Journal of Clinical Anesthesia (2016) 32, 224–235

Review

Use of direct oral anticoagulants with regional

anesthesia in orthopedic patients☆
Gianluca Cappelleri MD a,⁎, Andrea Fanelli MD b
a
Anaesthesia and Intensive Care Unit, Azienda Ospedaliera Istituto Ortopedico Gaetano Pini, 20122, Milan, Italy
b
Anaesthesia and Intensive Care Unit, Policlinico S. Orsola-Malpighi, 40138, Bologna, Italy

Received 28 May 2015; revised 5 January 2016; accepted 22 February 2016

Keywords:
Abstract The use of direct oral anticoagulants including apixaban, rivaroxaban, and dabigatran, which are
Direct oral anticoagulant;
approved for several therapeutic indications, can simplify perioperative and postoperative management
Major orthopedic surgery;
of anticoagulation. Utilization of regional neuraxial anesthesia in patients receiving anticoagulants carries
Neuraxial anesthesia;
a relatively small risk of hematoma, the serious complications of which must be acknowledged. Given
Perioperative management;
the extensive use of regional anesthesia in surgery and the increasing number of patients receiving direct oral
Postoperative management
anticoagulants, it is crucial to understand the current clinical data on the risk of hemorrhagic complications in
this setting, particularly for anesthesiologists. We discuss current data, guideline recommendations, and best
practice advice on effective management of the direct oral anticoagulants and regional anesthesia, including
in specific clinical situations, such as patients undergoing major orthopedic surgery at high risk of a thromboembolic
event, or patients with renal impairment at an increased risk of bleeding.
© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction as total knee or hip replacement surgery [4]; therefore, these

Venous thromboembolism (VTE), comprising deep vein
thrombosis (DVT) and pulmonary embolism (PE), and its
long-term complications cause significant morbidity, mortality
and healthcare costs [1–3]. The risk of VTE is particularly
high in patients who undergo major orthopedic surgery, such
☆
Conflicts of interest: Editorial support was funded by Bayer HealthCare
Pharmaceuticals and Janssen Scientific Affairs, LLC. GC reports no conflicts
of interest. AF has received speaker's honoraria from Bayer HealthCare
Pharmaceuticals.
⁎ Corresponding author at: Azienda Ospedaliera Istituto Ortopedico
Gaetano Pini, Piazza Cardinal Ferrari, 20122, Milan, Italy.
Tel.: +39 0258296297; fax: +39 0258296283.
E-mail addresses: gianluca.cappelleri@gpini.it (G. Cappelleri),
andre.fanelli@gmail.com (A. Fanelli).
patients routinely receive anticoagulants for short-term peri-
operative and postoperative thromboprophylaxis [4,5].
Whether a patient is receiving long-term anticoagulation (for
the treatment or prevention of VTE or for stroke prevention
in patients with non-valvular atrial fibrillation [AF]) prior to
orthopedic surgery should also be considered because appro-
priate anticoagulant management based on the risk of throm-
boembolism and bleeding is crucial in these patients [5].
Additionally, the use of regional neuraxial anesthesia poses a
risk of hematoma in patients receiving anticoagulants, because
of the insertion and removal of the needle and catheter.
The direct oral anticoagulants (OACs) apixaban, rivaroxa-
ban, and dabigatran are approved for the prevention of VTE
after elective knee or hip replacement surgery in the European
Union and/or United States, as well as for the prevention of

http://dx.doi.org/10.1016/j.jclinane.2016.02.028
0952-8180/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
Anticoagulation and anesthesia
stroke in patients with non-valvular AF, and the treatment of
VTE and prevention of recurrent VTE [6–11]. In Europe,
rivaroxaban is also indicated for co-administration with acetyl-
salicylic acid (ASA) alone or with ASA plus clopidogrel or
ticlopidine for the prevention of atherothrombotic events after
acute coronary syndrome with elevated cardiac biomarkers
[10]. Apixaban and rivaroxaban are direct inhibitors of Factor
Xa, whereas dabigatran is a direct inhibitor of thrombin.
All three agents have been found to exhibit predictable
pharmacokinetics and pharmacodynamics, and have a fast
onset of action—reaching maximum plasma concentration
rapidly after oral administration (apixaban, 3-4 hours; rivarox-
aban, 2-4 hours; dabigatran, 0.5-2.0 hours) [6,8,10,12–15].
The half-lives of apixaban, rivaroxaban, and dabigatran are
~ 12 hours, 5-13 hours, and 11-14 hours, respectively
[6,8,10]. Furthermore, the pharmacokinetic and pharmacody-
namic characteristics are not influenced to a clinically mean-
ingful extent by body weight, age, or gender, which
collectively indicate that these direct OACs can be given as
fixed dosing regimens without the need for routine coagulation
monitoring [16–20]. The routes of drug elimination differ be-
tween the 2 drug classes: apixaban and rivaroxaban have mul-
tiple pathways including renal excretion (~ 27% and 66%
[33% as active drug and 33% after metabolic degradation], re-
spectively), whereas elimination of dabigatran is predominant-
ly via the renal system (85%) [6,8,10,21]. In patients receiving
dabigatran for the prevention of VTE after knee or hip replace-
ment surgery, a dose reduction is required in those with mod-
erate renal impairment (creatinine clearance 30-50 mL min−1),
those aged 75 years or over, and those taking concomitant
mild-to-moderate P-glycoprotein inhibitors [8]. Owing to their
mode of action, all anticoagulants can increase the risk of
bleeding events. However, apixaban, rivaroxaban, and dabiga-
tran did not pose any significantly increased risk of major
bleeding events compared with enoxaparin in phase III clinical
trials in the prevention of VTE after knee or hip replacement
surgery [22–30]. Despite the clinical evidence on the safety
and efficacy profile of direct OACs demonstrated in clinical trials,
physicians—particularly anesthesiologists—need to be aware of
how to minimize the risks of bleeding complications when treat-
ing patients who are taking an anticoagulant and are due to under-
go surgery with regional anesthesia.
Regional anesthesia techniques have become increasingly pop-
ular because they offer several benefits over general anesthesia and
traditional systemic analgesia, including reduced risk of mortality
and less postoperative pain, thus facilitating early postoperative
mobilization of the limbs and consequently reducing the chances
of postoperative VTE [31,32]. Regional anesthesia is used in
millions of operations each year and, at a time when the use
of the direct OACs is growing, bleeding-related complications
could arise if appropriate guidance is not followed [33]. This
review aims to provide anesthesiologists with an overview of
current data on the risk of hemorrhagic complications with
direct OACs when using regional anesthesia, particularly
in patients at a high risk of VTE, such as those undergoing
major orthopedic surgery. Moreover, current guideline
225
recommendations will be discussed and best practice in specific
clinical situations, such as in patients with renal impairment who
are at an increased risk of bleeding, will be highlighted.
2. Regional anesthesia and complications
The most common complications of regional anesthesia
include postdural puncture headache (occurs in 0.1%-36% of
patients but rarely lasts longer than 7 days) [34], backache (af-
fects up to 11% of patients in the 5 days after the procedure)
[35], and peripheral nerve damage (eg, transient paresthesia
is estimated in up to 8%-10% of patients in the immediate days
after regional anesthesia) [36]. Serious complications, such as
spinal or epidural hematoma and epidural abscess, are rare and
therefore difficult to study in detail [37]. For peripheral nerve
block, neurological complications are extremely rare, ranging
between 0.02% and 0.04% [38,39].
2.1. Risk factors associated with regional anesthesia
In a systematic review of 141 studies (n = 9559),
neuraxial anesthesia was shown to be associated with lower
rates of mortality (2.1% vs 3.1%; odds ratio [OR] 0.7; 95%
confidence interval [CI] 0.54-0.90; P = .006), occurrence of
DVT (odds reduction of 44%; OR 0.56; 95% CI 0.43-0.72;
P b .001) and PE (odds reduction of 55%; OR 0.45; 95% CI
0.29-0.69; P b .001), among other outcomes [31]. A more re-
cent observational study showed that neuraxial anesthesia was
associated with a significantly reduced need for blood transfu-
sions compared with patients receiving general anesthesia
(28.5% vs 44.7%; OR 0.52; 95% CI 0.45-0.61; P b .0001) af-
ter simultaneous bilateral total knee replacement surgery [40].
2.2. Risk factors for the development of
spinal hematoma
The overall incidences of hematoma in patients receiving
neuraxial anesthesia (epidural and spinal) have been estimated
to be as low as 1 in 220 000 and 1 in 320 000, respectively, in
the absence of traumatic puncture and without the use of hep-
arin or ASA [41]. However, the incidence of spinal hematoma
increases with the presence of any risk factors, listed in Table 1,
and more so if heparin anticoagulation is accompanied by trau-
matic puncture (increasing incidence rates to 1 in 2000 and 1
in 2900 for epidural and spinal anesthesia, respectively). For
ASA therapy the risk is 1 in 8500 and 1 in 12 000 for epidural
and spinal anesthesia, respectively [41,42]. An incidence of
between 1 in 1000 and 1 in 10 000 has been estimated for neur-
axial hematoma after central neural blockade in patients under-
going orthopedic procedures and receiving preoperative
thromboprophylaxis with enoxaparin [43]. A recent review
assessing spinal/epidural anesthesia complications in Finland
from 2000 to 2009 showed the risk of developing a serious
complication (defined as a potentially fatal event or an event
of over 1 year in duration, including epidural hematoma) after
226
Table 1 Risk factors associated with spinal epidural hematoma
during central neuraxial block [33]
Patient related
Elderly
Female sex
Inherited coagulopathy
Acquired coagulopathies (liver/renal failure, malignancy,
HELLP syndrome, DIC etc)
Thrombocytopenia
Spinal abnormalities (spinal bifida/stenosis, spinal tumors,
ankylosing spondylitis, and osteoporosis)
Drug related
Anticoagulation/antiplatelet/fibrinolytic
Immediate (pre- and post-CNB) anticoagulant administration
Dual anticoagulant/antiplatelet therapies
Procedure related
Catheter insertion/removal
Traumatic procedure (multiple attempts)
Presence of blood in the catheter during insertion/removal
Indwelling epidural catheter N single-shot epidural block N
single-shot spinal block
CNB = central neuraxial block; DIC = disseminated intravascular coagulation;
HELLP = hemolysis, elevated liver enzymes, low platelet count.
central neuraxial block to be approximately 1 in 35 000
patients, with 1 in 53 000 patients presenting with irreversible
damage [44]. Of the 13 cases of neuraxial hematoma reported
from a total of 1.4 million procedures involving neuraxial
central blocks, 10 were associated with thromboprophylaxis
(enoxaparin, dalteparin, or fondaparinux); however, for
6 of 10 of these occurrences, the time elapsed between
cessation/initiation of thromboprophylaxis and puncture may
not have been sufficient to prevent a bleeding event [44]. A
recent retrospective study on the safety of epidural and spinal
neuraxial block showed that the incidence of perioperative
neurological complications in orthopedic patients was rela-
tively low (0.96/1000; 95% CI 0.77-1.16/1000), but was
higher than previously reported in other non-obstetric popula-
tions [45]. Risk factors associated with an increased risk of
Table 2 Pharmacokinetic characteristics of direct oral anticoagulants as per their Summary of Product Characteristics [6,8,10]
Apixaban
Bioavailability ~ 50% for doses up to 10 mg
Time to peak activity 3-4 h
Half-life ~ 12 h
Renal elimination ~ 27%
Pharmacokinetic interactions Strong inhibitors/inducers
of both CYP3A4 and P-gp
CYP3A4 = cytochrome P450 3A4; P-gp = P-glycoprotein.
G. Cappelleri, A. Fanelli
clinically significant bleeding causing spinal hematoma can
be divided into patient-, drug-, and procedure-related catego-
ries (Table 1).
2.3. Patient-related factors increasing the risk of
spinal hematoma
Regarding patient-related factors, clinicians must exercise
particular care with elderly patients requiring surgical inter-
vention—these patients are at increased risk of thrombo-
embolic disorders [46,47] and are, therefore, more likely to
be receiving anticoagulants. Furthermore, the bleeding risk in
elderly patients receiving anticoagulants is augmented
[48,49]. Elderly patients are also more likely to have renal or he-
patic impairment, causing increased drug plasma concentrations,
and consequently drug elimination may be slower in these
patients [50]. Real-world data from the RIETE (Registro Infor-
matizado de Pacientes con Enfermedad TromboEmbólica)
registry have shown major and fatal bleeding to be more com-
mon in patients receiving anticoagulation therapy who were
aged ≥ 80 years compared with those aged b 80 years (3.4%
vs 2.1% and 0.8% vs 0.4%, respectively) [51]. Therefore,
knowledge about the metabolism of the direct OACs approved
for VTE prevention after major orthopedic surgery is essential
when deciding which anticoagulant to prescribe to a particular
patient. Whereas the metabolism of dabigatran is mostly
dependent on renal clearance, the metabolism of apixaban
and rivaroxaban involves multiple pathways and is less
dependent on renal function (Table 2). The high frequency of
co-medication use in elderly patients also increases both the
potential for drug-drug interactions and the risk of bleeding [52].
2.4. Drug-related factors increasing the risk of
spinal hematoma
Some drug interactions of anticoagulants might increase the
risk of bleeding complications, including the risk of spinal hema-
toma. The direct OACs have fewer drug-drug and drug-food
Rivaroxaban Dabigatran
80%-100% ~ 7%
(for 10 mg dose and for 15 mg
and 20 mg doses taken with food)
2-4 h 0.5-2.0 h
5-9 h (young individuals) 11-14 h
to 11-13 h (elderly individuals)
33% as active drug 85%
(direct renal excretion) and 33%
after metabolic degradation
Strong inhibitors of both CYP3A4 and P-gp; Strong P-gp
strong CYP3A4 inducers inhibitors and
inducers
Anticoagulation and anesthesia
interactions compared with vitamin K antagonists. The most
significant interactions are those of apixaban and rivaroxaban
with systemic co-administration of strong inhibitors of both cyto-
chrome P450 3A4 and P-glycoprotein (such as the azole-
antimycotics ketoconazole and itraconazole and the HIV protease
inhibitor ritonavir), which is not recommended [6,10], and
dabigatran with amiodarone and verapamil that requires a
reduction in the daily dose [8]. For all 3 direct OACs, care
should be taken when co-administering with non-steroidal
anti-inflammatory drugs, ASA, or platelet aggregation inhibi-
tors, which may increase bleeding risk [6,10].
2.5. Procedural-related factors increasing the risk of
spinal hematoma
The risk of spinal hematoma has also been associated with
procedural factors, including unintentional needle/catheter-
related mechanical damage of neural or vascular components
of the spine due to a difficult or traumatic spinal procedure
[53–55]. The patient characteristics also have an influence
on procedure-related risk factors; for example, aging is associ-
ated with skeletal degeneration that may make the anesthesia
procedure technically more difficult [56].
3. Influence of anesthesia in patients receiving
direct oral anticoagulants: evidence from
phase III clinical studies with a focus on
major orthopedic surgery
Given the increasing utilization of direct OACs for the
treatment and prevention of thromboembolic disorders, it is
crucial to evaluate the risk of compressive hematoma and the
impact on clinical outcomes when regional anesthesia is used.
To discuss the effect of regional anesthesia on the risk of com-
pressive hematoma and bleeding risk, we searched PubMed
with no date restrictions for phase III clinical trials comparing
‘apixaban’, ‘rivaroxaban’, or ‘dabigatran’ with ‘standard of
care’/‘low molecular weight heparin’ for ‘VTE prevention’/
‘thromboprophylaxis’ after ‘total knee or hip replacement
surgery’/‘knee or hip arthroplasty’ and for studies investigating
‘spinal hematoma’ after ‘regional anesthesia’.
It is worth noting the risk of spinal hematoma with regional
anesthesia when receiving traditional anticoagulants. Vitamin
K antagonist therapy is a contraindication for neuraxial
anesthesia, owing to the high risk of bleeding associated with
therapeutic doses [57]. The risk of spinal hematoma in patients
receiving low molecular weight heparin (LMWH) concomi-
tantly with epidural anesthesia is reported to be 1:6600 for
single-shot epidural and 1:3100 with an indwelling catheter
for the LMWH dosage of 30 mg twice daily and 1:18 000
for a 40 mg once-daily dosage [57,58]. There are fewer data
for ASA, but it has been demonstrated that medical patients
receiving daily doses above 100 mg are at increased risk of
hemorrhagic complications [59].
227
Central nerve blocks have been classified as a high bleed-
ing risk procedure owing to their rare but severe complication,
eg, spinal-epidural hematoma [60,61]. Because of the absence
of evidence-based data, when neuraxial procedures are
performed in these conditions, a systematic follow-up of these
patients and a heightened awareness of bleeding complications
should be observed.
3.1. Apixaban
Studies specifically designed to investigate the relationship
between anesthesia and spinal hematoma risk in patients
receiving apixaban are lacking. However, phase III clinical
trials comparing apixaban (2.5 mg twice daily) with subcuta-
neous enoxaparin (30 mg twice daily or 40 mg once daily)
for VTE prevention after total knee or hip replacement surgery
found that apixaban was as effective as or better than enoxa-
parin at reducing the risk of the composite of VTE or death
with similar or lower rates of bleeding [22–24]. In these 3
trials, 15.8% of patients randomized to apixaban had regional
anesthesia. Experience of apixaban use in the presence of
neuraxial blockade is limited and, according to its product label
and guidance from the European Society of Anaesthesiology
(ESA), should only be done with extreme caution [6,57].
3.2. Rivaroxaban
The incidences of intraspinal bleeding or hemorrhagic
puncture were included under the definition for major bleed-
ing used in the RECORD (REgulation of Coagulation in
ORthopaedic surgery to prevent Deep vein thrombosis and
pulmonary embolism) clinical trial program of rivaroxaban
[27,62]. A post hoc analysis assessed 12 729 randomized
patients in the pooled RECORD1-4 program undergoing elec-
tive total knee or hip replacement surgery for events related to
neuraxial anesthesia, such as neuraxial hematoma [62].
Thromboprophylactic therapy was provided to patients as
either oral rivaroxaban (10 mg once daily, initiated 6-8 hours
after surgery) or subcutaneous enoxaparin (40 mg once daily,
started 12 hours prior to surgery, or 30 mg twice daily, started
12-24 hours after surgery) [62]. Although 66% of patients
(safety population, n = 12 383) received neuraxial anesthesia
(9% of patients also received general anesthesia), only 1
compressive hematoma after epidural catheter removal was
recorded. This event occurred after elective total knee replace-
ment surgery in a patient treated with enoxaparin, who was at
increased risk of bleeding as a result of advanced age and renal
insufficiency. The patient was adequately managed with a
laminectomy without further bleeding or neurological
complications [62]. The type of anesthesia (spinal with or
without general anesthesia, epidural, epidural with indwelling
catheter, general or spinal with femoral block, or general
alone) had no influence on the rates of total venous thrombo-
embolic events, which were lower with rivaroxaban than with
standard of care [62].
228
In the RECORD post hoc subanalysis, the incidence of total
venous thromboembolic events (the composite of any DVT,
non-fatal PE, and all-cause mortality) and safety profiles were
similar irrespective of the type of anesthesia used. Neuraxial
anesthesia was associated with a slightly lower rate of
symptomatic thromboembolic events compared with general
anesthesia in patients undergoing elective total knee or hip
replacement surgery [62]. However, available experience
using rivaroxaban with neuraxial blockade remains limited,
and real risk is difficult to evaluate owing to the low incidences
of spinal and epidural hematoma in this setting. The ESA
guidelines, published before the completion of the relevant
RECORD subanalysis, recommend extreme caution when
using rivaroxaban with neuraxial blockade [57]. The
American Society of Regional Anesthesia and Pain Medicine
(ASRA) guidelines for dabigatran, as well as rivaroxaban,
are still being evaluated. These guidelines do not provide
detailed information for the management of anticoagulation
with direct OACs owing to a lack of available information
on block performance [41].
3.3. Dabigatran
An analysis of the pooled population of patients from the
phase III RE-MODEL, RE-NOVATE, and RE-MOBILIZE
studies who underwent major hip or knee replacement surgery
and received thromboprophylaxis with dabigatran (220 mg or
150 mg once daily) or enoxaparin showed a higher use of neur-
axial anesthesia (n = 4212; 52%) compared with general anes-
thesia (n = 2311; 29%) or combination anesthesia, namely,
neuraxial or general anesthesia combined with a peripheral
nerve block (n = 1539; 19%) [63]. The use of neuraxial anes-
thesia was not associated with neuraxial hematoma—no cases
were reported [63]. The efficacy and safety outcomes of the
dabigatran groups did not differ from those of the standard
therapy groups, and were not significantly influenced by the
type of anesthesia used [63]. A reduced incidence of major
VTE and VTE-related mortality was observed with neuraxial
anesthesia compared with general anesthesia (4.2% vs 3.1%;
OR 1.40; 95% CI 1.03-1.90; P = .035) in the overall population,
but no significant differences or clear trends were recorded
regarding the safety outcomes of major bleeding or major
and non-major clinically relevant bleeding between the types
of anesthesia [63]. Experience with combined use of neuraxial
blockade and dabigatran is restricted by its manufacturer's
advice against this, as stated by the ESA guidelines [8,57].
4. Management of direct oral anticoagulants and
neuraxial anesthesia in major orthopedic surgery
Management strategies must balance the surgical risk of
hematoma in the anesthetized patient with effective thrombo-
prophylaxis. Understanding the pharmacodynamic and
pharmacokinetic properties of an anticoagulant and the influ-
ence of patient age and hepatic and renal function is essential.
G. Cappelleri, A. Fanelli
Providing neuraxial anesthesia and the timing of needle/catheter
insertion/removal in patients who are receiving or are to receive
anticoagulant therapy involves individual assessment of the
risks and benefits of such a procedure, together with rigorous
management of anticoagulation activity and monitoring for
signs of neurological dysfunction. It is of the utmost importance
to ensure that the anticoagulation effect is adequately reduced
before proceeding with a neuraxial block. It is possible to
measure the effect of the direct OACs either qualitatively or
quantitatively, if required.
4.1. Perioperative management of direct
oral anticoagulants
Adequate protocols for interrupting and resuming thrombo-
prophylaxis based on the pharmacokinetic properties of the direct
OACs are essential. Clinical practice guidelines, such as those of
the ESA [57]), ASRA [41], and the Scandinavian Society of
Anaesthesiology and Intensive Care Medicine (SSAI) [64], pro-
vide recommendations for the regional anesthetic management
of patients undergoing surgery and requiring anticoagulation,
including with direct OACs (Table 3). These recommenda-
tions, based on data from clinical trials, the pharmacokinetic
profile of each anticoagulant, and from clinical experience, ad-
vise a waiting time between interrupting anticoagulation and
performing neuraxial blockade that depends on the elimination
half-life of the anticoagulant agent [57]. The percentages of
drug remaining in the circulation after 1-6 half-lives are
50%, 25%, 12.5%, 6.3%, 3.1%, and 1.6%, respectively [65].
A recommendation for a waiting period of 2 half-lives, to re-
duce the bioavailability of an anticoagulant to less than 25%,
does not take into consideration how the half-life elimination
of a drug is influenced by patient characteristics. Patients
who undergo joint replacement surgery are typically elderly,
often with renal impairment and receiving antiplatelet therapy;
for these patients, a waiting time of 3-5 half-lives could be
more appropriate if hemostatic safety is not assured (Table 4).
To prevent VTE after major orthopedic surgery, the direct
OACs have to be administered in the postoperative period
when adequate hemostasis has been established, as determined
by the treating physician.
Recently, the direct OACs have been approved for long-term
prevention of thromboembolic events in non-valvular AF, and
for the treatment and secondary prophylaxis of VTE. Every
year, 15%-20% of patients receiving therapeutic doses of anti-
coagulants require perioperative temporary interruption, and
the characteristics of both the patients and the procedures should
be considered when scheduling interruption and resumption.
4.1.1. Perioperative management of apixaban
4.1.1.1. Interruption of apixaban before surgery. The
apixaban Summary of Product Characteristics recommends
that discontinuation should occur ≥ 48 hours prior to elective
surgery associated with a moderate or high risk of bleeding,
although a longer waiting period may be advisable in elderly
patients (who show a slower elimination rate and are at
Anticoagulation and anesthesia
Table 3 Recommendations provided by each direct oral anticoagulant’s Summary of Product Characteristics (SPC), the European Society
of Anesthesiology (ESA), and the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) for managing anticoagulation
interruption/initiation and puncture or catheter insertion/removal [6,8,10,57,64].
Time between last dose of anticoagulant and
puncture or catheter insertion or removal
SPC ESA
Apixaban b
20-30 h 26-30 h
Rivaroxaban c 18 h 22-26 h
Dabigatran d Contraindicated Contraindicated
by the manufacturer by the manufacturer
a
Recommended minimum time intervals between the last dose of anticoagulant and central neuraxial block, and between central neuraxial block and first
dose or re-initiation of anticoagulant; the same recommendations apply for manipulation or removal of a catheter.
b
For prophylaxis, 2.5 mg twice daily.
c
For prophylaxis, 10 mg once daily.
d
For prophylaxis, 150-220 mg once daily.
increased risk of bleeding) [6]. There is no clinical experience
with the use of apixaban with indwelling intrathecal or epidu-
ral catheters [6]. However, if required, the recommendation
provided by the Summary of Product Characteristics is to wait
20-30 hours (considering 2 times its elimination half-life) be-
tween interruption of anticoagulation therapy and neuraxial
puncture/catheter removal, with at least 1 dose being omitted
[6,66]. The ESA recommends 26-30 hours between stopping
anticoagulation and conducting a neuraxial anesthesia proce-
dure for management of anticoagulation with apixaban in the
context of elective orthopedic surgery [57].
4.1.1.2. Resumption of apixaban after surgery. The Sum-
mary of Product Characteristics of apixaban recommends start-
ing thromboprophylaxis 12-24 hours after the end of surgery,
provided hemostasis is achieved and allowing for a waiting
period of at least 5 hours to re-initiate treatment after catheter
removal [6]. The ESA recommends 4-6 hours between cathe-
ter removal and initiation of anticoagulation, for management
of anticoagulation with apixaban in the context of elective
orthopedic surgery [57]. No further recommendations were
provided by the ASRA for management of anticoagulation
with apixaban in the context of elective orthopedic surgery
[41]. The SSAI guidelines state that the lack of data prevents
any recommendation being made regarding the use of apixa-
ban and central neuraxial block, although a period of 6 hours
should be observed between central neuraxial block or catheter
manipulation and first dose of this anticoagulant [64].
4.1.2. Perioperative management of rivaroxaban
4.1.2.1. Interruption of rivaroxaban before surgery. The
Summary of Product Characteristics of rivaroxaban suggest
in patients with normal renal function a minimum of 24 hours
between the last therapeutic dose of the anticoagulant and the
start of the surgery [10]. For patients with severe renal impair-
ment, many authors recommend an interval of up to 4-5 days
[60,67,68]. Imberti et al suggested a discontinuation of rivar-
oxaban at least 48 hours prior to procedures involving a
229
Time between puncture or catheter insertion
or removal and initiation of anticoagulation
SSAI a SPC ESA SSAI
Data not available ≥5 h 4-6 h 6h
18 h ≥6 h 4-6 h 6h
(24 h in case
of traumatic puncture)
Not included ≥2 h 6h Not included
standard risk of bleeding, such as orthopedic surgery; for
procedures with a high risk of bleeding (neuraxial block),
rivaroxaban should be stopped 72 hours before the intervention
[69]. In the authors' opinion, patients with AF with standard
bleeding risk (HAS-BLED score b 3) could undergo neuraxial
anesthesia 48 hours after the last rivaroxaban intake, whereas
in patients with high bleeding risk, neuraxial anesthesia should
be delayed for 4 days, and this type of anesthesia should not be
considered in cases of severe renal impairment (creatinine
clearance b 30 mL min−1) [69].
In patients receiving ongoing rivaroxaban, if a central block
with an indwelling catheter is used, the SSAI guidelines
recommend a minimum of 18 hours between the last dose of
rivaroxaban and removal of an indwelling catheter [64].
Because of the prolongation of the half-life in elderly patients,
the ESA guidelines recommend a longer interval (22-26 hours)
between the last dose of rivaroxaban and removal of an
indwelling catheter [57]. These 2 recommendations are in
agreement with those in the report by Rosencher et al, which
recommends 2 half-lives between rivaroxaban discontinuation
and epidural catheter removal [66]. Furthermore, these guide-
lines highlight the fact that patients receiving anti-hemostatic
drugs and with impaired drug elimination, such as those with
renal impairment, may require waiting times to be prolonged
[64]. The ASRA guidelines issued for rivaroxaban recom-
mend a cautious approach owing to the lack of information
on the specifics (needle placement or catheter management)
of block performance and the prolonged half-life in elderly pa-
tients resulting from deterioration of renal function, even in the
absence of any reported spinal hematoma [41].
4.1.2.2. Resumption of rivaroxaban after surgery. Rivar-
oxaban should be started 6-10 hours after the end of surgery,
provided hemostasis is achieved [10]. The SSAI guidelines
recommend a minimum of 6 hours between central neuraxial
block and initiation of rivaroxaban, or a delay of 24 hours if
a traumatic puncture occurred during the performance of
central nerve block [10,64]. The ESA recommends an interval
 230
Table 4 Half-lives of direct oral anticoagulant drugs and recommended interval between discontinuation and surgery or neuraxial procedure, set as 2-3 half-lives or 4-5 half-lives depending
on the bleeding risk of the surgical procedure and the level of anticoagulant effect permitted at surgery [65,67,68].
Drug Variation Bleeding risk of surgical procedure Anticoagulant residual effect at surgery
of elimination Low bleeding Days High Days Mild to Days between No Days
half-life values risk surgery between bleeding between moderate last dose and or minimal between
(h) a [65] (2-3 half-lives) [67] last dose risk surgery last dose anticoagulant surgery [68] anticoagulant last dose
and surgery (4-5 half-lives) and surgery effect (2-3 half-lives) effect (4-5 half-lives) and surgery
[67] [67] [67] [68] [68] [68]
Apixaban 15 CrCl N 50 mL min−1 b 2d CrCl N 50 mL min−1 3d CrCl N 50 mL min−1 2d CrCl N 50 mL min−1 3d
CrCl 30-50 mL min−1 3d CrCl 30-50 mL min−1 4d CrCl 30-50 mL min−1 3d CrCl 30-50 mL min−1 4-5 d
Rivaroxaban 5-13 CrCl N 50 mL min−1 c 2d CrCl N 50 mL min−1 3d CrCl N 50 mL min−1 2d CrCl N 50 mL min−1 3d
CrCl 30-50 mL min−1 2d CrCl 30-50 mL min−1 3d CrCl 30-50 mL min−1 3d CrCl 30-50 mL min−1 4-5 d
CrCl 15-29.9 mL min−1 3d CrCl 15-29.9 mL min−1 4d
Dabigatran 12-17; CrCl N 50 mL min−1 e 2d CrCl N 50 mL min−1 3d CrCl N 50 mL min−1 2 d CrCl N 50 mL min−1 3 d
28 d CrCl 30-50 mL min−1 3d CrCl 30-50 mL min−1 4-5 d CrCl 30-50 mL min−1 3 d CrCl 30-50 mL min−1 4-5 d
CrCl = creatinine clearance.
a
Half-lives differ from those in the Summary of Product Characteristics of each agent.
b
Apixaban (5 mg twice daily) half-life for CrCl N 50 mL min−1 and CrCl 30-50 mL min−1 considered as 7-8 and 17-18 hours, respectively.
c
Rivaroxaban (20 mg once daily) half-life for CrCl N 50 mL min−1, CrCl 30-50 mL min−1 and CrCl 15-29 mL min−1 considered as 8-9, 9 and 9-10.5 hours, respectively.
d
End-stage renal disease.
e
Dabigatran (150 mg twice daily) half-life for CrCl N 50 mL min−1 and CrCl 30-50 mL min−1 considered as 14-17 and 16-18 hours, respectively.

G. Cappelleri, A. Fanelli
Anticoagulation and anesthesia
of 4-6 hours between epidural catheter removal and the next
dose of rivaroxaban [57]. Baron et al suggested a waiting time
of 48 hours before resuming anticoagulant after procedures
with a high risk of bleeding [60].
4.1.3. Perioperative management of dabigatran
4.1.3.1. Interruption of dabigatran before surgery. The
dabigatran Summary of Product Characteristics recommends
discontinuation of the anticoagulant for ≥ 2 days before elec-
tive surgery that carries a high risk of bleeding or is considered
to be ‘major’ surgery, depending on the patient's renal
function [8]. High-risk procedures, including cardiac surgery,
neurosurgery, abdominal surgery, or procedures requiring
spinal anesthesia, may require cessation of dabigatran 2-4 days
before surgery in patients with normal renal function and ≥ 4
days before surgery in patients with moderate renal impair-
ment (creatinine clearance 30-50 mL min− 1) [70]. Based on
the pharmacokinetic characteristics of dabigatran, a time inter-
val of 36 hours (skipping 1 dose) between the last dose of dabi-
gatran and puncture/catheter removal is suggested [66], but
this has not been studied or confirmed.
4.1.3.2. Resumption of dabigatran after surgery. Pro-
vided hemostasis is achieved, dabigatran should be started 1-4
hours after the end of surgery [8]. The ESA guidelines recom-
mend against the use of dabigatran in the presence of neuraxial
blockade, as also advised in the dabigatran Summary of
Product Characteristics [8]. If neuraxial anesthesia is used,
the first dose of dabigatran should not be administered within
2 hours of catheter removal, in accordance with the Summary
of Product Characteristics [8]. The ESA guidelines recom-
mend a waiting time of 6 hours after catheter removal before
re-initiating anticoagulation with dabigatran [57]. However,
the ASRA guidelines state simply that caution must be taken
owing to the paucity of information on the performance of
neuraxial block and the prolonged half-life of this anticoagu-
lant after multiple doses or in patients with renal impairment,
despite the absence of spinal hematomas reported up to the
publication of these guidelines [41]. The SSAI guidelines
make the sole recommendation of waiting for at least 6 hours
after a central neuraxial block or catheter removal before
the first dose of dabigatran is taken [64]. However, based on
the pharmacokinetic characteristics of dabigatran, it may be
prudent to wait at least 12 hours after catheter removal before
administration of dabigatran [66].
4.2. Laboratory measurement of direct
oral anticoagulants
In the context of perioperative management of patients who
are receiving a direct OAC, the concentration of the direct
OAC can be determined if, for example, an emergency
surgical intervention is required by an anticoagulated patient.
However, it is important to take into account the timing of
the last dose in relation to blood sampling time when interpreting
the test results [71].
231
4.2.1. Laboratory measurement of apixaban
The quantitative measurement of plasma concentrations of
apixaban can be performed using anti-Factor Xa chromogenic
assays and adequate standard calibration curves [72].
Although apixaban prolongs prothrombin time (PT), it is not
suitable for measuring the anticoagulant effect of apixaban
and there is no known relationship with bleeding risk [71].
4.2.2. Laboratory measurement of rivaroxaban
The PT can be used to determine the relative anticoagulant
activity of rivaroxaban [71,73]. However, PT is not specific
and can be influenced by factors such as cancer, hepatic
impairment, and vitamin K deficiency [74,75]. Furthermore,
there is marked variability in the sensitivity of the reagents
available for obtaining PT results for rivaroxaban; only a
sensitive reagent, such as Neoplastin Plus (Diagnostica Stago,
Asnières-sur-Seine, France), should be used [76]. Importantly,
the international normalized ratio must not be used for rivarox-
aban. The quantitative measurement of plasma concentrations
of rivaroxaban can be performed using anti-Factor Xa
chromogenic assays (eg, STA Rotachrom, Diagnostica Stago,
Asnières-sur-Seine, France) with validated calibrators [77].
When anti-Factor Xa assays are unavailable, a PT test with a
reagent sensitive to rivaroxaban may be used to confirm the
absence or presence of an anticoagulant effect (if the sampling
time after last tablet intake is known) [76,78,79].
4.2.3. Laboratory measurement of dabigatran
The activated partial thromboplastin time (aPTT) assay, for
example, provides a qualitative measure of the anticoagulant
effect of dabigatran [73]. Unfortunately, aPTT is influenced
by the coagulometers and reagents used [75]. In the case of
aPTT results for dabigatran, there is reasonable agreement
regardless of the reagent composition, and results are within
10% of reference measurements [70]. The aPTT assay may be
useful in dabigatran-treated patients who require emergency
interventions to exclude any clinically relevant dabigatran
anticoagulant effect [71,80]. The ecarin clotting time (ECT)
assay provides a direct measurement of the activity of dabiga-
tran, but is not readily available [71]. Calibrated ecarin chro-
mogenic assays are also available (eg, Ecarin Chromogenic
Assay, Diagnostica Stago, Asnières-sur-Seine, France) and
may allow faster ECT measurements than the ECT assay
[71]. Direct thrombin inhibitor assays (such as the
HEMOCLOT assay, HYPHEN BioMed, Neuville-sur-Oise,
France) can be used for the quantitative measurement of
plasma concentrations of dabigatran [81]. In the absence of
this assay, an aPTT test can be used [82].
5. Neurological complications and
regional anesthesia
Development of neurological complications is a major con-
cern in cases of regional anesthesia in patients receiving direct
232
OACs (eg, for stroke prevention). Assessment of neurological
function is the most reliable method for detecting neurological
injury, because standard laboratory tests may not provide ade-
quate information about the coagulation status of a patient
[83,84]. Monitoring of neurological function during regional
anesthesia alongside anticoagulant therapy is essential—but
may not be sufficient—to improve neurological outcomes.
Based on the pharmacokinetic properties of the direct OACs
and their rapid onset of action (within a few hours), confining
the assessment of neurological function to the period between
catheter removal or neuraxial puncture and 4 hours after
the initiation of therapy may seem reasonable. However, a
longer period of time during which neurological function
should be assessed may be required, because the development
of neurological injury may be slow, with the onset of
neurological symptoms potentially taking as long as 3 or more
days [55].
6. Use of non-neuraxial regional techniques and
direct oral anticoagulants in clinical practice
Total knee and hip replacement surgery causes intense
postoperative pain, which may impair rehabilitation and mobi-
lization, prolong hospitalization, and increase the risk of VTE
[85]. The use of continuous peripheral nerve blocks (femoral
and lumbar plexus blocks) for hip and knee surgery may offer
advantages as a first strategy to balance the risk of hematoma
in anticoagulated patients compared with epidural analgesia.
The results from a systematic review of randomized controlled
trials support the use of peripheral nerve blocks as a first
choice of analgesia after major orthopedic surgery; femoral
nerve block provided a similar analgesic profile to epidural
analgesia, with fewer side-effects after total knee replacement sur-
gery [86]. Lumbar plexus block represents the first analgesic
choice after total hip replacement surgery [87]. However, both
lumbar plexus and femoral nerve blocks are still associated
with loss of quadricep muscle strength [88,89]. A study has
suggested that an adductor canal block after knee surgery
may provide a similar analgesic profile but without quadricep
weakness after total knee replacement surgery [88]. Although
no difference was observed between the 2 anesthesia tech-
niques in terms of morphine use or level of pain, quadricep
strength was significantly better preserved with an adductor
canal block than with a femoral nerve block (52% median of
baseline vs 18%, P = .004) [88]. Peripheral nerve blocks have
been associated with a potential for wound hematoma with
administration of heparin in some studies [57,90–93] but not
others [94]. The potential severity of a hematoma in a non-
compressible site and the lack of evidence on which to base
recommendations for the particular use of continuous periph-
eral nerve blocks have led the ESA and ASRA guidelines to
suggest expanding the clinical recommendations for neuraxial
anesthesia to deeper peripheral nerve blocks, such as lumbar
plexus [41,57].
G. Cappelleri, A. Fanelli
Studies specifically investigating the use of apixaban after
non-neuraxial blocks in orthopedic surgery seem to be lacking.
However, there are some available data for rivaroxaban
and dabigatran. In a prospective observational study of 504
patients undergoing total knee replacement surgery who had
continuous femoral nerve block and whose femoral catheter
was removed 20 hours after starting rivaroxaban (10 mg once
daily), no incidences of hematoma causing neurovascular
compromise at the femoral catheter site or groin area were
reported [95]. Neither was rivaroxaban associated with an
increase in major bleeding in an observational analysis of
766 patients undergoing total knee or hip replacement surgery
and femoral, sciatic, and lumbar plexus blocks, although 3
hematomas in the operated knee requiring surgical evacuation
were noted during rivaroxaban administration [96].
In a post hoc pooled analysis of 3 phase III clinical trials of
dabigatran (220 mg or 150 mg once daily) versus enoxaparin
for VTE prevention after knee or hip replacement surgery, in
which 19% (n = 1539) received a combination of general anes-
thesia or neuraxial anesthesia plus peripheral nerve block, rates
of major VTE and VTE-related mortality were slightly higher
with general anesthesia compared with neuraxial or combina-
tion anesthesia, although not significantly so, and neither were
there significant differences in efficacy or safety outcomes
between dabigatran and enoxaparin [63].
7. Conclusions
Patients undergoing elective major orthopedic surgery
receive thromboprophylaxis because of their increased risk
of developing VTE. With the overall aging of the population,
more patients undergoing major orthopedic surgery are likely
to be receiving anticoagulation therapy for thromboembolic
disorders prior to their surgical procedure. Several direct
OACs are currently approved for different therapeutic indica-
tions, including prevention of VTE after elective knee or hip
replacement surgery, and their use in clinical practice has been
growing. Effective management of these direct OACs and
regional anesthesia is essential to avoid bleeding complica-
tions and is, therefore, a topic of crucial interest for anesthesi-
ologists. Thromboprophylaxis with all direct OACs may start
between 1 and 24 hours after surgery [6,8,10], provided that
hemostasis has been achieved, and thus should present a lower
theoretical risk of bleeding or neuraxial hematoma in case of
central blocks, in comparison with preoperatively initiated
LMWH. After surgery, restarting direct OACs can be delayed
by up to 48 hours in cases of bleeding or a difficult neuraxial
block, and protection against thromboembolic events is
achieved within hours after the first dose of these agents and
without the need for bridging therapy. The effect of the type
of anesthesia on clinical outcomes of the direct OACs is still
unclear. Subanalyses of RE-MODEL, RE-NOVATE, and
RE-MOBILIZE data suggest that, irrespective of the anesthe-
sia used, neuraxial anesthesia was associated with a lower risk
Anticoagulation and anesthesia
of thromboembolic events and VTE-related mortality than
general anesthesia [63]. Conversely, a subanalysis of pooled
RECORD data found no significant difference in the risk of
venous thromboembolic events between these types of
anesthesia used [62]. A growing body of clinical study and
real-world data, particularly with rivaroxaban, suggests that
neuraxial anesthesia can be undertaken in patients undergoing
major orthopedic surgery without increasing the risk of
compressive hematoma, provided that guideline recommenda-
tions are followed and bleeding risk is evaluated on an individ-
ual basis.
Acknowledgements
The authors would like to acknowledge Li Wan for
editorial support, with funding from Bayer HealthCare
Pharmaceuticals and Janssen Scientific Affairs, LLC.
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