SlideShare ist ein Scribd-Unternehmen logo
1 von 9
Downloaden Sie, um offline zu lesen
REVIEW ARTICLE

Anesthesiology 2010; 112:473–92
Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins

Review Article
David S. Warner, M.D., and Editor
David S. Warner, M.D., Editor

Ultrasound Imaging for Regional Anesthesia in Infants,
Managing New Oral Anticoagulants in the Perioperative
Children, and Adolescents
and Intensive Care Unit Setting
A Review of Current Literature and Its Application in the Practice of Extremity and
Trunk Blocks

Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M.,* David Faraoni, M.D.,† Jenna L. Spring, M.S.,‡
Ban C. H. Tsui, M.D., F.R.C.P.C.,* M. Samama, M.D., M.D., F.C.C.P.||
James D. Douketis, M.D.,§ CharlesSanthanam Suresh, Ph.D., F.A.A.P.†

This article has been selected for the ANESTHESIOLOGY CME Program. Learning
objectives and disclosure and ordering information can be found in the CME
section at the front of this issue.

ABSTRACT
ABSTRACT

O

NE of the be exciting recent advances summarizes the
warfarin) shouldmostconsidered. This review in technology in
pediatric regional anesthesia has been of bleeding with
available data regarding the managementthe introduction of
anatomically based ultrasound imaging for facilitating nerve lonovel oral anticoagulation agents. Hemodialysis is a therapeucalization. This is because regional anesthesia techniques studies
tic option for dabigatran-related bleeding, while in vitro in children have been considered complex concentrates are reported
showed that prothrombin challenging due to (1) target neural
structures that rivaroxaban-related bleeding. Additional (e.g.,
to be useful foroften course very close to critical structuresclininerves of are brachial determine close to the pleura as they
cal studies the needed toplexus run the best method for reversal
traverse the oral anticoagulation agents when bleeding occurs.
of the novelsupraclavicular region), and particularly during central neuraxial blocks where the safety margin is narrow for needle
placement particularly close tois routinely used(2) the prerequiNTICOAGULATION the spinal cord, in diverse clinical settings, including perioperative venous thromboemsite for sedation or general anesthesia masking potential warning
bolism (VTE) prophylaxisthe need for prevention in patients
signs (paresthesia), and (3) and stroke limiting the volume of
with anesthetic solution below toxic levels. With heparin, lowlocal atrial fibrillation (AF). Unfractionated the possibility
molecular-weighttarget structures, ultrasoundantagonists such
of visualizing the heparin, and vitamin K technology may
with any anticoagulant (including the known principles for
as warfarin many anesthesiologists who had previously abanencourage are widely used but have disadvantages. Although
Professor, Department of Anesthesiology/Critical Care, Duke
**Professor, Department of Anesthesiology and Pain Medicine,
there isregional techniques to resumeoptimal profile includes,
doned no “ideal” anticoagulant, an or increase their use of
University School of Medicine, Durham, North of Pediatric Assistant
University of Alberta. † Professor, Department Carolina. † Anesthein addition to established efficacy and safety, oral adminisProfessor, Queen Fabiola Children’s University Hospital, Brussels,
siology and Pediatrics, Children’s Memorial Hospital, Northwestern
regional anesthesia in children.
Belgium. ‡ Medical Student, of Medicine.
University, Feinberg School Emory University School of Medicine,
tration, no routine monitoring requirement, a for success
Although literature evaluating the evidence predictable
Atlanta, Georgia. Departmentof Medicine, Division of Hematology
Received from § Professor of Anesthesiology and Pain Medicine,
anticoagulant ultrasound in regional anesthesia has begun to
and safety of effect, a rapid onset and offset of action, and
and Thromboembolism, McMaster University, Hamilton, Ontario,
University of Alberta, Edmonton, Alberta, Canada, and the DepartCanada. |Pediatric Anesthesiology,of Anesthesiology and Intensive
| Professor, Department Northwestern University, Feinreversibility.1 Only a few anticoagulants are acutely reversible,
emerge, a comprehensive narrative review of the literature
ment of
Care, Hotel-DieuMedicine, Chicago, Illinois.France.
including unfractionated describedwith outcomes evaluating
berg School of University Hospital, Paris, Submitted for publicapertaining to techniques heparin and protamine and vitaReceived from the Department of Anesthesiology, Emory Unition April 17, 2009. Accepted for publication September 30, 2009.
min K antagonists with pediatric regional prothrombin comultrasound guidance in four-component anesthesia was not
versity School a Career Scientist Award in Anesthesia (to for publiSupported by of Medicine, Atlanta, Georgia. Submitted Dr. Tsui),
plex concentrates. The writingoral anticoagulants (NOACs)
available at the time of newer this article. This review aims
cation July Anesthesiologists’ Society-Abbott Laboratories 20, 2012.
Canadian 30, 2012. Accepted for publication December Ltd., ToSupport was provided solely fromScholar Award (to Dr. Tsui) from
ronto, Ontario, Canada, a Clinical institutional and/or departmeninclude the direct thrombin inhibitor with an overall sumto provide the pediatric anesthesiologist dabigatran etexilate
tal sources. Heritage Foundation for Medical Research,Boehringerthe Alberta JHL serves on Steering Committees for Edmonton,
(Pradaxa®,the techniques used and of the outcomes found
mary of Boehringer-Ingelheim Pharma GmbH, Ingelheim
Ingelheim, Ingelheim am Rhein, Germany; CSL Behring, King of
Alberta, Canada, and Foundation for Anesthesia Education and
am Rhein, controlled or comparativefactor Xa as described in
(based on Germany) and the direct studies) inhibitors rivaPrussia, Pennsylvania; and Johnson and Johnson, Dr. Suresh).
Research (FAER) Research in Education grant (to New Brunswick,
New Jersey. FiguresM.D., served ascreated by Editor for this article.
roxaban (Xarelto, ultrasound guidance of peripheral nerve
the literature on Johnson and Johnson/Bayer HealthCare
Mark A. Warner, 1 and 2 were Handling Annemarie B. Johnson, C.M.I., Medical Illustrator, Wake Forest University School of
AG, Leverkusen, Germany) trunk in pediatrics. A companblocks of the extremities and and apixaban (Eliquis, Bristol
AddressCreative Communications, Wake Department of Pediatric
correspondence to Dr. Suresh: Forest University MediMedicine
Anesthesiology, Children’s North Carolina.
Myers Squibb/Pfizer, Bristol-Myers Squibb House, Uxbridge,
ion article with similar objectives related to neuraxial blocks
cal Center, Winston-Salem,Memorial Hospital, 2300 Children’s Plaza,
P. O. Box 19, Chicago, Illinois 60614. ssuresh@childrensmemorial.org.
2
United Kingdom).inAdvantages of these NESTHESIOLOGY.1 In
will be published the next issue of A new agents include
Addressmay be accessed for personal use Duke charge through the
correspondence to Dr. Levy: at no University MediThis article
cal Center, 2301 www.anesthesiology.org.
Erwin Rd., 5691H, HAFS, Box 3094, Durham,
their relatively rapid onset clinical studies, descriptions from
addition to case series and and offset of action and predictJournal Web site,
North Carolina 27710. docmd2@yahoo.com. This article may be
able anticoagulant effect so that routine coagulation moniaccessed for personal use at no charge through the Journal Web site,
toring is not required. However, laboratory monitoring may
www.anesthesiology.org.• No 2
Anesthesiology, V 112
473
February 2010
be relevant in certain clinical situations, where an assessment
Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott
Williams & Wilkins. Anesthesiology 2013; 118:1466-74
of the anticoagulation status is needed. As the NOACs are
The use of ultrasound guidance has provided an opportunity to
perform many peripheral nerve blocks that would have been difficult
to perform in children based on pure landmark techniques due to the
Managing patients in the perioperative setting receiving novel
potential for injection into contiguous sensitive vascular areas. This
oral anticoagulation agents for thromboprophylaxisultrasoundreview article provides the readers with techniques on or stroke
guided peripheral nerve blocks of the important consideration
prevention with atrial fibrillation is an extremities and trunk with
currently available literature oral anticoagulation agents include
for clinicians. The novel to substantiate the available evidence for
the use of these techniques. Ultrasound images of the blocks with
direct Factor Xa inhibitors rivaroxaban and apixaban, and the
corresponding line diagrams to demonstrate the placement of the
direct thrombin have been provided for all the relevantsurgery, disultrasound probe inhibitor dabigatran. In elective nerve blocks
continuing The authors important,this review function must also
in children. their use is hope that but renal will stimulate further
research into because elimination is highly dependent on renal
be consideredultrasound-guided regional anesthesia in infants, children, and adolescents and stimulate more randomized
elimination. If bleeding occurs in patients who havecontrolled
received
trials to provide a greater understanding of the anatomy and physithese agents, common principles of bleeding management as
ology of regional anesthesia in pediatrics.

Anesthesiology, V 118 • No 6	

A

1466	

June 2013
EDUCATION

increasingly replacing older parenteral agents and vitamin K
antagonists in clinical practice, it is important to consider that
patients treated with these agents will be exposed to different clinical situations (spontaneous or postoperative bleeding,
overdose, trauma, and elective or emergent surgical procedures) that require an intervention. There are also increasing
concerns about managing patients on these therapeutic agents
following trauma or in a perioperative setting. The purpose
of this review is (1) to examine the NOACs, focusing on key
pharmacologic properties, and (2) to provide management
approaches for users of NOACs in the perioperative and critical care settings based on the available literature.

Oral Direct Thrombin Inhibitors
Thrombin has a pivotal role in hemostasis, making it an
appealing target for anticoagulant drugs. When thrombin is
activated from prothrombin, it converts soluble fibrinogen
to insoluble fibrin; activates coagulation factors V, VIII, and
XI (which generate more thrombin); and activates platelets
(fig. 1).3 Dabigatran is a reversible direct thrombin inhibitor
that directly inhibits free and fibrin-bound thrombin without
the need for antithrombin. Dabigatran etexilate is a prodrug
that has a rapid onset of action, no reported food interactions,
few drug interaction, and does not require routine
coagulation monitoring. The peak plasma concentration
is reached 1.25–3  after administration, and it has a halfh
life of 12–14  in healthy volunteers.4 Dabigatran is 35%
h
bound to plasma proteins and undergoes renal excretion,
with 80% of the drug entering the urine unchanged. The
anticoagulant effect of dabigatran accumulates in the setting
of renal insufficiency, and such bioaccumulation correlates
well with the degree of renal dysfunction.5 In contrast to

other NOACs that are highly protein bound, the relatively
low protein binding of dabigatran allows it to be eliminated
to a large extent by hemodialysis.6 In cases of moderate
hepatic impairment, dabigatran can be administered safely
and no dose adjustment is necessary.7
Dabigatran is approved in the United States, Canada,
Europe, and Japan for stroke prevention in patients with
non-valvular AF based on the results of the Randomized
Evaluation of Long-term anticoagulant therapY (RE-LY)
trial in which 150 mg of dabigatran twice-daily was superior
to dose-adjusted warfarin with a similar rate of major bleeding.8 Dabigatran, 75  twice-daily, is approved for use in
mg
the United States for patients with severe renal insufficiency
(CrCl 15–30 
ml/min), based on indirect pharmacokinetic
modeling and the assumed anticoagulant effect with this
level of renal dysfunction. In Europe and Canada, the 75-mg
dose is not approved for clinical use and dabigatran is contraindicated in patients with a CrCl < 30 
ml/min. Dabigatran is also is approved for VTE prophylaxis following total
hip or knee replacement surgery in Europe and Canada, but
not the United States. A recent indirect network meta-analysis suggests that treatment with dabigatran offers benefit for
the prevention of stroke, systemic embolism, and mortality
over antiplatelets and placebo without increased intracranial
or extracranial hemorrhage compared to antiplatelet agents.9
Further investigations are needed to confirm these results.

Oral Direct Factor Xa Inhibitors
Factor Xa is another important target for anticoagulant
drugs due to its role as the rate-limiting factor in thrombin generation and amplification, generating the Xa complex that converts prothrombin to thrombin (fig. 1).2 The
direct factor Xa inhibitors inhibit free Factor Xa, Factor Xa
in the prothrombinase complex, and Factor Xa found in
clots, independent of an antithrombin cofactor.2,10 This is
in contrast to low-molecular-weight heparin, unfractionated
heparin, and fondaparinux, which all are dependent on antithrombin to inhibit Factor Xa.

Rivaroxaban

Fig. 1. Effect sites of anticoagulation agents. The new oral anticoagulation agents directly inhibit one of two major targets in
the coagulation cascade. Rivaroxaban and apixaban directly
inhibit factor Xa, and dabigatran directly inhibits thrombin.
The parenteral anticoagulants that inhibit factor Xa include
low-molecular-weight heparin (LMWH) and fondaparinux
by antithrombin (AT)-dependent binding. Parenteral direct
thrombin inhibitors include argatroban, bivalirudin, and desirudin that also directly inhibit thrombin independent of AT.
Anesthesiology 2013; 118:1466-74	

Rivaroxaban is an oral, direct Factor Xa inhibitor that has
good bioavailability (80%), is highly protein-bound, and
has few drug interactions. Peak plasma concentrations occur
within 2–4 h of administration, and rivaroxaban has a halflife of 5–9 h in healthy subjects and 11–13 h in the elderly.10
It is selective for Factor Xa in relation to other serine proteases.2 Clearance of rivaroxaban may be decreased to some
extent in patients with renal impairment,11 but its primary
mode of clearance is by non-renal mechanisms. It should be
noted that although some reports may indicate that approximately 67% of rivaroxaban is eliminated by the kidney, such
total renal clearance reflects 33% clearance of active drug
and 33% clearance of inactive rivaroxaban, which is not clinically important. Thus, two-thirds of the active rivaroxaban

1467	Levy et al.
Perioperative Management of New Oral Anticoagulants

are cleared by nonrenal mechanisms. Based on pharmacokinetic study, 10-mg rivaroxaban administered once daily
offers the best efficacy profile while avoiding excessive bleeding complications.12 In patients with AF, the recommended
rivaroxaban dose is 20  daily, although a reduced dose
mg
(15 mg daily) is recommended in patients with a CrCl 15–
30 ml/min.13 Due to high plasma protein binding (>90%),
rivaroxaban cannot be eliminated during hemodialysis.
Rivaroxaban is approved in the United States, Canada,
and Europe for VTE prophylaxis after hip or knee
replacement surgery and for stroke prevention in patients
with non-valvular AF. Rivaroxaban was recently approved for
treatment of deep vein thrombosis, pulmonary embolism,
and reduction in the risk of recurrence. In the Regulation
of Coagulation in Orthopedic surgery to pRevent Deep
venous thrombosis and pulmonary embolism (RECORD)
trials, rivaroxaban, 10  daily, was superior to enoxaparin
mg
30 mg twice-daily, and 40 mg once-daily for the prevention
of VTE after knee and hip replacement, respectively, without
a significant increase in the rate of major bleeding.14–17 In
terms of stroke prevention, the Rivaroxaban Once Daily
Oral Direct Factor Xa Inhibition Compared with Vitamin K
Antagonism for Prevention of Stroke and Embolism Trial in
Atrial Fibrillation (ROCKET AF) trial randomly allocated
(in a double-blind manner) 14,264 patients with AF to
rivaroxaban 20  daily (15  daily if CrCl 15–50 
mg
mg
ml/
min) compared to dose-adjusted warfarin and found that
rivaroxaban was not inferior to warfarin in efficacy, with no
significant difference in major bleeding events.18 In patients
with an acute coronary syndrome, the Anti-Xa Therapy to
Lower Cardiovascular Events in Addition to Standard Therapy
in Subjects with Acute Coronary Syndrome–Thrombolysis
in Myocardial Infarction 51 (ATLAS ACS2–TIMI 51)
compared rivaroxaban, 2.5  or 5  daily, to placebo in
mg
mg
patients who were receiving aspirin and a thienopyridine
(usually clopidogrel). Although the 2.5-mg dose regimen
conferred a significant reduction in cardiovascular and allcause mortality (and also led to more bleeding), the Food
and Drug Administration issued a “complete response letter”
and requested additional data.19

Apixaban
Apixaban is another oral, direct Factor Xa inhibitor with
good oral bioavailability (80%), is highly protein bound,
reaches peak plasma concentration within 2–3 h after intake,
and has limited potential for drug interactions.10 Apixaban
2.5  twice-daily is the recommended dose for VTE promg
phylaxis based on pharmacokinetic study.20 In patients who
received apixaban 2.5  twice-daily for VTE prophylaxis,
mg
the risk of major bleeding was not influenced by renal function.21 Moreover, in the Apixaban for Reduction in Stroke
and Other Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) trial, assessing apixaban 5 mg twice-daily for
stroke prevention, patients were excluded only if they had a
CrCl < 25 ml/min. For these reasons, no dose adjustment is
Anesthesiology 2013; 118:1466-74	

recommended in patients with mild (CrCl, 50–80 ml/min)
or moderate (CrCl, 30–50 
ml/min) renal impairment. The
half-life in healthy subjects is 8–15  10 Apixaban has been
h.
approved in Canada and Europe for VTE prophylaxis after
total hip and knee replacement surgery based on the results
of the ADVANCE trials.22,23 Apixaban is currently under
Food and Drug Administration review in the United States
for this indication. In the ARISTOLE trial, apixaban was
superior to dose-adjusted warfarin in preventing stroke and
systemic embolism, with a decrease in bleeding complications, and a lower mortality.24 The Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients
Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) study is noteworthy as it is the
only trial comparing treatment with a NOAC, in this case
apixaban 5  twice-daily, against aspirin (81–325 
mg
mg) for
stroke prevention in AF.25 Although it would be expected
that apixaban conferred a lower risk for stroke, what is surprising, perhaps, is that this treatment was not associated
with more bleeding compared with aspirin.25

Monitoring Anticoagulation with the NOACs
Although routine laboratory testing is not required in
NOAC-treated patients, except for periodic monitoring of
renal function (especially in patients with preexisting renal
impairment), coagulation function tests should be ordered
for any anticoagulated patient presenting with an acute
bleed, suspected overdose, or requiring emergency surgery.26
Due to the effect of dabigatran on thrombin-mediated conversion of fibrinogen to fibrin, most of the routine coagulation assays will be prolonged except the prothrombin time.27
The maximum effect of dabigatran on coagulation parameters occurs at the same time as peak plasma concentration.
For this reason, the delay between the last dabigatran dose
and the time of blood sampling is needed to interpret the
tests. The effects of dabigatran can be best measured using
the thrombin time or a dilute thrombin time, available as
the Hemoclot assay.28 Other assays that have been studied
include the ecarin clotting time, although this test is not
widely available.2,29 The thrombin time provides a direct
assessment of thrombin activity and increases linearly with
increasing dabigatran concentration; however, experience
with this assay indicates that it is overly sensitive to dabigatran levels and, consequently, the thrombin time may be prolonged in the setting of a clinically insignificant dabigatran
effect.28 The Hemoclot assay has better linear correlation to
plasma levels of dabigatran and is probably the most reliable
method to measure the anticoagulant effect of dabigatran.28
In the ecarin clotting time assay, prothrombin is converted
to meizothrombin, a prothrombin–thrombin intermediate,
by the snake venom ecarin, and dabigatran directly inhibits
this meizothrombin intermediate in a dose-dependent fashion but this assay is not frequently used.30 A more universally
available test, the activated partial thromboplastin time, can
also be used; however, the relationship between dabigatran

1468	Levy et al.
EDUCATION

Table 1.  Preoperative Discontinuation of Dabigatran
Based on Renal Function

point-of-care monitoring or rapid laboratory assays might be
required.

Timing of Last
Dose before Surgery
Renal Function
(CrCl, ml/min)
>80
50–80
30–50
<30

Half-life, h

Normal
Bleeding
Risk

High
Bleeding
Risk

13 (11–12)
15 (12–34)
18 (13–23)
27 (22–35)

1d
1d
>2 d
2–5 d

Temporary Discontinuation before Surgery
and Neuraxial Anesthesia

2–4 d
2–4 d
>4 d
>5 d

CrCl = creatinine clearance (ml/min); d = days.

concentration and partial thromboplastin time is curvilinear,
resulting in decreased precision of the assay as plasma dabigatran concentrations increase,29 and there may be interassay
variability in measurements. Nonetheless, the partial thromboplastin time provides a reasonable alternative if other tests
are not available and a normal partial thromboplastin time
will likely indicate the absence of a clinically important anticoagulant effect. Additional laboratory studies are urgently
needed to correlate coagulation assay results with varying
plasma levels of dabigatran.
Rivaroxaban and apixaban inhibit factor Xa directly, which
is in complex with FVa and independ of antithrombin.2
Rivaroxaban causes a prolongation of the prothrombin time,
although there may be considerable inter-assay variability in
such measurements, and has less of an effect on the partial
thromboplastin time. However, these tests are not useful for
measuring the pharmacodynamic effects of oral factors Xa
inhibitors.31 More recently, a specific assay has been developed
for the direct Xa inhibitors that is different from an antiXa
assay used to monitor low-molecular-weight heparin, and
may provide the optimal method for determining the effect
of rivaroxaban, although further studies are needed.2,32,33
Rivaroxaban
produces
a
concentration-dependent
prolongation of clotting parameters on thromboelastometry,
including R and K time without significant modification
of maximal amplitude, making this assay not useful for
routine monitoring.31 Until now, the lack of readily available
means for assessing the degree of anticoagulation remains a
notable concern, especially in a life-threatening bleed where

Before discontinuing any anticoagulant medication, the risk
of bleeding must be carefully weighed against the risk of
thrombosis. For dabigatran, which is eliminated primarily
by renal mechanisms, the timing of discontinuation should
be based on patients’ CrCl and the bleeding risk associated
with the procedure (table 1).34,35 Renal impairment may
be less important in patients taking rivaroxaban, in which
a decreased creatinine clearance appears to have a limited
effect on the half-life of the drug. In a study of patients with
renal impairment who are receiving a single 10-mg dose of
rivaroxaban, the mean half-life only increased very slightly
from 8.3 h in healthy controls to 9.5 h in patients with severe
renal impairment (CrCl < 30 ml/min).11
The Working Group on perioperative hemostasis and
the French Study Group on thrombosis and hemostasis
published recommendations about the perioperative management of NOACs.36,37 For scheduled surgery or invasive
procedures with low risk of bleeding, they recommend
interruption 24  (≈2 half-lives) before the procedure and
h
to restart 24 h after. In case of scheduled surgery or invasive
procedures at moderate or high risk of bleeding, a 5 days
interruption before surgery is recommended, while treatment should be restarted according to the bleeding risk. For
patients at higher thrombosis risk, unfractionated heparin
or low-molecular-weight heparin at curative dose should
be initiated 12  after the last dose of oral anticoagulants.
h
Although these recommendations are easy to use and appear
sensible, there is a need for prospective studies assessing the
efficacy and safety of these (and other) perioperative management protocols for NOAC-treated patients who require
an elective surgery/procedure.
The safety of neuraxial anesthesia for patients treated with
NOACs will be based on the pharmacokinetic properties of
the anticoagulant (table 2).36 Catheter placement and, to a
lesser extent, removal should be considered when anticoagulant concentrations are at their lowest, and patients should
be monitored closely for signs of hematoma in the initial
days after catheter removal. Specific recommendations for

Table 2.  Pharmacokinetics of the New Oral Anticoagulation Agents
Dabigatran
Route of administration
Bioavailability
Time to maximal concentration (Tmax)
Half-life
Renal excretion
Plasma protein binding
Anesthesiology 2013; 118:1466-74	

Rivaroxaban

Apixaban

Oral twice daily
6.5%
1.25–3 h
12–14 h
80%
35%

Oral once daily
80%
2–4 h
5–13 h
66%
>90%

Oral twice daily
66%
1–3 h
8–15 h
25%
87%

1469	Levy et al.
Perioperative Management of New Oral Anticoagulants

Table 3.  Recommendations for Novel Anticoagulants for Venous Thromboembolic Prophylaxis in the Setting of
Peridural/Regional Anesthesia36
Dabigatran

Rivaroxaban

Apixaban

2–4 h
NR*
6h

4–6 h
22–26 h
4–6 h

6h
26–30 h
4–6 h

Time between epidural anesthetic technique and next anticoagulant dose
Time before last anticoagulant dose and epidural catheter removal
Time between removal of epidural catheter and next anticoagulant dose

* Dabigatran in not recommended in patients undergoing anesthesia with postoperative indwelling catheters.
NR = not recommended.

managing these agents for venous thromboembolic prophylaxis in the setting of peridural/regional anesthesia are listed
in table 3. Rosencher38 suggests allowing at least two halflives to pass before catheter removal, at which point only
25% of the drug remains active. Allowing a longer interval
would only slightly reduce the drug concentration, because
elimination slows after this point.38 The risk of the residual
anticoagulant activity and neuraxial hematoma needs to be
weighed against the risk of VTE. However, the authors suggest that anticoagulation should be restarted after 8 h minus
the time to reach maximum activity (Tmax), based on the
their suggestion that it takes 8 h to establish a stable clot, and
allowing time for the peak of anticoagulation to be reached.38
However, there may be considerable variability in the time
needed to attain a dry vascular bed, especially after major
orthopedic or oncologic surgery, and longer times may be
needed because of the risk of bleeding compared to the risk
of VTE.38 Recommendations for the use of the new anticoagulants in the setting of neuraxial anesthesia have been
proposed by Llau et al.39 based on existing guidelines and the
pharmacokinetics of each drug (table 3).
A recent report evaluated bleeding rates from 7 days
prior until 30 days following invasive procedures for
patients receiving dabigatran.40 Based on 4,591 patients
who had a first treatment interruption for an elective surgery
or invasive procedure, 24.7% of patients were receiving
dabigatran—110 
mg, 25.4% were on dabigatran—150 
mg,
and 25.9% were on warfarin. The procedures included the

following: pacemaker/defibrillator insertion (10.3%), dental
procedures (10.0%), diagnostic procedures (10.0%), cataract
removal (9.3%), colonoscopy (8.6%), and joint replacement
(6.2%). The last dose of dabigatran was given a mean of 49
(range: 35–85) h before the procedure, compared to a mean
of 114 (range: 87–144) h for the last preprocedure dose of
warfarin (P < 0.001). There was no significant difference in
the rates of periprocedural major bleeding between patients
receiving dabigatran, 110 mg (3.8%), or dabigatran, 150 mg
(5.1%), or warfarin (4.6%). The relative risk for major
bleeding with dabigatran-110  versus warfarin was 0.83
mg
(95% CI, 0.59–1.17; P = 0.28), and with dabigatran-150 mg
versus warfarin, it was 1.09 (95% CI, 0.80–1.49; P = 0.58).
Among patients having urgent surgery, major bleeding
occurred in 17.8% with dabigatran-110, 17.7% with
dabigatran-150, and 21.6% with warfarin: dabigatran-110.
There are no published data on perioperative outcomes
in patients receiving rivaroxaban or apixaban who require
elective or urgent surgery/procedures, although the same
management principles should apply that incorporate
procedure bleeding risk and drug elimination as with
dabigatran-treated patients.

Reversal of the Novel Anticoagulants and
Management of Acute Bleeding
Immediate reversal of anticoagulation is often needed in the
bleeding patient or patient requiring emergency surgery.
Current dosing and indications for these agents are listed in

Table 4.  Current Dosing Guidelines for New Oral Anticoagulation Agents
Dabigatran
Dosing for atrial fibrillation:
normal renal function
Dosing for atrial fibrillation:
  renal dysfunction

Rivaroxaban

Apixiban*

150 mg BID

20 mg QD

5 mg BID

15 mg QD with CrCl 15–50 ml/min

2.5 mg BID

DVT prophylaxis

110 mg BID
United States: 75 mg BID with CrCl
  15–30 ml/min
220 mg QD

10 mg QD†

2.5 mg BID

Renal dysfunction

150 mg QD

Avoid with CrCl < 30 ml/min

Not approved in the United States
  for this indication
* For apixaban, no data available for use with CrCl < 15 ml/min or on dialysis. † For hip and knee surgery.
BID = twice a day; CrCl = creatinine clearance; QD = daily.

Anesthesiology 2013; 118:1466-74	

1470	Levy et al.
EDUCATION

table 4. Although managing any anticoagulation agent in a
bleeding patient is a challenge, it is important to note that
warfarin and other vitamin K antagonist agents are not easily
reversible with therapies available in the United States, such
as vitamin K and/or fresh frozen plasma. Four-component
prothrombin complex concentrates (PCCs) are currently
preferred in Canada and most European countries and recommended in recent guidelines.37,41,42 Stopping a NOAC
and providing supportive care are the most important consideration and are often sufficient if the bleeding is not severe
or if surgery can be delayed. However, when patients present
with a major bleeding episode related to these agents and/or
require emergency surgery, other measures must be taken.
For any significant bleeding event, initial measures should
include volume resuscitation with fluids and/or packed red
blood cells, identification of the bleeding source, and attempts
at local hemostatic control. If an anticoagulant overdose is
the suspected cause, activated charcoal may be effective in
preventing additional drug absorption when administered
within 1–2  of ingestion. Activated charcoal has not been
h
used in the clinical setting and is limited by its narrow window of use and inability to use in a perioperative setting.
Hemodialysis or hemoperfusion is another potential
option for the emergent removal of anticoagulants.
Rivaroxaban and apixaban are too highly protein bound to
be effectively removed by these methods, but dabigatran is
an appropriate candidate for these therapies.10 In a study of
six volunteers with end-stage renal disease who were given a
50-mg dose of dabigatran before routine hemodialysis, an
average of 62% of the active dabigatran was removed after
2 h and 68% after 4 h.5 Unfortunately, attempting to perform
either of these procedures in a bleeding patient in shock may
not be possible.29 Therefore, the use of procoagulant agents
should be considered for a life-threatening bleed. However,
unlike when fresh frozen plasma or PCCs are used to replace
depleted factors II, VII, IX, and X in warfarin-treated
patients, the effectiveness of such clotting factor replacement
therapies may be limited in NOAC-treated patients who
do not harbor deficiencies of clotting factors but in whom
there is an ongoing clotting factor inhibitory effect. It may
be argued, therefore, that providing supraphysiologic levels
of clotting factors may be ineffective in the setting of an
ongoing NOAC-related inhibitory effect. On the contrary,
such clotting factors may overwhelm such an ongoing
inhibitory effect and, in cases of severe bleeding, may replace
clotting factors that are depleted due to consumption.
Although fresh frozen plasma is commonly administered
for initial control of bleeding in anticoagulated patients, its
use as a reversal agent for the NOACs has not been studied
in humans.43 In a study of mice pretreated with dabigatran
(4.5 
mg/kg or 9.0 
mg/kg) before induction of intracranial
hemorrhage, fresh frozen plasma administration successfully
limited hematoma expansion in the low-dose group but had
no effect in the high-dose group and did not significantly
Anesthesiology 2013; 118:1466-74	

decrease mortality. There is insufficient evidence to recommend its use.43,44
Recombinant factor VIIa (rFVIIa) is increasingly used in
an “off-label” manner as a universal hemostatic and reversal agent. However, it has not been studied in humans for
reversal of NOACs, and the results of studies in animal models are inconclusive. The benefit-to-risk balance for rFVIIa
must be carefully weighed, as rFVIIa has been associated
with an increased risk of arterial thrombosis among elderly
patients.45,46 In several animal models, rFVIIa reversed bleeding time prolongation associated with dabigatran and rivaroxaban, but it did not correct the underlying coagulopathy
as suggested by other laboratory markers.44 In one study, rats
received high-dose dabigatran before a standard tail incision,
prolonging the bleeding time from 125 s in controls to 1455
s. A 0.5 mg/kg dose of rFVIIa decreased this bleeding time to
135 s. The partial thromboplastin time was 58 s after dabigatran exposure, versus 7 s in controls, and administration of
rFVIIa reduced this to 27 s. In a similar study that exposed
rats to supratherapeutic dabigatran levels, administration of
rFVIIa rapidly corrected the bleeding time and preserved
this effect for the entire 2-h study period.47 However, of the
coagulation markers examined, only the prothrombin time
was completely corrected. The partial thromboplastin time,
the ecarin clotting time, and the thrombin time all failed to
normalize.47
PCCs are available as three-factor (II, IX, X) and fourfactor (II, VII, IX, X) varieties that are procoagulant and
enhance thrombin generation.42 The four-factor PCCs have
activated and nonactivated forms, and only three-factor
PCCs are available in the United States.44 Small quantities of
heparin, antithrombin, protein C, and protein S are added
to the concentrates to reduce coagulation activation through
endogenous pathways,48 but caution is required for off-label
use as thrombotic events in 1–3% of treated patients have
been reported with both formulations.49,50
Unlike the other procoagulant agents, four-factor PCCs
have been studied as potential reversal agents in humans. In a
small, randomized, double-blinded, placebo-controlled trial,
12 healthy men were given dabigatran 150  twice-daily
mg
or (supratherapeutic) rivaroxaban 20  twice-daily for 2.5
mg
days, and subsequently received either a 50 IU/kg bolus of a
four-factor PCC or saline.51 They were switched to the other
anticoagulant following a wash-out period and the procedure
was repeated. The addition of the PCC completely reversed
both the prothrombin time prolongation and inhibition of
endogenous thrombin potential associated with rivaroxaban, but
only laboratory parameters were evaluated in this study, and no
bleeding outcomes were measured in the volunteers. However,
dabigatran-associated prolongations in the clotting assays and
endogenous thrombin potential lag time were not corrected by
the administration of the PCC. Recently, in an animal model,
although both rFVIIa and PCC partially corrected laboratory
assays (thromboelastography and thrombin generation assay),
none of them reduced bleeding induced by rivaroxaban.52

1471	Levy et al.
Perioperative Management of New Oral Anticoagulants

Fig. 2. Management strategies for patients bleeding who have received the novel oral anticoagulation agents. In cases of mild
bleeding, stopping or delaying the next dose should be considered. The new agents including dabigatran, rivaroxaban, and
recently approved apixiban have relatively short half-lives, so stopping the drug in patients with normal renal function, the anticoagulant effect rapidly decreases compared to warfarin. In patients with moderate to severe bleeding, standard therapeutic
approaches should be considered, including supportive care that includes volume resuscitation, hemodynamic support with
vasoactive therapy, blood product transfusions as determined by testing, and identification of bleeding source that may require
surgical or another intervention. If the agents were taken within ≈2  of admission, administration of oral activated charcoal
h
should be considered. For dabigatran,† hemodialysis can remove ≈60% of the drug after several hours of dialysis and should be
considered in patients with impaired renal function who are bleeding and will have altered clearance. Apixaban and rivaroxaban
are highly protein bound and will not be cleared by hemodialysis. However, emergency access for hemodialysis requires vascular access with large bore catheters that may pose additional risk in the anticoagulated patient. For patients with life-threatening
bleeding, hemodynamic and hemostatic resuscitation should be considered, with therapy similar to that for a trauma patient
including the use of a massive transfusion protocol. Based on current data as discussed in the manuscript, the use of either
three-factor or four-factor prothrombin complex concentrates (PCCs) depending on their availability should be considered as
they have been shown to reverse or partially reverse the anticoagulation effect of the newer agents. ‡ In patients receiving
dabigatran, the use of an activated PCC may be more effective. † However, there are no studies reporting the use of PCCs on
actual bleeding in patients, and further studies including the development of specific reversal agents are underway currently. In
hypotensive patients, hemodialysis is unlikely to be tolerated, and alternate methods for hemofiltration should be considered if
needed. † The use of recombinant activated factor VIIa (rVIIa) decreases bleeding times in animal models, but there are no human studies to determine if this is effective. † = for dabigatran. ‡ = for rivaroxaban and apixiban.

Marlu et al.53 evaluated dabigatran and rivaroxaban reversal using thrombin generation tests evaluating 10 healthy
volunteers randomized to receive rivaroxaban (20 
mg) or
dabigatran (150 mg) orally in a cross-over study, and blood
was collected 2  post-ingestion. Anticoagulation reversal
h
was tested in vitro using PCC, rFVIIa, or factor eight inhibitory bypass activity at different concentrations.53 In rivaroxaban-treated patients, PCC and factor eight inhibitory
bypass activity corrected thrombin generation, but rFVIIa
only modified the kinetic parameters. In dabigatran-treated
patients, PCC increased thrombin generation as determined
by area under the curve, but only rFVIIa and factor eight
inhibitory bypass activity corrected the altered lag time.53

Ongoing clinical studies are needed to determine the
best method for reversal of the NOACs when bleeding
occurs. Based on the available evidence, supportive care
and interventions as discussed including dialysis for dabigatran should be considered in a bleeding patient and
potential therapeutic approaches as listed in figure 2. For
rivaroxaban-treated patients, studies in volunteers suggest the PCCs may be effective, but additional studies are
needed. When possible, these drugs should be stopped
preoperatively at times based on renal function and procedure.54 Additional drug-specific antidotes are also under
investigation.

Summary

	 1.	 Eikelboom JW, Weitz JI: New anticoagulants. Circulation
2010; 121:1523–32
	 2.	 Levy JH, Key NS, Azran MS: Novel oral anticoagulants:
Implications in the perioperative setting. Anesthesiology
2010; 113:726–45
	 3.	 Weitz JI: Factor Xa or thrombin: Is thrombin a better target?
J Thromb Haemost 2007; 5:65–7
	 4.	 Eriksson BI, Quinlan DJ, Weitz JI: Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and

Common principles of bleeding management as with any
anticoagulant (including the known principles for warfarin) should be followed in patients receiving dabigatran.
Hemodialysis is an additional, unique therapeutic option
for urgently reducing exposure to dabigatran that has not
been shown to be useful for other new oral anticoagulants.
Anesthesiology 2013; 118:1466-74	

‍References

1472	Levy et al.
EDUCATION

factor xa inhibitors in development. Clin Pharmacokinet
2009; 48:1–22
	 5.	 Stangier J, Rathgen K, Stähle H, Mazur D: Influence of renal
impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: An open-label, parallel-group,
single-centre study. Clin Pharmacokinet 2010; 49:259–68
	 6.	 Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti
V, Slowinski T, Neumayer HH, Liesenfeld KH, Lehr T, Hartter
S, Friedman J, Peters H, Clemens A: Effective elimination of
dabigatran by haemodialysis: A phase I single-centre study in
patients with end-stage renal disease. Thromb Haemost 2013
Feb 7; 109 [Epub ahead of print]
	 7.	 Stangier J, Stähle H, Rathgen K, Roth W, Shakeri-Nejad K:
Pharmacokinetics and pharmacodynamics of dabigatran
etexilate, an oral direct thrombin inhibitor, are not affected
by moderate hepatic impairment. J Clin Pharmacol 2008;
48:1411–9
	 8.	 Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J,
Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S,
Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener
HC, Joyner CD, Wallentin L; RE-LY Steering Committee and
Investigators: Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med 2009; 361:1139–51
	 9.	 Roskell NS, Lip GY, Noack H, Clemens A, Plumb JM:
Treatments for stroke prevention in atrial fibrillation: A network meta-analysis and indirect comparisons versus dabigatran etexilate. Thromb Haemost 2010; 104:1106–15
1
	 0.	 Eriksson BI, Quinlan DJ, Weitz JI: Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and
factor xa inhibitors in development. Clin Pharmacokinet
2009; 48:1–22
1
	 1.	 Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause
N, Lufft V, Wand DD, Philipp T, Bruck H: Effects of renal
impairment on the pharmacokinetics, pharmacodynamics
and safety of rivaroxaban, an oral, direct Factor Xa inhibitor.
Br J Clin Pharmacol 2010; 70:703–12
1
	 2.	 Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV,
Kakkar AK, Muehlhofer E, Dierig C, Misselwitz F, Kälebo
P; ODIXa-HIP Study Investigators: A once-daily, oral, direct
Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006;
114:2374–81
1
	 3.	 Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel
CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer
DE, Califf RM: Prevention of stroke and systemic embolism
with rivaroxaban compared with warfarin in patients with
non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32:2387–94
1
	 4.	 Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman
MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E,
Misselwitz F, Geerts W; RECORD1 Study Group: Rivaroxaban
versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358:2765–75
1
	 5.	 Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P,
Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2
Investigators: Extended duration rivaroxaban versus shortterm enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: A double-blind, randomised
controlled trial. Lancet 2008; 372:31–9
1
	 6.	 Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N,
Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators:
Rivaroxaban versus enoxaparin for thromboprophylaxis after
total knee arthroplasty. N Engl J Med 2008; 358:2776–86
1
	 7.	 Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M,
Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ,
Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators:
Rivaroxaban versus enoxaparin for thromboprophylaxis
after total knee arthroplasty (RECORD4): A randomised trial.
Lancet 2009; 373:1673–80
Anesthesiology 2013; 118:1466-74	

1
	 8.	 Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke
W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker
RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM;
ROCKET AF Investigators: Rivaroxaban versus warfarin in
nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91
1
	 9.	 Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL,
Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S,
Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW,
Gibson CM; ATLAS ACS 2–TIMI 51 Investigators: Rivaroxaban
in patients with a recent acute coronary syndrome. N Engl J
Med 2012; 366:9–19
2
	 0.	 Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M:
Quantification of apixaban’s therapeutic utility in prevention of venous thromboembolism: Selection of phase III trial
dose. Clin Pharmacol Ther 2010; 88:375–82
2
	 1.	 DeLoughery TG: Practical aspects of the oral new anticoagulants. Am J Hematol 2011; 86:586–90
2
	 2.	 Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick
P; ADVANCE-2 investigators: Apixaban versus enoxaparin for
thromboprophylaxis after knee replacement (ADVANCE-2):
A randomised double-blind trial. Lancet 2010; 375:807–15
2
	 3.	 Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez
LM; ADVANCE-3 Investigators: Apixaban versus enoxaparin
for thromboprophylaxis after hip replacement. N Engl J Med
2010; 363:2487–98
2
	 4.	 Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek
EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A,
Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia
D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG,
Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS,
Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu
J, Wallentin L; ARISTOTLE Committees and Investigators:
Apixaban versus warfarin in patients with atrial fibrillation.
N Engl J Med 2011; 365:981–92
2
	 5.	 Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R,
Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R,
Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky
P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem
W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo
A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis
G, Afzal R, Yusuf S; AVERROES Steering Committee and
Investigators: Apixaban in patients with atrial fibrillation. N
Engl J Med 2011; 364:806–17
2
	 6.	 Garcia D, Libby E, Crowther MA: The new oral anticoagulants. Blood 2010; 115:15–20
2
	 7.	 van Ryn J, Baruch L, Clemens A: Interpretation of point-ofcare INR results in patients treated with dabigatran. Am J
Med 2012; 125:417–20
2
	 8.	 Stangier J, Feuring M: Using the HEMOCLOT direct thrombin
inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23:138–43
2
	 9.	 van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W,
Feuring M, Clemens A: Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb
Haemost 2010; 103:1116–27
3
	 0.	 Stangier J, Rathgen K, Stähle H, Gansser D, Roth W: The
pharmacokinetics, pharmacodynamics and tolerability of
dabigatran etexilate, a new oral direct thrombin inhibitor, in
healthy male subjects. Br J Clin Pharmacol 2007; 64:292–303
3
	 1.	 Samama MM, Martinoli JL, LeFlem L, Guinet C, Plu-Bureau
G, Depasse F, Perzborn E: Assessment of laboratory assays
to measure rivaroxaban–an oral, direct factor Xa inhibitor.
Thromb Haemost 2010; 103:815–25
3
	 2.	 Favaloro EJ, Lippi G, Koutts J: Laboratory testing of anticoagulants: The present and the future. Pathology 2011;
43:682–92
3
	 3.	 Samama MM, Amiral J, Guinet C, Perzborn E, Depasse F: An
optimised, rapid chromogenic assay, specific for measuring

1473	Levy et al.
Perioperative Management of New Oral Anticoagulants

direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb
Haemost 2010; 104:1078–9
3
	 4.	 Stangier J, Rathgen K, Stähle H, Mazur D: Influence of renal
impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: An open-label, parallel-group,
single-centre study. Clin Pharmacokinet 2010; 49:259–68
3
	 5.	 Huisman MV, Lip GY, Diener HC, Brueckmann M, van Ryn
J, Clemens A: Dabigatran etexilate for stroke prevention in
patients with atrial fibrillation: Resolving uncertainties in
routine practice. Thromb Haemost 2012; 107:838–47
3
	 6.	 Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV,
Samama CM; European Scoeity of Anaesthesiology: Regional
anaesthesia and antithrombotic agents: Recommendations of
the European Society of Anaesthesiology. Eur J Anaesthesiol
2010; 27:999–1015
3
	 7.	 Sié P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV,
Van der Linden P, Pernod G, Lecompte T, Gouin-Thibault I,
Albaladejo P; Working Group on Perioperative Haemostasis;
French Study Group on Thrombosis and Haemostasis:
Surgery and invasive procedures in patients on long-term
treatment with direct oral anticoagulants: Thrombin or factor-Xa inhibitors. Recommendations of the Working Group
on Perioperative Haemostasis and the French Study Group
on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011;
104:669–76
3
	 8.	 Rosencher N, Bonnet MP, Sessler DI: Selected new antithrombotic agents and neuraxial anaesthesia for major
orthopaedic surgery: Management strategies. Anaesthesia
2007; 62:1154–60
3
	 9.	 Llau JV, Ferrandis R: New anticoagulants and regional anesthesia. Curr Opin Anaesthesiol 2009; 22: 661–6
4
	 0.	 Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J,
Yang S, Themeles E, Heidbuchel H, Heidbuchle H, Avezum
A, Reilly P, Connolly SJ, Yusuf S, Ezekowitz M; RE-LY
Investigators: Periprocedural bleeding and thromboembolic
events with dabigatran compared with warfarin: Results from
the Randomized Evaluation of Long-Term Anticoagulation
Therapy (RE-LY) randomized trial. Circulation 2012;
126:343–8
4
	 1.	 Garcia D: Rethinking warfarin reversal. Blood 2010;
116:675–6
4
	 2.	 Levy JH, Tanaka KA, Dietrich W: Perioperative hemostatic
management of patients treated with vitamin K antagonists.
Anesthesiology 2008; 109:918–26
4
	 3.	 van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W,
Feuring M, Clemens A: Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb
Haemost 2010; 103:1116–27

Anesthesiology 2013; 118:1466-74	

4
	 4.	 Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther
M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van
Cott EM, Ansell J: Guidance on the emergent reversal of
oral thrombin and factor Xa inhibitors. Am J Hematol 2012;
87:S141–5
4
	 5.	 Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde
C: Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane
Database Syst Rev 2012; 3:CD005011
4
	 6.	 Levi M, Levy JH, Andersen HF, Truloff D: Safety of recombinant activated factor VII in randomized clinical trials. N Engl
J Med 2010; 363:1791–800
4
	 7.	 van Ryn J, Schurer J, Knk-Elband M, Clemens A: The successful reversal of dabigatran induced bleeding by coagulation
factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood 2011;
118: Abst 2318
4
	 8.	 Patanwala AE, Acquisto NM, Erstad BL: Prothrombin complex concentrate for critical bleeding. Ann Pharmacother
2011; 45:990–9
4
	 9.	 Arnold DM, Dentali F, Crowther MA, Meyer RM, Cook RJ,
Sigouin C, Fraser GA, Lim W, Kelton JG: Systematic review:
Efficacy and safety of rituximab for adults with idiopathic
thrombocytopenic purpura. Ann Intern Med 2007; 146:25–33
5
	 0.	 Dentali F, Marchesi C, Pierfranceschi MG, Crowther M,
Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti
D, Ageno W: Safety of prothrombin complex concentrates
for rapid anticoagulation reversal of vitamin K antagonists. A
meta-analysis. Thromb Haemost 2011; 106:429–38
5
	 1.	 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC,
Buller HR, Levi M: Reversal of rivaroxaban and dabigatran by
prothrombin complex concentrate: A randomized, placebocontrolled, crossover study in healthy subjects. Circulation
2011; 124:1573–9
5
	 2.	 Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM,
Emmerich J, Marchand-Leroux C, Lecompte T, Samama CM:
Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit
model. Anesthesiology 2012; 116:94–102
5
	 3.	 Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL,
Pernod G: Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: A randomised
crossover ex vivo study in healthy volunteers. Thromb
Haemost 2012; 108:217–24
5
	 4.	 Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther
M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van
Cott EM, Ansell J: Guidance on the emergent reversal of
oral thrombin and factor Xa inhibitors. Am J Hematol 2012;
87:S141–5

1474	Levy et al.

Weitere ähnliche Inhalte

Was ist angesagt?

Pedaitric Cardiology 2016 Tentative Programme
Pedaitric Cardiology 2016 Tentative ProgrammePedaitric Cardiology 2016 Tentative Programme
Pedaitric Cardiology 2016 Tentative Programmekiara Samantha
 
Journal club gkrs residual pituitary macroadenoma
Journal club gkrs residual pituitary macroadenomaJournal club gkrs residual pituitary macroadenoma
Journal club gkrs residual pituitary macroadenomaMQ_Library
 
Journal club 5.2.19
Journal club 5.2.19Journal club 5.2.19
Journal club 5.2.19MQ_Library
 
Surgical versus non-surgical treatment for humeral shaft fractures in adults ...
Surgical versus non-surgical treatment for humeral shaft fractures in adults ...Surgical versus non-surgical treatment for humeral shaft fractures in adults ...
Surgical versus non-surgical treatment for humeral shaft fractures in adults ...mgosler
 
Mmd + aneurysms ebs
Mmd + aneurysms ebsMmd + aneurysms ebs
Mmd + aneurysms ebsMQ_Library
 
Repeat steroids for flm 2 (1)
Repeat steroids for flm 2 (1)Repeat steroids for flm 2 (1)
Repeat steroids for flm 2 (1)Asha Reddy
 
Ebs staged srs for large am vs_june - copy
Ebs staged srs for large am vs_june - copyEbs staged srs for large am vs_june - copy
Ebs staged srs for large am vs_june - copyMQ_Library
 
Radiologists Should Be Vigilant Of Alendronate
Radiologists Should Be Vigilant Of AlendronateRadiologists Should Be Vigilant Of Alendronate
Radiologists Should Be Vigilant Of Alendronatehatch_xanadu
 
Macquarie Neurosrgery Evidence Based Surgery
Macquarie Neurosrgery Evidence Based SurgeryMacquarie Neurosrgery Evidence Based Surgery
Macquarie Neurosrgery Evidence Based SurgeryMQ_Library
 
Giant intracranial aneurysms bervini
Giant intracranial aneurysms berviniGiant intracranial aneurysms bervini
Giant intracranial aneurysms berviniMQ_Library
 

Was ist angesagt? (20)

Tentative Programme
Tentative ProgrammeTentative Programme
Tentative Programme
 
Pedaitric Cardiology 2016 Tentative Programme
Pedaitric Cardiology 2016 Tentative ProgrammePedaitric Cardiology 2016 Tentative Programme
Pedaitric Cardiology 2016 Tentative Programme
 
Knight Seminar Series 11/15/11
Knight Seminar Series 11/15/11Knight Seminar Series 11/15/11
Knight Seminar Series 11/15/11
 
DCH knight flier olwin cme 121311
DCH knight flier olwin cme 121311DCH knight flier olwin cme 121311
DCH knight flier olwin cme 121311
 
Journal club gkrs residual pituitary macroadenoma
Journal club gkrs residual pituitary macroadenomaJournal club gkrs residual pituitary macroadenoma
Journal club gkrs residual pituitary macroadenoma
 
Journal club 5.2.19
Journal club 5.2.19Journal club 5.2.19
Journal club 5.2.19
 
Surgical versus non-surgical treatment for humeral shaft fractures in adults ...
Surgical versus non-surgical treatment for humeral shaft fractures in adults ...Surgical versus non-surgical treatment for humeral shaft fractures in adults ...
Surgical versus non-surgical treatment for humeral shaft fractures in adults ...
 
EVALUATION OF ANTERIOR SEGMENT IMAGING TECHNIQUES IN DIAGNOSIS OF KERATOCONUS
EVALUATION OF ANTERIOR SEGMENT IMAGING TECHNIQUES IN DIAGNOSIS OF KERATOCONUSEVALUATION OF ANTERIOR SEGMENT IMAGING TECHNIQUES IN DIAGNOSIS OF KERATOCONUS
EVALUATION OF ANTERIOR SEGMENT IMAGING TECHNIQUES IN DIAGNOSIS OF KERATOCONUS
 
Mmd + aneurysms ebs
Mmd + aneurysms ebsMmd + aneurysms ebs
Mmd + aneurysms ebs
 
Repeat steroids for flm 2 (1)
Repeat steroids for flm 2 (1)Repeat steroids for flm 2 (1)
Repeat steroids for flm 2 (1)
 
Ebs staged srs for large am vs_june - copy
Ebs staged srs for large am vs_june - copyEbs staged srs for large am vs_june - copy
Ebs staged srs for large am vs_june - copy
 
Radiologists Should Be Vigilant Of Alendronate
Radiologists Should Be Vigilant Of AlendronateRadiologists Should Be Vigilant Of Alendronate
Radiologists Should Be Vigilant Of Alendronate
 
Jurnal pediatric
Jurnal pediatricJurnal pediatric
Jurnal pediatric
 
P.natal
P.natalP.natal
P.natal
 
Macquarie Neurosrgery Evidence Based Surgery
Macquarie Neurosrgery Evidence Based SurgeryMacquarie Neurosrgery Evidence Based Surgery
Macquarie Neurosrgery Evidence Based Surgery
 
Wiedmann ebs
Wiedmann ebsWiedmann ebs
Wiedmann ebs
 
Ebs hfs + an
Ebs hfs + anEbs hfs + an
Ebs hfs + an
 
Giant intracranial aneurysms bervini
Giant intracranial aneurysms berviniGiant intracranial aneurysms bervini
Giant intracranial aneurysms bervini
 
4 07 14
4 07 144 07 14
4 07 14
 
Tlso ebs
Tlso ebsTlso ebs
Tlso ebs
 

Andere mochten auch

ICU topics for Final FRCA
ICU topics for Final FRCAICU topics for Final FRCA
ICU topics for Final FRCAAndrew Ferguson
 
New approaches to chronic anticoagulatio na
New approaches to chronic anticoagulatio naNew approaches to chronic anticoagulatio na
New approaches to chronic anticoagulatio naMario Wilmath
 
Meningitis antibiotics mechanism of action
Meningitis antibiotics mechanism of actionMeningitis antibiotics mechanism of action
Meningitis antibiotics mechanism of actionMario Wilmath
 
FICM RA/Faculty Tutor Day
FICM RA/Faculty Tutor DayFICM RA/Faculty Tutor Day
FICM RA/Faculty Tutor DaySteve Mathieu
 
Rob Mac Sweeney's FFICM Hot Topics Talk March 2016
Rob Mac Sweeney's FFICM Hot Topics Talk March 2016Rob Mac Sweeney's FFICM Hot Topics Talk March 2016
Rob Mac Sweeney's FFICM Hot Topics Talk March 2016robmacsweeney
 
Hot Topics - FFICM Preparation Course 230215
Hot Topics - FFICM Preparation Course  230215Hot Topics - FFICM Preparation Course  230215
Hot Topics - FFICM Preparation Course 230215robmacsweeney
 
Chest radiology in intensive care
Chest radiology in intensive careChest radiology in intensive care
Chest radiology in intensive careAndrew Ferguson
 

Andere mochten auch (8)

ICU topics for Final FRCA
ICU topics for Final FRCAICU topics for Final FRCA
ICU topics for Final FRCA
 
New approaches to chronic anticoagulatio na
New approaches to chronic anticoagulatio naNew approaches to chronic anticoagulatio na
New approaches to chronic anticoagulatio na
 
Meningitis antibiotics mechanism of action
Meningitis antibiotics mechanism of actionMeningitis antibiotics mechanism of action
Meningitis antibiotics mechanism of action
 
FICM RA/Faculty Tutor Day
FICM RA/Faculty Tutor DayFICM RA/Faculty Tutor Day
FICM RA/Faculty Tutor Day
 
Rob Mac Sweeney's FFICM Hot Topics Talk March 2016
Rob Mac Sweeney's FFICM Hot Topics Talk March 2016Rob Mac Sweeney's FFICM Hot Topics Talk March 2016
Rob Mac Sweeney's FFICM Hot Topics Talk March 2016
 
ICU Trials summary
ICU Trials summaryICU Trials summary
ICU Trials summary
 
Hot Topics - FFICM Preparation Course 230215
Hot Topics - FFICM Preparation Course  230215Hot Topics - FFICM Preparation Course  230215
Hot Topics - FFICM Preparation Course 230215
 
Chest radiology in intensive care
Chest radiology in intensive careChest radiology in intensive care
Chest radiology in intensive care
 

Ähnlich wie Managing new oral anticoagulants in the ICU

Current diagnosis-and-therapy-for-head-and-neck-mal
Current diagnosis-and-therapy-for-head-and-neck-malCurrent diagnosis-and-therapy-for-head-and-neck-mal
Current diagnosis-and-therapy-for-head-and-neck-malBurhan Khan
 
Soap consensus statement thrombocytopenia 2021
Soap consensus statement thrombocytopenia 2021Soap consensus statement thrombocytopenia 2021
Soap consensus statement thrombocytopenia 2021Omar C.
 
Vol 21.1_Spinal Cord Disorders.2015.pdf
Vol 21.1_Spinal Cord Disorders.2015.pdfVol 21.1_Spinal Cord Disorders.2015.pdf
Vol 21.1_Spinal Cord Disorders.2015.pdfssuser6895ff
 
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...SMA - Serviços Médicos de Anestesia
 
Challenges in pediatric ambulatory anesthesia kids are different
Challenges in pediatric ambulatory anesthesia kids are differentChallenges in pediatric ambulatory anesthesia kids are different
Challenges in pediatric ambulatory anesthesia kids are differentsxbenavides
 
Estudio antes después abcde bundle 2014
Estudio antes después abcde bundle 2014Estudio antes después abcde bundle 2014
Estudio antes después abcde bundle 2014Roccio Menzel
 
Aarc cpg managment of pediatric patietns with a trachesostomy tube
Aarc cpg managment of pediatric patietns with a trachesostomy tubeAarc cpg managment of pediatric patietns with a trachesostomy tube
Aarc cpg managment of pediatric patietns with a trachesostomy tubemariana celiz alonso
 
Closed Head Injury Essay
Closed Head Injury EssayClosed Head Injury Essay
Closed Head Injury EssayMyel Ramos
 
Fluorinated steroids do not improve
Fluorinated steroids do not improveFluorinated steroids do not improve
Fluorinated steroids do not improvegisa_legal
 
Mascarillas quirurgicas, N95 e influenza
Mascarillas quirurgicas, N95 e influenzaMascarillas quirurgicas, N95 e influenza
Mascarillas quirurgicas, N95 e influenzafranklinaranda
 
cancer de seno metastasico
cancer de seno metastasicocancer de seno metastasico
cancer de seno metastasicoGuillermo Sarah
 
Lower versus higher hemoglobin threshold for transfusion in septic shock
Lower versus higher hemoglobin threshold for transfusion in septic shockLower versus higher hemoglobin threshold for transfusion in septic shock
Lower versus higher hemoglobin threshold for transfusion in septic shockDr. Victor Euclides Briones Morales
 

Ähnlich wie Managing new oral anticoagulants in the ICU (20)

Current diagnosis-and-therapy-for-head-and-neck-mal
Current diagnosis-and-therapy-for-head-and-neck-malCurrent diagnosis-and-therapy-for-head-and-neck-mal
Current diagnosis-and-therapy-for-head-and-neck-mal
 
Soap consensus statement thrombocytopenia 2021
Soap consensus statement thrombocytopenia 2021Soap consensus statement thrombocytopenia 2021
Soap consensus statement thrombocytopenia 2021
 
Vol 21.1_Spinal Cord Disorders.2015.pdf
Vol 21.1_Spinal Cord Disorders.2015.pdfVol 21.1_Spinal Cord Disorders.2015.pdf
Vol 21.1_Spinal Cord Disorders.2015.pdf
 
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
Artigo - Practice Guidelines for the Perioperative Management of Patients wit...
 
Journal of Case reports
Journal of Case reportsJournal of Case reports
Journal of Case reports
 
Challenges in pediatric ambulatory anesthesia kids are different
Challenges in pediatric ambulatory anesthesia kids are differentChallenges in pediatric ambulatory anesthesia kids are different
Challenges in pediatric ambulatory anesthesia kids are different
 
Estudio antes después abcde bundle 2014
Estudio antes después abcde bundle 2014Estudio antes después abcde bundle 2014
Estudio antes después abcde bundle 2014
 
Anal cancer
Anal cancerAnal cancer
Anal cancer
 
EUGENE_MYERS.PDF
EUGENE_MYERS.PDFEUGENE_MYERS.PDF
EUGENE_MYERS.PDF
 
Aarc cpg managment of pediatric patietns with a trachesostomy tube
Aarc cpg managment of pediatric patietns with a trachesostomy tubeAarc cpg managment of pediatric patietns with a trachesostomy tube
Aarc cpg managment of pediatric patietns with a trachesostomy tube
 
Closed Head Injury Essay
Closed Head Injury EssayClosed Head Injury Essay
Closed Head Injury Essay
 
Propranolol_versus_Corticosteroids_in_the.27
Propranolol_versus_Corticosteroids_in_the.27Propranolol_versus_Corticosteroids_in_the.27
Propranolol_versus_Corticosteroids_in_the.27
 
BRUCEFINAL2
BRUCEFINAL2BRUCEFINAL2
BRUCEFINAL2
 
gudrunardottir et al 2016 on line
gudrunardottir et al 2016 on linegudrunardottir et al 2016 on line
gudrunardottir et al 2016 on line
 
International Journal of Orthopedics: Research & Therapy
International Journal of Orthopedics: Research & TherapyInternational Journal of Orthopedics: Research & Therapy
International Journal of Orthopedics: Research & Therapy
 
Fluorinated steroids do not improve
Fluorinated steroids do not improveFluorinated steroids do not improve
Fluorinated steroids do not improve
 
QUANTEC
QUANTECQUANTEC
QUANTEC
 
Mascarillas quirurgicas, N95 e influenza
Mascarillas quirurgicas, N95 e influenzaMascarillas quirurgicas, N95 e influenza
Mascarillas quirurgicas, N95 e influenza
 
cancer de seno metastasico
cancer de seno metastasicocancer de seno metastasico
cancer de seno metastasico
 
Lower versus higher hemoglobin threshold for transfusion in septic shock
Lower versus higher hemoglobin threshold for transfusion in septic shockLower versus higher hemoglobin threshold for transfusion in septic shock
Lower versus higher hemoglobin threshold for transfusion in septic shock
 

Mehr von Anestezioloģijas un reanimatoloģijas pulciņš

Mehr von Anestezioloģijas un reanimatoloģijas pulciņš (15)

DEBATES
DEBATESDEBATES
DEBATES
 
Goal directed hemodynamic therapy
Goal directed hemodynamic therapyGoal directed hemodynamic therapy
Goal directed hemodynamic therapy
 
Enoxaparin
EnoxaparinEnoxaparin
Enoxaparin
 
Preeklampsijas un eklampsijas vadīšanas taktika.
Preeklampsijas un eklampsijas vadīšanas taktika. Preeklampsijas un eklampsijas vadīšanas taktika.
Preeklampsijas un eklampsijas vadīšanas taktika.
 
Pulmo - renālais sindroms
Pulmo - renālais sindromsPulmo - renālais sindroms
Pulmo - renālais sindroms
 
NIV
NIVNIV
NIV
 
Ekstrakorporālās membrānas oksigenācija (ECMO) pacientiem ar H1N1 infekciju
Ekstrakorporālās membrānas oksigenācija (ECMO) pacientiem ar H1N1 infekcijuEkstrakorporālās membrānas oksigenācija (ECMO) pacientiem ar H1N1 infekciju
Ekstrakorporālās membrānas oksigenācija (ECMO) pacientiem ar H1N1 infekciju
 
Atorvastatīna efektivitātes izvērtējums sepses pacientiem.
Atorvastatīna efektivitātes izvērtējums sepses pacientiem.Atorvastatīna efektivitātes izvērtējums sepses pacientiem.
Atorvastatīna efektivitātes izvērtējums sepses pacientiem.
 
Septiskā šoka terapija: Vazopresori.
Septiskā šoka terapija: Vazopresori.Septiskā šoka terapija: Vazopresori.
Septiskā šoka terapija: Vazopresori.
 
Pacientu sedācija intensīvas terapijas nodaļā.
Pacientu sedācija intensīvas terapijas nodaļā.Pacientu sedācija intensīvas terapijas nodaļā.
Pacientu sedācija intensīvas terapijas nodaļā.
 
Saindēšanās ar etilēnglikolu
Saindēšanās ar etilēnglikoluSaindēšanās ar etilēnglikolu
Saindēšanās ar etilēnglikolu
 
Kombinēta spinālā/epidurālā analģēzija vs epidurālā analģēzija
Kombinēta spinālā/epidurālā analģēzija vs epidurālā analģēzijaKombinēta spinālā/epidurālā analģēzija vs epidurālā analģēzija
Kombinēta spinālā/epidurālā analģēzija vs epidurālā analģēzija
 
Sirds labās puses mazspēja intensīvās terapijas nodaļā
Sirds labās puses mazspēja intensīvās terapijas nodaļāSirds labās puses mazspēja intensīvās terapijas nodaļā
Sirds labās puses mazspēja intensīvās terapijas nodaļā
 
Šķīdruma pārslodze
Šķīdruma pārslodzeŠķīdruma pārslodze
Šķīdruma pārslodze
 
LUCAS
LUCASLUCAS
LUCAS
 

Kürzlich hochgeladen

CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentsaileshpanda05
 
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfSGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfHongBiThi1
 
ORAL HYPOGLYCAEMIC AGENTS - PART 2.pptx
ORAL HYPOGLYCAEMIC AGENTS  - PART 2.pptxORAL HYPOGLYCAEMIC AGENTS  - PART 2.pptx
ORAL HYPOGLYCAEMIC AGENTS - PART 2.pptxNIKITA BHUTE
 
Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024EwoutSteyerberg1
 
Adenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisAdenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisSujoy Dasgupta
 
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptxBreast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptxNaveenkumar267201
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets barmohitRahangdale
 
Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.kishan singh tomar
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondSujoy Dasgupta
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsMedicoseAcademics
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptxWINCY THIRUMURUGAN
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu Medical University
 
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfSGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfHongBiThi1
 
Using Data Visualization in Public Health Communications
Using Data Visualization in Public Health CommunicationsUsing Data Visualization in Public Health Communications
Using Data Visualization in Public Health Communicationskatiequigley33
 
"Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio..."Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio...Sujoy Dasgupta
 
Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.Vaikunthan Rajaratnam
 

Kürzlich hochgeladen (20)

CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing student
 
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfSGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
 
ORAL HYPOGLYCAEMIC AGENTS - PART 2.pptx
ORAL HYPOGLYCAEMIC AGENTS  - PART 2.pptxORAL HYPOGLYCAEMIC AGENTS  - PART 2.pptx
ORAL HYPOGLYCAEMIC AGENTS - PART 2.pptx
 
Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...
 
Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024
 
Adenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisAdenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosis
 
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptxBreast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets bar
 
Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and Beyond
 
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
 
Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...
Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...
Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functions
 
American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu
 
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfSGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
 
Using Data Visualization in Public Health Communications
Using Data Visualization in Public Health CommunicationsUsing Data Visualization in Public Health Communications
Using Data Visualization in Public Health Communications
 
"Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio..."Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio...
 
Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.
 

Managing new oral anticoagulants in the ICU

  • 1. REVIEW ARTICLE Anesthesiology 2010; 112:473–92 Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins Review Article David S. Warner, M.D., and Editor David S. Warner, M.D., Editor Ultrasound Imaging for Regional Anesthesia in Infants, Managing New Oral Anticoagulants in the Perioperative Children, and Adolescents and Intensive Care Unit Setting A Review of Current Literature and Its Application in the Practice of Extremity and Trunk Blocks Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M.,* David Faraoni, M.D.,† Jenna L. Spring, M.S.,‡ Ban C. H. Tsui, M.D., F.R.C.P.C.,* M. Samama, M.D., M.D., F.C.C.P.|| James D. Douketis, M.D.,§ CharlesSanthanam Suresh, Ph.D., F.A.A.P.† This article has been selected for the ANESTHESIOLOGY CME Program. Learning objectives and disclosure and ordering information can be found in the CME section at the front of this issue. ABSTRACT ABSTRACT O NE of the be exciting recent advances summarizes the warfarin) shouldmostconsidered. This review in technology in pediatric regional anesthesia has been of bleeding with available data regarding the managementthe introduction of anatomically based ultrasound imaging for facilitating nerve lonovel oral anticoagulation agents. Hemodialysis is a therapeucalization. This is because regional anesthesia techniques studies tic option for dabigatran-related bleeding, while in vitro in children have been considered complex concentrates are reported showed that prothrombin challenging due to (1) target neural structures that rivaroxaban-related bleeding. Additional (e.g., to be useful foroften course very close to critical structuresclininerves of are brachial determine close to the pleura as they cal studies the needed toplexus run the best method for reversal traverse the oral anticoagulation agents when bleeding occurs. of the novelsupraclavicular region), and particularly during central neuraxial blocks where the safety margin is narrow for needle placement particularly close tois routinely used(2) the prerequiNTICOAGULATION the spinal cord, in diverse clinical settings, including perioperative venous thromboemsite for sedation or general anesthesia masking potential warning bolism (VTE) prophylaxisthe need for prevention in patients signs (paresthesia), and (3) and stroke limiting the volume of with anesthetic solution below toxic levels. With heparin, lowlocal atrial fibrillation (AF). Unfractionated the possibility molecular-weighttarget structures, ultrasoundantagonists such of visualizing the heparin, and vitamin K technology may with any anticoagulant (including the known principles for as warfarin many anesthesiologists who had previously abanencourage are widely used but have disadvantages. Although Professor, Department of Anesthesiology/Critical Care, Duke **Professor, Department of Anesthesiology and Pain Medicine, there isregional techniques to resumeoptimal profile includes, doned no “ideal” anticoagulant, an or increase their use of University School of Medicine, Durham, North of Pediatric Assistant University of Alberta. † Professor, Department Carolina. † Anesthein addition to established efficacy and safety, oral adminisProfessor, Queen Fabiola Children’s University Hospital, Brussels, siology and Pediatrics, Children’s Memorial Hospital, Northwestern regional anesthesia in children. Belgium. ‡ Medical Student, of Medicine. University, Feinberg School Emory University School of Medicine, tration, no routine monitoring requirement, a for success Although literature evaluating the evidence predictable Atlanta, Georgia. Departmentof Medicine, Division of Hematology Received from § Professor of Anesthesiology and Pain Medicine, anticoagulant ultrasound in regional anesthesia has begun to and safety of effect, a rapid onset and offset of action, and and Thromboembolism, McMaster University, Hamilton, Ontario, University of Alberta, Edmonton, Alberta, Canada, and the DepartCanada. |Pediatric Anesthesiology,of Anesthesiology and Intensive | Professor, Department Northwestern University, Feinreversibility.1 Only a few anticoagulants are acutely reversible, emerge, a comprehensive narrative review of the literature ment of Care, Hotel-DieuMedicine, Chicago, Illinois.France. including unfractionated describedwith outcomes evaluating berg School of University Hospital, Paris, Submitted for publicapertaining to techniques heparin and protamine and vitaReceived from the Department of Anesthesiology, Emory Unition April 17, 2009. Accepted for publication September 30, 2009. min K antagonists with pediatric regional prothrombin comultrasound guidance in four-component anesthesia was not versity School a Career Scientist Award in Anesthesia (to for publiSupported by of Medicine, Atlanta, Georgia. Submitted Dr. Tsui), plex concentrates. The writingoral anticoagulants (NOACs) available at the time of newer this article. This review aims cation July Anesthesiologists’ Society-Abbott Laboratories 20, 2012. Canadian 30, 2012. Accepted for publication December Ltd., ToSupport was provided solely fromScholar Award (to Dr. Tsui) from ronto, Ontario, Canada, a Clinical institutional and/or departmeninclude the direct thrombin inhibitor with an overall sumto provide the pediatric anesthesiologist dabigatran etexilate tal sources. Heritage Foundation for Medical Research,Boehringerthe Alberta JHL serves on Steering Committees for Edmonton, (Pradaxa®,the techniques used and of the outcomes found mary of Boehringer-Ingelheim Pharma GmbH, Ingelheim Ingelheim, Ingelheim am Rhein, Germany; CSL Behring, King of Alberta, Canada, and Foundation for Anesthesia Education and am Rhein, controlled or comparativefactor Xa as described in (based on Germany) and the direct studies) inhibitors rivaPrussia, Pennsylvania; and Johnson and Johnson, Dr. Suresh). Research (FAER) Research in Education grant (to New Brunswick, New Jersey. FiguresM.D., served ascreated by Editor for this article. roxaban (Xarelto, ultrasound guidance of peripheral nerve the literature on Johnson and Johnson/Bayer HealthCare Mark A. Warner, 1 and 2 were Handling Annemarie B. Johnson, C.M.I., Medical Illustrator, Wake Forest University School of AG, Leverkusen, Germany) trunk in pediatrics. A companblocks of the extremities and and apixaban (Eliquis, Bristol AddressCreative Communications, Wake Department of Pediatric correspondence to Dr. Suresh: Forest University MediMedicine Anesthesiology, Children’s North Carolina. Myers Squibb/Pfizer, Bristol-Myers Squibb House, Uxbridge, ion article with similar objectives related to neuraxial blocks cal Center, Winston-Salem,Memorial Hospital, 2300 Children’s Plaza, P. O. Box 19, Chicago, Illinois 60614. ssuresh@childrensmemorial.org. 2 United Kingdom).inAdvantages of these NESTHESIOLOGY.1 In will be published the next issue of A new agents include Addressmay be accessed for personal use Duke charge through the correspondence to Dr. Levy: at no University MediThis article cal Center, 2301 www.anesthesiology.org. Erwin Rd., 5691H, HAFS, Box 3094, Durham, their relatively rapid onset clinical studies, descriptions from addition to case series and and offset of action and predictJournal Web site, North Carolina 27710. docmd2@yahoo.com. This article may be able anticoagulant effect so that routine coagulation moniaccessed for personal use at no charge through the Journal Web site, toring is not required. However, laboratory monitoring may www.anesthesiology.org.• No 2 Anesthesiology, V 112 473 February 2010 be relevant in certain clinical situations, where an assessment Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74 of the anticoagulation status is needed. As the NOACs are The use of ultrasound guidance has provided an opportunity to perform many peripheral nerve blocks that would have been difficult to perform in children based on pure landmark techniques due to the Managing patients in the perioperative setting receiving novel potential for injection into contiguous sensitive vascular areas. This oral anticoagulation agents for thromboprophylaxisultrasoundreview article provides the readers with techniques on or stroke guided peripheral nerve blocks of the important consideration prevention with atrial fibrillation is an extremities and trunk with currently available literature oral anticoagulation agents include for clinicians. The novel to substantiate the available evidence for the use of these techniques. Ultrasound images of the blocks with direct Factor Xa inhibitors rivaroxaban and apixaban, and the corresponding line diagrams to demonstrate the placement of the direct thrombin have been provided for all the relevantsurgery, disultrasound probe inhibitor dabigatran. In elective nerve blocks continuing The authors important,this review function must also in children. their use is hope that but renal will stimulate further research into because elimination is highly dependent on renal be consideredultrasound-guided regional anesthesia in infants, children, and adolescents and stimulate more randomized elimination. If bleeding occurs in patients who havecontrolled received trials to provide a greater understanding of the anatomy and physithese agents, common principles of bleeding management as ology of regional anesthesia in pediatrics. Anesthesiology, V 118 • No 6 A 1466 June 2013
  • 2. EDUCATION increasingly replacing older parenteral agents and vitamin K antagonists in clinical practice, it is important to consider that patients treated with these agents will be exposed to different clinical situations (spontaneous or postoperative bleeding, overdose, trauma, and elective or emergent surgical procedures) that require an intervention. There are also increasing concerns about managing patients on these therapeutic agents following trauma or in a perioperative setting. The purpose of this review is (1) to examine the NOACs, focusing on key pharmacologic properties, and (2) to provide management approaches for users of NOACs in the perioperative and critical care settings based on the available literature. Oral Direct Thrombin Inhibitors Thrombin has a pivotal role in hemostasis, making it an appealing target for anticoagulant drugs. When thrombin is activated from prothrombin, it converts soluble fibrinogen to insoluble fibrin; activates coagulation factors V, VIII, and XI (which generate more thrombin); and activates platelets (fig. 1).3 Dabigatran is a reversible direct thrombin inhibitor that directly inhibits free and fibrin-bound thrombin without the need for antithrombin. Dabigatran etexilate is a prodrug that has a rapid onset of action, no reported food interactions, few drug interaction, and does not require routine coagulation monitoring. The peak plasma concentration is reached 1.25–3  after administration, and it has a halfh life of 12–14  in healthy volunteers.4 Dabigatran is 35% h bound to plasma proteins and undergoes renal excretion, with 80% of the drug entering the urine unchanged. The anticoagulant effect of dabigatran accumulates in the setting of renal insufficiency, and such bioaccumulation correlates well with the degree of renal dysfunction.5 In contrast to other NOACs that are highly protein bound, the relatively low protein binding of dabigatran allows it to be eliminated to a large extent by hemodialysis.6 In cases of moderate hepatic impairment, dabigatran can be administered safely and no dose adjustment is necessary.7 Dabigatran is approved in the United States, Canada, Europe, and Japan for stroke prevention in patients with non-valvular AF based on the results of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial in which 150 mg of dabigatran twice-daily was superior to dose-adjusted warfarin with a similar rate of major bleeding.8 Dabigatran, 75  twice-daily, is approved for use in mg the United States for patients with severe renal insufficiency (CrCl 15–30  ml/min), based on indirect pharmacokinetic modeling and the assumed anticoagulant effect with this level of renal dysfunction. In Europe and Canada, the 75-mg dose is not approved for clinical use and dabigatran is contraindicated in patients with a CrCl < 30  ml/min. Dabigatran is also is approved for VTE prophylaxis following total hip or knee replacement surgery in Europe and Canada, but not the United States. A recent indirect network meta-analysis suggests that treatment with dabigatran offers benefit for the prevention of stroke, systemic embolism, and mortality over antiplatelets and placebo without increased intracranial or extracranial hemorrhage compared to antiplatelet agents.9 Further investigations are needed to confirm these results. Oral Direct Factor Xa Inhibitors Factor Xa is another important target for anticoagulant drugs due to its role as the rate-limiting factor in thrombin generation and amplification, generating the Xa complex that converts prothrombin to thrombin (fig. 1).2 The direct factor Xa inhibitors inhibit free Factor Xa, Factor Xa in the prothrombinase complex, and Factor Xa found in clots, independent of an antithrombin cofactor.2,10 This is in contrast to low-molecular-weight heparin, unfractionated heparin, and fondaparinux, which all are dependent on antithrombin to inhibit Factor Xa. Rivaroxaban Fig. 1. Effect sites of anticoagulation agents. The new oral anticoagulation agents directly inhibit one of two major targets in the coagulation cascade. Rivaroxaban and apixaban directly inhibit factor Xa, and dabigatran directly inhibits thrombin. The parenteral anticoagulants that inhibit factor Xa include low-molecular-weight heparin (LMWH) and fondaparinux by antithrombin (AT)-dependent binding. Parenteral direct thrombin inhibitors include argatroban, bivalirudin, and desirudin that also directly inhibit thrombin independent of AT. Anesthesiology 2013; 118:1466-74 Rivaroxaban is an oral, direct Factor Xa inhibitor that has good bioavailability (80%), is highly protein-bound, and has few drug interactions. Peak plasma concentrations occur within 2–4 h of administration, and rivaroxaban has a halflife of 5–9 h in healthy subjects and 11–13 h in the elderly.10 It is selective for Factor Xa in relation to other serine proteases.2 Clearance of rivaroxaban may be decreased to some extent in patients with renal impairment,11 but its primary mode of clearance is by non-renal mechanisms. It should be noted that although some reports may indicate that approximately 67% of rivaroxaban is eliminated by the kidney, such total renal clearance reflects 33% clearance of active drug and 33% clearance of inactive rivaroxaban, which is not clinically important. Thus, two-thirds of the active rivaroxaban 1467 Levy et al.
  • 3. Perioperative Management of New Oral Anticoagulants are cleared by nonrenal mechanisms. Based on pharmacokinetic study, 10-mg rivaroxaban administered once daily offers the best efficacy profile while avoiding excessive bleeding complications.12 In patients with AF, the recommended rivaroxaban dose is 20  daily, although a reduced dose mg (15 mg daily) is recommended in patients with a CrCl 15– 30 ml/min.13 Due to high plasma protein binding (>90%), rivaroxaban cannot be eliminated during hemodialysis. Rivaroxaban is approved in the United States, Canada, and Europe for VTE prophylaxis after hip or knee replacement surgery and for stroke prevention in patients with non-valvular AF. Rivaroxaban was recently approved for treatment of deep vein thrombosis, pulmonary embolism, and reduction in the risk of recurrence. In the Regulation of Coagulation in Orthopedic surgery to pRevent Deep venous thrombosis and pulmonary embolism (RECORD) trials, rivaroxaban, 10  daily, was superior to enoxaparin mg 30 mg twice-daily, and 40 mg once-daily for the prevention of VTE after knee and hip replacement, respectively, without a significant increase in the rate of major bleeding.14–17 In terms of stroke prevention, the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial randomly allocated (in a double-blind manner) 14,264 patients with AF to rivaroxaban 20  daily (15  daily if CrCl 15–50  mg mg ml/ min) compared to dose-adjusted warfarin and found that rivaroxaban was not inferior to warfarin in efficacy, with no significant difference in major bleeding events.18 In patients with an acute coronary syndrome, the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS2–TIMI 51) compared rivaroxaban, 2.5  or 5  daily, to placebo in mg mg patients who were receiving aspirin and a thienopyridine (usually clopidogrel). Although the 2.5-mg dose regimen conferred a significant reduction in cardiovascular and allcause mortality (and also led to more bleeding), the Food and Drug Administration issued a “complete response letter” and requested additional data.19 Apixaban Apixaban is another oral, direct Factor Xa inhibitor with good oral bioavailability (80%), is highly protein bound, reaches peak plasma concentration within 2–3 h after intake, and has limited potential for drug interactions.10 Apixaban 2.5  twice-daily is the recommended dose for VTE promg phylaxis based on pharmacokinetic study.20 In patients who received apixaban 2.5  twice-daily for VTE prophylaxis, mg the risk of major bleeding was not influenced by renal function.21 Moreover, in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, assessing apixaban 5 mg twice-daily for stroke prevention, patients were excluded only if they had a CrCl < 25 ml/min. For these reasons, no dose adjustment is Anesthesiology 2013; 118:1466-74 recommended in patients with mild (CrCl, 50–80 ml/min) or moderate (CrCl, 30–50  ml/min) renal impairment. The half-life in healthy subjects is 8–15  10 Apixaban has been h. approved in Canada and Europe for VTE prophylaxis after total hip and knee replacement surgery based on the results of the ADVANCE trials.22,23 Apixaban is currently under Food and Drug Administration review in the United States for this indication. In the ARISTOLE trial, apixaban was superior to dose-adjusted warfarin in preventing stroke and systemic embolism, with a decrease in bleeding complications, and a lower mortality.24 The Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) study is noteworthy as it is the only trial comparing treatment with a NOAC, in this case apixaban 5  twice-daily, against aspirin (81–325  mg mg) for stroke prevention in AF.25 Although it would be expected that apixaban conferred a lower risk for stroke, what is surprising, perhaps, is that this treatment was not associated with more bleeding compared with aspirin.25 Monitoring Anticoagulation with the NOACs Although routine laboratory testing is not required in NOAC-treated patients, except for periodic monitoring of renal function (especially in patients with preexisting renal impairment), coagulation function tests should be ordered for any anticoagulated patient presenting with an acute bleed, suspected overdose, or requiring emergency surgery.26 Due to the effect of dabigatran on thrombin-mediated conversion of fibrinogen to fibrin, most of the routine coagulation assays will be prolonged except the prothrombin time.27 The maximum effect of dabigatran on coagulation parameters occurs at the same time as peak plasma concentration. For this reason, the delay between the last dabigatran dose and the time of blood sampling is needed to interpret the tests. The effects of dabigatran can be best measured using the thrombin time or a dilute thrombin time, available as the Hemoclot assay.28 Other assays that have been studied include the ecarin clotting time, although this test is not widely available.2,29 The thrombin time provides a direct assessment of thrombin activity and increases linearly with increasing dabigatran concentration; however, experience with this assay indicates that it is overly sensitive to dabigatran levels and, consequently, the thrombin time may be prolonged in the setting of a clinically insignificant dabigatran effect.28 The Hemoclot assay has better linear correlation to plasma levels of dabigatran and is probably the most reliable method to measure the anticoagulant effect of dabigatran.28 In the ecarin clotting time assay, prothrombin is converted to meizothrombin, a prothrombin–thrombin intermediate, by the snake venom ecarin, and dabigatran directly inhibits this meizothrombin intermediate in a dose-dependent fashion but this assay is not frequently used.30 A more universally available test, the activated partial thromboplastin time, can also be used; however, the relationship between dabigatran 1468 Levy et al.
  • 4. EDUCATION Table 1.  Preoperative Discontinuation of Dabigatran Based on Renal Function point-of-care monitoring or rapid laboratory assays might be required. Timing of Last Dose before Surgery Renal Function (CrCl, ml/min) >80 50–80 30–50 <30 Half-life, h Normal Bleeding Risk High Bleeding Risk 13 (11–12) 15 (12–34) 18 (13–23) 27 (22–35) 1d 1d >2 d 2–5 d Temporary Discontinuation before Surgery and Neuraxial Anesthesia 2–4 d 2–4 d >4 d >5 d CrCl = creatinine clearance (ml/min); d = days. concentration and partial thromboplastin time is curvilinear, resulting in decreased precision of the assay as plasma dabigatran concentrations increase,29 and there may be interassay variability in measurements. Nonetheless, the partial thromboplastin time provides a reasonable alternative if other tests are not available and a normal partial thromboplastin time will likely indicate the absence of a clinically important anticoagulant effect. Additional laboratory studies are urgently needed to correlate coagulation assay results with varying plasma levels of dabigatran. Rivaroxaban and apixaban inhibit factor Xa directly, which is in complex with FVa and independ of antithrombin.2 Rivaroxaban causes a prolongation of the prothrombin time, although there may be considerable inter-assay variability in such measurements, and has less of an effect on the partial thromboplastin time. However, these tests are not useful for measuring the pharmacodynamic effects of oral factors Xa inhibitors.31 More recently, a specific assay has been developed for the direct Xa inhibitors that is different from an antiXa assay used to monitor low-molecular-weight heparin, and may provide the optimal method for determining the effect of rivaroxaban, although further studies are needed.2,32,33 Rivaroxaban produces a concentration-dependent prolongation of clotting parameters on thromboelastometry, including R and K time without significant modification of maximal amplitude, making this assay not useful for routine monitoring.31 Until now, the lack of readily available means for assessing the degree of anticoagulation remains a notable concern, especially in a life-threatening bleed where Before discontinuing any anticoagulant medication, the risk of bleeding must be carefully weighed against the risk of thrombosis. For dabigatran, which is eliminated primarily by renal mechanisms, the timing of discontinuation should be based on patients’ CrCl and the bleeding risk associated with the procedure (table 1).34,35 Renal impairment may be less important in patients taking rivaroxaban, in which a decreased creatinine clearance appears to have a limited effect on the half-life of the drug. In a study of patients with renal impairment who are receiving a single 10-mg dose of rivaroxaban, the mean half-life only increased very slightly from 8.3 h in healthy controls to 9.5 h in patients with severe renal impairment (CrCl < 30 ml/min).11 The Working Group on perioperative hemostasis and the French Study Group on thrombosis and hemostasis published recommendations about the perioperative management of NOACs.36,37 For scheduled surgery or invasive procedures with low risk of bleeding, they recommend interruption 24  (≈2 half-lives) before the procedure and h to restart 24 h after. In case of scheduled surgery or invasive procedures at moderate or high risk of bleeding, a 5 days interruption before surgery is recommended, while treatment should be restarted according to the bleeding risk. For patients at higher thrombosis risk, unfractionated heparin or low-molecular-weight heparin at curative dose should be initiated 12  after the last dose of oral anticoagulants. h Although these recommendations are easy to use and appear sensible, there is a need for prospective studies assessing the efficacy and safety of these (and other) perioperative management protocols for NOAC-treated patients who require an elective surgery/procedure. The safety of neuraxial anesthesia for patients treated with NOACs will be based on the pharmacokinetic properties of the anticoagulant (table 2).36 Catheter placement and, to a lesser extent, removal should be considered when anticoagulant concentrations are at their lowest, and patients should be monitored closely for signs of hematoma in the initial days after catheter removal. Specific recommendations for Table 2.  Pharmacokinetics of the New Oral Anticoagulation Agents Dabigatran Route of administration Bioavailability Time to maximal concentration (Tmax) Half-life Renal excretion Plasma protein binding Anesthesiology 2013; 118:1466-74 Rivaroxaban Apixaban Oral twice daily 6.5% 1.25–3 h 12–14 h 80% 35% Oral once daily 80% 2–4 h 5–13 h 66% >90% Oral twice daily 66% 1–3 h 8–15 h 25% 87% 1469 Levy et al.
  • 5. Perioperative Management of New Oral Anticoagulants Table 3.  Recommendations for Novel Anticoagulants for Venous Thromboembolic Prophylaxis in the Setting of Peridural/Regional Anesthesia36 Dabigatran Rivaroxaban Apixaban 2–4 h NR* 6h 4–6 h 22–26 h 4–6 h 6h 26–30 h 4–6 h Time between epidural anesthetic technique and next anticoagulant dose Time before last anticoagulant dose and epidural catheter removal Time between removal of epidural catheter and next anticoagulant dose * Dabigatran in not recommended in patients undergoing anesthesia with postoperative indwelling catheters. NR = not recommended. managing these agents for venous thromboembolic prophylaxis in the setting of peridural/regional anesthesia are listed in table 3. Rosencher38 suggests allowing at least two halflives to pass before catheter removal, at which point only 25% of the drug remains active. Allowing a longer interval would only slightly reduce the drug concentration, because elimination slows after this point.38 The risk of the residual anticoagulant activity and neuraxial hematoma needs to be weighed against the risk of VTE. However, the authors suggest that anticoagulation should be restarted after 8 h minus the time to reach maximum activity (Tmax), based on the their suggestion that it takes 8 h to establish a stable clot, and allowing time for the peak of anticoagulation to be reached.38 However, there may be considerable variability in the time needed to attain a dry vascular bed, especially after major orthopedic or oncologic surgery, and longer times may be needed because of the risk of bleeding compared to the risk of VTE.38 Recommendations for the use of the new anticoagulants in the setting of neuraxial anesthesia have been proposed by Llau et al.39 based on existing guidelines and the pharmacokinetics of each drug (table 3). A recent report evaluated bleeding rates from 7 days prior until 30 days following invasive procedures for patients receiving dabigatran.40 Based on 4,591 patients who had a first treatment interruption for an elective surgery or invasive procedure, 24.7% of patients were receiving dabigatran—110  mg, 25.4% were on dabigatran—150  mg, and 25.9% were on warfarin. The procedures included the following: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). The last dose of dabigatran was given a mean of 49 (range: 35–85) h before the procedure, compared to a mean of 114 (range: 87–144) h for the last preprocedure dose of warfarin (P < 0.001). There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran, 110 mg (3.8%), or dabigatran, 150 mg (5.1%), or warfarin (4.6%). The relative risk for major bleeding with dabigatran-110  versus warfarin was 0.83 mg (95% CI, 0.59–1.17; P = 0.28), and with dabigatran-150 mg versus warfarin, it was 1.09 (95% CI, 0.80–1.49; P = 0.58). Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran-110, 17.7% with dabigatran-150, and 21.6% with warfarin: dabigatran-110. There are no published data on perioperative outcomes in patients receiving rivaroxaban or apixaban who require elective or urgent surgery/procedures, although the same management principles should apply that incorporate procedure bleeding risk and drug elimination as with dabigatran-treated patients. Reversal of the Novel Anticoagulants and Management of Acute Bleeding Immediate reversal of anticoagulation is often needed in the bleeding patient or patient requiring emergency surgery. Current dosing and indications for these agents are listed in Table 4.  Current Dosing Guidelines for New Oral Anticoagulation Agents Dabigatran Dosing for atrial fibrillation: normal renal function Dosing for atrial fibrillation:   renal dysfunction Rivaroxaban Apixiban* 150 mg BID 20 mg QD 5 mg BID 15 mg QD with CrCl 15–50 ml/min 2.5 mg BID DVT prophylaxis 110 mg BID United States: 75 mg BID with CrCl   15–30 ml/min 220 mg QD 10 mg QD† 2.5 mg BID Renal dysfunction 150 mg QD Avoid with CrCl < 30 ml/min Not approved in the United States   for this indication * For apixaban, no data available for use with CrCl < 15 ml/min or on dialysis. † For hip and knee surgery. BID = twice a day; CrCl = creatinine clearance; QD = daily. Anesthesiology 2013; 118:1466-74 1470 Levy et al.
  • 6. EDUCATION table 4. Although managing any anticoagulation agent in a bleeding patient is a challenge, it is important to note that warfarin and other vitamin K antagonist agents are not easily reversible with therapies available in the United States, such as vitamin K and/or fresh frozen plasma. Four-component prothrombin complex concentrates (PCCs) are currently preferred in Canada and most European countries and recommended in recent guidelines.37,41,42 Stopping a NOAC and providing supportive care are the most important consideration and are often sufficient if the bleeding is not severe or if surgery can be delayed. However, when patients present with a major bleeding episode related to these agents and/or require emergency surgery, other measures must be taken. For any significant bleeding event, initial measures should include volume resuscitation with fluids and/or packed red blood cells, identification of the bleeding source, and attempts at local hemostatic control. If an anticoagulant overdose is the suspected cause, activated charcoal may be effective in preventing additional drug absorption when administered within 1–2  of ingestion. Activated charcoal has not been h used in the clinical setting and is limited by its narrow window of use and inability to use in a perioperative setting. Hemodialysis or hemoperfusion is another potential option for the emergent removal of anticoagulants. Rivaroxaban and apixaban are too highly protein bound to be effectively removed by these methods, but dabigatran is an appropriate candidate for these therapies.10 In a study of six volunteers with end-stage renal disease who were given a 50-mg dose of dabigatran before routine hemodialysis, an average of 62% of the active dabigatran was removed after 2 h and 68% after 4 h.5 Unfortunately, attempting to perform either of these procedures in a bleeding patient in shock may not be possible.29 Therefore, the use of procoagulant agents should be considered for a life-threatening bleed. However, unlike when fresh frozen plasma or PCCs are used to replace depleted factors II, VII, IX, and X in warfarin-treated patients, the effectiveness of such clotting factor replacement therapies may be limited in NOAC-treated patients who do not harbor deficiencies of clotting factors but in whom there is an ongoing clotting factor inhibitory effect. It may be argued, therefore, that providing supraphysiologic levels of clotting factors may be ineffective in the setting of an ongoing NOAC-related inhibitory effect. On the contrary, such clotting factors may overwhelm such an ongoing inhibitory effect and, in cases of severe bleeding, may replace clotting factors that are depleted due to consumption. Although fresh frozen plasma is commonly administered for initial control of bleeding in anticoagulated patients, its use as a reversal agent for the NOACs has not been studied in humans.43 In a study of mice pretreated with dabigatran (4.5  mg/kg or 9.0  mg/kg) before induction of intracranial hemorrhage, fresh frozen plasma administration successfully limited hematoma expansion in the low-dose group but had no effect in the high-dose group and did not significantly Anesthesiology 2013; 118:1466-74 decrease mortality. There is insufficient evidence to recommend its use.43,44 Recombinant factor VIIa (rFVIIa) is increasingly used in an “off-label” manner as a universal hemostatic and reversal agent. However, it has not been studied in humans for reversal of NOACs, and the results of studies in animal models are inconclusive. The benefit-to-risk balance for rFVIIa must be carefully weighed, as rFVIIa has been associated with an increased risk of arterial thrombosis among elderly patients.45,46 In several animal models, rFVIIa reversed bleeding time prolongation associated with dabigatran and rivaroxaban, but it did not correct the underlying coagulopathy as suggested by other laboratory markers.44 In one study, rats received high-dose dabigatran before a standard tail incision, prolonging the bleeding time from 125 s in controls to 1455 s. A 0.5 mg/kg dose of rFVIIa decreased this bleeding time to 135 s. The partial thromboplastin time was 58 s after dabigatran exposure, versus 7 s in controls, and administration of rFVIIa reduced this to 27 s. In a similar study that exposed rats to supratherapeutic dabigatran levels, administration of rFVIIa rapidly corrected the bleeding time and preserved this effect for the entire 2-h study period.47 However, of the coagulation markers examined, only the prothrombin time was completely corrected. The partial thromboplastin time, the ecarin clotting time, and the thrombin time all failed to normalize.47 PCCs are available as three-factor (II, IX, X) and fourfactor (II, VII, IX, X) varieties that are procoagulant and enhance thrombin generation.42 The four-factor PCCs have activated and nonactivated forms, and only three-factor PCCs are available in the United States.44 Small quantities of heparin, antithrombin, protein C, and protein S are added to the concentrates to reduce coagulation activation through endogenous pathways,48 but caution is required for off-label use as thrombotic events in 1–3% of treated patients have been reported with both formulations.49,50 Unlike the other procoagulant agents, four-factor PCCs have been studied as potential reversal agents in humans. In a small, randomized, double-blinded, placebo-controlled trial, 12 healthy men were given dabigatran 150  twice-daily mg or (supratherapeutic) rivaroxaban 20  twice-daily for 2.5 mg days, and subsequently received either a 50 IU/kg bolus of a four-factor PCC or saline.51 They were switched to the other anticoagulant following a wash-out period and the procedure was repeated. The addition of the PCC completely reversed both the prothrombin time prolongation and inhibition of endogenous thrombin potential associated with rivaroxaban, but only laboratory parameters were evaluated in this study, and no bleeding outcomes were measured in the volunteers. However, dabigatran-associated prolongations in the clotting assays and endogenous thrombin potential lag time were not corrected by the administration of the PCC. Recently, in an animal model, although both rFVIIa and PCC partially corrected laboratory assays (thromboelastography and thrombin generation assay), none of them reduced bleeding induced by rivaroxaban.52 1471 Levy et al.
  • 7. Perioperative Management of New Oral Anticoagulants Fig. 2. Management strategies for patients bleeding who have received the novel oral anticoagulation agents. In cases of mild bleeding, stopping or delaying the next dose should be considered. The new agents including dabigatran, rivaroxaban, and recently approved apixiban have relatively short half-lives, so stopping the drug in patients with normal renal function, the anticoagulant effect rapidly decreases compared to warfarin. In patients with moderate to severe bleeding, standard therapeutic approaches should be considered, including supportive care that includes volume resuscitation, hemodynamic support with vasoactive therapy, blood product transfusions as determined by testing, and identification of bleeding source that may require surgical or another intervention. If the agents were taken within ≈2  of admission, administration of oral activated charcoal h should be considered. For dabigatran,† hemodialysis can remove ≈60% of the drug after several hours of dialysis and should be considered in patients with impaired renal function who are bleeding and will have altered clearance. Apixaban and rivaroxaban are highly protein bound and will not be cleared by hemodialysis. However, emergency access for hemodialysis requires vascular access with large bore catheters that may pose additional risk in the anticoagulated patient. For patients with life-threatening bleeding, hemodynamic and hemostatic resuscitation should be considered, with therapy similar to that for a trauma patient including the use of a massive transfusion protocol. Based on current data as discussed in the manuscript, the use of either three-factor or four-factor prothrombin complex concentrates (PCCs) depending on their availability should be considered as they have been shown to reverse or partially reverse the anticoagulation effect of the newer agents. ‡ In patients receiving dabigatran, the use of an activated PCC may be more effective. † However, there are no studies reporting the use of PCCs on actual bleeding in patients, and further studies including the development of specific reversal agents are underway currently. In hypotensive patients, hemodialysis is unlikely to be tolerated, and alternate methods for hemofiltration should be considered if needed. † The use of recombinant activated factor VIIa (rVIIa) decreases bleeding times in animal models, but there are no human studies to determine if this is effective. † = for dabigatran. ‡ = for rivaroxaban and apixiban. Marlu et al.53 evaluated dabigatran and rivaroxaban reversal using thrombin generation tests evaluating 10 healthy volunteers randomized to receive rivaroxaban (20  mg) or dabigatran (150 mg) orally in a cross-over study, and blood was collected 2  post-ingestion. Anticoagulation reversal h was tested in vitro using PCC, rFVIIa, or factor eight inhibitory bypass activity at different concentrations.53 In rivaroxaban-treated patients, PCC and factor eight inhibitory bypass activity corrected thrombin generation, but rFVIIa only modified the kinetic parameters. In dabigatran-treated patients, PCC increased thrombin generation as determined by area under the curve, but only rFVIIa and factor eight inhibitory bypass activity corrected the altered lag time.53 Ongoing clinical studies are needed to determine the best method for reversal of the NOACs when bleeding occurs. Based on the available evidence, supportive care and interventions as discussed including dialysis for dabigatran should be considered in a bleeding patient and potential therapeutic approaches as listed in figure 2. For rivaroxaban-treated patients, studies in volunteers suggest the PCCs may be effective, but additional studies are needed. When possible, these drugs should be stopped preoperatively at times based on renal function and procedure.54 Additional drug-specific antidotes are also under investigation. Summary 1. Eikelboom JW, Weitz JI: New anticoagulants. Circulation 2010; 121:1523–32 2. Levy JH, Key NS, Azran MS: Novel oral anticoagulants: Implications in the perioperative setting. Anesthesiology 2010; 113:726–45 3. Weitz JI: Factor Xa or thrombin: Is thrombin a better target? J Thromb Haemost 2007; 5:65–7 4. Eriksson BI, Quinlan DJ, Weitz JI: Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and Common principles of bleeding management as with any anticoagulant (including the known principles for warfarin) should be followed in patients receiving dabigatran. Hemodialysis is an additional, unique therapeutic option for urgently reducing exposure to dabigatran that has not been shown to be useful for other new oral anticoagulants. Anesthesiology 2013; 118:1466-74 ‍References 1472 Levy et al.
  • 8. EDUCATION factor xa inhibitors in development. Clin Pharmacokinet 2009; 48:1–22 5. Stangier J, Rathgen K, Stähle H, Mazur D: Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: An open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49:259–68 6. Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, Neumayer HH, Liesenfeld KH, Lehr T, Hartter S, Friedman J, Peters H, Clemens A: Effective elimination of dabigatran by haemodialysis: A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013 Feb 7; 109 [Epub ahead of print] 7. Stangier J, Stähle H, Rathgen K, Roth W, Shakeri-Nejad K: Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol 2008; 48:1411–9 8. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–51 9. Roskell NS, Lip GY, Noack H, Clemens A, Plumb JM: Treatments for stroke prevention in atrial fibrillation: A network meta-analysis and indirect comparisons versus dabigatran etexilate. Thromb Haemost 2010; 104:1106–15 1 0. Eriksson BI, Quinlan DJ, Weitz JI: Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet 2009; 48:1–22 1 1. Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, Lufft V, Wand DD, Philipp T, Bruck H: Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010; 70:703–12 1 2. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, Muehlhofer E, Dierig C, Misselwitz F, Kälebo P; ODIXa-HIP Study Investigators: A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114:2374–81 1 3. Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM: Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32:2387–94 1 4. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group: Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358:2765–75 1 5. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators: Extended duration rivaroxaban versus shortterm enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: A double-blind, randomised controlled trial. Lancet 2008; 372:31–9 1 6. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators: Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358:2776–86 1 7. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators: Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): A randomised trial. Lancet 2009; 373:1673–80 Anesthesiology 2013; 118:1466-74 1 8. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91 1 9. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM; ATLAS ACS 2–TIMI 51 Investigators: Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366:9–19 2 0. Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M: Quantification of apixaban’s therapeutic utility in prevention of venous thromboembolism: Selection of phase III trial dose. Clin Pharmacol Ther 2010; 88:375–82 2 1. DeLoughery TG: Practical aspects of the oral new anticoagulants. Am J Hematol 2011; 86:586–90 2 2. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators: Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): A randomised double-blind trial. Lancet 2010; 375:807–15 2 3. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators: Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363:2487–98 2 4. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators: Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981–92 2 5. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators: Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806–17 2 6. Garcia D, Libby E, Crowther MA: The new oral anticoagulants. Blood 2010; 115:15–20 2 7. van Ryn J, Baruch L, Clemens A: Interpretation of point-ofcare INR results in patients treated with dabigatran. Am J Med 2012; 125:417–20 2 8. Stangier J, Feuring M: Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23:138–43 2 9. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A: Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116–27 3 0. Stangier J, Rathgen K, Stähle H, Gansser D, Roth W: The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64:292–303 3 1. Samama MM, Martinoli JL, LeFlem L, Guinet C, Plu-Bureau G, Depasse F, Perzborn E: Assessment of laboratory assays to measure rivaroxaban–an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103:815–25 3 2. Favaloro EJ, Lippi G, Koutts J: Laboratory testing of anticoagulants: The present and the future. Pathology 2011; 43:682–92 3 3. Samama MM, Amiral J, Guinet C, Perzborn E, Depasse F: An optimised, rapid chromogenic assay, specific for measuring 1473 Levy et al.
  • 9. Perioperative Management of New Oral Anticoagulants direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb Haemost 2010; 104:1078–9 3 4. Stangier J, Rathgen K, Stähle H, Mazur D: Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: An open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49:259–68 3 5. Huisman MV, Lip GY, Diener HC, Brueckmann M, van Ryn J, Clemens A: Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: Resolving uncertainties in routine practice. Thromb Haemost 2012; 107:838–47 3 6. Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV, Samama CM; European Scoeity of Anaesthesiology: Regional anaesthesia and antithrombotic agents: Recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010; 27:999–1015 3 7. Sié P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV, Van der Linden P, Pernod G, Lecompte T, Gouin-Thibault I, Albaladejo P; Working Group on Perioperative Haemostasis; French Study Group on Thrombosis and Haemostasis: Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: Thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104:669–76 3 8. Rosencher N, Bonnet MP, Sessler DI: Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: Management strategies. Anaesthesia 2007; 62:1154–60 3 9. Llau JV, Ferrandis R: New anticoagulants and regional anesthesia. Curr Opin Anaesthesiol 2009; 22: 661–6 4 0. Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S, Themeles E, Heidbuchel H, Heidbuchle H, Avezum A, Reilly P, Connolly SJ, Yusuf S, Ezekowitz M; RE-LY Investigators: Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: Results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012; 126:343–8 4 1. Garcia D: Rethinking warfarin reversal. Blood 2010; 116:675–6 4 2. Levy JH, Tanaka KA, Dietrich W: Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology 2008; 109:918–26 4 3. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A: Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116–27 Anesthesiology 2013; 118:1466-74 4 4. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J: Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87:S141–5 4 5. Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C: Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev 2012; 3:CD005011 4 6. Levi M, Levy JH, Andersen HF, Truloff D: Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363:1791–800 4 7. van Ryn J, Schurer J, Knk-Elband M, Clemens A: The successful reversal of dabigatran induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. Blood 2011; 118: Abst 2318 4 8. Patanwala AE, Acquisto NM, Erstad BL: Prothrombin complex concentrate for critical bleeding. Ann Pharmacother 2011; 45:990–9 4 9. Arnold DM, Dentali F, Crowther MA, Meyer RM, Cook RJ, Sigouin C, Fraser GA, Lim W, Kelton JG: Systematic review: Efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007; 146:25–33 5 0. Dentali F, Marchesi C, Pierfranceschi MG, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W: Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011; 106:429–38 5 1. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M: Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebocontrolled, crossover study in healthy subjects. Circulation 2011; 124:1573–9 5 2. Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, Marchand-Leroux C, Lecompte T, Samama CM: Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116:94–102 5 3. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G: Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108:217–24 5 4. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J: Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87:S141–5 1474 Levy et al.