BAY 59-7939 – JQ1 chemical

Novel (Oral) Anticoagulant Challenges in Surgery
Richard Blennerhassett, BAppSci, MBBS1,2 Emmanuel J. Favaloro, PhD, FFSc (RCPA)1,3 Leonardo Pasalic, PhD, MBBS, FRCPA, FRACP1,3

1 Department of Laboratory Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, NSW Health Pathology, Westmead, New South Wales, Australia
2 Sydney Medical School, University of Sydney, Westmead, New South
Wales, Australia
3 Sydney Centres for Thrombosis and Haemostasis, Westmead, New South Wales Australia

Summary Non-vitamin K oral anticoagulants (NOACs) are a relatively recent therapeutic modality for the prevention of systemic thromboembolic complications of atrial ﬁbrillation and the prevention and management of venous thromboembolic disease. Approved indications for this class of anticoagulants are likely to further expand as the results of ongoing and new clinical trials are published and clinical experience grows. Despite their convenience compared with traditional methods of anticoagulation, there remain

Keywords
► rivaroxaban
► apixaban
► dabigatran
► perioperative
► surgery
► NOACs
► anticoagulation

a few potential pitfalls associated with their use in the perioperative setting. In particular, there is limited experience and evidence base regarding anticoagulant management in the perioperative setting, especially given the different NOACs available, which in turn are different from the classical anticoagulants. This narrative review synthesizes the recent advances in development of speciﬁc NOAC reversal agents and the understanding of the complexities of laboratory measurement of NOAC anticoagulant effects, and aims to provide practicing clinicians with basic evidence- based tools for perioperative management of patients taking NOACs.

The term “NOACs” is one in a mineﬁeld of terminology referring to oral anticoagulants that directly target and inhibit speciﬁc components of the coagulation pathway. NOACs, as an abbreviation, may refer to “‘new” oral antic- oagulants; novel oral anticoagulants; or non-vitamin K an- tagonist oral anticoagulants; other related abbreviations and terms include DOAC (direct oral anticoagulants), and TSOAC (target speciﬁc oral anticoagulant). For the purpose of this review, we will use the term NOACs to refer to the drugs rivaroxaban, apixaban, edoxaban (anti-Xa agents), and da- bigatran (antithrombin agent).
The NOACs are utilized in prophylaxis, treatment, and secondary prevention of venous thromboembolic (VTE) dis-

ease, nonvalvular atrial ﬁbrillation (AF), and other cardiac indications.1–8 Most notably, in patients with AF, NOACs are noninferior with regard to prevention of stroke and systemic thromboembolic events.1,2,9 NOACs are also currently re- commended by international guidelines as the ﬁrst choice for anticoagulation in non-cancer-related VTE.10 Over the last decade, NOACs have been increasingly prescribed for a variety of indications that traditionally utilized vitamin K antagonists (VKAs) such as warfarin and/or low-molecular- weight heparin (LMWH).11 The usage patterns show geo-
graphic variability dependent on locally approved indica- tions, availability, cost, and health care funding models. Currently, around one in three patients with AF use a

Issue Theme Thrombosis and Hemostasis in Surgery; Guest Editors: Anne-Mette Hvas, MD, PhD, Julie Brogaard Larsen, MD, and Leonardo Pasalic, MD, PhD.

DOI https://doi.org/ 10.1055/s-0037-1602667. ISSN 0094-6176.

NOAC for stroke prophylaxis and the number of patients taking NOACs is expected to increase further as the list of recommended indications grows.11
Compared with VKAs, NOACs are associated with compar- able or reduced rates of bleeding; speciﬁcally, a lower occurrence of intracranial hemorrhage.1,2,9,12 Additional beneﬁts compared with VKAs include rapid anticoagulant effect without an initial prothrombotic risk period, owing to their direct/target speciﬁc effect. Unlike VKAs, NOACs are administered in a standard, indication-speciﬁc ﬁxed dose,
and do not require routine laboratory monitoring. Patient preference is another driving force behind increasing use of NOACs.13 Many patients ﬁnd the requirements for monitor- ing VKA anticoagulant effect and food–drug interactions burdensome and increasingly request their doctor a change to a NOAC.
Recent estimates suggest that annually, 10% of patients taking oral anticoagulation will undergo an interventional procedure.14 This is expected only to increase further due to an aging population and growing prevalence of indications for anticoagulation. Therefore, health practitioners will be expected to manage an ever-increasing number of patients, presenting with a more diverse array of anticoagulants, including NOACs in the perioperative setting.

Perioperative Management
The current practice of NOAC management in the periopera- tive setting is primarily based on expert opinion derived from knowledge of drug pharmacokinetics and pharmaco- dynamics, with associated experience derived from large registration studies and post hoc subgroup analyses15–19 as well as emerging retrospective trials in speciﬁc popula- tions.20 Management of inevitable clinical scenarios such
as urgent surgery or surgical bleeding is based on consensus opinion derived from preclinical studies, laboratory or in vitro studies, through to the occasional phase 3 study. The following narrative review aims to provide an integrated summary of our own practice, the expert opinion-based guidelines, and the associated data relevant to NOACs and the perioperative period.

Factors to Consider
The main factors to consider in patients taking NOACs, when approaching the perioperative period, are outlined in ►Fig. 1 and are discussed in detail below.

Pharmacokinetics and Pharmacodynamics
The mechanism of action of rivaroxaban, apixaban, and edoxaban is via direct inhibition of Xa, while dabigatran directly inhibits the action of thrombin. The pharmacoki- netics of each drug is summarized in ►Table 1.21–42
The number of NOAC drug–drug interactions is signiﬁ- cantly less compared with VKAs.43 The medications that may alter the NOAC anticoagulant effect and thus the risk of intra- and/or postoperative bleeding are speciﬁc to the type of NOAC and are listed in ►Table 2.38,39,44–47 Clearly, the concurrent use of NOACs with other antithrombotic medica-

tions will further compromise hemostasis.48 Drugs that increase bleeding risk via their antiplatelet effect, commonly aspirin or thienopyridine agents (clopidogrel, prasugrel, and ticagrelor), dipyridamole, as well as nonsteroidal anti-in- ﬂammatory drugs (NSAIDs) are relevant. There is an increas- ing interest in combining anticoagulation with a NOAC and dual antiplatelet therapy to create a triple therapy ap- proach.49 Thrombolytic drugs may occasionally be used in patients with acute stroke prior to a surgical intervention and would further impede normal hemostasis.50

Clinically Signiﬁcant Drug Levels
One of the advantages of the NOAC class over VKAs is the absence of requirement for regular laboratory monitoring. Conversely, when needed, it becomes more problematic to quantitate the anticoagulant effect of NOACs than with classical anticoagulants.51 Methods to measure drug levels directly or indirectly are available but usually not in routine use 24 hours a day in most laboratories. Even when it is possible to measure the drug concentration, interpretation is difﬁcult due to scarcity of data correlating drug levels with clinical outcomes, including bleeding risk. The vast majority of clinicians caring for patients requiring surgery will have a timely and rapid access to routine coagulation tests such as the prothrombin time/international normalized ratio (PT/ INR) and the activated partial thromboplastin time (APTT), while the thrombin time (TT) is somewhat less widely available. Notwithstanding their inadequacies for measuring the effect of NOACs,52 there are some circumstances where standard coagulation studies (PT, APTT, TT) may assist in the management of NOACs in the perioperative setting. Overall, these assays may have some ability to exclude the presence of therapeutic or supratherapeutic NOAC levels; this ability is greatest with regard to dabigatran, and it may be possible in the case of rivaroxaban, but is not reliable in the case of apixaban.52
Dabigatran results in signiﬁcant elevations of the TT, even when the drug is present in low concentrations.53 Therefore, a normal TT in a patient taking dabigatran generally indicates that the patient is not anticoagulated; however, occasionally normal TTs may be reported with certain instruments/re- agents in samples containing dabigatran.53 Therapeutic le- vels of dabigatran result in a prolonged APTT, and therefore a normal APTT suggests that the dabigatran level is unlikely to be high, and the bleeding risk is probably not signiﬁcantly increased above the baseline. Therefore, to exclude clinically relevant anticoagulant effect of dabigatran, laboratories should provide rapid access to the TT and APTT. Clinicians should, however, also be aware that the TT is very sensitive, resulting in prolonged times at dabigatran concentrations well below observed trough levels, and it is thus useful to interpret the TT and APTT together. Rivaroxaban results in elevation of the PT, but the relationship between rivaroxaban levels and prolongation of the PT is dependent on the speciﬁc thromboplastin reagents used in the assay. Nevertheless, the presence of a normal PT in a patient taking rivaroxaban
usually suggests that a signiﬁcant anticoagulation effect is unlikely.52,54

Fig. 1 Proposed management pathway of urgent surgery in patients taking non-vitamin K oral anticoagulants (NOACs). Notes: Edoxaban has not been included in view of limited clinical experience. Standard coagulation results may vary in different laboratories; suggest liaison with local laboratory regarding test/reagents in use and their sensitivity to the presence of NOAC. ωConsider the patient anticoagulated at the longer timeframe if bleeding risk of required operation is high and/or impaired renal function (especially if dabigatran). ^A normal activated partial thromboplastin time is associated with insigniﬁcant drug plasma levels in the majority, but not 100%, of cases. þIn the event of unacceptable risk of postoperative bleeding (e.g., neurosurgery), until further data are available, it may be reasonable to administer a further dose of idarucizumab. In other cases, further idarucizumab should be considered in the event of clinically relevant bleeding with evidence of rebound anticoagulation.

Table 1 Select NOAC pharmacokinetic data pertinent to perioperative management

Dabigatran Rivaroxaban Apixaban Edoxaban
Half-life
ClCr > 80 mL/min 12–14 h 7–8 h 11 h 9 h
50–80 mL/min 17 h 9 h 14 h 13 h
30–50 mL/min 19 h 9 h 18 h 17 h
Time to peak level 1.5 h 2 h 1–3 h 1.3 h
Peak levelsa (ng/mL)b Results expressed as mediana 133 (110 mg BD)89
183 (150 mg BD)89 249–274 μg/mL
(20 mg daily)23,90 67–123d (2.5 mg BD)24
132–171 (5 mg BD)24
251 (10 mg BD)24 85 (30 mg daily)22
175 (60 mg daily)22
Trough levelsa (ng/mL)b Results expressed as medianc 65 (110 mg BD)89
93 (150 mg BD)89 25–44 μg/mL (20 mg daily)23,90 32–79d (2.5 mg BD)24
63–103 (5 mg BD)24
120 (10 mg BD)24 18–27 (30 mg daily)25
36 (60 mg daily)25
Renal elimination 80% 66% 27% 50%
Dialysis effect Removed by dialysis Not removed by dialysis Not removed by dialysis Not removed by dialysis
Abbreviation: BD, twice daily.
aDaibgatran 1–3 hours post dose, rivaroxaban 2–4 hours post dose, apixaban 1–3 hours post dose, edoxaban 1–2 hours post dose. Levels expressed
derived from liquid chromatography and tandem mass spectrometry in dabigatran, apixaban, edoxaban.
bng/mL, except in the case of rivaroxaban: μg/mL
cA range of results represents a range of medians found either within a given study as a result of different populations assessed, or across different studies.
dWide variation of apixaban median ranges in context of dose-adjusted population in the ARISTOTLE study.24 Sources: Adapted from various studies.21–42,89,90

Table 2 Drug–drug interactions associated with the NOACs

Dabigatran Rivaroxaban Apixaban Edoxaban
Drugs that increase anticoagulant level Ketoconazolea Quinidineb Amiodarone Verapamil Ketoconazoled Clarithromycind Ritonavird Erythromycin Fluconazole Ketoconazolee Diltiazem Naproxen Ketoconazole Quinidine Verapamil Erythromycin Cyclosporine Amiodarone
Drugs that reduce anticoagulant level Rifampicin Carbamazepine Rifampicin Rifampicinf Atorvastatin Esomeprazole
Unknown effect Itraconazolec Tacrolimusc Cyclosporinec
aContraindicated.
bDose change to 150 mg daily dabigatran.
cUse not advised with dabigatran.
dAvoid concurrent use with rivaroxaban.
eAvoid concurrent use in apixaban if two of the following are present: age > 80, weight < 60 kg, serum creatinine > 1.5 mg/dL; else reduce to
2.5 mg BD.
fAvoid concurrent use in apixaban.
Source: Adapted from various studies.38,39,44–47

Apixaban, even at high levels, does not reliably elevate the PT, and there are no standard coagulation effects evidenced with routine assays that can help guide whether there is likely to be any signiﬁcant anticoagulation effect in a patient taking apixaban.52–54 Given that the sensitivity to NOACs of commercial PT and APTT reagents varies, coagulation labora- tories should assess the sensitivity of their particular meth-
ods and disseminate this information among the clinicians who they service.
There are specialized coagulation tests that can measure NOAC levels indirectly. These largely comprise dilute throm- bin time (dTT) for dabigatran and NOAC-calibrated anti-Xa activity assays.52–54 A commercially available dTT (Hemo- clot) is the assay often recommended to determine the dabigatran drug level51; however, it is not approved for clinical use in all jurisdictions. In-house developed dTT assays and Ecarin-based clotting or chromogenic assays provide suitable alternatives if properly validated.52,53 The Russel’s viper venom time (RVVT) assay, routinely used in the assessment of the lupus anticoagulant, demonstrates a near- linear relationship to the dabigatran level.52,53 However, further evaluation is required to demonstrate its utility, perhaps in a modiﬁed form, in the assessment of dabigatran level.
Chromogenic anti-Xa assays speciﬁc for rivaroxaban and apixaban can be performed to quantify these drug plasma levels,52,54 but require the use of drug-appropriate calibra- tors, which may not be available in routine use in all laboratories. It may be tempting to use more widely available anti-Xa assays intended for LMWH and calibrated against a LMWH standard to measure rivaroxaban or apixaban levels in urgent situations; however, the measured drug levels may
be overestimated by a factor of 10,54 and thus this practice is not recommended.
A main beneﬁt of knowing quantitative drug levels may arise in the setting of major trauma-related bleeding, or in

patients requiring urgent surgery. Elevated plasma levels do little more than provide conﬁrmation that the patient is indeed anticoagulated, as drug level ranges have not been correlated to clinical outcomes and further estimation of extent of anticoagulation is not possible. There are currently no empiric data that evaluate a strategy incorporating either standard coagulation testing or speciﬁc coagulation testing into a pre-procedural management protocol. Given these practical limitations, these nonroutine coagulation tests are unlikely to signiﬁcantly impact the management of NOACs in the perioperative setting.
Finally, whole blood viscoelastic point-of-care assays of hemostasis, such as thromboelastography (TEG) and rota- tional thromboelastometry (ROTEM), have been evaluated for measuring NOAC anticoagulant effects, although the majority of studies are small and/or used blood samples spiked with NOACs. While there is some evidence to suggest that these methods can differentiate between different NOACs and can indicate the magnitude of anticoagulant effect,55 a normal ROTEM/TEG does not exclude the presence of a NOAC. Other limiting issues are similar to the speciﬁc coagulation studies; the equipment may not be universally available, trained personnel are required to interpret ﬁnd- ings, and test ﬁndings do not necessarily reﬂect clinical utility. However, these point-of-care methods are increas- ingly being used in the setting of major trauma, or critical surgical bleeding, and so further work in this area is anticipated.

Type and Urgency of Surgery
The very fact that a patient is treated with a NOAC indicates that the patient has an underlying thrombotic tendency. The crux of perioperative management of anticoagulants is bal- ancing the risk of bleeding versus the risk of thrombotic complications, both of which are inﬂuenced by several complex and potentially related factors. Each of these

requires a careful evaluation on a case-by-case basis when a patient presents with a surgical issue.
Based on the type, complexity, and duration of surgery, surgical procedures can be classiﬁed according to the asso- ciated bleeding risk. The most widely cited classiﬁcation systems relating to NOACs are the European Heart Rhythm Association (EHRA),56 the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis.57 The EHRA guidelines divide surgical bleeding risk into three groups: insigniﬁcant bleeding risk, low bleed- ing risk, and high bleeding risk, while the latter group divides surgical bleeding risk into low bleeding risk and moderate/ high bleeding risk. Examples of such classiﬁcation systems
have previously been described in detail elsewhere.56,58 The
associated bleeding risk of the proposed surgery will ob- viously affect the clinical decision-making process in the setting of emergent or urgent surgery.

Availability of Reversal Agent In contrast to VKAs, which produce their anticoagulant effect by suppressing production of vitamin K–dependent coagula- tion factors, NOACs, with the exception of dabigatran,59 do not yet have reliable and clinically evaluated agents to reverse their anticoagulant effect. NOACs act as inhibitors of either factor Xa or thrombin; therefore, to reverse their anticoagulant effect is not as simple as adding exogenous coagulation factors to correct a deﬁciency. A more targeted and biologically plausible approach would be to neutralize the NOAC drug itself. Idarucizumab is now available as an antidote to dabigatran (and will be discussed below); how- ever, the drugs inhibiting factor Xa do not yet have an available antidote, although two pertinent NOAC-speciﬁc
antidotes are currently being investigated: ciraparantag and andexanet alfa.60,61
Somewhat counterintuitively, there is consistent evidence that despite the absence of NOAC antidotes (at the time of the studies), patients on NOACs do not appear to fare worse than those taking VKAs in the context of planned or unplanned surgical procedures, as well as in those with major bleed- ing.12,16,17 Regardless, the availability of a speciﬁc antidote would change the landscape when considering urgent sur- gery. Currently, consensus guidelines urge deferring surgical
procedures, if possible, for an additional 12 to 24 hours, to reduce the anticoagulation effect via continued drug elim- ination.19,56,57,62–64 Access to a speciﬁc antidote will help eliminate the often delicate balancing act facing the surgical team between the risks of delaying the surgery versus increased bleeding; however, the ﬁnancial cost and future
implications of reexposure to antidotes would need to be considered.
Idarucizumab was approved in the United States and European Union in 2015, and Canada and Australia in 2016, with a wholesale cost of approximately 3,500 USD per dose. In humans, time to plasma peak is immediately after intravenous infusion. In doses of at least 5 g, it com- pletely reverses abnormal standard coagulation tests for at least 72 hours.65 It is equally effective in those with impaired renal function.65 So far there does not appear to be any

concerns with regard to development of inactivating anti- bodies in those exposed to idarucizumab, and in general, its safety proﬁle appears adequate, including no evidence to suggest independent contribution to a prothrombotic state.65 In an interim analysis of 90 patients of the RE-VERSE AD trial, idarucizumab demonstrated complete reversal of laboratory parameters as well as improved clinical hemo- static outcomes, with clinician-determined hemostasis (e.g., cessation of bleeding) achieved at a median of 11.4 hours and normal intraoperative hemostasis reported in 92% of pa- tients.59 Surprisingly, despite the pharmacokinetic study ﬁndings, 18% of patients developed a “rebound,” with an increase of dabigatran levels (with associated standard coa- gulation study abnormalities) at 24 hours post idarucizumab administration. Putatively, some degree of rebound may be due to dabigatran’s volume of distribution, which is larger than that of idarucizumab.65 However, the idarucizumab dose of 5 g was speciﬁcally chosen to bind the 99th percen- tile of the total body dabigatran (based on the RE-LY study65) despite the practical implications of signiﬁcant cost. These discordant ﬁndings are of interest, and the ﬁnal analysis of the RE-VERSE AD trial is eagerly awaited.
In patients taking dabigatran, 5 g of idarucizumab should be administered prior to urgent surgery. The pharmacoki- netic data indicate that the timing of idarucizumab admin- istration prior to surgery is ﬂexible; it appears reasonable to give the dose any time prior to induction. Subsequent routine coagulation testing and monitoring of laboratory hematological parameters should occur at least 12 hourly for the ﬁrst 48 hours postoperatively, and liaison with the hematology laboratory service should be considered for evaluation of dabigatran level testing during this time. There may be clinical circumstances such as brain or spinal trau- matic injury, where it would be reasonable to consider repeat dosing of idarucizumab in the event of rebound anticoagulation effect, regardless of clinically relevant bleed- ing; however, we would recommend seeking an expert hematology consult.

Current Guidelines and the Quality of Evidence
The real-world data of NOAC-related perioperative manage- ment is scarce in comparison to VKAs. Management guides, created by independent groups/bodies, contain very similar suggestions for NOAC management in the perioperative period.19,56,57,62,63,66 ►Table 3 highlights pertinent informa- tion from some of the more recent management guides.56,57,62,67 The most recent guideline by EHRA56 pub- lished in 2015 incorporates the ﬁndings from a prospective study17 as well as subgroup analysis from a large phase 3 trial.15 The available published data for interruption of NOACs in the perioperative setting is essentially limited to patients with AF.17,68 Recently, a retrospective analysis of 190 consecutive patients treated with NOACs for VTE under- going surgery was presented at the American Society of Hematology 2016.20 A high bleeding risk operation was performed in 24% of cases with a low rate of recurrent VTE (1%) and major bleeding (0.5%), providing real-world evi-
dence that the perioperative strategy employed for patients

Table 3 Summary of some of the recent guides on preoperative cessation of NOACs based on bleeding risk and renal function

Guide Renal function CrCl mL/min Dabigatran Rivaroxaban Apixaban Edoxaban
Surgical bleeding risk
Low High Low High Low High
Heidbuchel et al (EHRA 2015)56 CrCl > 80 24 h 48 h 24 h 48 h 24 h 48 h As per rivaroxaban and apixaban
CrCl 50–80 36 h 72 h 24 h 48 h 24 h 48 h
CrCl 30–50 48 h 96 h 24 h 48 h 24 h 48 h
ClCr 15–30 N/a N/a 36 h 48 h 36 h 48 h
Sié et al (2013)57 Not considered Low bleeding risk: 24 h No guide
Moderate/high bleeding risk: 5 d
Liew and Douketis (2013)67 CrCl > 50 Low bleeding risk: 2 d High bleeding risk:3 d No guide
CrCl 30–50 Low bleeding risk: 3 d High bleeding risk: 4–5 d
Tran et al (2014)62 CrCl >50 Low bleeding risk: 24 h High bleeding risk: 48–72 h No guide
CrCl 30–50 Low bleeding risk: 48 h High bleeding risk: 72 h (96 for dabigatran)
Abbreviation: CrCl, creatinine clearance.

with AF is likely to be suitable for patients taking NOACs for prevention and management of VTE.

Bridging
Bridging is a term originally used to describe cessation of a long-acting anticoagulant, such as, VKAs, allowing the drug effect to wane, with administration of a short-acting alter- native anticoagulation (i.e., heparin or LMWH) prior to and immediately after an invasive procedure.69 It is becoming increasingly apparent that, in patients on VKAs, bridging is not necessary in certain well-deﬁned patient groups (throm- bogenic cardiac arrhythmias with low to intermediate CHADS2 scores), and indeed it may be harmful.70 It should be noted that the principle of bridging is even less applicable to anticoagulation with NOACs due to the nature of their short half-lives.
The subgroup analysis of the RE-LY study demonstrated that bridging, when used in patients on dabigatran, resulted in signiﬁcantly increased major bleeding (6.5 vs. 1.8%) with- out any improvement in rates of thromboembolic events.68 While these ﬁndings are reassuring, they are not automati- cally applicable to the majority of patients encountered in the perioperative settings, as the following patient groups were excluded: patients with high CHADS2 scores, patients with metallic cardiac prostheses, patients with recent major bleeding event, as well as patients with thromboembolic disease within the past 12 weeks. Nevertheless, as demon- strated by registry data from 2013 to 2015, the use of bridging is in decline.17 Data from the RE-LY trial demon- strate that although there is signiﬁcant geographical practice variation, 85% of patients receiving dabigatran did not re- ceive perioperative bridging therapy. Given their rapid onset and cessation of anticoagulant effect (provided oral intake,

absorption, and renal function are not impaired), we agree with the most recent publications that, in general, bridging anticoagulation should not be used in patients on NOAC therapy (meaning dabigatran, apixaban, and rivaroxaban) for approved indications.56,67,71

Resumption of Anticoagulation To reduce the risk of devastating and potentially fatal throm- boembolic events, a return to full anticoagulation should be established as soon as possible in the postoperative period. However, this needs to be weighed against the risk of post- operative bleeding, which will vary according to the type of procedure. The evidence base supporting recommendations on NOAC resumption after invasive procedures is derived predominantly from expert opinion.19,56,62,67,69,72–74 After
low bleeding risk operations and nontraumatic spinal punc- ture or epidural anesthesia, full-dose NOAC therapy can be recommenced 6 to 8 hours postprocedure. If the postopera- tive bleeding risk is deemed to be high, such that it would outweigh the risk of thromboembolic events, then thera- peutic anticoagulation can be withheld for 48 to 72 hours. However, during this period, low-dose medical thrombopro- phylaxis (usually using LMWH) should be considered. The risk–beneﬁt analysis needs to take into account the under- lying thromboembolic disorder and the risk of recurrence. There is currently no evidence to support the use of modiﬁed dose NOACs in this context and clinicians should refer to their local institution policies regarding medical thromboprophy- laxis dosing.

Emergency Surgery
First, there are no known clinical or laboratory-based pre- operative tools that adequately predict perioperative

bleeding, or perioperative thromboembolic events in any given individual.75,76 Although it may seem self-evident, in patients on anticoagulants, the strongest predictors of major bleeding and thromboembolic events is the need for urgent surgery.68 If a patient on a NOAC requires urgent surgery, the factors highlighted in ►Fig. 1 need to be considered. Where available, it is recommended to seek expert consultation. Unless the surgery can proceed regardless of anticoagulant
effect, then the anticoagulant should be stopped. An attempt to assess anticoagulant effect should be performed with standard and, if available, speciﬁc coagulation studies. If there is evidence that the NOAC is absent, or likely to be present at a clinically insigniﬁcant level, then the patient can proceed to surgery.
If there is evidence that the NOAC is present either by measuring drug levels or on the basis of prolongations of routine coagulation tests, then the patient should be con- sidered anticoagulated. In case of dabigatran, if idarucizu- mab is available, it should be administered as per the product information (5 g in two 2.5 g /50 mL vials intravenously over 5–10 minutes each) and the patient may then proceed to surgery. If idarucizumab is not available, hemodialysis may be considered in those with impaired renal function (GFR
< 50 mL/min) and/or evidence of supratherapeutic levels (i.e., plasma level >500 ng/mL or APTT >80).34 However, the patient should be monitored for rebound anticoagulant
effect once renal replacement therapy is discontinued.77 If the patient is taking a direct factor Xa inhibitor, then the surgery should be deferred if safe to do so, while maintaining normal physiology (to ensure ongoing renal NOAC elimina- tion), obtaining bleeding control via local hemostatic mea- sures, providing transfusion support to maintain normal physiology, and avoiding dilutional coagulopathy.
If the surgery cannot be deferred in patients on direct anti-Xa inhibitors or dabigatran where idarucizumab is not available, seek expert advice with regard to the use of prohemostatic factors such as prothrombin complex con- centrates (PCCs) and activated PCCs (aPCCs). The evidence for effectiveness of recombinant factor VIIa (rFVIIa) in this setting is even weaker, and thus should only be considered as a last resort in select cases.
However, clinicians should be aware that the prohemo- static products are not speciﬁc “reversal” agents when used in the context of NOACs. There is no clinical evidence to prove any reversal of clinical bleeding measures. Perhaps more importantly, owing to their prohemostatic nature, these products are known to cause thromboembolic events.78–80

Management of Intraoperative/Postoperative Bleeding
Management of intra- and postoperative bleeding in the context of recent NOAC therapy will depend on the NOAC type, presence of antiplatelet medications, and presence of conventional indicators such as dilutional coagulopathy from massive transfusion or concurrent disseminated intravascu- lar coagulation. In patients with critical bleeding, massive transfusion protocols should be implemented as per local institutional policy regardless of the availability of reversal

agents. Supportive care is crucial to successful resuscitation and it includes maintenance of adequate renal perfusion, control of blood loss where possible, and transfusion sup- port, including fresh frozen plasma (FFP), cryoprecipitate or ﬁbrinogen concentrate, and platelet transfusion as recom- mended by local policy. Notwithstanding the study design limitations, ﬁndings from experimental animal models and in vitro studies suggest that aPCC and PCC appear to restore
laboratory parameters toward normal baseline, although the effects seem to be NOAC and animal model dependent.80–85 The human studies are less extensive, and are limited to evaluation of in vitro parameters,81,86,87 and are difﬁcult to compare due to the use of a variety of PCC formulations containing either three or four factors. There is limited data to guide the use of FFP or ﬁbrinogen concentrate; however, based on knowledge of the drug pharmacokinetics and pharmacodynamics, exceedingly large volumes of FFP would be required to absorb the unbound drug if present and would confer unnecessary risk (e.g., of ﬂuid overload). As such, we
agree with existing recommendations against the use of FFP unless it is used in prevention of associated dilutional coagulopathy.56 Similarly, there are little data on the use of ﬁbrinogen concentrate; accordingly, it should be reserved as a part of maintenance of physiologic ﬁbrinogen levels. Current recommendations are PCC (three or four factors) 25 to 50 IU/kg and aPPC 30 to 50 IU/kg.56 In the event of ongoing bleeding despite the supportive measures and the administration of PCC or aPCC, discussion with the hematol- ogy service is recommended; rVIIa may be considered at this stage. There is very little evidence to support the use of antiﬁbrinolytics in patients taking NOACs.88

Conclusion
Managing patients on NOACs in the perioperative period remains a challenging clinical task. Patients taking dabiga- tran with life-threatening or uncontrolled bleeding or urgent surgery now have access to a speciﬁc reversal agent: idar- ucizumab. Although further phase 3 trial results are pending, this may obviate the need for nonspeciﬁc reversal agents such as PCC, aPCC, and rVIIa in this patient group. Speciﬁc reversal agents for the anti-Xa oral anticoagulants are cur- rently undergoing evaluation in preclinical studies. In the meantime, there are no speciﬁc reversal agents available for the anti-Xa oral anticoagulants and the use of nonspeciﬁc prohemostatic agents (PCC, aPCC, and rVIIa as a last resort) should only be considered in the context of life-threatening bleeding or requirement for immediate surgery, while being mindful of the potential prothrombotic risk proﬁle as well as uncertain impact on clinical bleeding outcomes.
Regardless of the availability of speciﬁc reversal agents, liaison with the hematology service is strongly recom- mended in patients presenting with clinically signiﬁcant bleeding or requirements for urgent surgery. Additionally, there are laboratory parameters that will affect evaluation of anticoagulation status that will vary depending on local laboratory factors. We suggest the laboratories engage with the clinicians to increase their awareness of the

availability and characteristics of laboratory assays per- formed within their local facilities to measure the antic- oagulant effect of NOACs used in their jurisdiction.

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