-14
9-13 (elderly)
Elimination 92% renal 80% renal 66% renal 27% renal
20% fecal 33% fecal 63% fecal
Monitoring INR adjusted Not needed Not needed Not needed
Peak effect (h) 72-96 2 2-4 3-4
Drug interactions CYP2C9, CYP1A2, and P-gp inducers/inhibitors CYP3A4 and P-gp CYP3A4 and P-gp inducers/
CYP3A4 inducers/inhibitors inhibitors
Antidote Vitamin K None None None
Reversal via hemodialysis No Yes No No
CYP cytochrome; INR international normalized ratio; P-gp P-glycoprotein.

25.3% (all VTE; no deaths) of those in the
enoxaparin arm compared with 31.1% (all VTE;
no deaths) of those in the dabigatran, 220-mg,
arm (P.02) and 33.7% (33.5% VTE; 0.2%
deaths) of those in the dabigatran, 150-mg, arm
(P<.001). The differences in efcacy between
the 2 trials may be due to the different dosing
schedules of enoxaparin because the primary
outcomes in dabigatran-treated patients were the
same for both studies. The RE-MOBILIZE used
the standard North American dose, which is
more dose intensive with a longer duration than
that used in Europe (RE-MODEL); thus, dabi-
gatran may not be an equally efcacious pro-
phylaxis option in this setting.
Safety. Among the 3 arms, the incidence of
major bleeding did not differ signicantly in
RE-MODEL (1.3% for enoxaparin vs 1.5%
for dabigatran, 220 mg, and 1.3% for dabi-
gatran, 150 mg) or in RE-MOBILIZE (1.4% for
enoxaparin vs 0.6% for dabigatran, 220 mg,
and 0.6% for dabigatran, 150 mg).
Postoperative VTE Prophylaxis for THA. The
European RE-NOVATE I9 and the North Amer-
ican RE-NOVATE II10 studies evaluated dabiga-
tran dosed at 220 or 150 mg/d (the 150-mg
dose arm was present only in RE-NOVATE I)
starting with half a dose 1 to 4 hours after surgery
in preventing VTE after THA compared with
enoxaparin, 40 mg/d, starting preoperatively the
evening before surgery for 28 to 35 days of
treatment.
Efcacy. In RE-NOVATE I, the incidence of
VTE or death was 6.7% (all VTE; no deaths) in
the enoxaparin arm vs 6.0% (5.7% VTE; 0.3%
deaths) in the dabigatran, 220-mg, arm
(P<.0001 for noninferiority) and 8.6% (8.3%
VTE; 0.3% deaths) in the dabigatran, 150-mg,
arm (P<.0001 for noninferiority). Further-
more, RE-NOVATE II detected total VTE and
death in 7.7% (all VTE; no deaths) in the
dabigatran, 220-mg, arm vs 8.8% (8.7% VTE;
0.1% deaths) in the enoxaparin arm (P.43).
Safety. In both RE-NOVATE studies, there was
no difference in major bleeding rates with either
dose of dabigatran compared with enoxaparin
(P.44 for 220 mg, P.60 for 150 mg in RE-
NOVATE I and P.40 for 220 mg in RE-
NOVATE II).
US Dosing Recommendations
Stroke Prevention in Patients With AF. In pa-
tients with creatinine clearance (CrCl) great-
er than 30 mL/min per 1.73 m2 (to convert

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 MAYO CLINIC PROCEEDINGS

TABLE 2. Efcacy and Safety Results of Dabigatran Etexilate in Major Phase 3 Clinical Trials
Dabigatran Comparator Primary efcacy % (N=); Primary safety % (N=);
Reference dose dose [P value] [P value]
RE-LY,4 2009 150 mg bid Warfarin Composite VTE per year: Major bleeding per year:
Atrial brillation 110 mg bid Warfarind1.69%/y, (N199/6022) Warfarind3.36%/y, (N397/6022)
N18,113 Dabigatran, 150 mgd1.11%/y, Dabigatran, 150 mg bidd3.11%/y,
(N134/6076); (N375/6076);
P<.001 for superiority P.31
Dabigatran, 110 mgd1.53%/y, Dabigatran, 110 mg bidd2.71%/y,
(N182/6015); (N322/6015);
P<.001 for noninferiority P.003
RE-MODEL,7 2007 150 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
Postop TKA 220 mg qd 40 mg Enoxaparin, 40 mgd37.7%, (N193/512) Enoxaparind1.3%, (N9/694)
N2076 Dabigatran, 150 mgd40.5%, (N213/526); Dabigatran, 150 mgd1.3%, (N=9/703);
P.017 for noninferiority P value not signicant
Dabigatran, 220 mgd36.4%, (N183/503); Dabigatran, 220 mgd1.5%, (N10/679);
P.0003 for noninferiority P value not signicant
RE-NOVATE I,9 150 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
2007 220 mg qd 40 mg Enoxaparin, 40 mgd6.7%, (N60/897) Enoxaparin, 40 mgd1.6%, (N18/1154)
Postop THA Dabigatran, 150 mgd8.6%, (N75/874); Dabigatran, 150 mgd1.3%, (N15/1163);
N3494 P<.0001 for noninferiority P.60
Dabigatran, 220 mgd6.0%, (N53/880); Dabigatran, 220 mgd2.0%, (N23/1146);
P<.0001 for noninferiority P.44
RE-NOVATE II,10 220 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
2011 40 mg Enoxaparin, 40 mgd8.8%, (N69/785) Enoxaparin, 40 mgd0.9%, (N9/1003)
Postop THA Dabigatran, 220 mgd7.7%, (N61/792); Dabigatran, 220 mgd1.4%, (N14/1010);
N2055 P.43 for superiority P.40
RE-MOBILIZE,8 150 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
2009 220 mg qd 30 mg bid Enoxaparin, 30 mgd25.3%, (N163/643) Enoxaparin, 30 mgd1.4%, (N12/868)
Postop TKA Dabigatran, 150 mgd33.7%, (N219/649); Dabigatran, 150 mgd0.6%, (N5/871);
N2615 P.0009 for inferiority P value not signicant
Dabigatran, 220 mgd31.1%, (N188/604); Dabigatran, 220 mgd0.6%, (N5/857);
P.0234 for inferiority P value not signicant
RE-COVER,6 2009 150 mg bid Warfarin Composite VTE and related mortality: Major bleeding:
Acute VTE Warfarind2.1%, (N27/1265) Warfarind1.9%, (N24/1265)
N2564 Dabigatran, 150 mg bidd2.4%, Dabigatran, 150 mg bidd1.6%,
(N30/1274); (N20/1274);
P<.001 for noninferiority P value not signicant
bid twice a day; Postop postoperative; qd every day; THA total hip arthroplasty; TKA total knee arthroplasty; VTE venous thromboembolic event.

to mL/s per m2, multiply by 0.0167), the rec-
ommended dose is 150 mg orally twice
daily.11
Renal Impairment. For patients with CrCl of
15 to 30 mL/min per 1.73 m2, the recommen-
ded dose per FDA approval is 75 mg twice
daily.11 Because patients with CrCl less than
30 mL/min per 1.73 m2 were excluded from
the RE-LY trial, and because more than 80% of
the drug is renally excreted, extreme caution
should be used in this group of patients, and
our recommendation is that dabigatran be
avoided or discontinued.
n n
498 Mayo Clin Proc.
Hepatic Impairment. Patients with moderate
hepatic impairment (Child-Pugh class B) demon-
strated no consistent change in pharmacody-
namic properties. However, in patients with
advanced liver disease causing impaired coagula-
tion, the use of dabigatran is not recommended.11
Pregnancy and Breastfeeding. At present, its
use in pregnant and nursing mothers is not
recommended.11
Adverse Events
Nonhemorrhagic Adverse Events. Across
all the clinical trials, approximately 10% of
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NEW ORAL ANTICOAGULANTS
patients experienced severe dyspepsia com-
pared with 5.8% taking warfarin, leading to
the discontinuation of dabigatran therapy in
21% of patients.4,7 This is possibly due to
dabigatrans tartaric acid core needed to create
a low pH for the drugs absorption. In the RE-
LY trial, approximately 0.8% of patients taking
dabigatran experienced a myocardial infarc-
tion compared with 0.64% taking warfarin
(hazard ratio, 1.29; 95% CI, 0.96-1.75; P.09
for dabigatran, 110 mg, and hazard ratio, 1.27;
95% CI, 0.94-1.71; P.12 for dabigatran, 150
mg)12; the pathogenesis for this is unclear. In a
meta-analysis, dabigatran therapy increased
the risk of myocardial infarction, cardiac death,
or unstable angina compared with the control
group (odds ratio, 1.27; 95% CI, 1.00-1.61).13
However, the magnitude of increase was small
compared with the benet of ischemic stroke
prevention.
Hemorrhagic Adverse Events. There was a
higher rate of major gastrointestinal (GI) bleed-
ing in patients receiving dabigatran, 150 mg,
than warfarin (1.5% vs 1.0%; P<.001), with a
trend toward a higher incidence in patients
older than 75 years (5.10% vs 4.37% per
year; P.07).4 In the months after FDA
approval, there were multiple reports in the
community of increased bleeding events with
dabigatran use. However, on reviewing insur-
ance claims from community practices, the
FDA concluded that the rate of bleeding with
dabigatran use was not higher than with
warfarin use in patients using either drug for
the rst time14 and was likely secondary to the
underreporting of bleeding events related to
warfarin use.15
RIVAROXABAN
Rivaroxaban (Xarelto) is the rst oral direct
coagulation factor Xa inhibitor approved for
clinical use in the United States.
Mechanism of Action
It reversibly binds to the active site of coagula-
tion factor Xa without antithrombin mediation
affecting free and platelet-bound factor Xa
(Supplemental Figure, available online at
http://www.mayoclinicproceedings.org).16 Its
pharmacokinetic and pharmacodynamic pro-
le is detailed in Table 1.
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Approved Indications
Rivaroxaban is approved by the FDA, EMA,
and HPFB for use in the primary prevention
of VTE in adult patients who have undergone
elective THA or TKA, the prevention of stroke
and systemic embolism in patients with non-
valvular AF, the treatment of deep venous
thrombosis (DVT) and pulmonary embolism
(PE), and to reduce the risk of recurrent
DVT and PE after initial treatment.
Clinical Trials
The efcacy and safety of rivaroxaban have
been evaluated in phase 3 clinical trials across
different clinical situations, which are summa-
rized as follows and in Table 3.
Postoperative VTE Prophylaxis for THA. The
Regulation of Coagulation in Orthopedic Sur-
gery to Prevent Deep Venous Thrombosis and
Pulmonary Embolism (RECORD) 1 and 2 tri-
als17,18 compared rivaroxaban, 10 mg/d,
initiated 6 to 8 hours after wound closure for
approximately 35 days with enoxaparin, 40
mg/d, given 12 hours before surgery and
restarted 6 to 8 hours after wound closure for
either 31 to 39 days as in RECORD 1 or 10 to
14 days as in RECORD 2 for the prevention of
VTE after THA.
Efcacy. In RECORD 1, the primary efcacy
outcome of VTE and mortality occurred in
1.1% (1% VTE; 0.1% deaths) of patients in
the rivaroxaban arm and in 3.7% (3.5%
VTE; 0.2% deaths) of those in the enoxaparin
arm (P<.001). In RECORD 2, the rates were
2.0% (1.8% VTE; 0.2% deaths) in the riva-
roxaban arm compared with 9.3% (8.6%
VTE; 0.7% deaths) in the enoxaparin arm
(P<.0001).
Safety. There was no difference in the inci-
dence of major bleeding between rivaroxaban
and enoxaparin in both trials (RECORD 1:
0.3% vs 0.1%, P.18 and RECORD 2: <0.1%
in both treatment groups).
Postoperative VTE Prophylaxis for TKA. The
RECORD 3 and 4 trials19,20 compared riva-
roxaban, 10 mg/d, initiated 6 to 8 hours after
wound closure with enoxaparin, 40 mg once
daily, initiated 12 hours before surgery in RE-
CORD 3 or enoxaparin, 30 mg every 12 hours,
499
 MAYO CLINIC PROCEEDINGS

TABLE 3. Efcacy and Safety Results of Rivaroxaban in Major Phase 3 Clinical Trialsa,b
Primary efcacy % (N); Primary safety % (N);
Reference Rivaroxaban dose Comparator dose [P value] [P value]
ROCKET AF,23,24 2011 20 mg qd Warfarin Composite VTE per year: All clinical bleeding events per year:
Atrial brillation (15 mg qd if Warfarind2.4%/y, (N306/7090) Warfarind14.5%/y, (N1449/7125)
N14,264 CrCl w30-49 Rivaroxaband2.1%/y, (N269/7081); Rivaroxaband14.9%/y, (N1475/7111);
mL/min/1.73 m2) P<.001 for noninferiority P.44
RECORD 1,17 2008 10 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
THA 40 mg Enoxaparind3.7%, (N58/1558) Enoxaparind0.1%, (N2/2224)
N4541 Rivaroxaband1.1%, (N18/1595); Rivaroxaband0.3%, (N6/2209);
P<.001 for superiority P.18
RECORD 2,18 2008 10 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
THA 40 mg Enoxaparind9.3%, (N81/869) Enoxaparind<0.1%, (N1/1229)
N2509 Rivaroxaband2.0%, (N17/864); Rivaroxaband<0.1%, (N1/1228);
P<.0001 for superiority P value not signicant
RECORD 3,19 2008 10 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
TKA 40 mg Enoxaparind18.9%, (N166/878) Enoxaparind0.5%, (N6/1239)
N2531 Rivaroxaband9.6%, (N79/824); Rivaroxaband0.6%, (N7/1220);
P<.001 for superiority P.77
RECORD 4,20 2009 10 mg qd Enoxaparin, Composite VTE and mortality: Major bleeding:
TKA 30 mg bid Enoxaparind10.1%, (N97/959) Enoxaparind0.3%, (N4/1508)
N3148 Rivaroxaband6.9%, (N67/965); Rivaroxaband0.7%, (N10/1526);
P.0118 for superiority P.1096
EINSTEIN,21 2010 15 mg bid 3 wk Enoxaparin Recurrent, symptomatic VTE: Any clinical bleeding:
Acute DVT followed by bridging Warfarind3.0%, (N51/1718) Warfarind8.1%, (N138/1711)
N3449 20 mg qd for to warfarin Rivaroxaband2.1%, (N36/1731); Rivaroxaband8.1%, (N139/1718);
3, 6, or 12 mo for 3, 6, or P<.001 for noninferiority P.77
12 mo
EINSTEIN-EXT,21 2010 Continued treatment Placebo Recurrent, symptomatic VTE: Major bleeding:
Continued 20 mg qd for an Placebod7.1%, (N42/594) Placebod0%, (N0/590)
treatment additional 6-12 mo Rivaroxaband1.3%, (N8/602); Rivaroxaband0.7%, (N4/598);
N1196 after completing P<.001 for superiority P.11
therapy in acute
DVT study
EINSTEIN-PE,22 2012 15 mg bid 3 wk Enoxaparin Recurrent, symptomatic VTE: Any clinical bleeding:
Symptomatic PE followed by bridging Warfarind1.8%, (N44/2413) Warfarind11.4%, (N274/2405)
N4832 20 mg qd for to warfarin Rivaroxaband2.1%, (N50/2419); Rivaroxaband10.3%, (N249/2412);
3, 6, or 12 mo for 3, 6, or P.003 for noninferiority P.23
12 mo
MAGELLAN25 10 mg qd Enoxaparin, Composite VTE and related mortality: Any clinical bleeding:
VTE 40 mg Day 10 Day 10
prophylaxis in Enoxaparind2.7%, (N82/2993) Enoxaparind1.2%, (N49/4001)
medically ill patients Rivaroxaband2.7%, (N78/2939); Rivaroxaband2.8%, (N111/3997);
N8101 P.0025 for noninferiority P<.001
Day 35 Day 35
Enoxaparind5.7%, (N175/3057) Enoxaparind1.7%, (N67/4001)
Rivaroxaband4.4%, (N131/2967); Rivaroxaband4.1%, (N164/3997);
P.021 for superiority P<.001
a
bid twice a day; CrCl creatinine clearance; DVT deep venous thrombosis; PE pulmonary embolism; qd every day; THA total hip arthroplasty; TKA total
knee arthroplasty; VTE venous thromboembolic event.
b
SI conversion factor: To convert CrCl values to mL/s/m2, multiply by 0.0167.

initiated 12 to 24 hours after surgery in RE-
CORD 4 for the prevention of VTE after TKA.
Efcacy. In the RECORD 3 trial, the primary
efcacy outcome of VTE and mortality within
17 days after surgery occurred in 9.6% (all
VTE events; no deaths) of patients in the
n n
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rivaroxaban arm and in 18.9% (18.7% VTE;
0.2% deaths) of those in the enoxaparin arm
(P<.001). In RECORD 4, the primary efcacy
outcome occurred in 6.9% (6.7% VTE; 0.2%
deaths) of patients in the rivaroxaban arm
and in 10.1% (9.8% VTE; 0.3% deaths) of pa-
tients in the enoxaparin arm (P.0118).
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NEW ORAL ANTICOAGULANTS
Safety. In either study, there was no difference
in the incidence of major bleeding between the
rivaroxaban and enoxaparin arms (RECORD
3: 0.6% vs 0.5%, P.77 and RECORD 4:
0.7% vs 0.3%, P.11).
Treatment of Acute VTE. The EINSTEIN
study21 compared oral rivaroxaban (15 mg
twice daily for 3 weeks followed by 20 mg once
daily) with enoxaparin followed by a VKA for 3, 6,
or 12 months in patients with acute, symptomatic
DVT (initial treatment study). A parallel, double-
blind, randomized study compared rivaroxaban
(20 mg/d) with placebo for an additional 6 or 12
months in patients who had completed 6 to 12
months of treatment for VTE (continued-treat-
ment study). The EINSTEIN-PE was a similar
study that evaluated the same dose of rivarox-
aban vs enoxaparin/VKA in patients with an
acute, symptomatic PE with or without DVT.22
Efcacy. In EINSTEIN, rivaroxaban therapy
was noninferior to enoxaparin/VKA therapy
with respect to recurrent VTE (2.1% vs 3.0%;
P<.001). In the continued-treatment study,
rivaroxaban therapy was superior to placebo use
with respect to recurrent VTE (1.3% vs 7.1%;
P<.001). The rates of symptomatic recurrent
VTE in the EINSTEIN-PE study were also
similar between the rivaroxaban and enox-
aparin/VKA groups (2.1% vs 1.8%; P.003 for
noninferiority).
Safety. In both studies, EINSTEIN and
EINSTEIN-PE, the principal safety outcome of
major or clinically relevant nonmajor bleeding
occurred at similar rates in both treatment
arms.21,22 In the continued-treatment study, 4
patients taking rivaroxaban (0.7%) and no pa-
tients taking placebo had nonfatal major
bleeding, which was not signicant.
Prevention of Stroke and Systemic Embo-
lism in Nonvalvular AF. The Rivaroxaban
Once Daily Oral Direct Factor Xa Inhibition
Compared with Vitamin K Antagonism for Pre-
vention of Stroke and Embolism Trial in Atrial
Fibrillation (ROCKET AF) study23,24 evaluated
rivaroxaban for prevention of stroke or systemic
embolization in patients with nonvalvular AF
(intermediate to high risk of stroke). Patients
were randomly assigned to receive either rivar-
oxaban 20 mg/day (15 mg/d in patients with
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CrCl of 30-49 mL/min per 1.73 m2) or warfarin
(target INR, 2.0-3.0).
Efcacy. Rivaroxaban was noninferior to
warfarin (2.1% vs 2.4% per year; P<.001 for
noninferiority) in the intention-to-treat anal-
ysis for the primary efcacy end point of stroke
and systemic embolism.
Safety. There was no difference between pa-
tients taking rivaroxaban and those taking
warfarin in terms of all bleeding events (14.9%
vs 14.5% per 100 patient-years; P.44) and
major bleeding events (3.6% vs 3.4% per 100
patient-years; P.58). In addition, the rates of
intracranial hemorrhage and fatal bleeding were
less with rivaroxaban therapy (0.4% vs 0.8%,
P.003 and 0.5% vs 0.7%, P.02, respectively).
Thromboprophylaxis in Medically Ill Patients.
The MAGELLAN study25 evaluated the efcacy
of rivaroxaban vs enoxaparin for VTE pro-
phylaxis in medically ill patients. Patients were
randomized to receive either rivaroxaban (10
mg/d) or enoxaparin (40 mg/d) to be given for
10 days (to assess noninferiority) or for 35 days
(to assess for superiority).
Efcacy. At day 10, rivaroxaban therapy was
noninferior to enoxaparin therapy in reducing
the composite risk of VTE and VTE-related
deaths (2.7% in each group; P.0025 for non-
inferiority). At day 35, rivaroxaban therapy was
superior to enoxaparin therapy in reducing the
composite risk of VTE and VTE-related deaths
(4.4% vs 5.7%; P.0211 for superiority).
Safety. The incidence of clinically relevant
bleeding was low but still higher with rivarox-
aban therapy (day 10: 2.8% vs 1.2%, P<.001
and day 35: 4.1% vs 1.7%, P<.001).
US Dosing Recommendations
Postoperative Thromboprophylaxis. For TKA,
use 10 mg/d for 12 to 14 days26 and for
THA, use 10 mg/d for 35 days.26 The use of
rivaroxaban is cautioned in patients with CrCl
of 30 to 49 mL/min per 1.73 m2. It is not
recommended for those with CrCl less than
30 mL/min per 1.73 m2.26
DVT/PE. For DVT/PE, use 15 mg twice daily
for 3 weeks followed by 20 mg once daily
501

for at least 3 to 6 months; this can be followed
by 20 mg/d for an additional 6 to 12 months
after initial treatment for further reduction in
the risk of recurrent DVT/PE.26 It is not rec-
ommended for those with CrCl less than 30
mL/min per 1.73 m2 and is contraindicated if
less than 15 mL/min per 1.73 m2.
Stroke Prevention in Nonvalvular AF. In the
setting of preserved renal function (CrCl 50
mL/min per 1.73 m2), the recommended dose is
20 mg once daily.26 The use of rivaroxaban is 15
mg/d in patients with CrCl of 30 to 49 mL/min
per 1.73 m2. It is not recommended for those
with CrCl less than 30 mL/min per 1.73 m2.
Hepatic Impairment. With mild impairment,
no dosage adjustment is required as data indicate
that the pharmacokinetic response is unchanged.
However, in moderate to severe hepatic dysfunc-
tion (Child-Pugh class B or C) or impaired coag-
ulation, its use is not recommended.26
Pregnancy and Breastfeeding. At present, its
use in pregnant and nursing mothers is not
recommended.26
Adverse Events
The most common adverse event noted with
the use of either therapeutic or prophylactic
doses of rivaroxaban was bleeding. The inci-
dence rates for major and all clinical bleeding
were 0.3% and 5.8%, respectively, in the com-
bined analysis from the RECORD trials and
1% and 28%, respectively, in a pooled analysis
from the EINSTEIN DVT and PE studies.26
Other nonhematologic events observed in the
phase 3 trials included musculoskeletal pain,
wound secretions, pruritus, blisters, upper
abdominal pain, and syncope.26
APIXABAN
Apixaban (Eliquis) is an oral direct coagulation
factor Xa inhibitor approved for clinical use in
the United States.
Mechanism of Action
Apixaban selectively and reversibly inhibits free
and clot-bound factor Xa as well as prothrom-
binase activity (Supplemental Figure, available
online at http://www.mayoclinicproceedings.
org).27 Its pharmacokinetic and pharmacody-
namic prole is detailed in Table 1.
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MAYO CLINIC PROCEEDINGS
Approved Indications
Apixaban is approved for use in the preven-
tion of stroke and systemic embolism in adult
patients with nonvalvular AF (FDA, EMA, and
HPFB) and in the primary prevention of VTE
in adult patients who have undergone elective
THA or TKA (EMA and HPFB).
Clinical Trials
The efcacy and safety of apixaban have been
evaluated in phase 3 clinical trials, which are
summarized as follows and in Table 4.
Postoperative VTE Prophylaxis for TKA. The
Apixaban Dose Orally vs Anticoagulation with
Enoxaparin (ADVANCE)-1 and ADVANCE-
228,29 trials compared apixaban, 2.5 mg twice
daily, initiated 12 to 24 hours after surgery
with enoxaparin, 30 mg twice daily, initiated at
the same time as apixaban in ADVANCE-1 or
enoxaparin, 40 mg/d, initiated 12 hours before
surgery in ADVANCE-2. All the treatments in
either arm of the 2 trials were continued for 10
to 14 days.
Efcacy. In ADVANCE-1, the primary efcacy
outcome of VTE and all-cause mortality was
9.0% (8.8% VTE; 0.2% deaths) with apixaban
therapy compared with 8.8% (8.6% VTE; 0.2%
deaths) with enoxaparin therapy (P.06 for
noninferiority). In contrast, the ADVANCE-2
study found the incidence of VTE and all-cause
mortality to be lower with apixaban therapy at
15% (14.9% VTE; 0.1% deaths) than with
enoxaparin therapy at 24% (all VTE events; no
deaths) (P<.0001 for noninferiority and superi-
ority). This difference in efcacy between the
2 trials may be related to the differences in
enoxaparin dosing in the 2 studies.
Safety. The combined incidence of major
bleeding and clinically relevant nonmajor
bleeding was less with apixaban use compared
with enoxaparin use (2.9% vs 4.3%; P.03) in
ADVANCE-1 but equivalent in ADVANCE-2
(3.5% vs 4.8%; P.09).
Postoperative VTE Prophylaxis for THA. The
ADVANCE-3 trial30 compared apixaban, 2.5
mg twice daily, initiated 12 to 24 hours after
surgery with enoxaparin, 40 mg/d, initiated 12
hours before surgery; both drugs were continued
for 35 days after surgery.
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NEW ORAL ANTICOAGULANTS

TABLE 4. Efcacy and Safety Results of Apixaban in Major Phase 3 Clinical Trials
Reference Apixaban dose Comparator dose Primary efcacy % (N); [P value] Primary safety % (N); [P value]
31
AVERROES, 2011 5 mg bid Aspirin (81-324 mg) Composite VTE per year: Major bleeding per year:
Atrial brillation Aspirind3.7%/y, (N113/2791) Aspirind1.2%/y, (N39/2791)
N5599 Apixaband1.6%/y, (N51/2808); Apixaband1.4%/y, (N44/2808);
P<.001 for superiority P.57
ARISTOTLE,32 2011 5 mg bid Warfarin Composite VTE per year: Major bleeding per year:
Postop TKA Warfarind1.60%/y, (N265/9081) Warfarind3.09%/y, (N462/9052)
N18,201 Apixaband1.27%/y, (N212/9120); Apixaband2.13%/y, (N327/9088);
P.01 for superiority P<.001
ADVANCE-1,28 2009 2.5 mg bid Enoxaparin, Composite VTE and mortality: Clinically relevant bleeding:
Postop TKA 30 mg bid Enoxaparind8.8%, (N100/1130) Enoxaparind4.3%, (N69/1588)
N3195 Apixaband9.0%, (N104/1157); Apixaband2.9%, (N46/1596);
P.06 for noninferiority P.03
ADVANCE-2,29 2010 2.5 mg bid Enoxaparin, 40 mg Composite VTE and mortality: Clinically relevant bleeding:
Postop TKA Enoxaparind24.4%, (N=243/997) Enoxaparind4.8%, (N=72/1508)
N3057 Apixaband15.1%, (N=147/976); Apixaband3.5%, (N=53/1501);
(1973 evaluable for P<.0001 for superiority P.09
primary efcacy)
ADVANCE-3,30 2010 2.5 mg bid Enoxaparin, 40 mg Composite VTE and mortality: Clinically relevant bleeding:
Postop THA Enoxaparind3.9%, (N74/1917) Enoxaparind5.0%, (N134/2659)
N5407 Apixaband1.4%, (N27/1949); Apixaband4.8%, (N129/2673);
(3866 evaluable for P<.001 for superiority P.72
primary efcacy)
AMPLIFY-EXT,33 2013 2.5 mg bid Placebo Symptomatic VTE/all-cause mortality: Major bleeding:
Extended VTE 5.0 mg bid Placebod11.6%, (N96/829) Placebod0.5%, (N4/829)
N2482 Apixaban, 2.5 mgd3.8%, (N32/840); Apixaban, 2.5 mgd0.2%, (N2/840);
P<.001 for superiority P value not signicant
Apixaban, 5.0 mgd4.2%, (N34/813); Apixaban, 5.0 mgd0.1%, (N1/813);
P<.001 for superiority P value not signicant
bid twice a day; HR hazard ratio; Postop postoperative; RR risk ratio; THA total hip arthroplasty; TKA total knee arthroplasty; VTE venous thromboembolic
event.

Efcacy. The primary efcacy outcome of
VTE and all-cause mortality in the intended
treatment period was 1.4% in the apixaban
group and 3.9% in the enoxaparin group
(P<.001 for noninferiority and superiority).
Safety. The incidence of major and clinically
relevant nonmajor bleeding was 4.8% in patients
treated with apixaban compared with 5.0% in
patients treated with enoxaparin (P.72).
Prevention of Stroke and Systemic Embolism
in Nonvalvular AF. Apixaban was evaluated for
stroke prevention in 2 large randomized con-
trolled trials enrolling patients with nonvalvular
AF. The Apixaban Versus Acetylsalicylic Acid to
Prevent Stroke in Atrial Fibrillation Patients
Who Have Failed or Are Unsuitable for Vitamin
K Antagonist Treatment (AVERROES) trial31
compared apixaban at a dose of 5 mg twice
daily with aspirin (81-324 mg) daily in patients
intolerant to a VKA, whereas the Apixaban for
Reduction in Stroke and Other Thromboem-
bolic Events in Atrial Fibrillation (ARISTOTLE)
trial32 compared a similar dose of apixaban with
warfarin (target INR, 2.0-3.0) in patients with
nonvalvular AF and at least one additional risk
factor for stroke.
Efcacy. In the AVERROES trial, the primary
efcacy outcome of any type of stroke or sys-
temic embolism was signicantly less with
apixaban use than with aspirin use (1.6% vs
3.7% per year; P<.001). This trial was termi-
nated earlier than planned owing to the supe-
riority of apixaban observed in the interim
analyses. Similarly, compared with warfarin
therapy in the ARISTOTLE trial, apixaban
therapy was superior in preventing stroke or
systemic embolism (1.27% vs 1.60% per
year; P<.001 for noninferiority and P.01
for superiority).

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Safety. The rate of major bleeding per year
with apixaban use was 1.4% compared with
1.2% with aspirin use in the AVERROES trial
(P.57) and 2.1% compared with 3.1% with
warfarin use in the ARISTOTLE trial (P<.001).
Extended Treatment of Acute VTE. The
Apixaban after the Initial Management of
Pulmonary Embolism and Deep Vein Throm-
bosis with First-Line TherapyExtended Treat-
ment (AMPLIFY-EXT) trial33 evaluated the
efcacy and safety of 2 doses of apixaban (2.5
and 5.0 mg twice daily) compared with
placebo use in patients with a recent VTE
who had completed 6 to 12 months of anti-
coagulation therapy and for whom there was
clinical equipoise regarding the continuation
or cessation of anticoagulation therapy. The
duration of this extended treatment was 12
months.
Efcacy. The incidence of recurrent VTE and
VTE-related mortality was 1.7% in both the
apixaban arms compared with 8.8% in the pla-
cebo arm (P<.001 for both doses of apixaban).
Safety. The rates of major bleeding were not
signicantly different across the 3 treatment
groups (placebo: 0.5%; 2.5 mg of apixaban:
0.2%; and 5 mg of apixaban: 0.1%).
US Dosing Recommendations
Stroke Prevention in Nonvalvular AF. The
recommended dose is 5 mg twice daily. A lower
dose of 2.5 mg twice daily should be used if a pa-
tient has any 2 of the following 3 factors; age
80 years or older, body weight of 60 kg or less,
or a serum creatinine level of at least 1.5 mg/dL
(to convert to mmol/L, multiply by 88.4).34 Pa-
tients with CrCl less than 25 mL/min per 1.73 m2
or a serum creatinine level greater than 2.5 mg/dL
were excluded from the AF clinical trials and the
extended treatment of acute VTE study, and
hence, until further data are available, this drug
should not be used in these patients.34
Hepatic Impairment. With mild hepatic
impairment, no dosage adjustment is needed.
However, in moderate hepatic dysfunction
(Child-Pugh class B), there is limited experi-
ence, and the intrinsic coagulation status should
be assessed before using the drug.34 Apixaban
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MAYO CLINIC PROCEEDINGS
should be avoided in the setting of severe he-
patic impairment (Child-Pugh class C).34
Pregnancy and Breastfeeding. At present,
the use of apixaban in pregnant and nursing
mothers is not recommended.34
Adverse Events
The most common adverse event noted with the
use of either therapeutic or prophylactic doses of
apixaban was bleeding.34 There was a low inci-
dence of GI symptoms, such as nausea (<3%)
and hepatic transaminitis (<1%).34 Other rare,
nonhematologic events (<1%) included syn-
cope, drug hypersensitivity (rashes), and ana-
phylactic reactions.34
DRUG INTERACTIONS WITH NOAs
The NOAs have a low potential for drug interac-
tions. Dabigatran etexilate, the prodrug, is a sub-
strate of the P-glycoprotein (P-gp) efux
transporter. Hence, its plasma concentration in-
creases with strong P-gp inhibitors (amiodarone,
verapamil, clarithromycin, and ketoconazole)
and reduces with potent P-gp inducers (ri-
fampicin, carbamazepine, or phenytoin)35,36;
although no signicant inuence on its efcacy
or safety has been reported, dosage adjustment
may be needed.37 No dabigatran dose adjustment
is recommended when coadministered with
amiodarone, quinidine, or clarithromycin; how-
ever, their concomitant use should be avoided
in patients with severe renal impairment (CrCl,
15-30 mL/min per 1.73 m2). Furthermore,
administration of dabigatran 2 hours before
verapamil ingestion is recommended, and when
coadministered with ketoconazole, the dabiga-
tran dose must be reduced to 75 mg twice daily
in patients with moderate renal impairment
(CrCl, 30-50 mL/min per 1.73 m2) and avoided
in those with severe renal impairment (CrCl,
15-30 mL/min per 1.73 m2).38 Coadministration
with inducers of P-gp should be avoided. Proton
pump inhibitors increase the gastric pH and
reduce dabigatran absorption by 12.5%, a phe-
nomenon that has not been shown to affect
drug efcacy.39
Rivaroxaban is metabolized by the cyto-
chrome (CYP) P450 (CYP3A4, CYP3A5, and
CYP2J2) enzymes and is also a substrate of
P-gp transporters.36 Inhibitors or inducers of
these CYP450 enzymes or P-gp transporters
can alter the clearance of rivaroxaban, making
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NEW ORAL ANTICOAGULANTS
its levels either too high or too low, respec-
tively.36,40 Drugs that inhibit or induce either
the CYP450 enzymes or P-gp transporters, as
opposed to both, do not signicantly alter
rivaroxaban to plasma levels that require dose
changes.36,40
Apixaban is a substrate of CYP3A4 and
P-gp such that inhibitors or inducers of CYP3A4
and P-gp will increase or decrease exposure
to apixaban, respectively.34,36 Coadministra-
tion with strong dual inhibitors of CYP3A4
and P-gp (eg, ketoconazole, itraconazole, rito-
navir, and clarithromycin) should preferably
be avoided, but, if necessary, the apixaban
dose should be decreased to 2.5 mg twice
daily.34,36 Similarly, concomitant use of strong
dual inducers of CYP3A4 and P-gp (eg, rifampin,
carbamazepine, phenytoin, and St Johns wort)
should be avoided as it may decrease the
bioavailability of apixaban.34,36
LABORATORY TESTING AND MONITORING
FOR THE NOAs
Given their rapid onset of action, stable phar-
macokinetic properties, and lack of signicant
drug interactions, the NOAs do not require
coagulation monitoring. However, overdoses,
emergency perioperative settings, and bleeding
events may warrant an assessment of the degree
of anticoagulation. Table 5 summarizes the ef-
fects of the NOAs and warfarin on various coag-
ulation parameters.
Prothrombin time (PT) is relatively insensitive
at therapeutic levels of dabigatran compared with
rivaroxaban and apixaban, whereas activated par-
tial thromboplastin time (aPTT) is more sensitive
to dabigatran.41,42 However, different aPTT and
PT reagents used in different laboratories have
different responsiveness to these NOAs, making
it difcult to standardize results. The thrombin
clotting time assay shows linear effects with dabi-
gatran plasma concentrations but no activity to
rivaroxaban or apixaban.43 Both these NOAs
cause a dose-dependent spurious decrease in
PT- and aPTT-based specic factor assays.44
These agents can also cause false-positives in
lupus anticoagulant screening or conrmatory
assays, incomplete corrections in mixing studies
(PT and aPTT), and falsely elevated activated
protein C ratio assays, thereby misclassifying
patients with a factor V Leiden mutation as
normal.45,46
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Dabigatran yields a dose-dependent pro-
longation of the ecarin clotting time, which
is a thrombin clotting timeelike assay, making
it a feasible monitoring test; however, it is not
widely used.47 Rivaroxaban and apixaban can
be monitored using modied chromogenic
anti-Xa assays that use specic rivaroxaban
and apixaban standards, respectively.40,48,49
SWITCHING THERAPIES
Safely switching patients between anticoagu-
lants is a frequent task faced by clinicians man-
aging their patients anticoagulation needs.
Suggested approaches are summarized in
Table 6.39,40,50 The underlying factor that de-
termines this approach is mainly based on ac-
curate assessment of renal function.
PERIOPERATIVE MANAGEMENT
Perioperative management of the NOAs is
based on the urgency of the procedure, level
of bleeding risk, and current renal func-
tion.39,40,50 The decision to stop treatment in
nonurgent or elective surgery should depend
on the risk of bleeding vs thrombosis.
Elective Surgery
Standard bleeding risk procedure. Standard
bleeding risk procedures include colonoscopy,
uncomplicated laparoscopic procedures, and
any aspirations not involving the spinal canal.
In patients with normal CrCl (50 mL/min
per 1.73 m2), dabigatran use should be
stopped at least 48 hours before the proce-
dure. Rivaroxaban and apixaban use should
be stopped at least 24 hours before the proce-
dure. In patients with impaired CrCl (<50
mL/min per 1.73 m2), dabigatran therapy
should be stopped at least 72 hours before
the procedure if CrCl is 30 to less than 50
mL/min per 1.73 m2 and at least 4 days earlier
if CrCl is less than 30 mL/min per 1.73 m2.
Rivaroxaban and apixaban administration
should be stopped at least 48 hours before
the procedure.
High bleeding risk procedure. High bleeding
risk procedures include major cardiac surgery,
insertion of pacemakers or debrillators, neu-
rosurgery, major cancer/urologic/vascular sur-
gery, spinal puncture, etc. In patients with
normal CrCl (50 mL/min per 1.73 m2),
505

dabigatran, rivaroxaban, and apixaban admin-
istration should be stopped at least 48 hours
before the procedure. In patients with im-
paired CrCl (<50 mL/min per 1.73 m2), dabi-
gatran use should be stopped at least 4 days
before the procedure if CrCl is 30 to less
than 50 mL/min per 1.73 m2 and at least
6 days earlier if CrCl is less than 30 mL/min
per 1.73 m2. Rivaroxaban and apixaban ad-
ministration should be stopped at least 4 days
before the procedure.
Emergency Surgery
Ideally, surgical intervention should be delayed
for the estimated time that the drugs are
cleared. If available, assays may provide infor-
mation on the presence or absence of residual
drug. However, if urgent surgery is needed
within a few hours after the last dose, clinicians
should anticipate bleeding complications.
Reinitiation of NOAs After the Procedure
This process depends on the nature of the sur-
gery, the urgency for restarting thrombopro-
phylaxis therapy, and the hemostatic state of
the patient.39,40,50 Given the rapid clearance
of the NOAs from the circulation and the
rapid onset of action when reintroduced, no
bridging therapy with LMWH or unfractio-
nated heparin is necessary. For procedures in
which good hemostasis is achieved, anticoagu-
lation may be resumed the same evening, at
least 4 to 6 hours after surgery with a reduced
dose (dabigatran, 75 mg; rivaroxaban, 10 mg;
or apixaban, 2.5 mg) for the rst dose and,
thereafter, the usual maintenance dose.50
For major abdominal surgery or urologic sur-
gery with incomplete hemostasis, resumption
should be delayed until there is adequate
hemostasis.50
COMPLEX CLINICAL SCENARIOS
Acute Stroke Requiring Thrombolytics
The safety of administration of thrombolytics
in patients receiving concurrent NOAs is not
established and poses a very high risk of
bleeding. Anecdotal reports have documented
the successful use of thrombolytics in patients
taking dabigatran who were at least 7 hours
past their last dose.51,52 Similar reports with
rivaroxaban and apixaban are lacking.
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MAYO CLINIC PROCEEDINGS
Cardioversion
For patients with AF of more than 48 hours
duration, therapeutic anticoagulation for at
least 3 weeks before and 4 weeks after cardio-
version is recommended.53 In the RE-LY trial,
the stroke and systemic embolism rates within
30 days of this procedure were 0.8% and
0.3% for the dabigatran, 150- and 110-mg
doses, respectively, vs 0.6% with the warfarin
arm; major bleeding rates were similar between
the groups.54 Hence, patients may continue
taking dabigatran for cardioversion; similar ef-
cacy and safety data with rivaroxaban and apix-
aban are lacking.
Mechanical Heart Valves
Currently, the use of NOAs in patients with
mechanical heart valves cannot be recommen-
ded owing to the lack of clinical evidence. A
phase 2 study (the RE-ALIGN trial) investi-
gated the use of dabigatran in patients with
mechanical heart valves55; however, it was
terminated early owing to excess thrombotic
complications in the dabigatran group. This
has led the FDA and EMA to consider me-
chanical heart valves as a contraindication for
dabigatran therapy.56
Heparin-Induced Thrombocytopenia
Krauel et al57 demonstrated that neither dabiga-
tran nor rivaroxaban had any effect on the interac-
tion of PF4 or anti-PF4/heparin antibodies with
platelets, thus making them potential options
for anticoagulation in patients with heparin-
induced thrombocytopenia (HIT) and possibly
even for the treatment of HIT-induced throm-
bosis.58 However, there are neither randomized
controlled trials nor anecdotal case reports
describing the off-label use of NOAs in the treat-
ment of HIT-induced thrombosis; hence, its use
cannot be recommended until more evidence is
available.
Cancer-Associated VTE
The LMWH is superior to VKAs in treating
cancer-associated VTE,59 but studies evaluating
NOAs for acute VTE were compared only with
VKAs. Nevertheless, the RE-COVER study6
found that dabigatran use was noninferior to
VKA use (3.1% vs 5.3%) in preventing recur-
rent symptomatic VTE/death in patients with
cancer (9.5% of the study population). In the
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NEW ORAL ANTICOAGULANTS

TABLE 5. Effects of the New Oral Anticoagulants on Routine and Special Coagulation Assaysa
Assay VKA Dabigatran Rivaroxaban/apixaban
aPTT Mild increase Variable, normal or prolonged Variable, normal or prolonged
PT/INR Moderate increase Variable, normal or prolonged Variable, normal or prolonged
TCT Unaffected Marked increase Unaffected
aPTT mixing study Complete correction Incomplete correction Incomplete correction
PT mixing study Incomplete correction Incomplete correction Incomplete correction
LA (screening and conrmatory) Normal or false-positive False-positive False-positive
Activated protein C resistance ratio Possible interference Falsely elevated Falsely elevated
Falsely elevated or decreased
aPTT-dependent clotting Decreased factor IX Falsely decreased factors Falsely decreased factors
factor assays VIII, IX, and IX VIII, IX, and XIb
PT-dependent clotting factor Decreased factors II, VII, Falsely decreased factors Falsely decreased factors
assays and X II, V, VII, and Xb II, V, VII, and X
Antithrombin activity
Factor Xa based Unaffected Unaffected Falsely elevated
Factor II based Unaffected Falsely elevated Unaffected
Protein C activity
Clot based Decreased Falsely elevated Falsely elevated
Chromogenic based Decreased Unaffected Unaffected
Protein S activity, clot based Decreased Falsely elevated Falsely elevated
a
aPTT activated partial thromboplastin time; INR international normalized ratio; LA lupus anticoagulant; PT prothrombin time; TCT thrombin clotting time;
VKA vitamin K antagonist.
b
Only at supratherapeutic levels.
Adapted from Hematology Am Soc Hematol Educ Program.44

EINSTEIN DVT and PE studies,21,22 patients
with cancer (12% and <5%, respectively, of
the study population) were included in the
analysis. Neither study showed a difference be-
tween rivaroxaban use and VKA use in prevent-
ing recurrent VTE (acute DVT: 3.4% vs 5.6%
and PE study: 1.8% vs 2.8%). Furthermore,
the incidence of clinical bleeding between the
treatment groups was comparable.21,22 Given
the small number of patients with cancer in
these studies, future trials testing the efcacy
and safety of NOAs in patients with cancer
are needed before they can be recommended.60
MANAGEMENT OF BLEEDING
COMPLICATIONS/OVERDOSE
Lack of specic agents that reverse the anticoagu-
lant effect complicates the management of NOA-
associated bleeding events or the periprocedural
reversal of anticoagulation. Management of mi-
nor bleeding, eg, epistaxis, consists of addressing
the potential anatomical defects, eg, cauteriza-
tion or nasal packing. The decision to hold the
next dose of drug will hinge on the comorbidities
and assessment of risks of drug discontinuation.
Given the relatively short half-lives of the NOAs
in patients with normal renal function, most of
the anticoagulant effect should dissipate within
48 hours.61
Administration of oral activated charcoal
retards absorption of recently ingested drug,
eg, within a couple hours of presentation.61,62
Given that only 35% of dabigatran is bound to
plasma proteins, hemodialysis typically re-
moves 60% of dabigatran and should be
considered, especially in patients with im-
paired renal function.63 However, given the
extensive volume of distribution (50-70 L) of
dabigatran, a rebound increase in dabigatran
plasma levels may occur after hemodialysis.
Although there are no data, dialysis is unlikely
to be effective for rivaroxaban and apixaban as
they are more than 85% to 90% protein
bound.
Recombinant Factor VIIa
This agent has been used in clinical practice to
help reverse life-threatening bleeds caused by
NOAs. It decreases the bleeding time in animal
models but does not reverse the anticoagulation
effect on most other laboratory coagulation
tests.64,65 Other than anecdotal case reports,

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 MAYO CLINIC PROCEEDINGS

TABLE 6. Suggested Approaches to Switching to and From the NOAs for Purposes of Therapeutic Anticoagulationa,b
NOA of choice Approach and timing of conversion
From VKAs to NOAs
Dabigatran Discontinue VKA and start dabigatran when the INR is <2
Rivaroxaban or apixaban Discontinue VKA and initiate rivaroxaban or apixaban when the INR falls to <3 or <2, respectively
From NOAs to VKAs
Dabigatran Transition to VKAs depends on CrCl:
d CrCl 50 mL/min/1.73 m , start VKA 3 d before stopping dabigatran
2

d CrCl 30 to <50 mL/min/1.73 m , start VKA 2 d before stopping dabigatran

2

2
d CrCl 15-30 mL/min/1.73 m , start VKA 1 d before stopping dabigatran

(VKA effect on INR truly reected only after dabigatran stopped for 2 d)
Rivaroxaban Transition to VKAs depends on CrCl:
d CrCl 50 mL/min/1.73 m , start VKA 4 d before stopping rivaroxaban
2

d CrCl 30 to <50 mL/min/1.73 m , start VKA 3 d before stopping rivaroxaban

2

2
d CrCl 15-30 mL/min/1.73 m , start VKA 2 d before stopping rivaroxaban

(VKA effect on INR truly reected only after rivaroxaban stopped for 1 d)
Apixaban d Due to insufcient data; based on the package insert, apixaban should be discontinued and warfarin coinitiated along

with a bridging parenteral anticoagulant until a therapeutic INR is achieved

From NOAs to parenteral anticoagulants
Dabigatran Parenteral anticoagulation should be initiated a minimum of 12 h (CrCl >30 mL/min/1.73 m2) or 24 h (CrCl <30 mL/min/
1.73 m2) after the last dose of dabigatran
Rivaroxaban or apixaban Discontinue rivaroxaban or apixaban and initiate parenteral anticoagulation at the time the next dose of rivaroxaban or
apixaban is due
From parenteral anticoagulants to NOAs
Dabigatran d Initiate dabigatran 2 h before the next regularly scheduled dose of the discontinued subcutaneous anticoagulant

d Continuous UFH: initiate dabigatran at the time of discontinuation of the continuous infusion

Rivaroxaban or apixaban d Initiate rivaroxaban or apixaban 2 h before the next regularly scheduled dose of the discontinued subcutaneous
anticoagulant
d Continuous UFH: initiate rivaroxaban or apixaban at the time of discontinuation of the continuous infusion

CrCl creatinine clearance; INR international normalized ratio; NOA new oral anticoagulant; UFH unfractionated heparin; VKA vitamin K antagonist.
a

b
SI conversion factor: To convert CrCl values to mL/s/m2, multiply by 0.0167.

there are no randomized controlled studies con-
rming its benet in these situations. One must
keep in mind the potential serious adverse
effects of recombinant factor VIIa, including
disseminated intravascular coagulation and sys-
temic thrombosis.
Prothrombin Complex Concentrates
In the United States, 3-factor prothrombin
complex concentrates (PCCs) (Bebulin [Baxter],
and Prolnine SD [Grifols]) are available with
relatively similar concentrations of nonacti-
vated factors II, IX, and X but low concentra-
tions of nonactivated factor VII. In addition,
there is an activated 4-factor PCC (FEIBA
NF, Baxter) that contains relatively similar
concentrations of nonactivated factors II, IX,
and X and activated factor VII. The use of ei-
ther PCC may increase the risk of thrombosis,
n n
508 Mayo Clin Proc.
with the 3-factor PCC being less likely to
do so.66
A randomized controlled study using a
nonactivated 4-factor PCC showed normaliza-
tion of the PT alone in patients taking rivarox-
aban but not dabigatran.67 No studies have
evaluated PCCs in patients receiving the
NOAs with clinical bleeding; however, its
use seems reasonable in the setting of serious
bleeding.
CHOOSING AN ORAL ANTICOAGULANT
When identifying a long-term oral anticoagu-
lant for a patient, it is important to adopt a
personalized approach.68 The NOAs are not
all superior in terms of efcacy compared
with warfarin; hence, patients who are stable
with warfarin therapy with acceptable/minimal
complications will not benet from switching
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NEW ORAL ANTICOAGULANTS
to an NOA. Warfarin remains the standard of
care for the management of patients with
valvular AF or mechanical heart valves until
further safety and efcacy data regarding the
use of NOAs in these situations is available.
Patients with hepatic dysfunction or associated
coagulopathies or impaired renal function
(CrCl <30 mL/min per 1.73 m2) are not
good candidates for NOAs owing to their he-
patic metabolism and renal excretion.68 If
compliance is an issue, rivaroxaban, with its
once-daily administration, might be a better
choice than dabigatran or apixaban. Dabigatran
is best avoided in patients with ulcer/nonulcer
dyspepsia given its tartaric acid core and
described associations with GI adverse effects.
In patients with a recent history of GI bleeding,
apixaban may be a better choice as it has a
lower incidence of GI bleeding than dabigatran
and rivaroxaban. Given the recent association
of dabigatran with a trend toward an increase
in the incidence of myocardial infarction, rivar-
oxaban or apixaban should possibly be consid-
ered when selecting an NOA in this subset of
patients. On the other hand, in patients with
a history of ischemic strokes while taking
warfarin, dabigatran and apixaban may be suit-
able alternatives as they are the only NOAs
with a lower rate of ischemic stroke than
warfarin.
CONCLUSION
The advent of NOAs represents a major develop-
ment in the eld of medicine. After more than
half a century in which warfarin was the only
oral anticoagulant available, the discovery of these
agents has provided us with more options. Several
more oral anticoagulants are in the development
pipeline (Supplemental Table; available online
at http://www.mayoclinicproceedings.org), and
their use will only increase in the years to
come. As we accumulate more experience with
these agents, we will need to have a better under-
standing of the appropriate selection of therapy
in given clinical situations and the management
of their adverse effects, particularly bleeding
complications.
SUPPLEMENTAL ONLINE MATERIAL
Supplemental material can be found online at
http://www.mayoclinicproceedings.org.
Mayo Clin Proc. n May 2013;88(5):495-511 n http://dx.doi.org/10.1016/j.mayocp.2013.03.006
www.mayoclinicproceedings.org
Abbreviations and Acronyms: AF = atrial brillation;
AMPLIFY-EXT = Apixaban after the Initial Management of
Pulmonary Embolism and Deep Vein Thrombosis with First-
Line TherapyExtended Treatment; aPTT = activated partial
thromboplastin time; ARISTOTLE = Apixaban for Red-
uction in Stroke and Other Thromboembolic Events in
Atrial Fibrillation; AVERROES = Apixaban Versus Acetylsa-
licylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who
Have Failed or Are Unsuitable for Vitamin K Antagonist Treat-
ment; CrCl = creatinine clearance; CYP = cytochrome; DVT =
deep venous thrombosis; EMA = European Medicines
Agency; FDA = Food and Drug Administration; GI = gastro-
intestinal; HIT = heparin-induced thrombocytopenia;
HPFB = Health Products and Food Branch; INR = interna-
tional normalized ratio; LMWH = low-molecular-weight hep-
arin; NOA = new oral anticoagulant; PCC = prothrombin
complex concentrate; PE = pulmonary embolism; P-gp =
P-glycoprotein; PT = prothrombin time; ROCKET AF =
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition
Compared with Vitamin K Antagonism for Prevention of
Stroke and Embolism Trial in Atrial Fibrillation; THA = total
hip arthroplasty; TKA = total knee arthroplasty; VKA =
vitamin K antagonist; VTE = venous thromboembolic event
Correspondence: Address to Mrinal M. Patnaik, MBBS,
Division of Hematology, Mayo Clinic, 200 First St SW,
Rochester, MN 55906 (patnaik.mrinal@mayo.edu).
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