Issues for surgery
For prevention or treatment of venous thromboembolism (VTE) - risk of VTE if omitted.
For prevention of stroke - risk of arterial embolism (e.g. cerebrovascular event, CVA) if omitted.
Risk of bleeding and / or complications of bleeding if continued.
Risk of epidural or spinal haematoma if continued prior to neuraxial anaesthesia.
Advice in the perioperative period
Elective surgery
Step 1 – determine indication, dose and frequency of administration
Confirm the dose, timing, and frequency of administration with patient / carer (this will affect pre-operative cessation advice).
For deep vein thrombosis (DVT) or pulmonary embolism (PE) within last 3 months – refer to Haematologist to determine appropriate course of action.
Step 2 – determine if dose appropriate for patient
The guidance below assumes that the patient is on an appropriate dose of edoxaban in relation to the indication, their renal function, age, weight, and concomitant interacting medication – see current product literature to establish that the patient is on the appropriate dose.
When estimating renal function use Cockcroft-Gault (C&G) creatinine clearance (CrCl) rather than estimated glomerular filtration rate (GFR), to avoid overestimating renal function, particularly in the elderly or at extremes of body weight. It is recommended to use actual weight rather than ideal body weight.
Edoxaban is not recommended if CrCl less than 15ml/min – such patients should be immediately referred to a Haematologist.
If there is any doubt as to whether the patient is on an appropriate dose, or if there is concern regarding patient specific factors such as CrCl < 30ml/min, weight < 50kg, concomitant use of interacting medication etc., advice should be sought from a Haematologist.
Step 3 – determine bleeding risk for surgery / procedure
For examples of minor, low / moderate and high bleeding risk surgical procedures and low and high-risk endoscopic procedures see Anticoagulants - Overview.
Step 4 – decision on pre-operative cessation
Minor bleeding risk surgery / procedure (not endoscopic)
Most minor bleeding risk procedures and those procedures where any bleeding is easily controllable, can be undertaken safely without edoxaban interruption (where possible time the procedure for 12 hours after the last dose).
Low bleeding risk endoscopic procedure
| Time of administration | Day -2 | Day -1 | Day of procedure | Total number of doses omitted |
|---|---|---|---|---|
| Once daily in the MORNING | Continue | Continue | Omit MORNING dose | ONE dose |
| Once daily in the EVENING | Continue | Evening dose taken by 8pm | N/A | None |
Low / moderate bleeding risk surgery / procedure (not endoscopic)
| Time of administration | Day -2 | Day -1 | Day of surgery / procedure | Total number of doses omitted |
|---|---|---|---|---|
| Once daily in the MORNING | Continue | Omit dose | Omit dose | TWO doses |
| Once daily in the EVENING | Continue | Omit dose | N/A | ONE dose |
High bleeding risk surgery (including cardiac surgery) / procedure (including endoscopic procedure) / patient to receive neuraxial anaesthesia
| Time of administration | Day -3 | Day -2 | Day -1 | Day of surgery / procedure | Total number of doses omitted |
|---|---|---|---|---|---|
| Once daily in the MORNING | Continue | Omit dose | Omit dose | Omit dose | THREE doses |
| Once daily in the EVENING | Continue | Omit dose | Omit dose | N/A | TWO doses |
Bridging therapy
Bridging with therapeutic dose low molecular weight heparin (LMWH) pre-procedure is not required for patients on edoxaban; see Anticoagulants – Overview.
Emergency surgery / procedure
Determine urgency of surgery / procedure.
For acute emergency procedures (which need to occur immediately)
Discontinue edoxaban.
Contact Haematologist to discuss:
- use of prohaemostatic agents (see below) - note there is no specific reversal agent for edoxaban
- appropriateness of coagulation studies, anti-Xa levels and where available edoxaban levels – note a normal PT or aPTT does not exclude an anticoagulant effect
For urgent procedures (which need to occur within hours)
Discontinue edoxaban.
Delay procedure, if possible, for 24 hours (and at least 12 hours) after last dose of edoxaban to allow plasma levels to fall.
If the procedure cannot be delayed the risk of bleeding should be weighed against the urgency of the intervention.
If an anticoagulant effect cannot be excluded neuraxial interventions should be avoided.
Expedited procedures (which need to occur within a few days)
Discontinue edoxaban.
Follow advice under Elective surgery.
Prohaemostatic agents
The use of prohaemostatic agents might reduce the risk of peri-surgical bleeding in patients on edoxaban who require emergency surgery. Discussion with a Haematologist should take place to review the measures that can be taken to control bleeding prior to and during urgent surgery.
The following agents may be considered: -
- Tranexamic acid is likely to reduce bleeding and should be considered for all patients on a DOAC prior to emergency surgery. It can be administered intravenously (IV) or orally (PO) (usual dose 1g three times a day)
- Prothrombin Complex Concentrate (PCC) can be considered, despite the lack of evidence for efficacy and safety, although routine use is not recommended. The usual view of clinicians is that PCC might improve outcomes, but this does not take into consideration the potential for adverse thrombotic events. A pragmatic approach might be to proceed with surgery, considering PCC in the event of diffuse coagulopathic bleeding. Consultant Haematologist advice must be sought before use of PCC.
Perioperative considerations
Neuraxial (spinal / epidural) interventions or lumbar punctures
Experience is limited with the use of edoxaban around neuraxial interventions and an acceptable level of residual edoxaban activity to proceed with neuraxial anaesthesia is undetermined; hence, there is a risk of developing an epidural or spinal haematoma that can result in long-term paralysis.
Risk factors include use of post-operative indwelling epidural catheters (vs ‘single-shot’ techniques), concomitant use of medications affecting haemostasis and traumatic or repeated epidural / spinal puncture. Before performing neuraxial intervention see Further information.
Indwelling catheter removal advice
Continuation of edoxaban should be avoided in patients requiring neuraxial interventions. Edoxaban should not be administered with an indwelling catheter in situ. If anticoagulation is required, prophylactic LMWH can be considered whilst a post-operative catheter is in situ.
The next dose of edoxaban should be administered at least 8 hours after neuraxial puncture or withdrawal of neuraxial catheter.
Post-operative advice
Attention to post-operative haemostasis is clinically important since too early resumption of edoxaban, especially within 24 hours of surgery, may be associated with increased risk of major bleeding. Edoxaban is rapidly absorbed and has a fast onset of action with peak anticoagulant activity at approximately 1 - 2 hours after the first dose.
For patients who have an indwelling catheter – see Indwelling catheter removal advice above.
Bleeding risk of surgery / procedure | Time to restart post surgery / procedure | Comments |
|---|---|---|
| Minor risk | 6 - 12 hours | With immediate and complete haemostasis |
| Low risk endoscopic | 6 - 12 hours | With immediate and complete haemostasis |
| Low / moderate risk (not endoscopic) | 24 hours | - |
High risk (including endoscopic) | 48 - 72 hours | Consider prophylactic LMWH starting 6 - 12 hours post-operatively until edoxaban can be safely restarted Treatment doses may be considered necessary depending on patient's thromboembolic risk. LMWH should be discontinued as soon as edoxaban can be restarted |
Patients undergoing cardiac surgery
Some cardiac surgery may warrant the use of post-operative unfractionated heparin (UFH). The UFH should be discontinued as soon as rivaroxaban can be restarted. However, re-initiation of edoxaban may not be appropriate following certain cardiac surgical procedures and advice should be sought from a Cardiologist / Haematologist as necessary.
Patients with reduced oral absorption post-operatively
For patients with a reduction in oral absorption post-operatively e.g. post-operative ileus, gastrointestinal (GI) surgery, nausea and vomiting; consider use of prophylactic LMWH starting 6 – 12 hours post-operatively until oral treatment can be safely resumed. Treatment doses may be necessary depending on the patient’s thromboembolic risk. The LMWH should be discontinued as soon as the edoxaban is restarted.
Patients undergoing bariatric surgery
Edoxaban is not recommended in the immediate post-operative period following bariatric surgery and patients should be commenced on low molecular weight heparin (as per local guidelines) for a period of at least 4 weeks. Advice should be sought from a Haematologist to ensure the most appropriate anticoagulant is used following bariatric surgery.
Interactions with common anaesthetic agents
None relevant.
Interactions with other common medicines used in the perioperative period
Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs are predicted to increase the risk of bleeding when given with edoxaban and are ideally avoided. If there is no suitable analgesic alternative and benefit outweighs risk, cautious use may be considered for the shortest time possible; consider use of a gastroprotective agent (e.g. proton pump inhibitor).
Low molecular weight heparin (LWMH) / unfractionated heparin (UFH)
The concurrent use of edoxaban with LMWH / UFH, increases the risk of bleeding and is contraindicated (unless under specific circumstances and as advised by a specialist). LMWH must be discontinued immediately upon recommencing edoxaban.
Antimicrobials
Erythromycin increases the exposure to edoxaban; dose reduction of edoxaban is recommended with concomitant use.
Clarithromycin may increase the exposure to edoxaban, especially with concurrent renal impairment.
Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring for excessive bleeding - consult current product literature.
Further information
Rationale for perioperative advice
The British Society for Haematology (BSH), the European Society of Cardiology (ESC) and the American College of Chest Physicians (ACCP) all support the standardised management of treatment dose DOAC in the majority of patients undergoing elective low or high bleeding risk procedures. This is based on the PAUSE study that utilised a standardised perioperative DOAC management protocol without routine pre-operative LWMH bridging. However, patients taking edoxaban were not included as it was not available for clinical use when the PAUSE study started, and the authors recommend that the results from the PAUSE study are not generalisable to edoxaban.
In 2023 a sub analysis of the EMIT-AF/VTE (edoxaban management in diagnostic and therapeutic procedures) was published. The study found that clinician-led decision on edoxaban interruption was associated with low rates of all bleeding, major bleeding, clinically relevant non-major bleeding, and thromboembolic events. The results from this sub analysis were comparable to the PAUSE study but without a standardised management protocol for edoxaban.
Individualisation of edoxaban cessation pre-operatively may still be required, however, based on individual patient characteristics. If there is any doubt as to the pre-operative cessation of DOAC therapy in a patient, due to specific patient characteristics i.e. CrCl < 30ml/min, weight < 50Kg, advanced age, concomitant interacting medication; it may be prudent to discuss with a Haematologist.
It should be noted that if edoxaban treatment is interrupted for > 72 hours the likelihood of any residual edoxaban level appears very low.
Neuraxial (spinal / epidural) anaesthesia or lumbar punctures
An acceptable level of residual edoxaban activity to proceed with neuraxial intervention remains undetermined. Suggested time intervals for neuraxial intervention after the last edoxaban administration depends on the half-life and patient’s renal function. There should be consideration of concomitant medicines that might increase plasma edoxaban levels, especially in the elderly or patients with concurrent renal impairment. Published guidelines suggest that the time interval between last edoxaban dose and neuraxial anaesthesia should be five half-lives for treatment doses. However, if there is any doubt to the safety of performing neuraxial anaesthesia the decision to proceed should involve a discussion between the anaesthetist and the patient, via a shared decision-making process, on the day of surgery.
Information for Patients / carers
All patients (or carers if applicable) should receive written information in relation to the anticipated date of their procedure, including the date and time of their last dose of edoxaban. The NUMBER of doses to omit pre-operatively should be communicated, not the number of days / hours, as this may lead to confusion about the appropriate time to stop.
References
Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com. Accessed on 14/01/2024
Bent C, Das R on behalf of the BSIR Safety and Quality Committee and Gomez K, Lester W on behalf of the BSH Haemostasis and Thrombosis Task Force. Joint guidance from the British Societies of Interventional Radiology and Haematology on manging Bleeding Risk during Procedures in Interventional Radiology (2023). Available from www.bsir.org. Accessed 14/01/24
Douketis JD, Spyropoulos AC, Duncan J et al. Perioperative Management of Patients with Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med 2019; 179(11): 1469 – 1478. DOI: 10.1001/jamainternmed.2019.2431
Douketis JD, Spyropoulos AC, Murad MH et al. Perioperative Management of Antithrombotic Therapy. An American College of Chest Physicians Clinical Practice Guideline. Chest 2022; https://doi.org/10.1016/j.chest.2022.07.025
Gosselin RC, Adock DM, Bates SM et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of Direct Oral Anticoagulants. Thromb. Haemost. 2018; 118: 437-450. DOI: 10.1055/s-0038-1627480
Horlocker TT, Vandermeulen E, Kopp SL et al. Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy. The American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Fourth Edition). Reg Anesth Pain Med. 2018; 43:263-309 DOI:10.1097/AAP.0000000000000763.
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 13th January 2024]
Keeling D, Campbell Tait R, Watson H et al on behalf of the British Committee for Standards in Haematology. Peri-operative management of anticoagulation and antiplatelet therapy. British Journal of Haematology. 2016; 175(4):602-613 DOI: 10.1111/bjh.14344
Kietaibl S, Ferrandis R, Godier A et al. Regional anaesthesia in patients on antithrombotic drugs Joint ESAIC/ESRA guidelines. Eur J Anaesthesiol 2022; 39:100–132 DOI: 10.1097/EJA.0000000000001600
Martin KA, Beyer-Westendorf J, Davidson BL et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost, 2021;19:1874 – 1882. DOI: 10.1111/jtg.15358
NHS North West Coast Strategic Clinical Networks. Consensus Statement on how to calculate the Creatinine Clearance (CrCl) which is necessary when assessing the Dose of Direct-Acting Oral Anticoagulants (DOACs). 2018. Available from consensus-statement-on-CrCl-calculation-for-DOACs-final.pdf (england.nhs.uk). Accessed 22/1/24
Saja, K. Addendum to the guideline on the peri-operative management of anti-coagulation and anti-platelet therapy. Haemostasis and Thrombosis Taskforce of the British Society for Haematology. Br J Haematol. 2022;197(2):188–189 DOI: 10.1111/bjh.18114
Sousa-Uva M, Head SJ, Milojevic M et al. 2017 EACTS Guidelines on perioperative medication in adult cardiac surgery. European Journal of Cardio-Thoracic Surgery 2018; 53: 5 – 33. DOI: 10.1093/ejcts/ezx314
Spyropoulos AC, Al-Badri A, Sherwood MW et al. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost 2016; 14(5): 875-85. DOI: 10.1111/jth.13305
Spyropoulos AC, Brohi K, Caprini J et al. Scientific and Standardization Committee Communication: Guidance document on the periprocedural management of patients on chronic oral anticoagulant therapy: Recommendations for standardized reporting of procedural / surgical bleed risk and patient-specific thromboembolic risk. J Thromb Haemost. 2019; 17: 1966-1972. DOI: 10.1111/jth.14598
Steffel J, Collins R, Antz M et al. European Society of Cardiology. 2021 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021; 23(10):1612-1676. DOI: 10.1093/europace/euab065
Steffel J, Collins R, Antz M et al. European Society of Cardiology. 2021 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Online supplement. Europace. 2021; 23(10):1612-1676. DOI: 10.1093/europace/euab065
Summary of Product Characteristics: Lixiana® (edoxaban tosilate) 30mg Film-Coated Tablets. Daiichi Sankyo UK Limited. Accessed via www.medicines.org.uk 13/01/2024 (date of revision of text July 2023)
Veitch A, Radaelli F, Alikhan R et al. Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update. Gut. 2021; 70:1611-1628. DOI:10.1136/gutjnl-2021-325184
Von Heymann C, Unverdorben M, Colonna P et al. Management of edoxaban therapy and clinical outcomes in patients undergoing major or nonmajor surgery: a subanalysis of the EMIT-AF/VTE study. Thrombosis Journal 2023; 21: 124. DOI: 10.1186/s12959-023-005468-2