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Journal of Clinical Anesthesia (2016) 34, 586599

Review article

Risk stratication, perioperative and


periprocedural management of the patient
receiving anticoagulant therapy,,,
Adriana D. Oprea MD (Assistant Professor of Anesthesiology),
Christopher J. Noto MD (Assistant Professor of Anesthesiology),
Thomas M. Halaszynski DMD, MD, MBA (Associate Professor of Anesthesiology)
Yale University School of Medicine, New Haven, CT

Received 7 January 2016; revised 2 June 2016; accepted 7 June 2016

Keywords:
Abstract As a result of the aging US population and the subsequent increase in the prevalence of coronary
Anticoagulation;
disease and atrial brillation, therapeutic use of anticoagulants has increased. Perioperative and periproce-
Bridging therapy;
dural management of anticoagulated patients has become routine for anesthesiologists, who frequently me-
Perioperative period
diate communication between the prescribing physician and the surgeon and assess the risks of both
thromboembolic complications and hemorrhage. Data from randomized clinical trials on perioperative man-
agement of antithrombotic therapy are lacking. Therefore, clinical judgment is typically needed regarding
decisions to continue, discontinue, bridge, or resume anticoagulation and regarding the time points when
these events should occur in the perioperative period. In this review, we will discuss the most commonly
used anticoagulants used in outpatient settings and discuss their management in the perioperative period.
Special considerations for regional anesthesia and interventional pain procedures will also be reviewed.
2016 Elsevier Inc. All rights reserved.

1. Introduction coronary artery disease, atrial brillation (AF), and other risk
factors of the aging US population [1]. Perioperative and peri-
Use of prophylactic or therapeutic regimens of antithrom- procedural management of anticoagulated patients has become
botics has increased because of the rise in prevalence of routine for anesthesiologists, who frequently mediate commu-
nication between the prescribing physician and the surgeon
and also assess risks of both thromboembolic and hemorrhagic
complications. Data from randomized clinical trials on periop-

Disclaimers: none. erative management of antithrombotic therapy are lacking.

Reprints: none applicable. Therefore, clinical judgment is required regarding decisions



Financial support: none. to continue, discontinue, bridge, or resume anticoagulation

Conicts of interest: none.


Corresponding author at: Department of Anesthesiology, Yale Universi-
and the time points when these events should occur in the peri-
ty, 333 Cedar St, TMP 3, PO Box 208051, New Haven, CT 06520- 8051. operative period [2,3]. This review discusses the commonly
Tel.: +1 203 785 2802; fax: +1 203 785 6664. used anticoagulants with emphasis on safe management
E-mail address: adriana.oprea@yale.edu (A.D. Oprea). and appropriate decision-making alternatives in the surgical

http://dx.doi.org/10.1016/j.jclinane.2016.06.016
0952-8180/ 2016 Elsevier Inc. All rights reserved.
Perioperative management of anticoagulants 587

setting. Special considerations for regional anesthesia and in- Fondaparinux (Arixtra, GlaxoSmithKline) is indicated as
terventional pain procedures have also been reviewed. an alternative to heparin or LMWH for initial treatment of ve-
nous thromboembolism (VTE) and for thromboprophylaxis in
medical, surgical, and high-risk orthopedic patients. Fondapar-
inux exerts its effect through factor Xa inhibition and exhibits
2. Anticoagulants
complete bioavailability following subcutaneous injection. Its
plasma half-life is 17 hours, and because it does not bind to en-
Unfractionated heparin (UFH) activates antithrombin III dothelial cells or plasma proteins, its clearance is dose inde-
(ATIII) and accelerates the rate of inhibition of thrombin (fac- pendent [5]. In addition, fondaparinux is eliminated
tor IIa) and factor Xa. Therapeutic heparin levels are achieved unchanged by the kidneys; therefore, it is contraindicated in
by a 2- to 3-fold prolongation of the activated partial thrombo- patients with renal insufciency.
plastin time (aPTT) or antifactor Xa levels between 0.3 and Warfarin (Coumadin, Bristol-Myers Squibb; Jantoven,
0.7 U/mL. Anticoagulation with heparin can be neutralized Upsher-Smith Laboratories, Inc) interferes with the synthesis
by protamine administration. Dosing protamine depends on of vitamin Kdependent clotting proteins (factors II, VII,
both the route and time elapsed since the last heparin adminis- IX, and X). Because there is a delay in achieving antithrombot-
tration. For example, if 100 U of heparin is given subcutane- ic effect with initiation of warfarin therapy, it is often com-
ously, then 1-1.5 mg of protamine should be used for bined with concomitant administration of a more rapidly
reversal. Similarly, if 100 U of heparin is administered intrave- acting parenteral anticoagulant such as heparin, LMWH, or
nously, 1-1.5 mg of protamine should be used for reversal if fondaparinux.
heparin administration has occurred within the last 30 minutes; Warfarin is rapidly absorbed from the gastrointestinal tract,
however, a smaller dose of protamine (0.25-0.375 mg) is and its levels within plasma peak in approximately 90 minutes
required if N2 hours have elapsed since the last heparin following administration; its plasma half-life is 36-42 hours
administration. [8]. Warfarin is metabolized in the liver by the cytochrome P
A potential complication of heparin administration is 450 system, and agents that either induce or inhibit cyto-
thrombocytopenia, the most serious form being heparin- chrome P 450 can alter warfarin metabolism and its clinical ef-
induced thrombocytopenia (HIT) thrombosis syndrome or fects. Monitoring warfarin treatment can be performed by
HIT type II. HIT type I (nonimmune mediated) can result measuring the prothrombin time (PT). The PT test measure-
in a mild decrease in platelet count but does not usually incur ment uses thromboplastin as its reagent, but because different
signicant bleeding risks. However, patients with HIT type II thromboplastins have variable sensitivities to levels of vitamin
(immune mediated) can have dangerously low platelet counts Kdependent clotting factors, PT results can vary depending
that occur 5-14 days after following initiation of heparin ther- on the reagent used. Therefore, the international normalized
apy [4]. There are also exceptions where HIT type II can occur ratio (INR) was introduced to monitor the effects of warfarin.
either sooner or later than the time frame described above [4]. For most clinical situations, warfarin is administered in doses
Lowmolecular weight heparin (LMWH) has replaced to achieve a target INR of 2.0-3.0. The exceptions are in
UFH in many clinical situations and is typically administered patients with mechanical mitral heart valves, older aortic
subcutaneously. Enoxaparin (Lovenox, Sano) and dalteparin mechanical valves (ball-in-cage, disk tilting), and newer-
(Fragmin, Pzer Inc) have several advantages over UFH such generation aortic mechanical valves in the presence of
as dose-independent clearance, a more predictable anticoagu- additional risk factors for thromboembolism (AF, previous
lant response, improved bioavailability following subcutane- thromboembolic event, left ventricular dysfunction, or hyper-
ous injection, and lower risks of osteoporosis and HIT [5]. coagulable state), where a higher target INR (2.5-3.5)
LMWH mechanism of action involves activating ATIII and is recommended.
subsequently inhibiting factor Xa, with little effect on The new oral anticoagulants (NOACs) available in the
thrombin inhibition. LMWH does not usually require United States include dabigatran (direct thrombin inhibitor)
monitoring of coagulation tests, but when necessary, and several anti-Xa agents (rivaroxaban, apixaban, and edoxa-
antifactor Xa levels should be measured, as LMWH has ban) (Table 1). The NOACs have a rapid onset of action, with
little effect on the aPTT. For LMWH prophylaxis, anti peak anticoagulant effects achieved within 1-4 hours, thereby
factor Xa levels of 0.2-0.5 U/mL are desired, but levels reducing the need for temporary parenteral anticoagulation.
should range between 0.5 and 1.2 U/mL for therapeutic an- Dabigatran (Pradaxa, Boehringer Ingelheim) is an oral
ticoagulant effects [6]. Monitoring anti-Xa levels is indicated direct thrombin inhibitor with a half-life of 12-14 hours
in patients with renal insufciency who have received and maximum anticoagulant effect achieved within 2-3
LMWH, but data do not support monitoring antifactor Xa hours of ingestion. The predominant elimination pathway
levels in obese patients [7]. is by unchanged renal excretion; therefore, clearance can
Although protamine has been used to reverse effects from be longer in older adults and in those with reduced renal
LMWH administration, it does not completely neutralize its function. Monitoring of coagulation is not typically per-
anticoagulant activity because protamine only binds to the lon- formed in patients taking dabigatran (INR should not be
ger chains of LMWH. used to monitor therapy) [9].
588 A.D. Oprea et al.

Table 1 Oral anticoagulants: properties and indications


Drug Mechanism Half-life Time to peak Metabolism Indications
serum level
Warfarin Vitamin K 36-42 h 90 min Hepatic, oxidative metabolism DVT/PE treatment
antagonist DVT prophylaxis
AF (valvular and nonvalvular)
Rivaroxaban Factor Xa 7-11 h 2-4 h 33% renal (remainder metabolized to DVT prophylaxis after
inhibitor inactive molecules and eliminated knee/hip surgery
in the feces and urine) DVT/PE treatment
Nonvalvular AF
Apixaban Factor Xa 8-15 h 3-4 h 25% renal DVT prophylaxis after
inhibitor knee/hip surgery
75% intestinal DVT/PE treatment
Nonvalvular AF
Edoxaban Factor Xa 9-10 h 1-2 h 50% renal DVT/PE treatment
inhibitor 50% metabolism and bile excretion Nonvalvular AF
Dabigatran Direct thrombin 12-14 h 2-3 h 80% renal DVT/PE treatment
inhibitor Nonvalvular AF

Rivaroxaban (Xarelto, Bayer) is an oral direct factor Xa in- but there may be a thrombotic risk during discontinuation, so
hibitor with a bioavailability of 80%, reaching peak plasma clinicians must decide whether bridging therapy should be
concentration within 2-4 hours following administration. It considered (ie, short-acting parenteral medications such as
has a half-life of 7-11 hours in patients with normal renal func- LMWH or UFH). However, given the short half-life of
tion, and it is not recommended in patients with renal insuf- NOACs, these can be stopped within a shorter time period be-
ciency or those with signicant hepatic impairment (because fore any planned procedure or surgery without a need for
of a prolonged half-life) [8]. bridging therapy under most clinical situations.
Apixaban (Eliquis, Bristol-Myers Squibb) is a direct and Perioperative management of patients prescribed both
selective inhibitor of factor Xa that reaches peak plasma con- vitamin K antagonists and NOACs should follow a stepwise
centrations in approximately 3 hours and has a half-life of 8- approach described as:
15 hours. It is approved for use in AF and treatment of VTE.
Apixaban is mostly eliminated through hepatic metabolism
Step 1: Assess bleeding risks (ie, does the anticoagulant
and the fecal route with about 25% excreted renally [10].
need to be stopped for proposed procedure/surgery, or
Edoxaban (Savaysa, Daiichi Sankyo) is another direct fac-
can the procedure be performed with patients continuing
tor Xa inhibitor with a peak plasma concentration of 1-2 hours
oral anticoagulants?) and also decide upon the duration
following administration and a half-life of 9-10 hours. It is in-
of preoperative interruption of antithrombotic agent.
dicated for extended treatment of deep vein thrombosis (DVT)
Step 2: Dene thrombotic risks (ie, risk of a thrombo-
and pulmonary embolism (PE) following 5-10 days of initial
embolic event due to perioperative interruption of
therapy with another parenteral anticoagulant. Edoxaban is
anticoagulation).
not recommended in patients with a creatinine clearance (Cr
Step 3: Consider bridging therapy, particularly for patients
Cl) N 95 mL/min because of decreased effectiveness and in-
taking warfarin (patients at high risk of a thromboembolic
creased risk of ischemic stroke in patients with nonvalvular
event from perioperative interruption of anticoagulation
AF when compared with warfarin. Approximately 50% of
should be considered for bridging therapy).
the drug is excreted by the kidneys, with the remainder elimi-
nated through metabolism and biliary excretion [11].
3.1. Management of patients on warfarin

3.1.1. Step 1: assessing bleeding risk(s)


3. Perioperative management of anticoagulants Assessment of risk involves an understanding of both pa-
tient comorbidities and the invasive nature of any proposed in-
Clinicians must always assess the risks of thrombosis asso- tervention. There are no clear or validated predictors for risk(s)
ciated with discontinuing antithrombotic medications against of bleeding during the perioperative period, but there is evi-
risk of potential bleeding inherent to the proposed procedure. dence linking active cancer, thrombocytopenia (platelets
Management of patients on warfarin therapy differs signi- b150 K), presence of a mechanical mitral valve, and a history
cantly from those taking NOACs. Warfarin is typically discon- of bleeding to an increased risk of perioperative/periprocedural
tinued 5-7 days before surgery to allow for INR normalization, bleeding [12].
Perioperative management of anticoagulants 589

Table 2 Bleeding risk based on the procedure (adapted with permission from Baron et al [16]
Procedure Low bleeding risk (b1.5%) High bleeding risk
(1.5% or in vulnerable areas)
Anesthesiology Endotracheal intubation Spinal and epidural anesthesia
Cardiac surgery None All
Cardiovascular Diagnostic coronary angiography (controversial) Pacemaker or debrillator placement
(3.5% on warfarin therapy, 16% with
bridging anticoagulation)
Coronary intervention
Electrophysiology testing and/or ablation
Dental Tooth extraction Reconstructive procedures
Endodontic procedures (root canal)
Dermatology Minor skin procedures (excision of basal and squamous cell cancers, nevi, Major procedures (wide excision of
actinic keratoses, premalignant lesions) melanoma)
Gastroenterology Passage of endoscope for diagnostic purposes (including balloon Large polypectomy (N1 cm)
enteroscopy) with or without mucosal biopsy
Endoscopic retrograde cholangiopancreatography without sphincterotomy Endoscopic mucosal and submucosal
dissection
Endoscopic ultrasound without ne-needle aspiration Biliary or pancreatic sphincterotomy
Nonthermal (cold) snare removal of small polyps Percutaneous endoscopic gastrostomy
Lumenal self-expanding metal stent placement (controversial) Endoscopic ultrasound with ne-needle
aspiration or needle biopsy
Coagulation or ablation of tumors, vascular
lesions
Percutaneous liver biopsy
Variceal band ligation (controversial)
General surgery Suture of supercial wounds Major tissue injury
Vascular organs (spleen, liver, kidney)
Bowel resection
Laparoscopy
Gynecologic Diagnostic colposcopy Laparoscopic surgery
surgery Hysteroscopy Bilateral tubal ligation
Dilation and curettage Hysterectomy
Endometrial biopsy
Insertion of intrauterine device
Interventional Simple catheter exchange in well-formed, nonvascular tracts (eg, Percutaneous transhepatic cholangiography
radiology gastrostomy, nephrostomy, cholecystostomy tubes) or nephrostomy
Thoracentesis Percutaneous drainage of liver abscess or
gallbladder
Paracentesis Chest tube placement
Aspiration of abdominal or pelvic abscesses, placement of small-caliber Aggressive manipulation of drains or
drains dilation of tracts
Peripheral catheter placement, nontunneled catheter (peripherally inserted Biopsy of organs
central catheter) placement
Inferior vena cava lter placement Hickman and tunneled dialysis catheter
Temporary dialysis catheter placement placement
Intravascular Venous access Arterial puncture
procedures Transvenous ablation
Neurology None Lumbar puncture
Myelography
Needle electromyography (controversial)
Neurosurgery None Intracranial, spinal surgery
Ophthalmology Cataract surgery Periorbital surgery
Intraocular injections Vitreoretinal surgery
(Avoid retrobulbar anesthesia; controversial)
(continued on next page)
590 A.D. Oprea et al.

Table 2 (continued)
Procedure Low bleeding risk (b1.5%) High bleeding risk
(1.5% or in vulnerable areas)
Orthopedic Arthrocentesis Joint replacement
surgery Arthroscopy
Otolaryngologic Diagnostic beroptic laryngoscopy or nasopharyngoscopy Any sinus surgery
surgery Sinus endoscopy Biopsy or removal of nasal polyps
Fine-needle aspiration Thyroidectomy
Vocal cord injection Parotidectomy
Septoplasty
Turbinate cautery
Plastic surgery Injection therapy Reconstruction
Pulmonary Diagnostic bronchoscopy with or without bronchioalveolar lavage Tumor ablation (laser)
Endobronchial ne-needle aspirate (controversial) Transbronchial biopsy
Airway stent placement (controversial) Stricture dilation
Rheumatology Arthrocentesis None
Urology Circumcision Extracorporeal shock-wave lithotripsy
Cystoscopy without biopsy Transurethral prostatectomy
Bladder resection
Tumor ablation
Kidney biopsy
Vascular None Carotid endarterectomy
Open or endovascular aneurysm repair
Vascular bypass grafting

The HAS-BLED score was developed in nonoperative and (Table 2). The rate of declining INR values following discon-
nonprocedural settings to facilitate the decision of whether to tinuation is related to the initial INR value rather than the pre-
initiate anticoagulation in patients with AF. Additionally, the scribed dose of warfarin [24]. Patients maintained at higher
HAS-BLED score has been found to be useful in assessing INR values (3-4), as well as the elderly patient population, of-
the bleeding risk when bridging therapy is being considered ten require a longer interruption period [25]. Normal hemosta-
[13]. The score takes into account a history of Hypertension, sis has been demonstrated with INR levels between 1 (100%
Abnormal renal/liver function, Stroke, Bleeding history or clotting factor activity) and 2 (30% clotting factor activity).
predisposition toward bleeding, Labile INR values, Elderly Despite that, an INR of b1.5 is currently accepted for most in-
(N65 years), and concomitant use of Drugs/alcohol [14,15]. terventions [16,26]. However, patients scheduled for very high
Current evidence supports that procedures with a low risk risk procedures (intracranial, neuraxial anesthesia) should
of bleeding (b1.5%) can be performed without interruption have a normal INR documented on the day of surgery [27].
of warfarin (ie, an INR of 2.5 or less is accepted as safe) It is possible for the INR to be elevated despite holding warfa-
[16]. Minor dermatologic procedures such as removal of squa- rin for 5-7 days before scheduled intervention(s). If the INR is
mous or basal cell carcinomas and treatment for actinic kerato- measured to be between 1.4 and 1.9 the day before the planned
sis can be safely performed with higher INR values (b3.5) procedure, then administering a small oral dose of vitamin K
[17]. Patients undergoing mild- to moderate-risk dental proce- (1-2.5 mg) may be helpful [28,29].
dures (extractions, biopsies, and periodontal surgical proce- 3.1.1.1. Special considerations for high-risk bleeding
dures) may continue their warfarin therapy as long as the procedures. For certain high-risk bleeding procedures
INR is b4 [18,19]. Cataract surgery and joint injections can (N1.5%), it has been recommended that warfarin therapy
also be performed without discontinuing warfarin therapy should be continued instead of initiating bridging therapy with
[20,21]. Endoscopic procedures (respiratory or gastroentero- LMWH because of an increased risk of bleeding with the lat-
logic) are safe in those taking warfarin as long as there is no ter. During AF ablation procedures, the recommendation is
planned mucosal disruption [22,23]. to continue warfarin administration (target INR between 2
Warfarin therapy should be discontinued for surgical proce- and 3), instead of starting bridging therapy, to reduce the risks
dures that carry an intermediate to high risk of bleeding of both periprocedural stroke and bleeding that can be associ-
(N1.5%), with treatment typically discontinued 5 days before ated with LMWH [30,31]. Pacemaker and defibrillator im-
the proposed procedure for the INR to normalize [20] plantation may also be performed without interruption of
Perioperative management of anticoagulants 591

warfarin administration, as bridging therapy can lead to a Table 4 CHADS2 and CHA2DS2-VASc risk stratication
higher risk of implant pocket hematoma formation [32]. scores for subjects with nonvalvular AF
CHADS2 CHA2DS2
3.1.2. Step 2: dening the thrombotic risk and score VASc score
considerations for bridging
C: Congestive heart failure 1 1
The 2012 American College of Chest Physicians Evidence-
H: Hypertension 1 1
Based Clinical Practice Guidelines, 9th Edition, on periopera- A: Age 75 y 1 2
tive management of antithrombotic therapy (2012 ACCP D: Diabetes 1 1
guidelines) provide a framework for managing patients taking S: Stroke/TIA 2 2
anticoagulation medication and scheduled for elective surgery V: Vascular disease (prior MI, PAD, or 1
[20]. These guidelines stratify patients based on the indication aortic plaque)
for warfarin therapy (AF, presence of mechanical heart A: Age 65-74 y 1
valves, and history of DVT or PE) and potential thrombotic S: Sex category (female sex) 1
risk (Table 3). Patients in the high-risk category have an annu- Maximum score 6 9
al risk of thrombosis of N10%, those within the moderate risk
category have a 5%-10% risk, and patients in the low-risk cat-
egory have b5% risk of thrombosis [2,20]. treatment. For those with intermediate CHADS2 scores of 3-
3.1.2.1. Warfarin for treatment of AF. Atrial brillation is 4, the decision to start bridging therapy is at the discretion of
the most commonly encountered cardiac arrhythmia diag- the patient's cardiologist [20]. More recent literature suggests
nosed in elderly patients, with a 5%-8% annual risk of stroke initiating bridging therapy for patients with AF and a CHA2-
in the absence of anticoagulation. This risk can decrease to DS2-VASc score of 2 or higher, but only the CHADS2 score
1.6% in those treated with warfarin [33]. The risk of stroke was found helpful in predicting postoperative stroke [37].
during interruption of warfarin therapy can be estimated using Recent literature challenges the antithrombotic benet of
the CHADS2 and CHA2DS2-VASc scores; however, these pa- bridging. A meta-analysis involving 34 studies described a
rameters have not been validated in the perioperative setting 13%-15% risk for perioperative bleeding and a 3%-4% in-
(Table 4). One attributing factor is that iatrogenic trauma from creased risk of major bleeding, with no evidence of decreased
surgery induces a proinammatory and prothrombotic state risk for thrombosis, with bridging as compared with stopping
capable of resulting in an increased risk of stroke in the pres- warfarin alone [38]. Another study on 1884 patients with a
ence of AF [34,35]. mean CHADS2 score of 2.3, the BRIDGE trial, concluded that
The CHA2DS2-VASc is more discriminating than the foregoing bridging therapy in patients requiring warfarin inter-
CHADS2 score when identifying patients at low risk for ruption decreased the risk of bleeding and was found to be
thromboembolism (CHA2DS2-VASc of 0) vs at intermediate noninferior in terms of stroke protection when compared with
risk in the setting of AF [36]. Evidence indicates that CHA2- bridging therapy [39]. However, considerations from the
DS2-VASc is superior in identifying which patients should re- BRIDGE trial cannot be universally applied because patients
ceive anticoagulation. However, the CHADS2 score is more with a prior history of stroke and those with high CHADS2
useful in determining whether bridging should be initiated. scores (5-6) were underrepresented in the study.
Based on the 2012 ACCP guidelines, patients with Therefore, it appears safe to discontinue anticoagulant ther-
CHADS2 scores of 0-2 do not require bridging therapy, but pa- apy in patients treated with warfarin for AF, without bridging,
tients with CHADS2 scores of 5-6 can benet from such if the CHADS2 score is b4 and/or if there is no history of a

Table 3 Thromboembolic risk based on indication for warfarin (adapted with permission from Douketis et al [20]
Indication for warfarin Low risk Moderate risk High risk
AF CHA2DS2-VASc score of 2-3 or CHA2DS2-VASc score of CHA2DS2-VASc score of 6 or CHADS2
CHADS2 score of 0-2 (assuming 4-5 or CHADS2 score of 3-4 score of 5-6
no prior stroke or transient Recent (within 3 mo) stroke or transient
ischemic attack) ischemic attack
Mechanical heart valve Bileaet aortic valve prosthesis Bileaet aortic valve prosthesis Any mitral valve prosthesis
without AF or risk factors for stroke and AF, history of stroke or Any caged-ball or tilting-disk
transient ischemic attack, or aortic valve prosthesis
risk factors for stroke History of recent stroke, transient ischemic
attack, or cardioembolic event (within 3 mo)
VTE VTE N12 mo previously and no VTE within previous 3-12 mo, VTE within previous 3 mo, severe
other risk factor (eg, provoked nonsevere thrombophilia, or thrombophilia, unprovoked VTE, or
and transient) recurrent VTE active cancer (cancer diagnosed 6 mo or
patient undergoing cancer therapy)
592 A.D. Oprea et al.

prior stroke. For those with a history of recent stroke or that patients in the high- and moderate-risk categories be con-
CHADS2 scores of 5-6, bridging therapy should be sidered for bridging therapy [2,42].
considered.
3.1.2.2. Warfarin for treatment of DVT and PE. Patients 3.1.3. Step 3: bridging therapy considerations
with a history of a provoked DVT or PE (ie, due to recent sur- Patients at high risk for thromboembolism should be con-
gery, estrogen treatment, pregnancy, lower extremity injury, sidered for bridging therapy, but periprocedural bleeding must
ight time N8 hours) should be considered candidates for be weighed against antithrombotic benet. Several trials have
anticoagulation with warfarin for a 3-month period. Patients described increased bleeding risks and major bleeding events
with unprovoked or recurrent DVT (unless conned to distal in those prescribed bridging therapy with no evidence of sig-
venous vessels) or PE are candidates for longer-term (inde- nicant benet toward thromboembolic events [38,39,43].
nite) anticoagulation therapy [40]. Those with a history of pro- Therefore, until additional evidence becomes available, bridging
voked DVT or PE at an increased risk for recurrence are with therapeutic doses of parenteral anticoagulants should only
patients with active thrombophilic conditions such as ATIII be considered in those with a high risk of thrombosis such as:
deciency, antiphospholipid antibody syndrome, or active
cancer. These patients should be considered for long-term - Patients with AF and a history of recent stroke or
anticoagulation. CHADS2 score 5-6,
The most important factor in the deciding to discontinue - Those with a recent DVT/PE event (within 3 months),
warfarin therapy for 5 days preoperatively vs bridging with - Individuals with mechanical mitral valves, and
LMWH is the time elapsed since the last incident of DVT/ - Patients with older and/or bileaet aortic valves along
PE. In patients with a documented very recent thrombotic with a history of stroke or other cardioembolic event
event (within the previous 3 months), elective surgery should [2,44].
be postponed until the appropriate duration of anticoagulation
has been achieved. For those patients with a recent DVT/PE When bridging treatment is being considered in high-risk
(within 3 months) and requiring surgery that cannot be post- patients, therapeutic doses of either LMWH or UFH (LMWH
poned, bridging therapy should be initiated because of a 50% is used more than UFH) should be administered. Both LMWH
risk of thrombosis recurrence in the absence of anticoagulation and UFH are recommended when bridging therapy is antici-
[20]. In patients at low risk of recurrence (DVT/PE history N12 pated for individuals with AF and recent history of DVT/PE
months) and no additional apparent prothrombotic risk factors, [45] (Table 5). However, for patients with mechanical heart
warfarin can be discontinued for the recommended 5 days valves, European and American bridging guidelines differ.
without bridging. For patients at a moderate thromboem- The 2014 American College of Cardiology/American Heart
bolic risk (ie, history of DVT/PE between 3 and 12 months Association Guidelines for Management of Patients With Val-
before elective surgery, active thrombophilia, or cancer), vular Heart Disease and the 2012 ACCP Guidelines on Periop-
such a risk needs to be balanced against any periprocedural erative Management of Antithrombotic Therapy recommend
concern for bleeding in the event of initiating bridging that both UFH and LMWH can be used in those with mechan-
therapy. This patient population can either forgo bridging ical heart valves [20,42]. This is in contrast to the European
or receive prophylaxic doses of LMWH when the intra- Society of Cardiology guidelines where only UFH is approved
or postoperative risk of bleeding is considered to be high for patients with mechanical heart valves because of a lack of
[2,37]. studies assessing efcacy of LMWH in this patient population
3.1.2.3. Warfarin for mechanical heart valves. There is an [46].
increased risk of a major embolic event (4 per 100 patient- In patients prescribed warfarin for DVT/PE that occurred
years) for patients with mechanical cardiac valves in the ab- N3 months before the planned procedure and not categorized
sence of anticoagulation [41]. However, such risks can be de-
creased (1 per 100 patient-years) with warfarin therapy Table 5 Bridging regimens
following prosthetic valve replacement surgery. The risk of
embolism is estimated to be twice as high for those with mitral Anticoagulant Therapeutic dose Prophylactic dose
mechanical heart valves when compared with aortic valves Enoxaparin 1 mg/kg twice a day 30 mg twice a day
[41]. Patients with bileaet aortic valve prostheses, in the ab- subcutaneously subcutaneously
sence of a history of stroke or cardioembolic event, are consid- 1.5 mg/kg daily 40 mg daily
ered low risk and could discontinue warfarin 5 days subcutaneously subcutaneously
preoperatively [20]. Individuals with bileaet mechanical aor- Dalteparin 120 U/kg twice a day 5000 U daily
subcutaneously subcutaneously
tic valves in the presence of AF are considered a moderate risk,
200 U/kg daily
whereas patients at high risk of thromboembolism in the ab- subcutaneously
sence of anticoagulation include those with mechanical valves UFH Intravenous dose needed 5000-7500 U twice/
in the mitral position, older aortic valves (ball-cage, tilting- to achieve an aPTT 1.5-2 three times a day
disk), multiple mechanical heart valves, and a history of cere- times the control aPTT subcutaneously
brovascular/cardioembolic events [20]. It has been suggested
Perioperative management of anticoagulants 593

Table 6 Recommendations for NOAC discontinuation before elective surgery


Guideline Drug Dabigatran Rivaroxaban Apixaban Edoxaban
High-risk Low-risk High-risk Low-risk High-risk Low-risk High-risk Low-risk
bleeding bleeding bleeding bleeding bleeding bleeding bleeding bleeding
European Heart
Rhythm Cr Cl 80 mL/min 48 h 24 h 48 h 24 h 48 h 24 h 48 h 24 h
Association Cr Cl 50-80 mL/min72 h 36 h 48 h 24 h 48 h 24 h 48 h 24 h
Cr Cl 30-50 mL/min96 h 48 h 48 h 24 h 48 h 24 h 48 h 24 h
Cr Cl 15-30 mL/minNot Not 48 h 36 h 48 h 36 h 48 h 36 h
indicated indicated
Australasian Society Cr Cl 50 mL/min 72 h 48 h 72 h 24 h 72 h 24 h Not addressed
of Thrombosis and Cr Cl 30-49 mL/min 96-120 h 72 h 72 h 24 h 96 h 72 h
Hemostasis
Working Group on Cr Cl not addressed 5 d 24 h 5 d 24 h 5 d 24 h Not addressed
Perioperative
Hemostasis and
the French
Study Group
on Thrombosis
and Hemostasis
Manufacturer Cr Cl 50 mL/min 24-48 h 24 h 48 h 24 h 24 h
recommendations Cr Cl b 50 mL/min 72-120 h (Cr Cl and bleeding (Cr Cl not (Cr Cl and bleeding
risk not addressed) addressed) risk not addressed)

as high risk for thromboembolism, prophylactic doses of when treated with therapeutic doses (7.5 mg subcutaneously)
LMWH or UFH can be used as bridging therapy. Such an ap- and for 24 hours when on prophylactic doses (2.5 mg subcuta-
proach would reduce thromboembolic risk and minimize con- neously). The only clinical data for perioperative management
cern for perioperative bleeding when compared with a of those on fondaparinux are for coronary artery bypass sur-
therapeutic dose bridging model [20,44]. gery patients, and ndings support discontinuation 36 hours
Bridging therapy with either LMWH or UFH can be started before such surgery [47].
24-48 hours following warfarin cessation (3 days before the
planned surgery). Because UFH has the shorter half-life, the 3.3. Management of patients on NOACs
infusion should be stopped 4-6 hours before surgery, but when
LMWH is used for bridging, the last dose should be adminis- The relatively short half-life of the NOAC class of medica-
tered 24 hours before the planned operation and at half the dai- tions permits discontinuation of these agents closer to the day
ly dose [16]. of scheduled elective surgery. In addition, bridging therapy is
not typically required, as thrombotic risks are not signicantly
3.1.4. Restarting warfarin therapy increased when interrupting NOAC therapy but also because
Warfarin is usually restarted within 12-24 hours following of concerns that bridging can increase periprocedural bleeding
surgery provided adequate hemostasis has been established. [48-50].
When perioperative bridging was administered, LMWH can Data are emerging that certain surgical procedures can be
be restarted 24 hours after surgery for procedures with a low performed without stopping warfarin, and the same may be ap-
bleeding risk (HAS-BLED scoreb 3) and 48-72 hours follow- plied to continuing perioperative NOAC treatment. For exam-
ing surgery for patients with a high bleeding risk (HAS-BLED ple, evidence from a registry involving 2179 patients taking
scoreN 3). Perioperative bridging therapy can be discontinued NOACs and undergoing superficial skin surgical procedures,
after surgery as long as INR levels have been in the desired dental extractions, cataract surgery, and endoscopic proce-
therapeutic range for at least 48 hours [37]. dures detected rare bleeding events (0.5%) when such proce-
dures were conducted while patients continued NOAC
3.2. Management of patients on fondaparinux therapy [51]. It has also been shown that dermatologic proce-
dures can be safely performed on those taking NOACs [52].
Preoperative treatment with anticoagulants exposes pa- Another retrospective study on patients undergoing pace-
tients undergoing surgery to higher risks of perioperative maker/AICD implantation while continuing dabigatran con-
bleeding. There is limited information for perioperative man- cluded that there are no risks of major bleeding and
agement of those taking fondaparinux. Its effects last for 3-4 determined that it was safe to proceed with such surgery
days (3-5 half-lives). Before elective surgery, patients pre- [53]. However, until additional studies assessing the safety of
scribed fondaparinux should discontinue it for 72-96 hours continuing perioperative NOAC therapy become available, it
594 A.D. Oprea et al.

Table 7 Classication of pain procedures according to bleeding risk (adapted with permission from Narouze et al [65])
High risk Intermediate risk Low risk
Spinal cord stimulation trial and implant Interlaminar and transforminal epidural Peripheral nerve block
steroid injections (all spinal levels)
Intrathecal catheter and pump implant Facet medial branch nerve block and Peripheral joint and musculoskeletal
radiofrequency ablation injections
Vertebral augmentation (kyphoplasty/vertebroplasty) Intradiscal procedures Trigger point injections (including
piriformis injection)
Epiduroscopy/epidural decompression Sympathetic blocks Sacroiliac joint injection
Paravertebral block Sacral lateral branch blocks
Peripheral nerve stimulation and implant
Pocket revision and IPG/ITP replacement
IPG = implantable pulse generator; ITP = intrathecal pump.

may be prudent to stop these agents for most planned surgical Fresh frozen plasma (10-15 mL/kg) in addition to a slow
procedures, except for those procedures with minimal bleed- infusion of vitamin K (5-10 mg) can reverse effects of warfa-
ing risk (dental cleaning/fillings, cataract removal, minor skin rin. Warfarin can also be reversed with prothrombin complex
procedures) [54,55]. concentrate (PCC) that has been found to be superior to fresh
Several guidelines exist for perioperative management frozen plasma in reversing vitamin K antagonists. Advantages
of NOACs, and these recommendations are summarized of PCC treatment are the rapid speed of infusion, lack of need
in Table 6 [56-58]. Considerations for the guidelines have for cross-matching, the small volume to be infused, and effec-
been based on patient renal function and potential bleeding tiveness of reversal, but there is also a higher risk of thrombo-
risks. These guidelines classify surgical procedures with a 2- embolism. A 4-factor PCC (K Centra, CSL Behring; contains
day postoperative hemorrhagic risk of 2%-4% as high risk factors II, VII, IX, and X) is currently Federal Drug Adminis-
and include major cardiac, orthopedic, thoracic, vascular, ab- tration approved for warfarin reversal [8].
dominal, intracranial, head and neck, breast cancer, and Risk assessment as to timing or urgency of a surgical proce-
urologic surgery; liver and kidney biopsy; or procedures dure is warranted in patients taking NOACs, as discontinuing
lasting longer than 45 minutes (bleeding risk has been de- these agents for 24-48 hours usually results in a normal
ned somewhat differently than in Table 2). In contrast, coagulation status. Dabigatran reversal can be achieved with
cholecystectomy, hysterectomy, endoscopy, arthroscopy, hemodialysis in those scheduled for urgent procedures. Idaru-
dilation and curettage, hernia repairs, and biopsies (blad- cizumab (Praxbind, Boehringer Ingelheim; administered in 2
der, prostate, thyroid, breast) are considered low consecutive infusions or boluses of 2.5 g each) has recently
bleeding risk procedures (0%-2% two-day risk of major been Federal Drug Administration approved for dabigatran
bleeding) [29]. reversal but should be reserved for patients requiring truly
emergent surgery. Idarucizumab is an antibody fragment
3.4. Oral anticoagulation reversal therapies and that attaches to the thrombin-binding site of dabigatran, lead-
urgent/emergent surgery ing to complete reversal of anticoagulation effects within
minutes [59].
Patients taking oral anticoagulants and presenting for emer- No reversal agents are currently available for reversal of the
gency or trauma surgery should have these medications dis- anti-Xa inhibitors, but several drugs are in development.
continued in addition to immediately instituting supportive Therefore, in emergency situations, off-label administration
measures protecting against hemorrhagic risks. The degree of of PCC and recombinant factor VII can be used in circum-
anticoagulation for those prescribed warfarin can be assessed stances of life-threatening bleeding [8,60]. Andexanet alfa, a
with INR levels, but effects from NOAC treatment cannot al- modied recombinant factor Xa, is being studied for reversal
ways be quantied with coagulation testing. As an example, of all anti-Xa inhibitors (both oral and intravenous) and has
an elevated PT would be expected in patients taking rivaroxa- been shown to be effective within minutes of administration
ban, a prolonged aPTT in the presence of dabigatran, but [61] Aripazine (ciraparantag, PER 977) is a small molecule
PT measurements are insensitive in those on apixaban. that interacts with anticoagulants through noncovalent hydro-
In addition, INR, PT, and aPTT values do not correlate well gen bonding and electrostatic interactions. This agent has en-
with levels of NOAC medications found in the plasma; these tered phase II clinical trials and appears to inhibit nearly all
tests merely conrm the presence of such agents in the anticoagulants with the exception of vitamin K antagonists
patient's circulation. and argatroban [60,62].
Perioperative management of anticoagulants 595

Table 8 Periprocedural management of antithrombotics


Drug 2015 Interventional Pain ASRA guidelines 2015 Update/2010 ASRA
guidelines for neuraxial anesthesia
When to discontinue When to restart When to discontinue When to restart
High and Low bleeding risk
intermediate
bleeding risk
Intravenous heparin 4h 4h 2h 2-6 h before to 1-4 h after
needle placement nontraumatic
needle placement
24 h if traumatic 2-4 h before catheter 1 h after catheter
pass (eg, bloody) removal (normal removal
aPTT documented)
Subcutaneous heparin 8-10 h 8-10 h 2h No time restriction as to needle placement or catheter
removal as long as the total dose of daily heparin is
b10,000 U
LMWH 12 h 12 h 4 h after a low-risk 10-12 h before needle Single daily dosing
Prophylactic dosing procedure placement
Enoxaparin 30 mg First dose 6-8 h after
twice a day needle placement
Enoxaparin 12-24 h after an 12 h before catheter removal Second dose 24 h
40 mg daily intermediate- or after the rst dose
Deltaparin high-risk procedure At least 2 h after
5000 U daily catheter removal

Twice-daily dosing

Not recommended
with catheter in place
At least 24 h after
needle placement
2 h after catheter
removal
LMWH 24 h 24 h 4 h after a low-risk 24 h Epidural catheter
Therapeutic dosing procedure contraindicated
Enoxaparin 1.5 mg/kg 12-24 h after an 2-4 h after catheter
daily or 1 mg/kg intermediate- or removal
twice a day high-risk procedure
Dalteparin 120 U twice
a day or 200 U daily
Warfarin 5 d and normal Discontinuation 24 h 4-5 d and normal INR Remove catheter
INR may not be when INR is b1.5
necessary if INR b3 Restart any time after
catheter removal

Fondaparinux 5 half-lives 2 half lives 24 h 36 h 12 h after catheter


2.5 mg daily (3-4 d) removal
Epidural catheter
not indicated

Dabigatran 4-5 d (normal 24 h 5 d before puncture, catheter 6 h after puncture,


renal function) manipulation, or removal catheter manipulation,
6 d (impaired Shared assessment or removal
renal function) and risk stratication,
Rivaroxaban 3d a 2half-life interval 24 h 3 d before puncture, catheter 6 h after puncture,
discontinuation manipulation, or removal catheter manipulation,
may be considered or removal
596 A.D. Oprea et al.

Table 8 (continued)
Drug 2015 Interventional Pain ASRA guidelines 2015 Update/2010 ASRA
guidelines for neuraxial anesthesia
When to discontinue When to restart When to discontinue When to restart
High and Low bleeding risk
intermediate
bleeding risk
Apixaban 3-5 d 24 h 3 d before puncture, 6 h after puncture,
catheter manipulation, catheter manipulation,
or removal or removal

4. Periprocedural management of patients altered vertebral anatomy (ie, spondylosis) or are to undergo
on anticoagulants (interventional pain, procedures with large-gauge needles and stiff sytletted
leads such as spinal cord stimulation, risk of bleeding may
regional and neuraxial procedures)
be higher than when performing neuraxial techniques for anes-
thesia in the operating room. Also, longer time intervals to re-
A major consideration for anticoagulated patients undergo- start some anticoagulants following pain procedures are
ing regional anesthesia or interventional pain medicine proce- recommended [65].
dures within the neuraxial space is dealing with the potential Regardless of which published guidelines are consulted, it
development of a spinal or epidural hematoma. This complica- remains important to follow a formal risk assessment with
tion can result in permanent neurologic damage and paralysis management decisions performed in conjunction with the phy-
[27] Peripheral and soft tissue injections in anticoagulated pa- sician managing a patient's anticoagulation therapy when nec-
tients can also lead to hematoma formation, with an increased essary. A thorough discussion of all published guidelines is
concern when planning deep peripheral nerve blockade (PNB) beyond the scope of this review (please see www.asra.com),
where manual vessel compression could be difcult. Such a but current recommendations for neuraxial anesthesia and in-
compromising hematoma could result in a compartment syn- terventional pain procedures are summarized in Table 8. In ad-
drome or neurologic compromise and nerve injury from me- dition to the timing of the procedure in relation to the
chanical compression [63,64]. anticoagulant administration, a few comments and caveats
The scope of interventional pain procedures is multiface- are necessary.
ted, including PNBs, vertebral augmentation, joint injections,
and cancer pain interventions, along with soft tissue proce-
dures and trigger point injections. Bleeding complications 1. Intravenous heparin
from these techniques include hematoma formation, hemar- - All patients receiving heparin longer than 4 days should
throses, and subcutaneous ecchymoses. The American Society have platelet count checked before neuraxial blockade
of Regional Anesthesia and Pain Medicine (ASRA) and sever- or removal of an epidural catheter to exclude thrombo-
al European societies have issued guidelines for management cytopenia that may suggest HIT [27,65].
of patients taking antiplatelet, anticoagulant, and antibrinoly- - Intravenous heparin can be used intraoperatively follow-
tic medications and subsequently planning either neuraxial an- ing neuraxial procedures; however, dilute concentra-
esthesia or interventional pain procedures [27,65-67]. tions of local anesthetics should be used, and close
The 2015 Interventional Pain ASRA guidelines classify postoperative monitoring remains necessary to detect
bleeding risk following interventional spine and pain proce- evidence of a developing hematoma [27].
dures [65] (Table 7). Several of the published recommenda- - In situations of traumatic neuraxial needle placement (ie,
tions for moderate- and high-risk pain procedures are similar bloody tap or requiring multiple needle passes) during
to the 2010 ASRA advisory third edition and its 2015 update neuraxial procedures performed before surgical proce-
for patients on antithrombotics undergoing regional anesthesia dures where intraoperative heparin administration is
(2010 ASRA guidelines for neuraxial anesthesia) [27]. planned (ie, vascular surgery), the risk of hematoma for-
However, additional distinctions do exist, as the 2015 mation is unknown, and proceeding with surgery should
Interventional Pain ASRA guidelines indicate that, when be considered on an individual basis [27].
performing low-risk pain procedures, less stringent criteria - Risk of developing a compromising hematoma from full
would be acceptable [27,65]. In contrast, for certain pain heparin anticoagulation during cardiac bypass surgery
interventions in those on anticoagulants, the 2015 Interven- also remains unknown [27].
tional Pain ASRA guidelines suggest more stringent criteria 2. Subcutaneous UFH
than identied in the 2010 ASRA guidelines for neuraxial - For patients receiving subcutaneous UFH N10,000 U
anesthesia. For example, in patients who have signicantly daily or more than twice-daily dosing, insufcient data
Perioperative management of anticoagulants 597

are available for ASRA to make formal recommenda- before neuraxial procedures and resuming 6 hours post-
tions. There are reports that thrice-daily heparin dosing intervention may be appropriate.
can increase bleeding risks; however, epidural catheters - When performing low-risk interventional pain proce-
have been maintained in patients on thrice-daily heparin dures, a 2half-life discontinuation interval should be
at several institutions [27,68-70]. considered for patients taking NOACs, a shared risk de-
3. Warfarin cision that should be made in conjunction with the pre-
- In patients receiving preoperative warfarin (typically scribing physicians.
the night before neuraxial manipulation), an INR - When performing moderate- and high-risk intervention-
should be checked before performing neuraxial al pain procedures on these patients, a 5half-life period
blockade if the rst dose was given N24 hours before of discontinuation of the agent is recommended.
placement of the block or if a second warfarin dose was - In clinical situations with a high risk of VTE, it is recom-
administered [27]. mended to use an LMWH bridge that will be discontin-
- All patients receiving warfarin in conjunction with neur- ued 24 hours before performing any interventional pain
axial or deep PNB catheters should have daily INR procedure and to have a 24-hour delay before resuming
monitoring. Both motor and sensory function should these agents following the intervention [65].
be assessed, and dilute concentrations of local - In those with very high risks of VTE, half the usual dose of the
anesthetics should be used to facilitate neurological oral anticoagulant can be initiated 12 hours after performing
evaluation [27]. interventional pain procedures (Table 8) [27,65,7175].
- Concurrent medications affecting hemostatic mecha-
nisms such as antiplatelet agents (aspirin, nonsteroidal
anti-inammatory drugs) should be avoided [27].
5. Conclusions
- Removal or manipulation of neuraxial and deep PNB
catheters should occur when the INR is b1.5 (correlates
with clotting factor levels of at least 40%), and neuro- Management of anticoagulation therapy in the periopera-
logic evaluation should be continued for 24 hours fol- tive period should be based on patient-specic conditions (re-
lowing catheter removal. nal, hepatic, cardiac) and surgery-related (trauma, cancer)
- With an INR between 1.5 and 3, caution should be used issues to safely proceed with surgery and anesthetic care. Peri-
when removing neuraxial and deep PNB catheters, along operative management can differ depending on whether the
with a review of patient medical records to determine if patient is receiving a prophylactic or a therapeutic anticoagu-
other agents affecting hemostasis (including those with lant regimen. Therefore, understanding the complexity of
no effect on INR) are present. In this situation, routine anticoagulation management is essential, and decisions about
neurologic evaluation should occur before catheter re- proceeding with surgery, regional procedures, and interven-
moval and until INR has reached the desired level. tional techniques in patients receiving such therapy need to
- There are no recommendations regarding management be made on an individual basis. It should also be recognized
of patients receiving therapeutic levels of warfarin in that the risk of hematoma formation, thrombosis, or bleeding
conjunction with neuraxial or deep PNB catheters. For will not be completely eliminated even when preventative
patients with an INR N3, warfarin should be held or re- strategies and existing guidelines are followed. Alternative an-
duced in the presence of indwelling neuraxial or deep esthetic and analgesic planning may be required for patients at
PNB catheters [27] (Table 8). unacceptable risk.
4. Fondaparinux
- Placing indwelling catheters in patients on fondaparinux
is not recommended by ASRA [27]. References
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