SPECIAL FEATURES  Oral anticoagulants

SPECIAL FEATURES

Management of bleeding and reversal strategies

for oral anticoagulants: Clinical practice
considerations
Edith A. Nutescu, William E. Dager, James S. Kalus, John J. Lewin III, and Mark D. Cipolle

O
ral anticoagulants are used to
manage a variety of common
age-related conditions (e.g.,
atrial fibrillation), and the frequency
of their use will likely rise significant-
ly in the United States as the popu-
lation ages. The number of elderly
Americans 65 years of age or older is
expected to increase markedly over
the next two decades, from 39.6 mil-
lion in 2009 to 72.1 million by 2030.1
Nearly one in five Americans will be
elderly in 2030.
Warfarin has been widely used
since it was introduced more than 50
years ago, but it is a less-than-ideal
anticoagulant because of its narrow
therapeutic range, interactions with
numerous drugs and foods, and
need for routine laboratory monitor-
ing.2 Warfarin is a common cause of
emergency hospitalization in elderly
patients and of serious, disabling, or
fatal injury from bleeding in patients
of all ages.3,4
The recent introduction of the
oral direct thrombin (factor IIa)
Purpose. Currently available clinical data
and optimal strategies for reversing oral
anticoagulants in patients who are bleed-
ing or need an urgent invasive procedure
or operation are reviewed.
Summary. Bleeding from oral antico-
agulants, including new target-specific
oral agents (TSOAs), is a common cause
of morbidity and mortality, especially in
elderly patients. Limited clinical data are
available to guide the reversal of warfarin
or TSOAs in patients who are bleeding or
need an urgent invasive procedure or op-
eration. A panel of five experts with diverse
backgrounds in anticoagulation therapy,
cardiology, critical care, and emergency
medicine and with experience in managing
complications of anticoagulation therapy
was convened to develop practical strate-
gies for managing patients receiving oral
anticoagulants who are bleeding or have
an urgent need for an invasive procedure.
The strategies were designed to guide
inhibitor dabigatran and the direct
factor Xa inhibitors rivaroxaban and
apixaban was eagerly anticipated
clinicians in the acute care setting by pro-
viding efficient and potentially effective
management concepts to avoid delays in
initiating treatment that could adversely
affect patient outcomes. The consensus
of this expert panel is summarized herein.
Recommendations are based on currently
available evidence from a comprehensive
review of the literature and other pertinent
data, along with the experience and expert
opinion of the panelists.
Conclusion. Bleeding is a serious compli-
cation of the use of oral anticoagulants,
and limited information is available to
guide the reversal of warfarin or TSOAs in
patients who are bleeding or are in need
of an urgent invasive procedure. Use of
a systematic approach to assessing and
treating these patients based on available
evidence and expert opinion can help
avoid delays that could adversely affect
patient outcomes.
Am J Health-Syst Pharm. 2013; 70:1914-29
because these agents do not require
routine coagulation monitoring and
are associated with a lower number

Edith A. Nutescu, Pharm.D., FCCP, is Clinical Professor, Department
of Pharmacy Practice, Center for Pharmacoepidemiology and Phar-
macoeconomic Research, College of Pharmacy, University of Illinois
at Chicago, and Director, Antithrombosis Center, and Co-Director,
Pharmacogenetics Service, University of Illinois Hospital and Health
Sciences System, Chicago. William E. Dager, Pharm.D., BCPS (AQ-
Cardiology), FCSHP, FCCP, FCCM, FASHP, is Pharmacist Specialist,
University of California (UC) Davis Medical Center, Sacramento, and
Clinical Professor of Medicine, School of Medicine, UC Davis. James S.
Kalus, Pharm.D., BCPS (AQ-Cardiology), is Senior Manager, Patient
Care Services, Department of Pharmacy Services, Henry Ford Hospital,
Detroit, MI, and Adjunct Assistant Professor of Pharmacy Practice,
Eugene Applebaum College of Pharmacy and Health Sciences, Wayne
State University, Detroit. John J. Lewin III, Pharm.D., M.B.A., FASHP,
is Division Director, Critical Care and Surgery Pharmacy Services,
Johns Hopkins Hospital, Baltimore, MD, and Clinical Professor, Uni-
versity of Maryland School of Pharmacy, Baltimore. Mark D. Cipolle,
M.D., Ph.D., FACS, FCCM, is Medical Director, Trauma Program,
Christiana Care Health System, Wilmington, DE.
Address correspondence to Dr. Nutescu at the Department of
Pharmacy Practice, Center for Pharmacoepidemiology and Phar-
macoeconomic Research, College of Pharmacy, University of Illinois
at Chicago, 833 South Wood Street, MC 886, Chicago, IL 60612
(enutescu@uic.edu).

1914 Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

 SPECIAL FEATURES  Oral anticoagulants

of clinically significant drug interac-
tions. Also, unlike warfarin, which
inhibits hepatic production of the
vitamin-K-dependent clotting fac-
tors II, VII, IX, and X, these new oral
anticoagulants act on specific com-
ponents in the coagulation cascade.
In separate clinical trials com-
paring dabigatran, rivaroxaban, or
apixaban with warfarin for stroke
prevention in patients with atrial
fibrillation, the risk for major bleed-
ing was significantly lower with
apixaban compared with warfarin,
and there was no significant differ-
ence in the risk of major bleeding
between dabigatran (the larger of
two dosages evaluated) or rivaroxa-
ban when compared with warfarin.5-7
The rate of intracranial hemorrhage
was significantly lower with all three
target-specific oral anticoagulants
(TSOAs) when compared with war-
farin. However, the rate of major
gastrointestinal bleeding was signifi-
cantly higher with dabigatran (the
larger of two dosages evaluated) and
rivaroxaban compared with warfarin,
though there was no significant dif-
ference in gastrointestinal bleeding
between apixaban and warfarin.
Whether the safety profile of the
TSOAs in clinical practice will mirror
event rates reported in large clinical
trials remains to be determined. It
is also unclear if outcomes may be
different between agents once ma-
jor bleeding occurs. Observational
studies and postmarketing surveil-
lance will assist in further clarifying
the real-world safety profile of these
agents. Elderly patients with renal
impairment are particularly vulner-
able to bleeding during treatment
with dabigatran.8 During 2011, the
FDA MedWatch adverse-event-
reporting program received more
reports of dabigatran-associated
serious, disabling, or fatal injury
due to bleeding compared with war-
farin.4 For the second quarter of
2012, reports to the MedWatch pro-
gram indicated that dabigatran was
associated with a fivefold higher risk
of death than warfarin after adjust-
ing for age, sex, and the type and
source of the report.9 However, in a
subsequent FDA analysis of insur-
ance claims and administrative data,
gastrointestinal and intracranial
bleeding rates associated with newly
initiated dabigatran did not appear
to be higher than bleeding rates as-
sociated with newly initiated warfa-
rin.9-11 Therefore, the differences be-
tween dabigatran and warfarin in the
MedWatch data may reflect reporting
biases, such as a greater tendency
to report problems with the newer
drug.10 Interestingly, in the second
quarter of 2012, rivaroxaban was
also associated with a larger number
of serious injury reports to the FDA
MedWatch program and a nearly
twofold higher risk of death in cases
of bleeding compared with warfarin.9
Data on apixaban were not collected
because the drug did not have FDA-
approved labeling at that time. Re-
gardless, the use of any anticoagulant
carries a risk of bleeding, so it is vital
to have a strategy to manage or pre-
vent bleeding complications.
Guidelines developed by the
American College of Chest Physi-
cians (ACCP) address options for
reversing the anticoagulant effects
of warfarin and mitigating the risk
of warfarin-associated bleeding. 12
These guidelines involve withholding
warfarin and, because of the time
needed for the depletion of vitamin
K-dependent clotting factors, ad-
ministration of exogenous vitamin
K (phytonadione) and clotting fac-
tor concentrates when urgent rever-
sal is needed. Because clinical trials
exploring the emergent reversal of
war-farin and TSOAs in patients
who are bleeding or need an urgent
invasive procedure are limited or
nonexistent, there is a certain degree
of subjectivity involved in the avail-
able guidelines, leaving knowledge
gaps in how to best manage these
patients.
In light of these knowledge and
management gaps, a panel of five
experts (the authors of this article)
with diverse backgrounds in antico-
agulation therapy, cardiology, critical
care, and emergency medicine and
with experience in managing com-
plications of anticoagulation therapy
was convened during the ASHP Mid-
year Clinical Meeting in Las Vegas,
Nevada, on December 5, 2012, for
the purpose of developing practical
strategies for managing patients re-
ceiving oral anticoagulants who are
bleeding or have an urgent need for
an invasive procedure. The strategies
were designed to guide clinicians in
the acute care setting by providing
efficient and potentially effective
management concepts to avoid de-
lays in initiating treatment that could
adversely affect patient outcomes.
This article summarizes the con-
sensus of this expert panel. Recom-
mendations are based on currently
available evidence from a compre-
hensive review of the literature and
other pertinent data, along with the
experience and expert opinion of

The assistance of Carla J. Brink, M.S., B.S.Pharm., and Susan
R. Dombrowski, M.S., B.S.Pharm., in manuscript development is
acknowledged.
Based on the proceedings of an expert panel meeting on December
5, 2012, during the ASHP Midyear Clinical Meeting and Exhibition in
Las Vegas, NV. The expert panel comprised the authors of this article.
Supported by an educational grant from CSL Behring.
All authors received an honorarium for participating in the expert
panel and preparing this article. Dr. Nutescu has served as a consul-
tant for Daiichi-Sankyo and has received a research grant from and
served as a consultant for Janssen Pharmaceuticals. Dr. Cipolle has
served as a consultant for CSL Behring.
Copyright © 2013, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/13/1101-1914$06.00.
DOI 10.2146/ajhp130243

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013 1915

 SPECIAL FEATURES  Oral anticoagulants

the panelists. Tools and strategies for
patient assessment are provided for
use with a user-friendly algorithm
and tables for patient assessment and
treatment as part of paper-based or
electronic systems. These materi-
als can be readily updated to reflect
emerging data and adapted to meet
the unique needs of individual insti-
tutions and the patient populations
they serve. The lists, algorithm, and
tables can be hyperlinked as part
of a clinical decision-support sys-
tem. These materials provide only
a framework for clinical decision-
making; applying them to the care of
individual patients requires clinical
judgment.
This article does not represent
consensus guidelines of the American
Society of Health-System Pharmacists
or any other organization, and the
recommendations are not graded on
level of evidence.
Pharmacokinetics and
pharmacodynamics of oral
anticoagulants
The pharmacokinetics and phar-
macodynamics of warfarin are well
characterized and described else-
where.13 The pharmacokinetics of
TSOAs are summarized in Table 1.
The kidneys play a more important
role in the elimination of dabigatran
compared with rivaroxaban and
apixaban. Therefore, the potential
for drug accumulation and bleeding
in patients with impaired renal func-
tion, a common condition in elderly
patients, is of greater concern with
the direct thrombin inhibitor dabi-
gatran than the other two TSOAs.
The plasma protein binding of dabi-
gatran is low, enabling removal by
hemodialysis (e.g., at least half of the
dabigatran in plasma was removed
over a four-hour hemodialysis ses-
sion in experimental models).14,19 By
contrast, rivaroxaban and apixaban
are highly protein bound and un-
likely to be dialyzable.15,16
Dabigatran is a substrate for the
efflux transporter P-glycoprotein
and can interact with P-glycoprotein
inhibitors and inducers. Concomi-
tant use with potent P-glycoprotein
inhibitors can increase the bioavail-
ability of dabigatran and the risk of
bleeding.14 In renally impaired pa-
tients who are receiving dabigatran
and a P-glycoprotein inhibitor, the
enhanced dabigatran bioavailability
and reduced clearance are likely to
lead to even greater systemic expo-
sure and risk of bleeding.
Rivaroxaban and apixaban are
substrates for P-glycoprotein and
cytochrome P-450 (CYP) isoenzyme
3A4 and can interact with inhibitors
and inducers of P-glycoprotein and
CYP3A4. Concomitant use of these
TSOAs with potent inhibitors of
P-glycoprotein or CYP3A4 can in-
crease the risk of bleeding, especially
when doses are given closely together
or at the same time.15,16 Additional
details about drug interactions involv-
ing TSOAs are available in the product
labeling and published literature.2,20
As with warfarin, the antico-
agulant effects of TSOAs are highly
influenced by their pharmacokinet-
ics. The pharmacodynamic effects
of these drugs, however, also reflect
their effects on the clotting cascade,
resulting in changes in coagulability
not predicted by pharmacokinetics
alone. For example, there is evidence
to suggest that discontinuation of
rivaroxaban could be followed by a
rebound increase in coagulation (i.e.,
a procoagulable state) mediated by
prothrombin and clotting factors V
and X.21 The clinical significance of
this phenomenon is unclear.

Table 1.
Pharmacokinetics of Target-Specific Oral Anticoagulants14-18,a
Characteristic Dabigatran Rivaroxaban Apixaban
Renal elimination of unchanged
drug, % 80 36 27
Half-life by age, hr
Young, healthy adults 12–14 5–9 8–15
Elderly 12–14 11–13 . . .b
Half-life by renal function, hr
CLcr >80 mL/min 14 8 15
CLcr 50–79 mL/min 17 9 15
CLcr 30–49 mL/min 19 9 18
CLcr <30 mL/min 28 10 17
Protein binding, % 35 92–95 87
Dialyzable? Yes Unlikely Unlikely
Key drug interactions Potent inhibitors and Potent inhibitors and Potent inhibitors and
inducers of P-glycoprotein inducers of P-glycoprotein inducers of P-glycoprotein
or CYP3A4 or CYP3A4
CLcr = creatinine clearance, CYP = cytochrome P-450 isoenzyme.
a

Data not available.

b

1916 Am J Health-Syst Pharm—Vol 70 Nov 1, 2013


Laboratory assessment of
anticoagulation effects
The prothrombin time (PT) and
International Normalized Ratio
(INR) are common assays used to
assess the anticoagulation effects of
warfarin therapy. Although routine
anticoagulant monitoring is not re-
quired during treatment with TSOAs,
laboratory assessment could provide
valuable insight into the level of an-
ticoagulation during treatment with
these agents or after interruption of
therapy in patients with bleeding.
Laboratory assays may be used to
assist in decisions about when it is
safe for a patient to undergo surgery
or restart anticoagulant therapy. The
response to therapeutic interven-
tions to reverse anticoagulation (e.g.,
hemodialysis) also may be monitored
using laboratory tests, though most
tests are of limited value, and care
must be taken in interpreting these
results.
The usefulness of laboratory tests
varies with the anticoagulant being
used (Table 2). The availability of
certain tests in clinical practice is lim-
ited. For example, the ecarin clotting
time (ECT) test is the most useful for
assessing dabigatran anticoagulation
because it is sensitive to the drug at
all concentrations, but the ECT test is
not widely available.22 The commer-
cially available nondiluted thrombin
time (TT) test is very sensitive to
the level of dabigatran, making the
test useful at low concentrations
but not higher concentrations of
dabigatran.24 The activated partial
thromboplastin time (aPTT) and PT
tests are widely available but are not
ideal for quantifying the amount of
dabigatran present.24 The PT test is
less sensitive than the aPTT test at
usual concentrations of dabigatran.22
Limited data are available for
laboratory assessment of coagula-
tion during treatment with the fac-
tor Xa inhibitors rivaroxaban and
apixaban. Chromogenic antifactor
Xa assays are useful for monitoring
coagulation during therapy with
SPECIAL FEATURES  Oral anticoagulants
these agents. However, the need to
calibrate the assay for the specific
factor Xa inhibitor and the contribu-
tion of variables that can influence
results present notable challenges in
using these assays.27 Given that such
calibrators are becoming available,28
some laboratories are now bringing
this test onsite. As with any test, it
is important to know the reliability
of the assay and assess the clinical
presentation when incorporating
results into management decisions.
Several newer coagulation assays
have been developed and may be
used in certain specialized situa-
tions, though data are not currently
available to determine the clinical
usefulness of these tests. These newer
tests include thromboelastography,
thrombin generation curve, plasma-
diluted TT, chromogenic ECT, and
diluted PT.22 Thromboelastography
has been used as a tool to guide
transfusions in the presence of bleed-
ing, and it may be used during sur-
gery or in trauma centers to provide
insight into the possible causes of
and ways to mitigate bleeding. The
usefulness of thromboelastography
in the presence of TSOAs, however,
has not been established.
As noted, interpretation of labo-
ratory coagulation test values and
therapeutic decision-making require
consideration of each patient’s spe-
cific scenario and clinical status.
For example, administration of
hemostatic agents may stem bleed-
ing without affecting laboratory
coagulation test results in a patient
needing an urgent invasive proce-
dure.29 In addition, the timing of
the last anticoagulant dose should
be considered when scheduling and
interpreting coagulation test values.
Turnaround time is also a critical
point in the practical applicability
of these assays, particularly in the
hemorrhaging patient. Frequent
reassessment of the patient’s clini-
cal status and laboratory tests may
be needed to accommodate acute
changes in unstable patients.
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
Reversal agents
Various interventions may be used
to reverse the effects of warfarin, in-
cluding oral and i.v. phytonadione,
fresh frozen plasma (FFP), and clot-
ting factor concentrates. Concen-
trated clotting factor products, FFP,
activated charcoal, and hemodialysis
also have been considered for revers-
ing the effects of TSOAs. Various
antidotes for reversal of TSOAs are
in development, but they are not yet
available.30-32 FFP is obtained from
human blood and contains all of the
vitamin K-dependent clotting factors
in plasma. The large volume of fluid
administered is a potential disadvan-
tage of using FFP.33 The limited data
from FFP use for reversing TSOAs to
date have not been encouraging.34
Concentrated clotting factor prod-
ucts include three- and four-factor
prothrombin complex concentrate
(PCC) products, recombinant factor
VIIa (rFVIIa), and activated PCC
(aPCC, also known as antiinhibitor
factor complex, factor VIII inhibitor
bypassing activity, or FEIBA). The
PCC products vary in their clotting
factor content, but all three-factor
PCC (PCC3) products contain inac-
tivated clotting factors II, IX, and X
and only small amounts of factor VII
in an inactivated form. Four-factor
PCC (PCC4) products contain a
larger amount of inactivated clotting
factor VII than PCC3 products as
well as clotting factors II, IX, and X in
an inactivated form. Activated PCC
contains clotting factor VII in an
activated form and clotting factors II,
IX, and X primarily in an inactivated
form. The risk for thrombosis is a
concern with clotting factor concen-
trates, especially activated products.
This risk must be weighed against the
potential benefit of using these prod-
ucts for anticoagulant reversal.
Some PCC4 products and aPCC
contain the natural regulatory an-
ticoagulant protein C, protein S, or
both.22,35,36 Some PCC3 and PCC4
products (but not aPCC or rFVIIa)
contain heparin, which is a concern
1917
1918
Table 2.
Various Laboratory Tests To Consider When Concerned About Bleeding With Warfarin and Target-Specific Oral Anticoagulants (TSOAs)22-26,a

Laboratory
Test Warfarin Dabigatran Rivaroxaban Apixaban Comments
SCr and CBC with Potentially useful Potentially useful Potentially useful Potentially useful Monitor serum calcium concentration if
platelets transfusing blood
INR or PT Potentially useful; value Potentially useful; value Potentially useful; value Potentially useful; value PT may be considered because INR may
increased increased; use central increased increased not be calibrated for the TSOAs; PT
laboratory because point- more responsive to factor Xa inhibitors
of-care test can give than to dabigatran; limited ability to
much higher values quantify amount of drug
aPTT Potentially useful; value Potentially useful; value Potentially useful; value Potentially useful; value aPTT more responsive to dabigatran than
somewhat increased increased, but aPTT increased increased to factor Xa inhibitors; limited ability to

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

response flattens at quantify amount of drug
higher serum drug
SPECIAL FEATURES  Oral anticoagulants

concentration
TT Clinical use limited Potentially useful; very Inadequate measure Inadequate measure Limited ability to quantify amount of
sensitive at low dabigatran
concentration but
not useful at higher
concentration
ECT Clinical use limited Potentially useful if Inadequate measure Inadequate measure Limited availability; potential quantitative
available; potential ability test
to quantify amount of
drug present
Diluted TT Clinical use limited Potentially useful if Inadequate measure Inadequate measure Lack of standardization and potential
available; potential ability differences in measured results among
to quantify amount of laboratories; may have limitations at
drug present low dabigatran concentration
Chromogenic Inadequate measure Inadequate measure Potentially useful; value Potentially useful; value Limited availability; nonstandardized;
antifactor Xa increased increased results may vary among laboratories
assay where available
a
SCr = serum creatinine, CBC = complete blood count, INR = International Normalized Ratio, PT = prothrombin time, aPTT = activated partial thromboplastin time, TT = thrombin time, ECT = ecarin clotting time.
 manufacturers.

treated participants.
and additional sources.22,36-38

ages of PCC are expressed as units of

mation about the composition of

garding the benefits of concen-

chloride injection). After an 11-day

controlled, crossover study of 12

uct had no effect on aPTT, ECT, or

product or placebo. The PCC4 prod-
reversing TSOAs in humans. In
in patients with recent heparin-

of rivaroxaban were also evaluated in

(Cofact) on the anticoagulant effects
anticoagulant followed by the PCC4
washout period, volunteers received
PCC4 product per kilogram of body
healthy male volunteers.46 Dabigat-

The effects of a PCC4 product

randomized, double-blind, placebo-
addition, the dosages of these re-

blood samples from healthy volun-

an in vitro study.47 Plasma and whole
(a measure of thrombin generation)
and endogenous thrombin potential
The PCC4 product normalized the PT
2.5 days of treatment with the other
for 2.5 days followed by 50 units of the
The effects of a PCC4 product
and other regulators of coagula-
the factor IX component, and aPCC
summarized elsewhere.18,33,53-56 Dos-
Data from animal testing have been
to date may not reflect the dosages
trated clotting factor products for
Limited data are available re-

within 15 minutes in rivaroxaban-

weight or a placebo (0.9% sodium
varoxaban 20 mg twice daily was given
ran etexilate 150 mg twice daily or ri-
and rivaroxaban were evaluated in a
concentrated clotting factor products
induced thrombocytopenia. Infor-

anticoagulant effects of dabigatran

tion in PCC products varies among
The composition of clotting factors
is available in the product labeling

versal agents used experimentally

teers were spiked with rivaroxaban

Amsterdam, Netherlands) on the
(Cofact, Sanquin Blood Supply,

TT in dabigatran-treated volunteers.
dosages are expressed as FEIBA units.
used in clinical practice (Table 3).
Table 3.
Recommended Dosing of Concentrated Clotting Factor Products for Oral Anticoagulant Reversal29,33,34,39-52,a,b

Dose(s) for Reversal of Specific Anticoagulant

Reversal Clotting Factor(s)
Agent Replaced Warfarin Dabigatran Rivaroxaban
33,34,40,41 c 42
PCC3 II, IX, and X (inactivated) 25–50 units/kg ... 50 units/kg
PCC4 II, VII, IX, and X (inactivated) 25–50 units/kg36,43,44 25–50 units/kg45,46 25–50 units/kg42,45-47
rFVIIa VII (activated) 17.7–53.4 mg/kg48-50,d 20–120 mg/kg45,d,e 20–120 mg/kg45,d,e
aPCC II, IX, X (inactivated) and VII 500 units for INR of <5 and 1000 units Up to 25 units/kg initiallyf with Up to 25 units/kg initially; no data
(activated) for INR of ≥551 subsequent doses based on available in patients with active
response29; 80 units/kg45,g bleeding; 80 units/kg45,g
Building of PCC4 PCC3: II, IX, and X PCC3 50 units/kg (or a fixed dose of No data available; possibly extrapolate No data available; possibly extrapolate
(inactivated); rFVIIa: VII 4000 units for an 80-kg patient) + doses from warfarin reversal doses from warfarin reversal
(activated) rFVIIa 1 mg52; if rFVIIa is not available,
the addition of a small dose of
FFP (1–2 units) to PCC3 could be
considered
a
PCC3 = three-factor prothrombin complex concentrate, PCC4 = four-factor prothrombin complex concentrate, rFVIIa = recombinant factor VIIa, aPCC = activated prothrombin complex concentrate, INR = International
Normalized Ratio, FFP = fresh frozen plasma.
b
Experience with the doses listed in this table for reversal of oral anticoagulants is limited. Aside from one abstract at the time of writing,39 there are insufficient data to make specific dosing recommendations for apixaban.
Current references and the product labeling should be consulted for the most recent information about appropriate dosing of concentrated clotting factor products. Depending on the urgency of bleeding and estimated
anticoagulant effect, lower doses can be used initially and increased as necessary to achieve the desired effect. Doses of PCC and aPCC products are expressed as units of the factor IX component and FEIBA units, respectively.
The composition of PCC products varies, so doses of different products may not be equivalent.
c
Data are not available on PCC3 use for target-specific oral anticoagulant reversal. Doses of 25–50 units/kg can be considered if a PCC4 product or aPCC is not available.
d
Higher doses of rFVIIa have been associated with increased thrombosis risk. If this option is selected, a lower dose of approximately 20 mg/kg is suggested.

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

e
Limited effects noted in vitro or ex vivo even at higher doses; usefulness unclear.
f
Based on limited case reports.
g
Larger aPCC doses corresponding to 80 units/kg were evaluated in an ex vivo study of dabigatran and rivaroxaban.45 The initial aPCC dose should be based on the severity of bleeding, keeping in mind that additional doses
SPECIAL FEATURES  Oral anticoagulants

can be given. Lower doses (e.g., 1 vial or ~5–10 units/kg) can be considered initially for emergent procedures, such as vascular line placement; however, limited supportive evidence is currently available.

1919
 SPECIAL FEATURES  Oral anticoagulants
(up to 800 mg/L), and PCC4 was add-
ed to these samples in concentrations
used clinically to reverse the effects of
vitamin K antagonists. PT (Innovin,
Dade Behring, Liederbach, Germa-
ny), endogenous thrombin potential,
and calibrated automated thrombo-
graphy assays were performed with
varying tissue factor concentrations.
The PCC4 product did not neutral-
ize the increase in PT and lag time of
rivaroxaban-anticoagulated blood in
vitro, suggesting that the Innovin PT
may not be applicable for the in vitro
assessment of rivaroxaban reversal by
PCC4. However, the total thrombin
potential was normalized, and the
response of the different thrombin
generation tests was found to be
dependent on assay conditions. In
contrast to these findings, the ex vivo
study by Eerenberg et al.46 found that
the PT of healthy human volunteers
receiving rivaroxaban could be nor-
malized using PCC4.
Another in vitro study evaluated
the impact of different clotting factor
concentrates in reversing the actions
of apixaban.39 Whole-blood samples
from healthy volunteers were mixed
with apixaban (200 ng/mL), and var-
ious clotting factor concentrates were
added to these samples. The clotting
factor concentrates PCC4 (50 units/
kg; Beriplex, CSL Behring, Marburg,
Germany), aPCC (75 units/kg; Feiba,
Baxter, Westlake Village, CA), and
rFVIIa (270 mg/kg; NovoSeven, Novo
Nordisk, Bagsvaerd, Denmark) com-
pensated for or reversed apixaban’s
anticoagulant action with varying
degrees of efficacy. Thrombin gen-
eration improved most with the
administration of PCC4, followed by
aPCC and then rFVIIa. Correction
of clotting time responded best to
rFVIIa, followed by aPCC and then
PCC4.
The effects of another PCC4 prod-
uct (Kanokad, LFB-Biomedicaments,
Paris, France), rFVIIa, and aPCC on
the anticoagulant effects of dabiga-
tran and rivaroxaban were evaluated
by Marlu and colleagues45 in an ex
1920 Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
vivo, crossover study of 10 healthy
male volunteers. Venous blood sam-
ples were obtained immediately
before and two hours after single
150-mg doses of dabigatran etexilate
or 20-mg doses of rivaroxaban and
exposed to several concentrations
of PCC4 (0.25, 0.5, and 1 unit/mL,
with the intermediate concentra-
tion corresponding to a dose of 25
units per kilogram of body weight),
rFVIIa (0.5, 1.5, and 3 mg/mL, with
the highest concentration corre-
sponding to a dose of 120 mg/kg),
and aPCC (0.25, 0.5, 1, and 2 units/
mL, with the 1-unit/mL concentra-
tion corresponding to a dose of 80
units per kilogram of body weight).
After a two-week washout period,
blood samples were obtained im-
mediately before and two hours after
the volunteers received the other
anticoagulant. The PCC4 product
and rFVIIa had inconsistent effects
on laboratory values of throm-
bin generation in dabigatran- and
rivaroxaban-treated blood samples.
However, aPCC had a consistent
impact on thrombin generation
in rivaroxaban-treated blood. The
impact of aPCC on thrombin gen-
eration in dabigatran-treated blood
was less consistent than the effect on
rivaroxaban-treated blood, though
the impact of aPCC on dabigatran-
treated blood was greater than that
of PCC4 and rFVIIa. These findings
suggest that aPCC may play a role in
reversing the anticoagulant effects of
rivaroxaban and perhaps dabigatran.
Levi et al.42 evaluated the effects of
PCC4 (Beriplex) and PCC3 (Profiln-
ine, Grifols Biologicals, Los Angeles,
CA) products on PT and thrombin
generation in an open-label, parallel-
group study in 35 healthy adult
volunteers treated with rivaroxaban
20 mg twice daily for four days to at-
tain steady-state concentrations. On
day 5, four hours after rivaroxaban
administration, participants were
randomized to receive a single bolus
dose of PCC3 50 units/kg, PCC4 50
units/kg, or 100 mL of 0.9% sodium
chloride injection (control). The PT
and endogenous thrombin potential
were measured before and serially
after the administration of PCC or
the control. While PCC4 reduced
the mean PT by 2.5–3.5 seconds,
PCC3 resulted in a mean reduction
of only 0.6–1.0 second. In contrast
to its effect on the PT, PCC3 more
effectively reversed rivaroxaban-
induced changes in endogenous
thrombin generation (area under the
concentration–time curve, peak, and
time-to-peak values) than did PCC4.
Changes in lag time values did not
differ greatly. The discrepancy in
these results on PT and thrombin
generation may reflect the absence
of factor VII in PCC3 (Profilnine)
and the presence of heparin in
PCC4 (Beriplex). Additional stud-
ies are needed to further clarify
these issues. The administration of
the PCC products in this study was
deemed safe and well tolerated, with
no signs of prothrombotic response
reported.
The limited availability of data
in humans requiring reversal of the
anticoagulant effects of TSOAs using
the reversal agents listed in Table 3
leaves large gaps in knowledge about
the best approach to use in clinical
practice. Further research is under-
way to fill these gaps. Examples in-
clude the REVNEWANTICO study, a
randomized, open-label, controlled,
crossover, Phase IV study examining
the use of PCC, rFVIIa, and aPCC af-
ter the administration of single 150-
mg dabigatran etexilate doses and the
use of a specific rivaroxaban decoy
(Gla-domainless activated factor X)
after the administration of a single
20-mg rivaroxaban dose in 10 young,
healthy, male volunteers.57
The antifibrinolytic agents ami-
nocaproic acid and tranexamic acid
have been used to minimize blood
loss during surgery.58 However, data
are not available to characterize the
role of these agents in managing se-
rious bleeding in patients receiving
oral anticoagulants.
 SPECIAL FEATURES  Oral anticoagulants

Clinical management of bleeding
The management of patients re-
ceiving oral anticoagulants who are
bleeding or need an urgent invasive
procedure requires weighing the risks
for thrombosis and bleeding and
consideration of short- and long-
term treatment goals. Individualiza-
tion of therapy is needed, taking into
consideration these goals, age, renal
function, clinical status, and labora-
tory test results.
If a patient has bleeding or needs
an urgent invasive procedure, a med-
ication history should be obtained
(Figure 1). If the medication history
reveals the use of an anticoagulant,
therapy should immediately be dis-
continued and the patient’s risk for
thrombosis should be assessed (Table
4). The time since the last antico-
agulant dose should be determined.
Institutional or published tools (e.g.,
CHADS 2 or CHA 2 DS 2 -Vasc risk
scoring system for atrial fibrillation)
should be used to determine the risk
for thrombosis.59,60 The reasons for
anticoagulation therapy (e.g., atrial
fibrillation, venous thromboembo-
lism prophylaxis or treatment, car-
diac valve) and the use of antiplatelet
therapy or other medications that
contribute to bleeding or excessive
anticoagulation effects (e.g., drug
interactions) should be taken into
consideration.
If the patient is bleeding, the con-
siderations listed in Table 5 should be
used to further evaluate the patient.
The bleeding location, bleeding se-
verity (i.e., volume of blood loss),
and accessibility of the bleeding site
should be assessed. The feasibility
of surgical intervention, including
mechanical procedures and the abil-
ity to drain or remove blood, can
affect patient outcomes. Bleeding in
enclosed spaces, especially the central
nervous system (e.g., intracranial
hemorrhage), eyes, and pericardium,
can have devastating consequences.
Imaging and other diagnostic test
results (e.g., endoscopy), physical
examination findings, overt evidence
of bleeding, and vital signs provide
insight about the bleeding location
and its severity. Laboratory test re-
sults, including a complete blood
count, and the patient’s clinical status
also must be considered when evalu-

Figure 1. Management of patients with bleeding or needing an urgent invasive procedure.

Is the patient on an oral anticoagulant?

Exit
Yes No algorithm

Is the patient bleeding?

(See Tables 2 and 5)

Does the patient need

Yes No an invasive procedure?

Exit
Yes No algorithm

Urgent reversal Yes

(See Table 4) (See Table 6) Urgent?

Rivaroxaban or No
Warfarin Dabigatran
apixaban (See Tables 4, 6,
(See Tables 3 and 7) (See Tables 3 and 7)
(See Tables 3 and 7) and 8)

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013 1921

 SPECIAL FEATURES  Oral anticoagulants

ating and managing a patient with

Table 4.
bleeding.
Considerations in Assessing Risk of Thrombosis in Patients
If the anticoagulated patient is
Receiving Oral Anticoagulantsa
not bleeding and requires an invasive
Oral anticoagulant therapy procedure, the considerations and
• Drug and dosing regimen strategies listed in Table 6 should be
• Time since last dose used to further evaluate the patient.
History of or current hypercoagulable condition The risk for bleeding and thrombosis
Nonvalvular atrial fibrillation (use CHADS2 or CHA2DS2-Vasc risk scoring systemb) from the procedure must be balanced
Presence of cardiac thrombus on recent echocardiogram
with the risk of thrombosis from the
VTE prophylaxis (use institutional or published guidelines for risk assessment)
interruption of anticoagulant thera-
• Positive history of recent VTE (within past 6–12 mo) (assess time since last event
py, taking into consideration the in-
and number of events)
• Negative history of VTE but at high risk for VTE
dication for the anticoagulant before
Cardiac valve an invasive procedure is planned.
• Type (mechanical valve has higher thrombotic risk compared with tissue valve) Institutional or published guide-
• Position (mitral valve has higher thrombotic risk compared with aortic valve) lines (e.g., ACCP guidelines) can be
Other consulted to guide the risk assess-
• Mechanical device or vascular hardware, arterial thromboembolic disease (indi- ment.61-65 The urgency and timing
vidualize risk assessment) of the planned procedure in relation
• Recent administration of concentrated clotting factors to the last dose of anticoagulant, the
Use of medications that contribute to thrombosis pharmacokinetics and pharmacody-
• Indication for use namics of the anticoagulant therapy
• Type of therapy in use, concurrent drug interactions,
• Risk associated with withholding therapy and laboratory test results (e.g., level
a
VTE = venous thromboembolism. of anticoagulation, renal impair-
b
CHADS2 score estimates stroke risk based on the following factors: congestive heart failure, hypertension,
age of ≥75 years, diabetes mellitus, and history of embolic stroke or transient ischemic attack. CHA2DS2-Vasc ment) should be considered.61
score is a modification of the CHADS2 score that aims to improve stroke risk prediction in patients with atrial The actions taken after complet-
fibrillation by adding three risk factors: age of 65–74 years, female sex, and history of vascular disease.
ing the assessments in Tables 4–6
depend on the type of oral antico-
agulant and the urgency of the need
Table 5. for intervention (Table 7). Patients
Considerations in Assessing Bleeding in Patients Receiving Oral may be stratified based on the ur-
Anticoagulantsa gency of the need for intervention in
one of three categories: (1) patients
Vital signs
for whom no action is needed within
Physical examination for external evidence of hemorrhage (e.g., epistaxis, open
fracture, scalp laceration)
24 hours (i.e., when there is no rush
Diagnosis of internal hemorrhage (e.g., endoscopy, CT scan, ultrasound) to make a decision), (2) patients
Access to bleeding site and feasibility of intervention for whom an expedited decision is
Bleeding severity (i.e., assessment of significance of blood loss) needed within 1–24 hours, and (3)
Laboratory test results (see Table 2) patients with an emergent need for
• Level of anticoagulation intervention within 1 hour (i.e., pa-
• Markers for blood loss (e.g., CBC, serum lactate concentration, arterial blood gas tients with life-threatening bleeding
and basic metabolic panel to evaluate for presence of acidosis) or an urgent need for a procedure).
• Organ function (e.g., LFT values, SCr) The clinical status and laboratory
• Additional test considerations (e.g., serum calcium concentration if transfusing test values of anticoagulated patients
with blood products, fibrinogen, thromboelastrogram)
with or at risk for bleeding are sub-
Clinical status
Need for emergent procedures
ject to change, so these classifications
Rebound anticoagulant effect after administering concentrated clotting factors are not fixed. For example, a patient
Allergies and any recent concern for heparin-induced thrombocytopenia with an expedited need for interven-
a
Because the clinical and laboratory status of patients with bleeding is subject to change, frequent
tion may need to be reclassified as
monitoring is needed. CT = computed tomography, CBC = complete blood count, LFT = liver function test, SCr having an emergent need for inter-
= serum creatinine.
vention if his or her condition deteri-
orates and becomes life threatening.
The choice of therapeutic options

1922 Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

 SPECIAL FEATURES  Oral anticoagulants

may be limited by the resources and

agents available at each institution.
Follow-up clinical decision-making
should address whether and when to
reinitiate oral anticoagulant therapy
to reduce the risk of thrombosis and
the use of alternative shorter-acting
agents.
Warfarin. In all patients who are
bleeding or need an urgent invasive
procedure, warfarin should be with-
held and laboratory test values (i.e.,
INR or PT) should be used to assess
the level of anticoagulation (Table 7).
In patients for whom an interven-
tion is not needed for more than 24
hours, oral phytonadione should be
Table 6.
Considerations in Assessing Nonbleeding Patients Receiving Oral
Anticoagulants Who Require Invasive Procedures61,a
Indication for oral anticoagulant use
Risk for thromboembolic events associated with interruption of oral anticoagulant
therapy for invasive procedure
Need for bridging with alternative anticoagulant
Planned procedure or surgery
• Urgency (e.g., emergent, elective)
• Risk for bleeding and thrombosis from intervention (use published or institutional
guidelines for risk assessment)
Laboratory test results
• Level of anticoagulation
• Organ function (e.g., LFT values, SCr)
a
Because the clinical and laboratory status and risk for bleeding and thrombosis in patients with indications
for oral anticoagulant therapy who undergo invasive procedures are subject to change, frequent clinical and
laboratory monitoring and risk assessment are needed. LFT = liver function test, SCr = serum creatinine.

Table 7.
Therapeutic Interventions for Reversal of Oral Anticoagulants Based on Urgency12,15,16,18,19,45,46,66-69
Level of
Urgency Warfarin Dabigatran Rivaroxaban or Apixaban
No rush Withhold warfarin and consider Withhold drug and monitor Withhold drug and monitor clinical
(>24 hr)a oral phytonadione, with dose clinical status and pertinent status and pertinent laboratory tests
based on INR laboratory tests
Expedited Withhold drug and give oral Withhold drug, give activated Withhold drug and give activated
(1–24 hr)a phytonadione (1–5 mg) or low- charcoalb if last dose was charcoalb if last dose was taken within
dose i.v. phytonadione (0.25–5 taken within past 2 hr, and past 2 hr and repeat 6 hr after the last
mg), with dose based on initial use prolonged hemodialysis dose
INR and postreversal INR (>2 hr)
(checked 24 hr after dose)
Emergent Withhold drug, consider high-dose Withhold drug, give activated Withhold drug, give activated charcoalb
(<1 hr) i.v. phytonadionec (depending charcoalb if last dose was if last dose was taken within past
on anticipated need to restart taken within past 2 hr, use 2 hr and repeat 6 hr after the last
warfarin), and consider clotting prolonged hemodialysis (>2 dose, and consider clotting factor
factor supplement (listed in hr), and consider clotting supplement (listed in order of
order of preference): factor supplement (listed in preference):
• PCC4 order of preference): • PCC4
• Build PCC4 with PCC3 plus • aPCC • aPCC
rFVIIad • PCC4 • Build PCC4 with PCC3 plus rFVIIad
• aPCC • Build PCC4 with PCC3 plus • PCC3f
• PCC3 rFVIIad
• rFVIIa
• FFPe
a
The intervention may need to be modified based on changes in the patient’s clinical status (e.g., if status worsens, expedited or emergent treatment options should be
considered). INR = International Normalized Ratio, PCC4 = four-factor prothrombin complex concentrate, PCC3 = three-factor prothrombin complex concentrate, rFVIIa =
recombinant factor VIIa, aPCC = activated prothrombin complex concentrate, FFP = fresh frozen plasma.
b
Contraindicated in the setting of gastrointestinal bleeding.
c
I.V. phytonadione doses exceeding 2 mg may not increase the rate or extent of INR reversal after 24–48 hours compared with 2-mg doses. Large doses (i.e., 5–10 mg)
could be considered if there is no plan to restart warfarin in the near future.
d
In some health systems, rFVIIa is used in combination with PCC3 to enhance the factor VII effects of the reversal strategy. If rFVIIa is not available, the addition of a small
dose of FFP (1–2 units) to PCC3 could be considered.
e
While FFP is currently the most widely used option for warfarin reversal in the United States, the expert panel ranked the other options higher than FFP based on
current evidence and existing guidelines.12
f
The order of PCC3 in this listing was based on the availability of a single abstract at the time of writing.42 Pending release of the full study data, clinician preference for
these listed options may change.

Am J Health-Syst Pharm—Vol 70 Nov 1, 2013 1923

 SPECIAL FEATURES  Oral anticoagulants

considered, with the dose based on the drug is restarted). The lower- for providing factor VII. Use of PCC3
the initial INR and postreversal tar- dose phytonadione strategy may be plus FFP appears more effective for
get INR.12 In patients for whom an attractive in situations without life- reducing the INR than PCC3 alone
intervention is needed within 1–24 threatening bleeding and where war- or FFP alone.34,75 There is evidence
hours, oral or low-dose i.v. phytona- farin may be reinitiated within one to that PCC3 plus rFVIIa is more effec-
dione should be administered, with two weeks. tive for reducing the INR than PCC3
the dose depending on the INR. Given the paucity of comparative plus FFP, though it may carry an in-
Warfarin-treated patients with trials, a definitive strategy for rever- creased risk of thromboembolism if
an emergent need for intervention sal of the INR in warfarin-treated the dose of factor VIIa is high.52
(e.g., life-threatening bleeding) or patients is not clear, and the expert The use of aPCC is an alternative
no plans to subsequently restart panel’s suggested therapeutic inter- to building a PCC4 product, with ev-
warfarin can receive high-dose (5–10 ventions are based on the available idence suggesting that aPCC appears
mg) i.v. phytonadione along with evidence and clinical experience to be more effective for INR reversal
concentrated clotting factor prod- (Table 7). The expert panelists’ first than FFP alone.51 In addition, use of
ucts or FFP. Phytonadione 5–10 mg choice for reversal of the INR in a small doses (11–25 mg/kg) of rFVIIa
by slow i.v. injection plus PCC4 is warfarin-treated patient with seri- has been shown to completely reverse
recommended for emergent warfarin ous bleeding or an emergent need the INR, though the impact of this
reversal by ACCP.12 There is increas- for intervention is PCC4, which has intervention on bleeding outcomes is
ing evidence suggesting that i.v. been shown to promptly—but only unclear.48,52,76
phytonadione doses exceeding 2–3 partially—reverse the INR.44,52,71,72 Dabigatran. The approach to re-
mg are no more effective for revers- PCC3 doses of 25–50 units/kg may versing dabigatran in a patient with
ing the INR in acutely ill patients also be considered for INR reversal bleeding or the need for an invasive
treated with warfarin, and higher in warfarin-treated patients, though procedure depends on the urgency
doses may increase the need for and complete correction of the INR may of the need for intervention. Guid-
duration of bridging therapy (i.e., not occur, even when doses at the up- ance is available for how much time
dual anticoagulation with another per end of this range are used.40,41,72-74 should elapse between the last dose
anticoagulant plus warfarin to pre- If premade PCC4 is not available, of dabigatran and an invasive pro-
vent thrombosis once bleeding has the expert panelists suggest that a cedure based on renal function and
resolved) compared with smaller better option than using PCC3 alone the risk of bleeding, which varies by
doses.27,68-70 These phenomena may is building a PCC4 product by us- surgery type (Table 8).77-80
reflect the fat-soluble nature of ing low-dose rFVIIa in combination In patients for whom no inter-
vitamin K (i.e., storage of excess with PCC3 to enhance the factor vention is needed within 24 hours
vitamin K in adipose tissues) and VII effects of the reversal strategy. (i.e., when there is no rush to make
warfarin refractoriness (i.e., resis- Using FFP with PCC3 may also be a decision), withholding dabigatran
tance to the effects of warfarin when considered as an alternative method and monitoring clinical status and
laboratory coagulation test values
may suffice, especially in the setting
Table 8. of normal renal function (Table 7).
Interruption of Target-Specific Oral Anticoagulant Therapy TT, aPTT, and INR/PT are com-
for Invasive Procedures and Surgery14-16,77-79,a monly available tests for detection of
the presence of dabigatran, but the
Drug Time of Last Dose Time of Last Dose results are not quantitative (Table 2).
(Renal Function) Before Minor Procedure Before Major Surgery
Diluted TT and ECT may be more
Dabigatran useful for quantifying the amount of
CLcr >50 mL/min 1 day (24 hr) 2 days dabigatran present, but these tests are
CLcr 30–50 mL/min 2 days 4 days
not commonly available in practice.
CLcr ≤30 mL/min 4 days 6 days
Rivaroxaban or apixaban
Thromboelastography and activated
CLcr >50 mL/min 1 day (24 hr) 2 days clotting time may be considered,
CLcr 30–50 mL/min 1–2 days 3–4 days depending on the availability of the
CLcr ≤30 mL/min 2 days 4 days test and the clinical situation. How-
a
Therapy should generally be resumed 24–48 hours after a minor procedure and 48–72 hours after major ever, one trauma group reported
surgery. If unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is used as bridging therapy in that the only abnormal thrombo-
patients with atrial fibrillation or with venous thromboembolism who are at high risk for thromboembolism, oral
anticoagulant therapy with a target-specific agent should be resumed when the UFH infusion is discontinued elastographic value in a patient
and when the next scheduled dose of LMWH would have been given. CLcr = creatinine clearance. who died from a dabigatran-related

1924 Am J Health-Syst Pharm—Vol 70 Nov 1, 2013


massive subdural hemorrhage was
a prolonged activated clotting time.
The remainder of the values, which
measured clot kinetics, clot strength,
and clot stability, were within the
normal ranges.81
In patients who need an expedited
intervention within 1–24 hours,
dabigatran should be withheld. If the
last dose was taken within the past
2 hours, activated charcoal should
be given to reduce drug absorption
unless contraindicated (e.g., gas-
trointestinal source of bleeding).18
Hemodialysis should be initiated and
continued until sufficient dabigatran
removal occurs. The mode and dura-
tion of dialysis and blood flow rates
may depend on the level of antico-
agulation and follow-up laboratory
coagulation test results. Case reports
suggest that prolonged dialysis (more
than 2 hours) is needed to remove
substantial amounts of the drug.
In addition, a rebound in plasma
drug concentrations after stopping
dialysis has been observed.19,66,67,82,83
The actual duration of dialysis will
depend on the assessed anticoagu-
lation state using available tests to
guide decision-making (Table 2).
Laboratory coagulation tests should
be repeated 1 hour after the comple-
tion of dialysis because of the risk
of a rebound increase in plasma
dabigatran concentration due to re-
distribution of the drug from tissues
into the plasma.67 If the clinical situ-
ation is such that waiting for dialysis
to reverse the effects of dabigatran is
not an option, the reversal strategies
listed for emergent reversal in Table 7
should be considered.
The expert panelists’ first choice
for reversal of dabigatran in a patient
with serious bleeding or an emergent
need for intervention is aPCC (in
addition to withholding dabigatran
and using activated charcoal and
prolonged hemodialysis).8 This sug-
gestion is based on limited available
evidence (ex vivo studies in healthy
volunteers) and case reports.29,45,46
The optimal aPCC dose is unclear
SPECIAL FEATURES  Oral anticoagulants
and may be lower than that explored
by Marlu et al.45 or used in the man-
agement of hemophilia. Although
the evidence is very limited, low
doses of aPCC (i.e., ≤25 units/kg)
may suffice.29 Since additional aPCC
doses can be given and the onset of
effect is rapid, therapy can be initi-
ated with a low dose, and additional
doses can be given based on an as-
sessment of bleeding. The initial and
any subsequent doses may depend in
part on the vial size to avoid unneces-
sary wastage. An additional vial may
need to be readily available for use if
bleeding persists.29
The expert panelists suggest PCC4
as the next option for the reversal of
dabigatran. An alternative would be
using PCC3 plus rFVIIa to build a
PCC4 product or using PCC3 plus
FFP, though currently available data
are limited and do not support the
use of these combinations for dabig-
atran reversal. While acknowledg-
ing the lack of supporting data, the
expert panelists prefer a combination
of PCC3 plus rFVIIa over PCC3 plus
FFP in a life-threatening bleeding
event based on limited clinical expe-
rience. Since no studies have evalu-
ated the impact of PCC3 plus rFVIIa
for dabigatran reversal, dose selec-
tion is difficult. It may be reasonable
to consider doses that have been used
with relative safety for warfarin re-
versal (Table 3).52 If rFVIIa is the only
therapeutic option available, it may
be considered, but case reports and
an animal model suggest that rFVIIa
has a limited ability to reverse the
effects of dabigatran.8,53,84 If rFVIIa
is used, the panelists recommend an
initial dose of approximately 20 mg/kg,
extrapolated from lower doses shown
effective with warfarin.48 Currently,
no data are available to support the
use of a PCC3 product alone for the
reversal of dabigatran.
It is important to be aware of the
potential for a rebound anticoagula-
tion effect after an attempt at dabiga-
tran reversal because of the relatively
short half-life of the clotting factors
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
used for reversal compared with the
half-life of dabigatran. A rebound in-
crease in the INR has been observed
with the use of rFVIIa in patients
taking warfarin who have traumatic
hemorrhage.85 Follow-up laboratory
coagulation tests should be consid-
ered 10–15 minutes after completing
the infusion of concentrated clot-
ting factor products to monitor for
the desired reversal effect. However,
clinical judgment about whether the
bleeding has stopped or improved
may be more useful, especially given
the limited availability of assays as
well as their limitations in measuring
the effects of dabigatran.
Clinicians could consider admin-
istering small doses of aPCC (e.g.,
8–10 units/kg) immediately before
the insertion of dialysis catheters
or other invasive procedures in pa-
tients receiving dabigatran, as life-
threatening bleeding could develop.
This suggestion is based on two
case reports in which hemostasis
was rapidly achieved with aPCC
at these doses in patients receiving
dabigatran who developed bleeding
while undergoing cardiac ablation or
the placement of a dialysis catheter
for emergent hemodialysis.29,67 Mini-
mally invasive procedures (e.g., use
of the right femoral vein to establish
dialysis access) are preferred to re-
duce the risk of bleeding in patients
receiving dabigatran.
Rivaroxaban and apixaban. In pa-
tients receiving factor Xa inhibitors
for whom there is no need to reverse
the anticoagulant effects within 24
hours, withholding the drug and
monitoring laboratory coagulation
test values should suffice (Table 7).
Guidance is available for how much
time should elapse between the last
dose of rivaroxaban or apixaban and
an invasive procedure based on the
risk of bleeding, which varies with
the type of procedure being per-
formed (Table 8).77,78,80
In patients receiving factor Xa
inhibitors with an emergent need for
intervention, most of the anticoagu-
1925
 SPECIAL FEATURES  Oral anticoagulants
lant effects should be absent ideally
within 24 hours after discontinua-
tion of the drug. If the last dose of the
factor Xa inhibitor was taken within
2 hours, activated charcoal may be
administered unless contraindicated
(e.g., gastrointestinal source of bleed-
ing) and repeated approximately 6
hours after the last dose of factor Xa
inhibitor, though it should be noted
that this recommendation is extrapo-
lated from existing data for apixaban;
data supporting the effectiveness of
this intervention are lacking for riv-
aroxaban.15,16 Hemodialysis probably
does not have a role in removing
factor Xa inhibitors because they are
highly protein bound (Table 1).
In patients with an emergent need
for intervention, PCC4 is preferred
by the expert panel based on cur-
rently available, albeit very limited,
data and clinical experience.39,42,45-47
Limited data suggest that aPCC
might be an alternative to PCC4, but
the expert panelists prefer PCC4 be-
cause of the potential for thrombosis
with aPCC.45,51 Alternatively, a com-
bination of PCC3 plus rFVIIa could
be used to build a PCC4. If rFVIIa is
not available, using FFP in combina-
tion with PCC3 may be considered
as an alternative option for provid-
ing factor VII. While no data are
available in the literature to support
the approach of combining clotting
factor products to build a PCC4 for
reversal of factor Xa antagonists, this
approach may be considered because
it has been studied in the setting of
warfarin reversal. If building a PCC4
is considered for reversal of factor Xa
antagonists, extrapolation of doses
used safely for reversing the effects
of warfarin may be considered (Table
3).52 If PCC4 is not available, PCC3
may also be considered as a potential
reversal option.42
Systematic approach
A plan for managing patients re-
ceiving oral anticoagulants who are
bleeding or need an urgent invasive
procedure should be developed us-
1926 Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
ing a systematic approach to ensure
that appropriate laboratory tests
and therapeutic interventions for
anticoagulant reversal are promptly
ordered when needed. The antico-
agulant reversal plan must be readily
accessible so that it can be promptly
implemented in emergent situations
at any time of day. Implementation
of such a plan should be facilitated
by information technology (e.g.,
clinical decision-support system).
A pragmatic approach is needed to
ensure that the plan is user-friendly.
The plan should be sufficiently flex-
ible to address other patient care
needs.
The anticoagulant reversal plan
should contain provisions to gain ac-
cess to reversal agents and other ther-
apeutic interventions that are not
available in the institution (e.g., small
or rural health care facilities lacking
hemodialysis services). Clinicians
need timely access to these therapies
in emergent situations to avoid com-
promising patient outcomes. The
plan should ensure that policies and
procedures are established to avoid
delays in obtaining reversal therapies
or transferring the patient to an-
other institution where the necessary
therapy is available. The plan should
address transporting the patient and
communicating about the patient’s
status (e.g., time since last oral an-
ticoagulant dose, laboratory results,
use of activated charcoal and reversal
agents) with health care providers at
the facility receiving the patient. Pa-
tient transfer agreements should be
established before an emergent need
arises. Such provisions will ensure a
smooth transition of care.
The anticoagulant reversal plan
may be communicated with local
emergency medical services person-
nel (especially first responders) so
that they are aware of institutional
capabilities to manage bleeding
from oral anticoagulants. Valuable
time can be saved in addressing
life-threatening bleeding events if
patients are taken to a health care
facility where the necessary interven-
tions are available.
In devising the anticoagulant re-
versal plan, interprofessional input
should be obtained from key clinical
decision-makers and stakeholders
involved in the use of reversal agents
in the institution. These include
emergency and trauma physicians,
hematologists, nephrologists, phar-
macists, intensivists (including neu-
rointensivists), neurosurgeons and
other surgeons, nurses, clinical labo-
ratory personnel, blood bank repre-
sentatives, risk managers, and health
informatics professionals. This input
could be obtained in conjunction
with the formulary decision-making
process for reversal agents or through
the formation of institutional com-
mittees responsible for issues related
to anticoagulation. The cost of these
agents is a consideration in formu-
lary decisions and the anticoagulant
reversal plan. Volume discounts and
manufacturer rebates vary widely
among institutions and can have
a substantial effect on product ac-
quisition cost. The acquisition cost
may also reflect local practice and
physician preference. For example,
the acquisition cost may be higher
when PCC3 plus rFVIIa is used to
build a PCC4 product instead of us-
ing aPCC.33 The clinical situation and
therapeutic goals (e.g., need for mul-
tiple doses instead of a single dose to
achieve management goals) can also
affect the cost of treatment.
Reversal agents placed on the for-
mulary may be subject to prescrib-
ing restrictions or requirements for
approval by key individuals who are
knowledgeable about anticoagulant
reversal due to safety and economic
concerns. Although prescribing re-
strictions can ensure that reversal
agents are used only by personnel
who are aware of their risks and
benefits and prevent inappropriate
use, restrictions have the potential to
delay treatment. Provisions should
be made to ensure that prescribing
restrictions do not cause an undue

delay in treatment. Ideally, persons
charged with approving the use of
reversal agents should be available
at any hour. In addition, a method
for some flexibility in reversal agent
use beyond what is formally outlined
in institutional protocols should be
devised because of the uncertainty
about the optimal approach for using
reversal agents.
Many clinicians may be unfamil-
iar with and ill equipped to handle
questions that arise regarding the
use of anticoagulant reversal agents,
as many of these agents are new, the
use of these agents is infrequent,
and guidelines and supporting lit-
erature are limited. Many tertiary
references for concentrated clotting
factor products provide information
on dosing and monitoring recom-
mendations that are appropriate
for treating hematology issues (e.g.,
hemophilia), not for reversing an-
ticoagulation. Confusion may arise
among staff about which department
or location in the institution stores
and dispenses reversal agents (e.g.,
blood bank, pharmacy department),
because it varies among health care
facilities. Knowledgeable individuals
in the institution who can respond
to questions about the use of anti-
coagulant reversal agents should be
identified. Policies and procedures
for promptly referring questions
to these individuals should be
established as part of the antico-
agulant reversal plan to expedite the
resolution of questions. Emergency
department or intensive care unit
clinicians, neurointensivists, hema-
tologists, or designated pharmacists
often have this expertise and can
serve in this capacity. To minimize
delays in providing treatment in
emergent situations, contact infor-
mation (e.g., pager number) for
these individuals should be made
available to personnel who may have
questions and concerns.
Education of pharmacists and
other clinicians is needed to in-
crease their knowledge of the oral
SPECIAL FEATURES  Oral anticoagulants
anticoagulants and available reversal
strategies. Although reversal agents
are not often used, their use is ac-
companied by a high risk of harm if
used inappropriately. In education
departments at some health care
systems, case studies with simulated
clinical scenarios involving reversal
agents have been developed to train
emergency medicine residents, and
these simulations would be helpful
for pharmacists, nurses, and other
staff. Continuing education about
anticoagulant reversal is needed to
maintain competence due to the
continually evolving and limited
information currently available to
guide the use of reversal agents and
the rapid emergence of new data.
The anticoagulant reversal plan
should be periodically revised to
accommodate institutional needs.
A mechanism should be established
to update the plan as new reversal
agents are introduced and new
information about the use of estab-
lished reversal agents becomes avail-
able. In revising the anticoagulant
reversal plan, an assessment of past
patient cases should be performed.
This assessment can provide valu-
able insight into pitfalls encountered
in managing bleeding associated
with oral anticoagulants and strat-
egies to avoid these pitfalls in the
future. In addition, clinical scenario
simulations with key stakeholders
may be useful for understanding
the clinical process and preparing
staff to respond to the need for an
emergency anticoagulant reversal
around-the-clock.
Conclusion
Bleeding is a serious complication
of the use of oral anticoagulants.
Limited information is available to
guide the reversal of warfarin or
TSOAs in patients who are bleeding
or are in need of an urgent invasive
procedure. Use of a systematic ap-
proach to assessing and treating these
patients based on available evidence
and expert opinion can help avoid
Am J Health-Syst Pharm—Vol 70 Nov 1, 2013
delays that could adversely affect pa-
tient outcomes.
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