Beruflich Dokumente
Kultur Dokumente
Review
Anaesthesia and Intensive Care Unit, Azienda Ospedaliera Istituto Ortopedico Gaetano Pini, 20122, Milan, Italy
Anaesthesia and Intensive Care Unit, Policlinico S. Orsola-Malpighi, 40138, Bologna, Italy
Keywords:
Direct oral anticoagulant;
Major orthopedic surgery;
Neuraxial anesthesia;
Perioperative management;
Postoperative management
Abstract The use of direct oral anticoagulants including apixaban, rivaroxaban, and dabigatran, which are
approved for several therapeutic indications, can simplify perioperative and postoperative management
of anticoagulation. Utilization of regional neuraxial anesthesia in patients receiving anticoagulants carries
a relatively small risk of hematoma, the serious complications of which must be acknowledged. Given
the extensive use of regional anesthesia in surgery and the increasing number of patients receiving direct oral
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 specic 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
Venous thromboembolism (VTE), comprising deep vein
thrombosis (DVT) and pulmonary embolism (PE), and its
long-term complications cause signicant morbidity, mortality
and healthcare costs [13]. The risk of VTE is particularly
high in patients who undergo major orthopedic surgery, such
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/).
225
recommendations will be discussed and best practice in specic
clinical situations, such as in patients with renal impairment who
are at an increased risk of bleeding, will be highlighted.
226
G. Cappelleri, A. Fanelli
Pharmacokinetic characteristics of direct oral anticoagulants as per their Summary of Product Characteristics [6,8,10]
Apixaban
Rivaroxaban
Dabigatran
Bioavailability
~ 7%
3-4 h
~ 12 h
Renal elimination
~ 27%
Pharmacokinetic interactions
Strong inhibitors/inducers
of both CYP3A4 and P-gp
80%-100%
(for 10 mg dose and for 15 mg
and 20 mg doses taken with food)
2-4 h
5-9 h (young individuals)
to 11-13 h (elderly individuals)
33% as active drug
(direct renal excretion) and 33%
after metabolic degradation
Strong inhibitors of both CYP3A4 and P-gp;
strong CYP3A4 inducers
0.5-2.0 h
11-14 h
85%
Strong P-gp
inhibitors and
inducers
227
Central nerve blocks have been classied as a high bleeding 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 specically 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 subcutaneous 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 enoxaparin at reducing the risk of the composite of VTE or death
with similar or lower rates of bleeding [2224]. 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 denition for major bleeding 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 elective 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 replacement surgery in a patient treated with enoxaparin, who was at
increased risk of bleeding as a result of advanced age and renal
insufciency. 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 inuence on the rates of total venous thromboembolic 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 proles 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 difcult 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 neuraxial anesthesia (n = 4212; 52%) compared with general anesthesia (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 anesthesia was not associated with neuraxial hematomano cases
were reported [63]. The efcacy and safety outcomes of the
dabigatran groups did not differ from those of the standard
therapy groups, and were not signicantly inuenced 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 signicant 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].
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 benets 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.
229
Table 3 Recommendations provided by each direct oral anticoagulants 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
SSAI a
SPC
ESA
SSAI
Apixaban
Rivaroxaban c
20-30 h
18 h
26-30 h
22-26 h
4-6 h
4-6 h
6h
6h
Dabigatran d
Contraindicated
by the manufacturer
Contraindicated
by the manufacturer
Not included
5 h
6 h
(24 h in case
of traumatic puncture)
2 h
6h
Not included
a
Recommended minimum time intervals between the last dose of anticoagulant and central neuraxial block, and between central neuraxial block and rst
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.
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
Apixaban
Variation
of elimination
half-life values
(h) a [65]
Days
between
last dose
and surgery
[67]
High
bleeding
risk surgery
(4-5 half-lives)
[67]
Days
between
last dose
and surgery
[67]
Mild to
moderate
anticoagulant
effect (2-3 half-lives)
[68]
Days between No
last dose and or minimal
surgery [68]
anticoagulant
effect (4-5 half-lives)
[68]
15
CrCl N 50 mL min1 b
CrCl 30-50 mL min1
CrCl N 50 mL min1 c
CrCl 30-50 mL min1
CrCl 15-29.9 mL min1
CrCl N 50 mL min1 e
CrCl 30-50 mL min1
2d
3d
2d
2d
3d
2d
3d
CrCl N 50 mL min1
CrCl 30-50 mL min1
CrCl N 50 mL min1
CrCl 30-50 mL min1
CrCl 15-29.9 mL min1
CrCl N 50 mL min1
CrCl 30-50 mL min1
3d
4d
3d
3d
4d
3d
4-5 d
CrCl N 50 mL min1
CrCl 30-50 mL min1
CrCl N 50 mL min1
CrCl 30-50 mL min1
2d
3d
2d
3d
Rivaroxaban 5-13
Dabigatran
12-17;
28 d
CrCl N 50 mL min1 2 d
CrCl 30-50 mL min1 3 d
CrCl N 50 mL min1
CrCl 30-50 mL min1
CrCl N 50 mL min1
CrCl 30-50 mL min1
Days
between
last dose
and surgery
[68]
3d
4-5 d
3d
4-5 d
CrCl N 50 mL min1 3 d
CrCl 30-50 mL min1 4-5 d
G. Cappelleri, A. Fanelli
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 specic
and can be inuenced by factors such as cancer, hepatic
impairment, and vitamin K deciency [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,
Asnires-sur-Seine, France), should be used [76]. Importantly,
the international normalized ratio must not be used for rivaroxaban. The quantitative measurement of plasma concentrations
of rivaroxaban can be performed using anti-Factor Xa
chromogenic assays (eg, STA Rotachrom, Diagnostica Stago,
Asnires-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 conrm 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 inuenced
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 dabigatran, but is not readily available [71]. Calibrated ecarin chromogenic assays are also available (eg, Ecarin Chromogenic
Assay, Diagnostica Stago, Asnires-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].
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 adequate information about the coagulation status of a patient
[83,84]. Monitoring of neurological function during regional
anesthesia alongside anticoagulant therapy is essentialbut
may not be sufcientto improve neurological outcomes.
Based on the pharmacokinetic properties of the direct OACs
and their rapid onset of action (within a few hours), conning
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].
G. Cappelleri, A. Fanelli
Studies specically 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 anesthesia 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 combination anesthesia, although not signicantly so, and neither were
there signicant differences in efcacy 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 indications, 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 complications and is, therefore, a topic of crucial interest for anesthesiologists. 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 difcult neuraxial
block, and protection against thromboembolic events is
achieved within hours after the rst 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 anesthesia used, neuraxial anesthesia was associated with a lower risk
Acknowledgements
The authors would like to acknowledge Li Wan for
editorial support, with funding from Bayer HealthCare
Pharmaceuticals and Janssen Scientic Affairs, LLC.
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