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Clinical Review & Education

JAMA Surgery | Review

What Surgeons Should Know About Non–Vitamin K Oral


Anticoagulants
A Review
Atul Verma, MD, FRCPC; Andrew C. T. Ha, MD; James T. Rutka, MD, PhD; Subodh Verma, MD, PhD

Supplemental content
IMPORTANCE Non–vitamin K oral anticoagulants (NOACs) are increasingly prescribed for
patients to treat or prevent arterial or venous thromboembolism. The following 4 NOAC
agents are approved by the US Food and Drug Administration for clinical use: dabigatran
etexilate, apixaban, edoxaban tosylate, and rivaroxaban. A good understanding of these
agents’ pharmacologic properties is important for surgeons given their marked differences
compared with warfarin sodium. This review highlights key practical issues surrounding the
use of NOACs in the perioperative setting.

OBSERVATIONS The PubMed and Cochrane Library databases were searched for
English-language studies from May 1, 2009, until May 1, 2017, for randomized clinical trials,
meta-analyses, systematic reviews, observational studies, and clinical guidelines. From a
systematic review of the published literature that included 70 articles and 166 404 patients,
this study identified 5 key practical issues surrounding the use of NOACs in the perioperative
setting. These include patient populations for which NOAC use is indicated and
contraindicated, the timing of NOAC treatment cessation before invasive interventions,
management of NOAC-treated patients requiring urgent interventions, the need for
“bridging,” and the timing of NOAC treatment’s reinitiation after invasive interventions.
Important findings are as follows: NOAC agents are not recommended for patients with
mechanical heart valves or advanced kidney disease (creatinine clearance, <15 mL/min);
minimal to no anticoagulant effect remains when therapy with a NOAC is withheld for 48 to
72 hours before surgery in the context of normal kidney function; a reversal agent is clinically
available for dabigatran, while reversal agents for apixaban, edoxaban, and rivaroxaban are
under regulatory review; and laboratory testing of the anticoagulant effects of NOACs are not
routinely available. There is a paucity of high-quality data on the optimal timing of NOAC
cessation and resumption in the perioperative period, particularly for patients who undergo
procedures with high bleeding risk.

CONCLUSIONS AND RELEVANCE The anticoagulant effect of NOAC agents is predictable but
not readily measurable in routine clinical practice. A number of uncertainties remain
surrounding the use of these agents in the perioperative setting. Ongoing prospective studies
and randomized clinical trials will provide greater clarity on these management issues in the
near future.

Author Affiliations: Department of


Surgery, University of Toronto,
Toronto, Ontario, Canada (A. Verma,
Rutka, S. Verma); Department of
Medicine, University of Toronto,
Toronto, Ontario, Canada (Ha).
Corresponding Author: Atul Verma,
MD, FRCPC, Department of Surgery,
University of Toronto, 30 Bond St,
JAMA Surg. doi:10.1001/jamasurg.2018.0374 Toronto, ON M5B 1W8, Canada (atul
Published online April 18, 2018. .verma@utoronto.ca).

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Clinical Review & Education Review What Surgeons Should Know About Non–Vitamin K Oral Anticoagulants

Table 1. Characteristics of Non–Vitamin K Oral Anticoagulants

Last Dose Before Surgery


Mechanism of Modified
Agent Action Standard Dosing Dosinga Low Bleeding Risk High Bleeding Risk Reversal Agents
Dabigatran Direct thrombin Twice-daily 150 Twice-daily Last dose 2 d before if CrCl >50 Last dose 3 d before if CrCl Idarucizumab, PCC
etexilate inhibitor mg 75 or 110 mL/min >50 mL/min (efficacy is not well
mg Last dose 3 d before if CrCl Last dose 4-5 d before if CrCl established),b FEIBAb
30-50 mL/min 15-50 mL/min
Last dose 4-5 d before if CrCl
15-29 mL/min
Apixaban Activated factor X Twice-daily 5 mg Twice-daily Last dose 2 d before if CrCl >30 Last dose 3 d before if CrCl Andexanet alfa,
inhibitor 2.5 mg mL/min >30 mL/min PCC,b FEIBAb
Last dose 3 d before if CrCl Last dose 3-4 d before if
15-29 mL/min CrCl, 15-29 mL/min
Edoxaban Activated factor X Once-daily 60 mg Once-daily Last dose 2 d before if CrCl >30 Last dose 3 d before if CrCl Andexanet alfa,
tosylate inhibitor 30 mg mL/min >30 mL/min PCC,b FEIBAb
Last dose 3 d before if CrCl Last dose 3-4 d before if CrCl
15-29 mL/min 15-29 mL/min
Rivaroxaban Activated factor X Once-daily 20 mg Once-daily Last dose 2 d before if CrCl >30 Last dose 3 d before if CrCl Andexanet alfa,
inhibitor 15 mg mL/min >30 mL/min PCC,b FEIBAb
Last dose 3 d before if CrCl Last dose 3-4 d before if CrCl
15-29 mL/min 15-29 mL/min
Abbreviations: CrCl, creatinine clearance; FEIBA, factor VIII inhibitor bypassing or age older than 80 years. Edoxaban requires having impaired CrCl (CrCl,
activity; PCC, 4-factor prothrombin complex concentrate. ⱖ30 to <50 mL/min) or concomitant use of a P-glycoprotein inhibitor.
SI conversion factor: To convert creatinine clearance to milliliter per second, Non–vitamin K oral anticoagulants are generally avoided in patients with stage
multiply by 0.0167. IV chronic kidney disease (CrCl, 15-25 mL/min) and are contraindicated for CrCl
a
less than 15 mL/min.
Modified dosing is recommended for patients with impaired renal function
b
(CrCl, <50 mL/min [See Should All Patients Requiring Oral Anticoagulation Be Not a specific antidote, and reversal properties are based on limited in vitro or
Treated With NOACs Instead of Warfarin? subsection for explanation of units healthy human in vivo experiments. The efficacy of PCC has only been
of measure being used here.]). Apixaban requires meeting 2 of the following 3 discussed in case reports.
criteria: serum creatinine level at least 1.5 mg/dL, body weight less than 60 kg,

N
on–vitamin K oral anticoagulants (NOACs) are clinically ap-
Figure. Pathways of Activated Factor X (FXa) Inhibitors and Direct
proved by the US Food and Drug Administration (FDA) for
Thrombosis Inhibitors (DTIs)
prevention of thromboembolism in patients with non-
valvular atrial fibrillation (AF) and treatment or prevention of deep Intrinsic pathway Extrinsic pathway
vein thrombosis (DVT) and pulmonary embolism (PE). Given the in-
creasing number of patients being treated with NOACs, surgeons will XII XIIa VII VIIa + tissue factor

encounter more patients who will be treated with NOAC agents. The XI XIa
objective of this review was to provide an evidence-based update FXa Inhibitors
IX IXa + VIIIa Apixaban
on the perioperative management of patients receiving NOAC Edoxaban tosylate
therapy. X Xa + Va Rivaroxaban

Prothrombin Thrombin DTI


Dabigatran etexilate
Fibrinogen Fibrin
Methods
We searched the PubMed and Cochrane Library databases for Eng- XIII XIIIa Stable clot

lish-language studies from May 1, 2009, until May 1, 2017, for ran-
domized clinical trials (RCTs), meta-analyses, systematic reviews, ob-
servational studies, and clinical guidelines (search terms are outlined fibrinogen to fibrin (Figure). The only oral DTI that is approved by
in the eAppendix in the Supplement). We also performed a manual the FDA for clinical use is dabigatran etexilate; other oral DTI agents
search of references listed in selected articles, reviews, meta- may be developed in the future. In contrast, FXa inhibitors inhibit
analyses, and practice guidelines. Selected articles were agreed on FXa, which is involved in cleaving prothrombin to form thrombin.
by all of us. Emphasis was given to articles outlining the periopera- In several large, well-designed RCTs, NOACs have been shown to be
tive management of patients receiving NOAC therapy and to ar- noninferior to warfarin sodium for prevention of AF-related throm-
ticles of interest to a broad surgical readership. boembolism and venous thromboembolism (VTE).1-6 Treatment with
NOACs has a lower risk of fatal bleeding and intracranial hemor-
Clinical Presentation rhage compared with warfarin,1,2 although the risk of gastrointes-
Increasing numbers of patients are seeking to undergo surgery when tinal bleeding seems to be increased with NOACs vs warfarin.1 Non–
receiving treatment with a NOAC. The 2 major classes of NOACs are vitamin K oral anticoagulant agents are prescribed at fixed dosages,
direct thrombin inhibitors (DTIs) and activated factor X (FXa) inhibi- with limited dose adjustment for renal function or body weight, ob-
tors. Non–vitamin K oral anticoagulant agents approved by the FDA viating the need for serial blood coagulation monitoring and con-
are listed in Table 1. The DTIs bind the active site of thrombin stant dose adjustment. In addition, NOACs have short half-lives, with
(univalent inhibitor), thus inhibiting the enzyme’s capacity to convert approximately 80% of their anticoagulant effect gone at 24 hours

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What Surgeons Should Know About Non–Vitamin K Oral Anticoagulants Review Clinical Review & Education

Table 2. Clinical Indications Approved by the US Food and Drug Administration for the Use of Non–Vitamin K Oral Anticoagulants
Reduction in Risk of
Stroke and Systemic Reduction in Risk Prophylactic Therapy Prophylactic Therapy for
Embolism in Patients Treatment of DVT of Recurrent DVT for DVT or PE After VTE During Hospitalization
Indication With Nonvalvular AF or PE or PE Hip or Knee Surgery for an Acute Medical Illness
Direct thrombin Dabigatran etexilate Approved Approved Approved Approved NA
inhibitor
Activated factor Apixaban Approved Approved Approved Approved NA
X inhibitor
Edoxaban tosylate Approved Approved NA Approved NA
Rivaroxaban Approved Approved Approved Approved NA
Betrixaban NA NA NA NA Approved

Abbreviations: AF, atrial fibrillation; DVT, deep vein thrombosis; NA, not applicable; PE, pulmonary embolism; VTE, venous thromboembolism.

after ingestion of the last dose when kidney function is preserved.


For all of these reasons, many practice guidelines now advocate first- Box. Contraindications to the Use of Non–Vitamin K Oral
line use of NOACs for treatment of nonvalvular AF, treatment of acute Anticoagulants
DVT and PE, prevention of VTE after hip or knee surgery, and as sec- • Valvular atrial fibrillation (prosthetic valve, rheumatic mitral val-
ondary preventive therapy from recurrent DVT or PE.7-9 Recently, vular disease, prior mitral valve repair)
a new FXa inhibitor, betrixaban, has been approved by the FDA for • Mechanical prosthetic heart valve
VTE prevention among adults who are hospitalized because of acute • Severe renal dysfunction with creatinine clearance <15 mL/min or
medical illnesses. Indications for NOAC use approved by the FDA are receiving hemodialysis
• Severe liver dysfunction (Child-Pugh C)
listed in Table 2.
• Pregnancy
• Need to take concomitant potent inhibitors of P-glycoprotein
Management (all) and potent inhibitors of cytochrome P450 3A4 (CYP3A4)
For patients treated with oral anticoagulants undergoing surgery, the (apixaban, rivaroxaban)
key management issues are focused around minimizing the risk of
a thromboembolic event when the patient is not receiving therapy,
while at the same time minimizing the risk of perioperative bleed-
ing, which may be increased without adequate cessation of the patient group. Non–vitamin K oral anticoagulants should be avoided
therapy. For surgeons to make sound judgments on how to bal- in patients with severe renal failure (creatinine clearance [CrCl], <15
ance these risks, this review focuses on the following 5 key practi- mL/min) or in those receiving hemodialysis (note that the unit of
cal management questions that commonly arise in the care of a peri- measure is expressed in mL/min instead of the usual SI unit of mL/
operative patient receiving NOAC therapy based on a systematic min/1.732 because the renal dosing recommendations for NOAC
review of the published literature that included 70 articles and agents were calculated from the Cockcroft-Gault formula, which re-
166 404 patients. ports creatinine clearance as mL/min; accordingly, this unit of mea-
surement is used in the product monographs of NOAC agents as it
Should All Patients Requiring Oral Anticoagulation Be Treated With pertains to renal dosing).14-17 Finally, the use of NOACs during preg-
NOACs Instead of Warfarin? nancy is not recommended because their potential effect on the fe-
For stroke prevention in nonvalvular AF, NOACs are considered first- tus has not been studied. All contraindications to the use of NOACs
line treatment in patients requiring oral anticoagulation based on are listed in the Box.
their superior safety profile.1,2,7,8 However, not all patients are can-
didates for a NOAC. Among patients with AF, NOACs are only ap- When Should a NOAC Be Withheld Before Surgery?
proved by the FDA for those with nonvalvular AF, referring specifi- The decision on whether and when to temporarily interrupt NOAC
cally to AF in the absence of a prosthetic heart valve, rheumatic mitral therapy for patients during the perioperative period is determined
stenosis, or mitral valve repair.10 Non–vitamin K oral anticoagulant by the following 2 factors: (1) the bleeding risk of the procedure and
agents are contraindicated for patients with mechanical heart valves (2) the expected clearance time of the specific NOAC agent in the
because of a greater risk of thrombosis and bleeding compared with context of the patient’s kidney function. Another theoretical con-
warfarin.11 Based on substudies and a systematic review, it would ap- sideration would be an increased risk of stroke associated with abrupt
pear that the use of NOACs is not associated with increased com- cessation of NOAC therapy. However, results from the washout pe-
plications in patients with bioprosthetic (tissue) heart valves,12,13 but riods of the major NOAC trials have shown that cessation of therapy
such use in the United States would be considered off-label. While results in resumption of the normal off-treatment risk of stroke and
there are limited data on the use of NOACs in patients with rheu- not a “rebound” prothrombotic state associated with NOAC
matic mitral stenosis or prior mitral valve repair, neither of these pa- cessation.3,5,6 Fortunately, the risk of a thrombotic event for most
tient groups were allowed in the NOAC trials; therefore, NOAC use patients is small during the few days when NOACs are withheld for
in these patients is generally not recommended. Among patients with surgery.
cancer and DVT or PE, low-molecular-weight heparin remains the
agent of choice,9 although clinical trials are under way to assess the Bleeding Risk of the Procedure | The anticipated bleeding risks asso-
efficacy of NOACs vs low-molecular-weight heparin in this specific ciated with various invasive procedures have been categorized by

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Clinical Review & Education Review What Surgeons Should Know About Non–Vitamin K Oral Anticoagulants

surgical and subspecialty societies.18,19 A summary of these proce- Table 3. Anticipated Bleeding Risk of Specific Invasive
dures and their perceived bleeding risks are listed in Table 3. The or Surgical Proceduresa
bleeding risk of a given procedure can be categorized as minimal,
Intervention
low (2-day risk of bleed, <2%), or intermediate/high (2-day risk of Type Low Bleeding Risk Intermediate/High Bleeding Risk
bleed, ⱖ2%). According to current recommendations from expert Breast surgery FNA biopsy; core Minimally invasive biopsy; excisional
breast biopsy; breast biopsy; duct excision; sentinel
consensus documents,7,18-21 procedures deemed to be at low or mini- needle aspiration; lymph node biopsy; incision and
mal bleeding risk can be safely performed if treatment with the NOAC skin punch biopsy drainage of abscess; lumpectomy;
axillary dissection; mastectomy;
drug is withheld for only 24 hours before a procedure, It is believed reduction mammoplasty;
that such procedures can be performed without excessive bleed- lumpectomy with oncoplastic
reconstruction
ing risk when approximately 12% to 25% of the residual anticoagu-
Cardiac surgery NA CABG; valve repair/replacement;
lant effect is present at the time of intervention. This concept has pericardiectomy; pericardial cyst
been prospectively evaluated in a prospective German cohort resection; cardiac tumor resection;
epicardial pacemaker lead implant;
study22 and in a Canadian study23 involving 595 rivaroxaban- surgical arrhythmia ablation; LAA
treated patients and 541 dabigatran-treated patients who under- ligation; aortic surgery; surgical
myectomy; heart transplant;
went elective invasive procedures. The timing of dabigatran treat- implant/removal of VAD; ECMO
ment cessation was prespecified according to the procedural Cardiac Coronary LAAO; transfemoral PCI;
interventions, angiography; pericardiocentesis; MCS; IABP;
bleeding risk and the patients’ kidney function.23 Bleeding events percutaneous pacemaker/ICD transfemoral/iliac TAVR;
were adjudicated by an independent committee.22,23 The Cana- implant with transapical/axillary/direct-access
endocardial leadsb; TAVR; aortic valvuloplasty; mitral
dian study23 included 324 procedures (59.9%) with “standard” bleed- ILR implant; valve interventions; mechanical or
ing risk. The incidence of major bleeding at 30 days was low (0.6%) transradial PCI; laser lead extraction; epicardial
right heart ablation
in this subgroup. Other researchers have even advocated that cer- catheterization;
tain procedures may be performed without interruption of NOAC diagnostic
electrophysi-
therapy, such as those with “minimal” bleeding risks. Some ex- ological study;
amples in which NOAC treatment interruption is not thought to be endocardial AF
ablationb;
obligatory include simple or superficial dermatologic excisions or endocardial SVT/VT
biopsies,24 simple cataract and glaucoma surgical procedures,25 mi- ablationa
nor dental procedures that include extraction of 1 or 2 teeth,26 and Gastrointestinal Diagnostic Polypectomy; biliary or pancreatic
endoscopy endoscopy (EGD, sphincterotomy; PEG/PEJ placement;
gastrointestinal endoscopy without biopsy.27 In these cases, it is rec- colonoscopy, therapeutic balloon-assisted
ommended that such procedures be scheduled at a time when flexible enteroscopy; EUS with FNA;
sigmoidoscopy, endoscopic hemostasis; tumor
trough NOAC drug levels are anticipated. However, there are lim- including mucosal ablation; cystogastrostomy;
biopsy); ERCP ampullary resection; endoscopic
ited randomized trial data examining the safety of performing inva- without mucosal resection; endoscopic
sive procedures with uninterrupted NOAC therapy. Of those trials sphincterotomy; submucosal dissection; variceal
diagnostic interventions
that are published, they are focused on patients who undergo cath- balloon-assisted
eter-based AF ablation. These trials demonstrated that patients who enteroscopy;
capsule endoscopy;
underwent AF ablation with uninterrupted rivaroxaban or dabiga- EUS without FNA;
tran therapy had either equivalent or lower rates of bleeding, re- argon plasma
coagulation;
spectively, compared with uninterrupted warfarin therapy.28,29 There Barrett ablation
is an ongoing randomized trial comparing uninterrupted vs inter- Nephrology Tunneled Kidney biopsy; insertion of tunnel or
rupted NOAC therapy for patients receiving a pacemaker or implant- hemodialysis temporary central venous
catheter removal or hemodialysis catheter; banding of AV
able cardioverter-defibrillator.30 exchange; fistula; AV fistula or graft
If a patient is undergoing an invasive procedure in which the an- angiogram for AV stenting/angioplasty/thrombectomy;
fistula; arteriogram; placement/removal of
ticipated bleeding risk is intermediate or high, it is believed that the intermittent peritoneal dialysis catheter
hemodialysis;
procedure should be performed when less than 10% of the re- CRRT;
sidual anticoagulant effect exists.18-21 This typically means that the peritoneogram;
venogram
NOAC drug should be withheld for 48 to 72 hours before perfor-
Neurosurgery NA Craniotomy; craniectomy; all spinal
mance of such procedures (Box). Data supporting this approach are surgeries; cerebral angiogram;
primarily from substudies of the pivotal NOAC trials. In these sub- carotid stenting; intracranial or spinal
embolization; stroke embolectomy;
studies, for each of the NOAC agents, there was no difference ob- peripheral decompression; deep brain
served in either thromboembolism or bleeding rates with minimal or spinal cord stimulation;
ventriculoperitoneal shunt; lumbar
(usually 48-72 hours) NOAC interruption vs interruption of warfa- puncture; pituitary surgery
rin with or without “bridging.”31 For example, in the Randomized Obstetrics and Diagnostic Hysterectomy (laparoscopic, vaginal,
Evaluation of Long-term Anticoagulation Therapy (RE-LY) study32,33 gynecology laparoscopy; endoscopic); adnexectomy
diagnostic or (laparoscopic, endoscopic); radical
comparing dabigatran with warfarin, the perioperative 30-day bleed- operative hysterectomy; node dissection;
hysteroscopy; peritoneal (ovarian cancer)
ing rate was approximately 3%, while the thromboembolic rate was cervical LEEP or debulking; operative laparoscopy;
only 0.5%. In the Rivaroxaban Once Daily, Oral, Direct Factor Xa In- LLETZ; cervical cervical conization; myomectomy;
biopsy; vulvar skin vulvectomy; vaginal reconstructive
hibition Compared With Vitamin K Antagonism for Prevention of biopsy; D&C surgeries
Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study,34
(continued)
perioperative thromboembolic risk was only 0.3% vs 0.4% at 30 days

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Table 3. Anticipated Bleeding Risk of Specific Invasive Table 3. Anticipated Bleeding Risk of Specific Invasive
or Surgical Proceduresa (continued) or Surgical Proceduresa (continued)
Intervention Intervention
Type Low Bleeding Risk Intermediate/High Bleeding Risk Type Low Bleeding Risk Intermediate/High Bleeding Risk
Ophthalmology Cataract surgery; NA Thoracic Bronchoscopy Chest tube insertion; chemical
intravitreous interventions, without biopsy; pleurodesis; bronchoscopy with
injection with a percutaneous bronchial/tracheal biopsy; percutaneous lung biopsy;
pharmacologic stenting; insertion large chest drain insertion
agent; tear duct or removal of
surgery; eyelash tunneled pleural
revision; catheter with cuff;
photocoagulation esophageal
for retinopathy; stenting;
revision of iris; pars esophageal
plana vitrectomy; dilation; EGD; small
orbital surgery; chest drain
blepharoplasty; insertion;
trabeculoplasty by subclavian central
laser surgery venous catheter
Orthopedics Minor soft-tissue Major elective lower extremity insertionb;
resection of the surgery; major lower extremity endotracheal
lower extremity; fracture open or closed reduction and intubation;
minor hand surgery internal fixation; traumatic thoracentesisb
(eg, carpal tunnel lower/upper extremity surgery Urology Cystoscopy; Prostate outlet procedures;
release, trigger without tourniquet; traumatic urodynamic transurethral resection of bladder
release finger, hip/pelvic/acetabular fracture; procedures; routine tumor; renal enucleation procedures
benign tumor); moderate hand/upper extremity catheter without capsular closure; incisional
upper or lower surgery (eg, total elbow or shoulder placement; biopsy (renal capsule/parenchyma,
extremity trauma arthroplasty, ORIF); all spine uncomplicated tunica albuginea of testes);
surgery with surgeries ureteral percutaneous ablative therapy of the
tourniquet stenting/exchange; kidney; pelvic dissection; shock wave
Oral and Local anesthesia by Surgical (complex) dental extraction endoscopic lithotripsy; retroperitoneal
maxillofacial inferior alveolar >3 teeth; dental implant surgery; procedures with or dissection; anterior colporrhaphy
nerve blocks; bone grafting for alveolar ridge; without laser sling; sacrocolpopexy; hysterectomy
simple or complex biopsy or excision of oral soft-tissue lithotripsy for prolapse; prostatic biopsy;
dental extraction lesions; preprosthetic surgery; facial drainage of lymphocele, hydrocele, or
(1-3 teeth); trauma repair by open techniques; abscess; percutaneous nephroscopy;
incision and corrective jaw or facial surgery; bone urethroplasty; penile
drainage for or large soft-tissue pathology prosthesis/artificial sphincters
intraoral swellings excision Vascular surgery Percutaneous Carotid endarterectomy; vascular
Regional Block of a Block of a peripheral, deep, and arterial procedures surgery involving the head and neck
anesthesia and peripheral, noncompressible nerve; involving <8F region; open abdominal vascular
pain medicine superficial, and paravertebral block; intradiscal sheaths; surgery; open thoracic vascular
compressible injection; sympathetic block; percutaneous surgery; arterial revascularization;
plexus or nerve; peripheral nerve stimulator implant; venous procedures; deep vein reconstruction of the lower
peripheral intrathecal catheter and pump stab phlebectomy; extremity; EVAR; extra-anatomic
joint/ implant; spinal cord stimulator temporal artery bypass surgery; percutaneous arterial
musculoskeletal implant; IPG or ITP pocket revision; biopsy procedures with ≥8F sheaths
injection; vertebral augmentation Bedside/office- Arterial puncture; Bone marrow aspiration; lumbar
sacroiliac/sacral (vertebroplasty and kyphoplasty); based invasive arthrocentesis; puncture; wound debridement;
lateral branch epiduroscopy and epidural procedures abdominal central venous catheter insertionb
nerve block compression; block of a deep and paracentesis; skin
noncompressible nerve/plexus; biopsy
neuraxial block
Abbreviations: AF, atrial fibrillation; AV, arteriovenous; CABG, coronary artery
Rheumatology Arthrocentesis; NA
trigger point bypass graft; CRRT, continuous renal replacement therapy; D&C, dilation and
injection; curettage; ECMO, extracorporeal membrane oxygenation; EGD,
soft-tissue (bursa esophagogastroduodenoscopy; ERCP, endoscopic retrograde
or tendon) injection cholangiopancreatography; EUS, endoscopic ultrasound; EVAR, endovascular
Thoracic surgery Thoracotomy for VATS; thoracotomy; thoracostomy; aneurysm repair; FNA, fine-needle aspiration; IABP, intra-aortic balloon pump;
resection of bullae decortication; pneumonectomy; ICD, implantable cardioverter-defibrillator; ILR, implantable loop recorder; IPG,
or spontaneous lobectomy; tumor resection; internal pulse generator; ITP, intrathecal pump; LAA, left atrial appendage;
pneumothorax sternotomy for thymectomy;
tracheostomy; carina reconstruction; LAAO, LAA occlusion; LEEP, loop electrosurgical excision procedure; LLETZ,
lung transplant; esophagectomy; large loop excision of the transformation zone; MCS, mechanical circulatory
esophageal myectomy; mediastinal support; NA, not applicable; ORIF, open reduction and internal fixation; PCI,
surgery; diaphragmatic surgery; percutaneous coronary intervention; PEG, percutaneous endoscopic
paraesophageal hernia surgery gastrostomy; PEJ, percutaneous endoscopic jejunostomy; SVT, supraventricular
(continued) tachycardia; TAVR, transaortic valve replacement; VAD, ventricular assist
device; VATS, video-assisted thoracoscopic surgery; VT, ventricular tachycardia.
a
Adapted from the study by Doherty et al19 and reproduced with permission
in the rivaroxaban and warfarin arms, respectively. In the Apixaban from Elsevier. This list reflects the opinions from various medical and surgical
for Reduction in Stroke and Other Thromboembolic Events in Atrial subspecialties from the United States on the bleeding risk associated with
Fibrillation (ARISTOTLE) trial35 comparing apixaban with warfarin, specific invasive procedures or surgeries. The anticipated bleeding risk
associated with a specific procedure is also influenced by other factors, such
there were significantly lower rates of both major bleeding and as the bleeding risk and clinical status of the patient.
thromboembolism in patients who interrupted apixaban vs those b
The bleeding risk associated with this procedure was categorized as low by
who continued use of the drug around the time of a procedure. some societies but as intermediate/high by others.
The use of neuraxial (spinal or epidural) anesthesia raises the
risk of spinal or epidural hematoma, which could have serious

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Clinical Review & Education Review What Surgeons Should Know About Non–Vitamin K Oral Anticoagulants

consequences. Therefore, it would seem reasonable that the same antidote or drug-level measurement is required. Unfortunately, stan-
guidelines for stopping a NOAC before a high-risk surgery would ap- dard coagulation tests, such as the international normalized ratio, ac-
ply equally to spinal and epidural anesthesia. Limited data from the tivatedpartialthromboplastintime(aPTT),andprothrombintime(PT),
Xarelto for VTE Prophylaxis After Hip or Knee Arthroplasty are not sensitive or specific enough to reflect how much of the NOAC
(XAMOS) and Regulation of Coagulation in Orthopaedic Surgery to drug is in circulation. Patients who are treated with dabigatran may still
Prevent Deep Vein Thrombosis and Pulmonary Embolism have aPTT values that are in the “normal” range, although a low aPTT
(RECORD) studies36-38 suggest that postoperative risk of bleeding suggests that most of the drug effect may be gone.43 Using PT to mea-
with resumption of NOAC therapy is not affected by type of anes- sure the anticoagulant effect of FXa inhibitors (apixaban, edoxaban,
thesia, including neuraxial. However, the most recent guidelines from andrivaroxaban)isunreliablebecauseanormalvaluemayindicatethat
the American Society of Regional Anesthesia and Pain Medicine sug- most of the drug is gone but does not rule out some residual drug
gest withholding dabigatran therapy for 4 to 5 days before spinal or effect.41,43 Furthermore, an elevated PT gives no indication as to how
epidural anesthesia and a minimum of 3 days for apixaban and much of the FXa inhibitor is in the patient’s circulation. More precise
rivaroxaban.39 These durations are somewhat longer than recom- tests are available to measure the plasma level or anticoagulant activ-
mended for other high-risk surgical procedures and were based on ity of NOAC agents. More accurate tests to measure plasma dabigatran
an intent to stop use of the drug at least 5 half-lives before spinal include the diluted thrombin time assay, the ecarin clotting time assay,
instrumentation surgery. These recommendations also apply to in- or the ecarin chromogenic assay.44,45 Measurement of the anticoagu-
termediate-risk pain procedures, such as paravertebral blocks and lant activity of apixaban, edoxaban, and rivaroxaban can be achieved
sympathetic blocks. Peripheral nerve and sacral lateral branch blocks with calibrated, agent-specific anti-Xa levels.46,47 Unfortunately, these
are considered lower risk, and the guidelines suggest that a shorter more sensitive tests are not available in all hospitals and thus are not
cessation interval of 2 half-lives may be considered according to in- readily accessible in routine clinical practice. Even if the test is available
dividual case requirements39; however, these guidelines are based locally, turnaround time may not be fast enough if the patient requires
on expert recommendation and not on clinical trial data.39 surgery on an urgent basis. If available rapidly, such tests can accurately
measure plasma NOAC levels, but there still exists within-patient vari-
NOAC Clearance in the Setting of Abnormal Kidney Function | Among ability that can occasionally complicate their interpretation.21
patients with preserved kidney function (CrCl, >50 mL/min), withhold- For the patient who requires urgent surgical intervention and in
ing use of a NOAC for 48 hours will provide sufficient assurance that whom time may not permit measurement of a specific NOAC assay, re-
little,ifany,residualanticoagulanteffects(<10%,equivalentto3-4half- versal agents for NOACs have been developed. Idarucizumab is an an-
lives) remain. For patients with abnormal renal function, there is a dif- tidote approved by the FDA for dabigatran-treated patients in whom
ference in the way that dabigatran is managed compared with the FXa urgent reversal is needed owing to life-threatening bleeding or emer-
inhibitors. This is because dabigatran is most dependent on renal clear- gencysurgerybasedondatafromtheReversalEffectsofIdarucizumab
ance (approximately 80%). Patients receiving an FXa inhibitor with a on Active Dabigatran (REVERSE-AD) trial.48 This humanized monoclo-
CrCl of 30 to 50 mL/min may continue to withhold use of the drug 48 nal antibody fragment is intravenously administered in 2 boluses (5-
hours before surgery. In contrast, dabigatran needs to be withheld for 15minutesapart),withcompleteandsustainedreversalofdabigatran’s
an additional 24 to 48 hours for patients with impaired kidney func- anticoagulant effect. Andexanet alfa is a specific antidote for all of the
tion (CrCl, 30-50 mL/min) to ensure that the residual anticoagulant ef- FXa inhibitors and was shown to reverse FXa inhibition in both healthy
fect is minimized and commensurate with expected levels if kidney volunteersandactivelybleedingpatientsinTheAndexanetAlfa,aNovel
function is preserved (Table 1).40,41 Antidote to the Anticoagulation Effects of FXa Inhibitors (ANNEXA-4)
TheperiproceduralanticoagulationmanagementofNOAC-treated trial.49 The studies on this agent are at an advanced stage, and it is likely
patients with severe chronic kidney disease (CrCl, 15-29 mL/min) thatandexanetalfawillbethenextreversalagentapprovedbytheFDA,
deserves additional discussion (Table 1). Patients with this degree of but it is not yet available for routine clinical use. Another FXa inhibitor
renal impairment were excluded from major randomized trials that reversalagentcalledciraparantagisunderdevelopmentbutisstillearly
compared the safety and efficacy between NOACs and warfarin.3-6 in its evaluation.50 Results of several observational studies51-55 sug-
However,intheUnitedStatesandEurope,alloftheNOACsmaybepre- gestedthat4-factorprothrombincomplexconcentrate(containingfac-
scribed for patients whose CrCl is down to 15 mL/min. These recom- tors II, VII, IX, and X and proteins C and S) may be effective in revers-
mendations were based on pharmacokinetic data modeling and not ing the anticoagulant effect of healthy volunteers who are treated with
on clinical trial evidence. For these patients, practice guidelines sug- FXa inhibitors, but this finding has not been tested in a randomized trial
gest that FXa inhibitors should be withheld for a minimum of 72 hours in bleeding patients. The effectiveness for reversal of dabigatran is not
beforeperformanceofinvasiveprocedures,19 acknowledgingthatlittle as well established.56 Factor VIII inhibitor bypassing activity is an
to no pharmacokinetic data exist for this special patient subset. How- activated form of prothrombin complex concentrate that contains fac-
ever, dabigatran should be withheld for 96 to 120 hours beforehand.42 tors II, IX, and X and also some activated factor VII (its action is primar-
None of the NOACs are recommended for patients with CrCl less than ily mediated by prothrombin [factor II] and FXa) and may be more ef-
15 mL/min or those receiving hemodialysis. fective in reversing the effect of dabigatran, as well as the FXa
inhibitors.56
What If a Patient Treated With a NOAC Requires Urgent Surgery? Generally, reversal agents are only indicated for patients requir-
If the last NOAC dose is taken at least 24 hours before urgent surgery, ing urgent surgery. If surgery can be delayed by even 24 hours, then
it is likely that more than 80% of the therapeutic effect will be gone in reversal may not be required. One of the disadvantages of acute re-
the presence of normal kidney function. If the timing of the last dose versal is that patients may be at increased risk of thromboembolic
is unknown and surgery can be delayed by more than 24 hours, no events immediately after reversal. In the 30 days after reversal in

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What Surgeons Should Know About Non–Vitamin K Oral Anticoagulants Review Clinical Review & Education

the ANNEXA-4 study,49 there was an 18% incidence of thrombotic major bleeding. For patients at low bleeding risk who undergo un-
events, similar to findings in the REVERSE-AD trial.48 This is higher complicated surgery with good postoperative hemostasis, NOACs
than the annualized rate of thromboembolic events, although many can be safely resumed after 24 hours. For patients who undergo sur-
of these patients were hospitalized and very ill and had high base- gery with higher bleeding risk, the decision to restart NOACs can be
line risk for thromboembolism in the absence of oral made after 48 to 72 hours.
anticoagulation.48,49 The special scenario of initiating NOAC therapy after surgery for
prevention of VTE is also relevant. To our knowledge, NOACs have
Do I Need to Bridge Patients With Heparin When Therapy With never been evaluated for prevention of venous thrombosis in non-
NOACs Is Withheld? orthopedic surgery; therefore, current guidelines do not make any
When patients require temporary interruption of their NOAC therapy, recommendations for their use in the nonorthopedic setting.59 How-
bridging with heparin sodium is generally not required or recom- ever, there have been a number of studies evaluating the use of
mended around the time of surgery. For most patients, the risk of a NOACs for prevention of venous thrombosis in the orthopedic set-
thrombotic event is small during the 2 to 3 days when NOACs are ting, specifically after hip or knee arthroplasty.60 Dabigatran,61,62
withheld. Conversely, routine bridging may increase the risk of peri- rivaroxaban,63-65 and apixaban66-68 have all been studied in the spe-
operative bleeding, as has been demonstrated in recent reports of cific setting of total hip or knee arthroplasty and have been shown
perioperative bridging on cessation of warfarin therapy. In the Ef- to be at least as effective as low-molecular-weight heparin prophy-
fectiveness of Bridging Anticoagulation for Surgery (BRIDGE) trial,57 laxis, with a similar safety profile. One trial did not meet the pre-
heparin bridging for warfarin-treated patients around the time of sur- specified noninferiority criterion because of small sample size68 but
gery did not reduce the risk of thromboembolic events but in- showed reduced bleeding risk. Therapy was typically initiated be-
creased major bleeding. To our knowledge, there are no published tween 4 and 12 hours after surgery and continued for 10 to 14 days,
trials examining the effect of perioperative heparin bridging among although some data have shown better outcome with extended
NOAC-treated patients, and it is unlikely that any such trial will be therapy to 35 days.69 The role of NOACs for orthopedic surgery, ex-
performed. Substudies from the pivotal NOAC trials showed that for cluding hip and knee arthroplasty, is less certain, and they are not
patients receiving bridging therapy the risk of bleeding was approxi- considered first-line therapy in those cases.59
mately 3 times that of patients who were not bridged, with no re- Betrixaban, an oral factor Xa inhibitor, has been recently ap-
duction in thromboembolism.22,34,58 Only in the rare circumstance proved by the FDA as VTE prophylaxis for adult patients who are hos-
where reinitiation of the NOAC regimen may be delayed after sur- pitalized because of an acute medical illness (decompensated heart
gery because of an inability of a patient to tolerate oral medications failure, respiratory failure, infection, rheumatic condition, or ische-
would temporary bridging with a parenteral or subcutaneous anti- mic stroke). Specifically, it is indicated for patients who are at el-
coagulant be considered. evated risk for VTE owing to moderate or severe restricted mobility.70

When Can I Restart NOAC Therapy for My Patient After Surgery? Limitations
The timing of restarting NOAC therapy depends on the following: Further research is required from prospective observational regis-
(1) the type of surgery performed, (2) hemostasis, (3) unexpected tries and randomized clinical trials. Evidence is needed to confirm
complications or findings at the time of surgery, and (4) the condi- and provide additional granularity on the findings from this litera-
tion of the patient. Unlike warfarin, the anticoagulant effect of ture review.
NOACs can be quickly achieved because peak plasma levels are
reached by approximately 3 hours after intake. Therefore, the tim-
ing of NOAC reinitiation after surgery should mirror that of paren-
Conclusions
teral heparin or subcutaneous low-molecular-weight heparin. While
to date there have been no prospective studies analyzing the ideal Non–vitamin K oral anticoagulants offer a safe and practical initial
time of reinitiation, most patients undergoing NOAC reinitiation af- option for oral anticoagulation in most patients with AF, DVT, or PE.
ter surgery had full-dose NOAC therapies started after 24 hours of The shorter therapeutic half-lives of NOACs and the absence of read-
adequate hemostasis. In a large rivaroxaban registry, reinitiation of ily available tests to measure their anticoagulant effect create spe-
NOACs 24 hours after surgery was associated with a 1.2% risk of ma- cial management issues during the perioperative period. A good un-
jor bleeding within the first 30 days.22 Most of these procedures were derstanding of NOAC pharmacology will facilitate optimal
low risk. For procedures with higher bleeding risk, reinitiation was management of NOACs during the perioperative period to reduce
sometimes delayed for up to 48 to 72 hours. Even in this scenario, the risk of perioperative bleeding, while minimizing the risk of on-
the thromboembolic risk was only 1.8% at 30 days vs a 0.2% risk of going thromboembolism.

ARTICLE INFORMATION Study concept and design: All authors. Conflict of Interest Disclosures: Dr A. Verma
Accepted for Publication: January 10, 2018. Acquisition, analysis, or interpretation of data: Ha, reported receiving research funding from Bayer and
S. Verma. Bristol-Myers Squibb. Dr Ha reported receiving
Published Online: April 18, 2018. Drafting of the manuscript: A. Verma, Ha. speaker’s fees from Bayer, Boehringer Ingleheim,
doi:10.1001/jamasurg.2018.0374 Critical revision of the manuscript for important and Servier and reported receiving research
Author Contributions: Drs A. Verma and Ha had intellectual content: All authors. funding from Bayer. Dr S. Verma reported receiving
full access to all of the data in the study and take Administrative, technical, or material support: speaker’s fees from Bayer and Boehringer
responsibility for the integrity of the data and the A. Verma, Ha, S. Verma. Ingleheim. No other disclosures were reported.
accuracy of the data analysis. Study supervision: Rutka, S. Verma.

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Clinical Review & Education Review What Surgeons Should Know About Non–Vitamin K Oral Anticoagulants

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