2025 直接口服抗凝剂指南—处方、实验室检测、围手术期及出血管理

2025 Guidelines for direct oral anticoagulants: a practical guidance on the prescription, laboratory testing, peri-operative and bleeding management

Huyen A. Tran $\mathbb{O},^{1,2}$ Eileen Merriman , 3 Ross Baker, 4 Jennifer Curnow, 5 Laura Young, 6 Chee Wee Tan, 7 Simon McRae 8 and Sanjeev D. Chunilal 9

1 Haemostasis Thrombosis Unit, The Alfred Hospital, 2 Australian Centre for Blood Diseases, Monash University, and 9 Haematology Department, Monash Medical Centre, Melbourne, Victoria, 4 Haematology Department, Perth Blood Institute, Perth, Western Australia, 5 Haematology Department, Westmead Hospital, Sydney, New South Wales, 7 Haematology Department, Royal Adelaide Hospital, Adelaide, South Australia, 8 Department of Haematology, Launceston General Hospital, Launceston, Tasmania, Australia, and 3 Haematology Department, Royal North Shore Hospital, and 6 Haematology Department, Auckland City Hospital, Auckland, New Zealand

Key words

direct oral anticoagulant, major bleeding, reversal agent, perioperative anticoagulation.

Correspondence

Huyen A. Tran, Australian Centre for Blood Diseases, Monash University, Melbourne, Vic. 3800, Australia. Email: huyen.tran@monash.edu

Received 30 September 2024; accepted 24 April 2025.

Abstract

Direct oral anticoagulants (DOACs) are widely prescribed to prevent and treat venous and arterial thromboembolism, supported by published evidence, and are preferred over warfarin in many guidelines. Although the risk of major bleeding, in particular intracranial haemorrhage (ICH), is decreased with DOACs, gastrointestinal bleeding is increased with some DOACs, and the case fatality rate of bleeding remains high. Therefore, it is important to (i) prescribe DOACs appropriately, (ii) have strategies to manage major bleeding including the use of speci fi c reversal agents and (iii) interrupt and resume DOACs for procedures. The main recommendations are as follows: (i) Select the appropriate dose of DOAC according to indications and consider patient factors to minimise bleeding risks; (ii) DOACs do not require routine laboratory testing; (iii) for life-threatening uncontrollable bleeding, speci fi c agents can be used to reverse the anticoagulant effects of DOACs; and (iv) DOACs can be interrupted for planned procedures without the need for ‘ bridging ’ with low-molecular-weight heparin (LMWH). The anticoagulant effects of DOACs can be reversed with speci fi c agents, such as andexanet for apixaban and rivaroxaban and idarucizumab for dabigatran. If not available, pro-haemostatic agents such as prothrombin complex concentrates or activated prothrombin complex concentrates can be considered. DOACs can be interrupted and resumed for procedures without the need for ‘ bridging ’ with LMWH.

Background

Oral factor Xa inhibitors (FXaI, apixaban and rivaroxaban) and oral thrombin inhibitors (dabigatran) target speci fi c activated coagulation factors and are referred to as direct oral anticoagulants (DOACs). 1 With a fi xed dosing regimen, less drug and food interactions, and no need for routine laboratory monitoring when compared to warfarin, their use has become widespread. The current indications for the DOACs are for the primary and secondary prevention of venous and arterial thromboembolism (Table 1 ), but there are speci fi c

circumstances when they should be avoided (Box 1 ). Overall, their introduction has impacted positively on the quality of life of patients needing anticoagulants. 2

The ef fi cacy of DOACs has been established in multiple large, multicentre randomised controlled trials (RCTs) involving patients with atrial fi brillation (AF), chronic stable atherosclerotic disease and venous thromboembolism (VTE; including deep vein thrombosis (DVT) and pulmonary embolism (PE)) (GRADE 1A). 3 – 5 Compared with warfarin, all DOACs achieved non-inferiority with regard to prevention of stroke, systemic embolism and recurrent VTE events. Dabigatran at a dose of 150 mg twice daily also demonstrated superiority over warfarin in stroke prevention in patients with AF. 6 Preventive doses of

† Table 1 Currently approved indications for the use of direct oral anticoagulant drugs

||VTE prevention|VTE treatment*|VTE treatment*|Atrial fbrillation (AF)| Stable atherosclerotic vascular disease | |---|---|---|---|---|---| |||initiation|Maintenance||| |Apixabant.s.1I| 2.5 mg twice daily post hip and knee replacements | 10 mg twice daily for 7days | 5 mg twice daily; consider 2.5 mg twice daily beyond 6 months | 5 mg twice daily/or 2.5 mg twice daily* || |Rivaroxaban*| 10 mg daily post hip and knee replacements | 15 mg twice daily for 21 days | 20 mg daily; consider 10 mg daily beyond 6 months | 20 mg daily / 15 mg dails | 2.5 mg twice daily (combined with aspirin)iIl.a | |Dabigatranbc| 110 mg 1-4 h post- surgery, then 220 mg once daily post hip and knee replacementsd ||150 mg twice daily|150 mg oral twice daily|| |||||110 mg oral twice daily|| ||||110 mg twice dailye|||

† Approved indications: Therapeutics Goods Association of Australia (TGA) and/or Medsafe, New Zealand (NZ). ‡ Dabigatran is not reimbursed for VTE treatment by the Pharmaceutical Bene fi ts Scheme, Australia; apixaban is not reimbursed by Pharmac, New Zealand. § Not funded for this indication in New Zealand.

¶ Use not recommended with CrCl < 25 mL/min.

†† Apixaban 2.5 mg twice daily, two out of three (serum creatinine ≥ 133 mmol/L, $\mathsf{a g e\ge80}$ years and weight $\leq60\;\mathrm{kg}\mathrm{g}$ . ‡‡ Use not recommended with CrCl <15 mL/min.

§§ Rivaroxaban 15 mg once daily in patients with moderate renal impairment (creatinine clearance 15 – 49 mL/min).

Coronary artery disease with one additional risk factor; peripheral arterial disease with one additional risk factor.

a Peripheral arterial disease after acute revascularisation (not PBS funded but ef fi cacy and safety established in large phase RCT). b Not funded for VTE prevention or VTE treatment in Australia.

c Use not recommended with CrCl < 30 mL/min.

d Consider reducing the dose to 150 mg once daily for those with CrCl 30 – 50 mL/min or in those with increased risk of bleeding. e Dabigatran 110 mg twice daily for patients ${\ge}80$ years or with increased risk of major bleeding. f Dabigatran 110 mg twice daily, CrCl, 30 – 50 mL/min.

VTE, venous thromboembolism.

Box 1 Scenarios where use of direct oral anticoagulants is not advised.

• Mechanical prosthetic heart valves

• Moderate to severe mitral stenosis, including rheumatic mitral stenosis • Pregnancy and breast-feeding women • Severe kidney disease † • Severe liver disease ‡ • High-risk anti-phospholipid syndrome (APLS), including triple positive APLS § , history of arterial thrombosis † Apixaban, dabigatran and rivaroxaban are not recommended with CrCl <25 mL/min, $\mathrm{<30~mL/min}$ and ${<}15$ mL/min respectively. ‡ Apixaban is contraindicated in Child-Pugh C; rivaroxaban in Child-Pugh B and C; dabigatran with liver enzymes $\times2$ upper limit of normal. § Lupus anticoagulant (non-speci fi c inhibitor), anticardiolipin antibodies and anti-B2 glycoprotein antibodies.

apixaban 2.5 mg twice daily and rivaroxaban 10 mg once daily maintained ef fi cacy in preventing recurrent VTE beyond 6 months, without a signi fi cant increase in bleeding compared to aspirin or placebo. 7,8

The clearance of DOACs relies primarily on renal function, though the extent varies between the different DOACs. A careful assessment of risk – bene fi t should be undertaken for use of DOACs in patients with CrCl ${<}30$ mL/min. In Australia and New Zealand, dose adjustment of dabigatran is recommended with CrCl ≤ 50 mL/min, with contraindication of use if CrCl ≤ 30 mL/min. Apixaban and rivaroxaban use is not recommended for CrCl $<\!25\,\mathrm{~mL/min}$ and $\mathrm{CrCl\underset{\left.<15}{}\ m L/m i n\right.}$ respectively. DOACs should also be used cautiously in patients with liver dysfunction (Box 1 ). DOACs are contraindicated in Childs-Pugh class C cirrhosis (apixaban but not rivaroxaban may be used in class B). There is a paucity of data regarding the use of DOACs at the extremes of body weight (body mass index $>40\;\mathrm{\kg/m}^{2})$ ). Hence, the use of DOACs remains challenging in patients with signi fi cant renal or liver impairment, in low-body-weight and morbidly obese patients.

DOACs have less drug – drug interactions, but signi fi - cant interactions can occur with medications which interact with P-glycoprotein and/or CYP3A4. Combining antiplatelet drugs and certain other medicines with DOACs increases the risk of bleeding. Utilising online speci fi c drug interaction checkers is highly recommended ( https://amhonline.amh.net.au/ ). 9

10

An important safety advantage re fl ected in all of the RCTs involving DOACs, and con fi rmed by metaanalyses, is the signi fi cant reduction in intracranial haemorrhage (ICH) compared to warfarin. 3,5,10 DOACs have also been associated with less major bleeding, less clinically relevant non-major bleeding (CRNMB) and less fatal bleeding in patients with VTE. 5 In the VTE population, the rates of major bleeding and CRNMB per year with DOACs have been $1.1\%$ and $6.3\,\%$ respectively, compared to $1.8\,\%$ and $8.0\%$ with warfarin.

Compared to warfarin, the estimates of major bleeding are lower with DOACs overall $(1\%-4\%$ per year). 3,5 However, when major bleeding occurs, there is an associated case fatality rate of $6\%{-}8\,\%$ , and even higher with ICH (up to $48\,\%$ ). 10,11 Consequently, there remains a signi fi cant need for safe and effective management of major bleeding episodes when they occur.

Finally, up to $10\%$ of patients receiving long-term anticoagulants require urgent or time-critical procedures each year. 12 Some can be managed by withholding anticoagulation for a fi nite period, but in an emergency, an effective reversal strategy to avoid or minimise bleeding is needed.

This document, endorsed by Thrombosis and Haemostasis Society of Australia and New Zealand (THANZ), aims to provide guidance on:

1 DOAC prescription

2 Laboratory measurements of DOACs in appropriate scenarios

3 Strategies to manage bleeding including the use of reversal agents and interruption of DOACs during perioperative periods.

Methods

Eight experts in thromboembolic diseases of the THANZ conducted three virtual and one face-to-face meeting (2 and 30 September 2022; 3 November 2023; and 17 July 2024) together with recurring emails, during which speci fi c questions and drafts and revisions of the guidelines were discussed (refer to Appendix S1 for description of development process). The guidelines followed methods outlined by the National Health and Medical Research Council and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. 13 Recommendations have been graded as strong or weak, rated according to quality of the levels of available evidence (GRADE) (Table 2 ). 14 The views of DOAC users were not sought.

Recommendations

See Table 2 .

Prescription of DOACs

In both Australia and New Zealand, apixaban, rivaroxaban and dabigatran are indicated for the prevention of stroke and systemic embolism in patients with AF, chronic stable atherosclerotic disease, the treatment of new DVT and PE, and secondary prevention of VTE, as well as the prevention of venous thrombosis in hip and knee arthroplasty. Table 1 summarises the dosing and indication for each DOAC.

DOACs and laboratory testing

DOACs do not routinely require laboratory monitoring because of predictable pharmacokinetics and pharmacodynamics (GRADE 1A). Unlike warfarin, DOACs have peaks and troughs because of a relatively short half-life, producing a peak anticoagulant effect at 2 – 3 h after intake. Therefore, any DOAC laboratory measurements must be interpreted in the context of the DOAC prescribed, known dosage and time of last administration. Clinical circumstances under which measurement of anticoagulant effect may impact management are in Box 2 . 16,17

An activated partial thromboplastin time (aPTT) or prothrombin time (PT) within the normal range does not exclude elevated DOAC levels (up to $100{\mathrm{-}}150\ {\mathrm{ng/mL}})$ ) that may contribute to ongoing bleeding or impairment of haemostasis with surgery. 18,19 The sensitivity of each laboratory ’ s aPTT and PT to increasing DOAC concentration is wide-ranging and depends on the instrument and reagent. There is no international DOAC coagulation method to standardise results such as the international normalised ratio (INR) for warfarin. With knowledge of this limitation, some clinicians may still consider reviewing the aPTT for dabigatran and PT for rivaroxaban in emergencies; the PT is generally insensitive to apixaban. Conversely, even small concentrations of dabigatran prolong the thrombin time (TT), such that a normal result excludes the presence of dabigatran but should not be used to estimate dabigatran concentration or for correction before surgery. 20,21

Quanti fi cation of plasma DOAC drug levels determined by speci fi c coagulation assays (dilute TT, ecarin clotting time for dabigatran and calibrated anti-FXa chromogenic assays for apixaban and rivaroxaban) are well validated for precision and monitored by external quality assurance programmes. 21 – 23 However, the awareness of clinicians of the need to obtain a rapid DOAC level, as with an INR result for warfarin in an emergency, is lacking. Approximately one in fi ve patients taking DOACs who present with bleeding or require urgent surgery have no detectable DOAC present. 18,19,24 In contrast, a timely result would signi fi cantly impact decisions regarding speci fi c DOAC haemostatic reversal agents or blood

Table 2 Summary of key recommendations

|Recommendation|GRADEt|GRADEt| |---|---|---| ||strength|quality| |DOACs are indicated for the prevention of||| |stroke and systemic embolism in patients||| |with atrial fbrillation (AF), chronic stable||| | atherosclerotic disease, the treatment of new deep vein thrombosis and pulmonarynew deep vein thrombosis and pulmonary embolism, and secondary prevention of ||| |VTE, as well as the prevention of venous||| |thrombosis in hip and knee arthroplasty.||| |DOACs do not routinely require laboratory||| |||3| | Idarucizumab can be administered to patients with uncontrolled bleeding related to dabigatran or prior to an urgent proceduredabigatran or prior to an urgent procedure as it rapidly and safely reverses the ||| | anticoagulant effect and achieves adequate haemostasis. ||| | Andexanet can be administered to patients with life-threatening and uncontrolled |n|3| |||| |rivaroxaban as it effectively reduces the||| |anticoagulant effects and achieves adequate||| | Four-factor prothrombin complex concentrates (4F-PCC) an activated |n|| | prothrombin complex concentrates (FEIBA) can improve haemostasis in patients with life-threatening and uncontrolled bleeding ||| |related to apixaban and rivaroxaban.||| | Activated charcoal should be considered in patients with moderate/severe bleeding who ||| | present within 2 h of the last dose of DOAC. Tranexamic acid can be prescribed as an adjunct in DOAC-related major bleeds. ||| |||| | Anticoagulation can be resumed 1-6 weeks after major bleeding, depending on ||| | individual bleeding and thrombosis risk. DOAC-specific reversal agents and ||| |||| | haemostatic agents are unlikely to improve outcome in patients taking dabigatran with ||| |a drug level of |||

Table 2 Continued

|Recommendation||GRADEt| |---|---|---| ||Strength|Quality| |FXa inhibitors can be safely interrupted 72 h||3| | prior to neuraxial anaesthesia in patients with adequate renal function. ||| |||| |Dabigatran should be interrupted 96 h prior||| | to neuraxial anaesthesia in patients with CrCl 30-50 mL/min. ||| |Therapeutic dose anticoagulation with DOACs||3| |can be resumed 48--72 h after a procedure||3| |(provided there are no ongoing bleeding||| |risks).|||

† Grading system employed to append recommendations 13,15 : Strength of recommendation: 1 – Strong; 2 – Weak. Levels of Evidence: A – Highquality systematic reviews or RCTs; B – SR or individual cohort studies; C – Well-designed phase 2 studies or good-quality case series; D – Expert panel consensus. Strength of recommendation and grading of evidence as reviewed by the expert panel. Statements graded 1A are strong consensus recommendations supported by high-quality metaanalyses, while statements graded 2C are weak recommendations supported by phase 2 studies or case series. The strength of recommendation rating re fl ects the extent to which the panel is con fi dent that the desirable effects (i.e. bene fi ts, such as improved outcome) of a recommendation considerably outweigh the undesirable effects (i.e. harms, such as adverse events) based on the available evidence. GRADE, Grading of Recommendations, Assessment, Development and Evaluation.

products. In this context, it falls to individual organisations to develop work fl ows which afford a prompt turnaround time of relevant coagulation testing, which would likely improve patient safety, clinical outcomes and cost effectiveness of DOAC reversal.

Box 2 Circumstances where measuring direct oral anticoagulantsspeci fi c anticoagulant effect may be warranted

Major bleeding

• Urgent surgery • New or deteriorating renal impairment • Extremes in body weight (weight $>120~\mathrm{kg}$ ) • Recurrence or extension of thromboembolism when therapeutic adherence is assumed • Using concomitant medications which induce or inhibit liver enzymes • Before instituting thrombolysis for treatment of acute ischaemic stroke and other indications for thrombolysis

10

Reversal agents

Idarucizumab

Idarucizumab, a monoclonal antibody fragment that binds directly to dabigatran, has been shown to reverse rapidly and safely its anticoagulant effect in patients with uncontrolled bleeding or prior to an urgent procedure. 25,26 It can also be considered in other clinical situations, for example, prior to thrombolysis in patients with acute coronary syndrome or ischaemic stroke. In patients with adequate renal function, idarucizumab is unlikely to provide a clinically signi fi cant bene fi t if the last dose of drug was more than 24 h prior. There are no reliable cut-off values to decide whether surgery or invasive procedures can be carried out. Still, it is generally agreed that it is safe to proceed (without using idarucizumab) if the dabigatran level is ${<}50~\mathrm{ng/mL}$ or ${<}30~\mathrm{ng/mL}$ where any excess bleeding is unacceptable, such as neurosurgery. 27 In patients with high dabigatran levels, particularly with renal impairment, further doses of idarucizumab may be required to avoid the reappearance of dabigatran in the circulation $^{12-24}\mathrm{~h~}$ after the last dose. 28

Andexanet-alfa

Andexanet-alfa is a recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors, with a cohort study showing that $82\%$ of patients with acute major bleeding had excellent or good haemostatic ef fi cacy and a greater $90\%$ reduction in the anti-FXa level from baseline; patients requiring urgent surgery were not assessed. 29 The thrombotic event rate was $10\%$ in this cohort at day 30, but no events occurred after the resumption of anticoagulants among patients who did restart. Andexanet use in FXaI-related acute ICH was associated with an increased rate of ischaemic stroke, but not other thrombotic events compared with standard of care. 30 Therefore, the use of andexanet should be carefully considered, weighing up the bene fi ts and risks for adult patients on apixaban or rivaroxaban where reversal is required due to life-threatening or uncontrolled bleeding, and where the last known dose of apixaban or rivaroxaban was $\mathrm{<l8~h}$ prior. If the timing of the last dose is unknown, an urgent drug-speci fi c anti-FXa level should be obtained and andexanet given if the level is ${>}75~\mathrm{ng}/\mathrm{mL}$ . 29 The use of andexanet is not indicated in those having planned surgery without current major bleeding, for those expected to receive heparin or other haemostatic agents within 12 h of andexanet treatment, those who have received PCC or rFVIIa products within the last 7 days and those with a recent history of thrombosis ( $^{'<2}$ weeks). There is currently no evidence supporting the use of andexanet prior to thrombolysis among patients taking a FXaI who present

with an ischaemic stroke or other indications for thrombolysis. As the pharmacodynamic half-life of andexanet is relatively short, approximately 4 h, reappearance of plasma rivaroxaban and apixaban was observed after cessation of the 2-h infusion. Subsequent monitoring of anti-FXa levels may be useful, particularly in those with renal impairment or who are still bleeding; however, anti-FXa measurements after andexanet administration are not accurate due to its interference with currently available assays. 28 The andexanet dosing (low vs. high) depends on the XaI, dose and timing of the last dose (Fig. 1 ), as per the product datasheet. 30

Tranexamic acid

Tranexamic acid (TXA) reduces bleeding by reducing clot breakdown ( fi brinolysis) and is used in most algorithms for moderate to major bleeding, particularly for bleeding at sites with high fi brinolytic activity such as the GI tract. TXA has been shown to reduce bleeding in the setting of trauma (CRASH trials) and post-partum haemorrhage (WOMAN trial) but did not reduce death from GI bleeding in the HALT-IT trial. 31 – 33 The HALT-IT trial also showed increased rates of VTE events and seizures, and as there are no data to demonstrate improved outcomes or otherwise in DOAC-related bleeding, no fi rm recommendations can be made.

Managing DOAC-related bleeding

General principles in management of patients with bleeding while receiving DOACs

1 Drug discontinuation: The anticoagulant should be ceased at least temporarily in all patients presenting with signi fi cant bleeding. The timing of recommencement will depend on the severity of bleeding, the presence of ongoing risk factors for bleeding, the risk of thrombosis and the initial indication for anticoagulant therapy.

2 Baseline laboratory assessment: The time of the last DOAC ingestion should be established (if known). Baseline assessment of haemoglobin should be performed to assess bleeding severity. Standard coagulation tests (aPTT, TT and PT) and, where available, anticoagulant-speci fi c drug level assessments should be performed to assess the contribution of the drug to the bleeding event and to guide the need for intervention. Creatinine should also be measured to assess renal function and allow prediction of expected rate of anticoagulant drug clearance.

3 General supportive care measures: Patients with minor bleeding should be managed with local measures (e.g. mechanical compression). Surgical and radiological procedures to identify the bleeding source and to limit

 Figure 1 Management of direct oral anticoagulant (DOAC)-related bleeding. \* Clinically signi fi cant bleeding – reduction in Hb ${\geq}20g/L$ , transfusion of ${\geq}2$ units of red cells and haemodynamically stable. \*\* Life-threatening bleeding – bleeding in critical area or organ (e.g. intraocular, intracranial, intraspinal, compartment syndrome, retroperitoneal or pericardial, hypotension not responding to resuscitation). † Give as IV bolus at rate 30 mg/min over 15 min (low dose) or 30 min (high dose), followed by continuous infusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 min. High dose should be used for those taking rivaroxaban ${\geq}10\;\mathsf{m g}$ or unknown within 8 h (or if time unknown) and apixaban >5 mg or unknown within 8 h (or unknown time); all others should receive low-dose protocol. #This is an off-licence use of factor eight inhibitor bypass activity (FEIBA) and PCC; the thrombotic complications with these agents when used for this indication is unclear. 4F-PCC, four-factor prothrombin complex concentrate; aPTT, activated partial thromboplastin time; FBC, full blood count; PT, prothrombin time; TT, thrombin time.

ongoing bleeding should be performed as appropriate, considering the risk of procedure-related bleeding in an anticoagulated patient. Red cell transfusion should be administered as clinically appropriate. Platelet transfusion should be considered in patients on concurrent

anti-platelet therapy or with signi fi cant thrombocytopenia (platelets ${<}50\times10^{9}/\mathrm{L}$ ).

4 Activated charcoal: Administration of activated charcoal should be considered in patients with moderate/ severe bleeding who present within 2 h of the last dose

10

of DOAC, although there is potential for ef fi cacy up to 8 h after DOAC administration 34 (GRADE 2C).

5 Administration of haemostatic agents: Where available, a drug-speci fi c reversal agent can be given for major, life-threatening bleeding. In its absence, an alternative haemostatic agent may need to be considered. Four-factor prothrombin complex concentrates (PCCs) at a dose of $25{-}50~\mathrm{U}/\mathrm{kg}$ have been shown to be moderately effective in the treatment of patients on factor Xa inhibitors presenting with major bleeding $(69.1\%)$ with a low thromboembolic event rate $\left(2.3\%\right)^{35,36}$ (GRADE 2C). Alternatively, a fi xed dose of 2000 IU can be used, with a recent meta-analysis of 25 studies showing no difference in the reduction in bleeding, thromboembolic rates or mortality when comparing weight-based with fi xed dosing. 37 Activated prothrombin complex concentrate (FEIBA) has been shown to be effective at obtaining haemostasis in DOAC-related bleeding events at 25 – 50 U/kg doses 38 (GRADE 2C). Use of rFVIIa is not recommended, based on less consistent data on its ability to reverse anticoagulant effect derived from animal and laboratory models and its association with the risk of thrombosis when used outside patients with haemophilia. 39

6 Of all the DOACs, only dabigatran is removed by haemodialysis, but it is rarely performed because of the availability of idarucizumab. DOAC-speci fi c reversal agents and haemostatic agents are unlikely to improve outcome in patients taking dabigatran with a drug level of ${<}50~\mathrm{ng/mL}$ or in patients on rivaroxaban or apixaban with drug level ${<}75~\mathrm{ng/mL}$ (GRADE 2C). 29 Tranexamic acid should also be considered.

Figure 1 shows the algorithm to manage DOACrelated bleeding.

Resumption of AC after major bleeding

Following the cessation of bleeding, treatment of identifi able underlying causes, the need for anticoagulation and its bene fi t should be reviewed, including the choice and dose of anticoagulant. This needs to be weighed against the risk of recurrent bleeding, and risk factors for bleeding should be addressed and modi fi ed if feasible. For most patients, resumption of anticoagulation is favoured unless the recurrent bleeding risk is high and cannot be reduced to an acceptable level with treatments or interventions targeted at addressing the underlying cause of bleeding. The optimal timing for anticoagulant resumption based on current available evidence is between 1 and 6 weeks depending on individual bleeding and thromboembolism risk 40 (GRADE 2C).

Perioperative management of patients receiving a DOAC undergoing elective surgery

Optimal management of the interruption of DOAC therapy for procedures remains an area of ongoing research. A meta-analysis of eight studies of perioperative DOAC interruption reported a thromboembolic risk of $0.41\%$ and a major bleeding rate of $1.8\,\%$ . 41

The Perioperative Anticoagulation for Use in Surgery Evaluation (PAUSE) study was a pragmatic multicentre prospective management study of periprocedural management involving 3007 patients with AF taking apixaban, rivaroxaban or dabigatran, where a standard protocol of interruption and resumption was followed depending on the type of procedure (low or high bleeding risk) and renal function, designed to minimise the window with no anticoagulation and simplify protocols for ease of adherence. 42 The overall 30-day rate of arterial thromboembolism and major bleeding was $0.16\%-$ $0.6\% $ and $0.9\%{-1.85\%} $ for different DOACs respectively. 43

Practical summary for perioperative interruption of DOAC 43,45

For apixaban 5 mg twice daily and rivaroxaban 20 mg daily:

• Omit for 2 days before and the day of surgery for surgeries with a high risk of bleeding. • Omit for 1 day before and the day of surgery for surgeries with low to moderate risk of bleeding (GRADE 1B).

For apixaban 2.5 mg twice daily $(\mathrm{CrCl}\ge25\ \mathrm{mL}/\mathrm{min})$ and rivaroxaban $10~\mathrm{~mg~}$ daily $(\mathrm{CrCl~\ge15~\,~mL/min})$ , rivaroxaban 2.5 mg twice daily

• Omit 1 day before and the day of surgery (GRADE 1B).

For dabigatran

• For surgery with high bleeding risk ' Omit for 4 days and the day of surgery if CrCl is <50 mL/min ' Omit for 2 days and the day of surgery if CrCl is ≥ 50 mL/min (GRADE 1B) • For surgery with low to moderate bleeding risk ' Omit for 2 days and the day of surgery if CrCl is <50 mL/min ' Omit for 1 day and the day of surgery if CrCl is ${\ge}50$ mL/min (GRADE 1B)

Perioperative bridging with heparin is not indicated because of the short half-lives and rapid onset-offset of action of the DOACs

The measurement of FXaI-speci fi c anti-Xa levels prior to surgery is generally not necessary except in patients with chronic kidney disease (for FXaI, stage 4, CrCl 15 – 29 mL/min or less; for dabigatran Stage 3a, CrCl ≤ 45 – 59 mL/min (GRADE 1B)).

Surgery involving neuraxial anaesthesia in patients receiving DOACs

International guidelines and data from management studies recommend a 72-h interruption of FXaI prior to surgery or until the direct FXa drug level is ${<}30$ $\mathrm{{ng/mL^{43,44,46}}}$ (GRADE 1B). For dabigatran, 72 h was recommended in correlation with anticoagulant drug levels with renal impairment by European guidelines. 45 However, it is reasonable to follow the PAUSE recommended interval of 96 h for patients taking dabigatran with a CrCl of $30{-}50\ \ \mathrm{mL/min}$ , but levels should be considered in elderly patients, particularly if renal function is close to $30\,\mathrm{\mL/min}$ , ensuring a drug level of ${<}30~\mathrm{ng/mL^{43}}$ (GRADE 1B).

Resumption of DOAC after surgery

In all patients who have their therapeutic anticoagulation interrupted, pharmacological thromboprophylaxis should be prescribed when safe and continued until therapeutic oral anticoagulants are restarted.

• Therapeutic doses of apixaban, rivaroxaban and dabigatran can be resumed 48 – 72 h after surgery with high bleeding risk (GRADE 1B). For patients at continued high risk for bleeding, a prophylactic dose of anticoagulant (e.g. apixaban $2.5~\mathrm{mg}$ twice daily or rivaroxaban 10 mg daily, orally, or enoxaparin $40\;\mathrm{\mb{~meg}}$ subcutaneously daily) can continue until it is safe to resume therapeutic dosing.

• If patients are usually on the prophylactic dose of FXaI (e.g. apixaban $2.5\,\mathrm{\:m g}$ bd or rivaroxaban 10 mg daily), these can be resumed $^{12-24}\,\mathrm{~h~}$ after surgery in the absence of increased bleeding risk.

• LMWH as thromboprophylaxis can be used in patients with unpredictable oral drug absorption.

Conclusion

This is the fi rst evidence-based update on the management of patients receiving DOACs in a decade in Australia and New Zealand. We encourage following the recommendations to standardise practice. More evidence is needed to establish whether andexanet is associated with a net clinical outcome bene fi t in life-threatening bleeds, given the increased rate of thrombosis associated with its use.

Acknowledgements

The co-authors ’ contribution to this guideline is unfunded. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.

References

1 Barnes GD, Ageno W, Castellucci LA, Chiasakul T, Eslick R, Ferreiro JL et al . Recommendation on the nomenclature for anticoagulants: updated communication from the International Society on Thrombosis and Haemostasis Scienti fi c and Standardization Commitee on the Control of Anticoagulation. J Thromb Haemost 2023; 21 : 1381 – 4. 2 Keita I, Aubin-Auger I, Lalanne C, Aubert JP, Chassany O, Duracinsky M et al . Assessment of quality of life, satisfaction with anticoagulation therapy, and adherence to treatment in patients receiving long-course vitamin K antagonists or direct oral anticoagulants for venous thromboembolism. Patient Prefer Adherence 2017; 11 : 1625 – 34.

3 Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD et al . Comparison of the ef fi cacy and safety of new oral anticoagulants with warfarin in patients with atrial fi brillation: a meta-analysis of randomised trials. Lancet 2014; 383 : 955 – 62. 4 Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O et al . Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 : 1319 – 30. 5 van Es N, Coppens M, Schulman S, Middeldorp S, Buller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124 : 1968 – 75. 6 Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al .

Dabigatran versus warfarin in patients with atrial fi brillation. N Engl J Med 2009; 361 : 1139 – 51. 7 Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M et al . Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 : 699 – 708. 8 Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H et al . Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 : 1211 – 22. 9 Australian Medicines Handbook. Drug interactions search . [cited 2024 Sep 30]. Available from URL: https://amhonline. amh.net.au/ 10 Held C, Hylek EM, Alexander JH, Hanna M, Lopes RD, Wojdyla DM et al . Clinical outcomes and management

10

associated with major bleeding in patients with atrial fi brillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015; 36 : 1264 – 72. 11 Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13 : 2012 – 20. 12 Douketis JD, Berger PB, Dunn AS, Jaffer AK, Spyropoulos AC, Becker RC et al . The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133 : 299S – 339S. 13 National Health and Medical Research Council. Guidelines for Guidelines: Adopt, Adapt or Start from Scratch (Version 5.2) . Canberra: NHMRC; 2018 (cited 2024 July 15). Available from URL: https://www.nhmrc.gov.au/guidelines . 14 Schunemann HJ, Wiercioch W, Brozek J, Etxeandia-Ikobaltzeta I, Mustafa RA, Manja V et al . GRADE evidence to decision (EtD) frameworks for adoption, adaptation, and de novo development of trustworthy recommendations: GRADEADOLOPMENT. J Clin Epidemiol 2017; 81 : 101 – 10. 15 Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG et al . 2021 European heart rhythm association practical guide on the use of nonvitamin K antagonist Oral anticoagulants in patients with atrial fi brillation. Europace 2021; 23 : 1612 – 76. 16 January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr et al . 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/ American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74 : 104 – 32. 17 Marsch A, Macha K, Siedler G, Breuer L, Strasser EF, Engelhorn T et al . Direct Oral anticoagulant plasma levels for the Management of Acute Ischemic Stroke. Cerebrovasc Dis 2019; 48 : 17 – 25. 18 Albaladejo P, Bonhomme F, Blais N, Collet JP, Faraoni D, Fontana P et al . Management of direct oral anticoagulants in patients undergoing elective surgeries and invasive procedures: updated guidelines from the French working group on perioperative hemostasis (GIHP) - September 2015. Anaesth Crit Care Pain Med 2017; 36 : 73 – 6. 19 Renon F, Rago A, Liccardo B, D ’ Andrea A, Riegler L, Golino P et al . Direct Oral anticoagulants plasma levels measurement: clinical usefulness from trials and real-world data. Semin Thromb Hemost 2021; 47 : 150 – 60. 20 Doux fi ls J, Adcock DM, Bates SM, Favaloro EJ, Gouin-Thibault I, Guillermo C et al . 2021 update of the International Council for Standardization in Haematology recommendations for laboratory measurement of direct Oral anticoagulants. Thromb Haemost 2021; 121 : 1008 – 20. 21 Akpan IJ, Cuker A. Laboratory assessment of the direct oral anticoagulants: who can bene fi t? Kardiol Pol 2021; 79 : 622 – 30. 22 Jaffer IH, Chan N, Roberts R, Fredenburgh JC, Eikelboom JW, Weitz JI. Comparison of the ecarin chromogenic assay and diluted thrombin time for quanti fi cation of dabigatran concentrations. J Thromb Haemost 2017; 15 : 2377 – 87. 23 Baker RI, Gilmore G, Chen V, Young L, Merriman E, Curnow J et al . Direct oral anticoagulants or vitamin K antagonists in emergencies: comparison of management in an observational study. Res Pract Thromb Haemost 2023; 7 : 100196. 24 Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA et al . Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 : 431 – 41. 25 Kozek-Langenecker SA, Ahmed AB, Afshari A, Albaladejo P, Aldecoa C, Barauskas G et al . Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: fi rst update 2016. Eur J Anaesthesiol 2017; 34 : 332 – 95. 26 Tripodi A. To measure or not to measure direct oral anticoagulants before surgery or invasive procedures: reply. J Thromb Haemost 2016; 14 : 2559 – 61. 27 van Es N, De Caterina R, Weitz JI. Reversal agents for current and forthcoming direct oral anticoagulants. Eur Heart J 2023; 44 : 1795 – 806. 28 Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH et al . Full study report of andexan et al fa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380 : 1326 – 35. 29 Connolly SJ, Sharma M, Cohen AT, Demchuk AM, Czlonkowska A, Lindgren AG et al . Andexanet for factor Xa inhibitor-associated acute intracerebral hemorrhage. N Engl J Med 2024; 390 : 1745 – 55. 30 Andexxa. Step-by-step dosing and administration. [cited 2024 Sep 30]. Available from URL: https://www. andexxa.com/dosing-administration. html 31 Collaborators C-t. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 2019; 394 : 1713 – 23. 32 Collaborators H-IT. Effects of a highdose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebocontrolled trial. Lancet 2020; 395 : 1927 – 36. 33 Collaborators WT. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, doubleblind, placebo-controlled trial. Lancet 2017; 389 : 2105 – 16. 34 Ollier E, Hodin S, Lanoiselee J, Escal J, Accassat S, De Magalhaes E et al . Effect of activated charcoal on rivaroxaban complex absorption. Clin Pharmacokinet 2017; 56 : 793 – 801. 35 Majeed A, Agren A, Holmstrom M, Bruzelius M, Chaireti R, Odeberg J et al . Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017; 130 : 1706 – 12. 36 Schulman S, Gross PL, Ritchie B, Nahirniak S, Lin Y, Lieberman L et al . Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost 2018; 118 : 842 – 51. 37 Chiasakul T, Crowther M, Cuker A. Four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fi xed versus variable dosing. Res Pract Thromb Haemost 2023; 7 : 100107. 38 Hunt AR, Coffeen SN, Shiltz DL, Ice C, Parker J. Factor VIII inhibitor bypassing activity (FEIBA) reversal for apixaban and rivaroxaban in patients with acute intracranial and nonintracranial hemorrhage. Ann Pharmacother 2021; 55 : 1455 – 66. 39 Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363 : 1791 – 800. 40 Grainger BT, McFadyen JD, Tran H. Between a rock and a hard place: resumption of oral anticoagulant therapy after intracranial hemorrhage. J Thromb Haemost 2023; 22 : 594 – 603. 41 Shaw JR, Wood fi ne JD, Douketis J, Schulman S, Carrier M. Perioperative interruption of direct oral anticoagulants in patients with atrial fi brillation: a systematic review and meta-analysis. Res Pract Thromb Haemost 2018; 2 : 282 – 90. 42 Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ et al . Perioperative management of patients with atrial fi brillation receiving a direct oral anticoagulant. JAMA Intern Med 2019; 179 : 1469 – 78. 43 Douketis JD, Gross M, Schulman, S P. PAUSE-2 randomized pilot trial to compare two strategies (PAUSE vs. ASRA) for perioperative DOAC management. Res Pract Thromb Haemost 2022; 6 : e12787. 44 Douketis JD, Spyropoulos AC, Murad MH, Arcelus JI, Dager WE, Dunn AS et al . Executive summary: perioperative management of antithrombotic therapy: an American College of Chest Physicians Clinical Practice Guideline. Chest 2022; 162 : 1127 – 39. 45 Kietaibl S, Ferrandis R, Godier A, Llau J, Lobo C, Macfarlane AJ et al . Regional anaesthesia in patients on antithrombotic drugs: joint ESAIC/ ESRA guidelines. Eur J Anaesthesiol 2022; 39 : 100 – 32.

Supporting Information

Additional supporting information may be found in the online version of this article at the publisher ’ s web-site:

Appendix S1. Method of guidelines for DOACs development.

10