Direct Oral Anticoagulants (DOACs)


 

Apixaban, Dabigatran, Edoxaban, Rivaroxaban

 

NB: Due to the complexity of DOAC management in the perioperative period and recent publication of new evidence, this monograph is under continual review and will be updated accordingly


  Issues for Surgery


Risk of venous thromboembolism if omitted.

Risk of cerebrovascular event (CVA) if omitted.

Risk of bleeding and / or complications of bleeding if continued.


  Advice in the Perioperative period


Elective Surgery / Procedures

Perioperative DOAC decision-making should take into account the patient’s underlying thrombotic risk balanced against the bleeding risk associated with the surgery / procedure – see Anticoagulants (Oral) – A General Overview.

Assessment of Renal Function
Dosing of DOACs can be based on a number of factors, which includes renal function. It would be prudent to confirm that the patient is on the appropriate dose of DOAC. See current product literature or seek specialist advice if necessary.

DOACs have stable pharmacokinetics and a predictable elimination half-life. If the decision is made to interrupt DOAC therapy, the patient’s current renal function should be used to guide when to stop DOAC therapy.

The Cockcroft-Gault creatinine clearance (also see calculation below) should be used to accurately calculate renal function. The eGFR may overestimate renal function, particularly in elderly or underweight patients and must not be used.

Use of DOAC therapy is contra-indicated if creatinine clearance (CrCl) < 15 ml/min (< 30ml/min for dabigatran) and any patient found to have a CrCl that contra-indicates the use of the DOAC should be immediately referred to a Haematologist. If there is any doubt as to the safe management of DOAC therapy in patients with reduced renal function (particularly CrCl < 30 ml/min), the advice of a Haematologist should be sought.

Minor Bleeding Risk Surgery / Procedures
Minor bleeding risk procedures can often be undertaken safely without DOAC interruption. A pragmatic approach would be to conduct the intervention 18–24 h after the last DOAC intake1 (i.e. omit any DOAC doses due on the morning of procedure).

For examples of minor bleeding risk surgery / procedures – see Anticoagulants (Oral)– A General Overview.

General Surgical Procedures (High / Low Risk Bleeding)
For examples of low and high risk bleeding general surgical procedures see Anticoagulants (Oral) - A General Overview.

Follow the advice in figure 1 below.

Figure 1: Number of doses of DOAC to be omitted prior to general surgical procedures2

* Low dose Rivaroxaban (2.5mg Twice Daily) is licensed for use in conjunction with aspirin +/- clopidogrel3. Refer to individual monographs for the perioperative management of aspirin and clopidogrel and discuss arterial thrombotic risk with a cardiologist or vascular surgeon (depending on indication for therapy). Pre-operative cessation of low-dose rivaroxaban has not been studied and patients should be managed on a case-by-case basis.

Endoscopy / Interventional Procedures
For examples of low and high bleeding risk endoscopy / interventional procedures – see Anticoagulants (Oral) – A General Overview.

Low risk bleeding procedures4: -

  • Omit DOAC dose on the morning of surgery if due
  • Doses due the evening prior to procedure can be taken as usual

High-risk bleeding procedures – follow the advice in figure 2 below.

Figure 2: Number of doses of DOAC to be omitted prior to endoscopy4 / interventional procedures** 

* Low dose Rivaroxaban (2.5mg Twice Daily) is licensed for use in conjunction with aspirin +/- clopidogrel3. Refer to individual monographs for the perioperative management of aspirin and clopidogrel and discuss arterial thrombotic risk with a cardiologist or vascular surgeon (depending on indication for therapy). Pre-operative cessation of low-dose rivaroxaban has not been studied and patients should be managed on a case-by-case basis.

** The advice given above is taken from the advice for endoscopy procedures but it seems pragmatic to extrapolate to other interventional procedures (e.g. bronchoscopy).

Bridging Therapy
Bridging with therapeutic dose low molecular weight heparin (LMWH) is not required for patients on a DOAC – see Anticoagulants (Oral) – A General Overview.

Prophylactic dose LMWH may be considered in the post-operative period prior to DOAC resumption (see under Post-operative Advice below).

Emergency Surgery / Procedures

If there is not sufficient time to follow the guidance for elective surgery / procedures as above:

  • The procedure should be delayed for 12 – 24 hours, if possible, to allow plasma levels of the drug to fall1, 5.
  • Establishing therapeutic effect: -
    • for dabigatran – a normal thrombin time excludes the presence of therapeutic effect.
    • for apixaban, edoxaban and rivaroxaban – the INR, APTT and thrombin time cannot be used to immediately exclude therapeutic effect and should not be used for decision-making.
    • if DOAC levels are rapidly available and < 30 ng/ml, no reversal is required6.
  • If the procedure cannot be delayed the risk of bleeding should be weighed against the urgency of the intervention1, 7.
  • Use of a specific reversal agent should be considered (see Prohaemostatic Agents below)1.
  • If an anticoagulant effect cannot be excluded neuraxial anaesthesia should be avoided1.
  • Discussion with a Haematologist should take place to review the measures that can be taken to control bleeding prior to and during urgent surgery.

Prohaemostatic Agents

  • Tranexamic acid is a safe and effective adjunct and should be considered for all patients on a DOAC prior to and following emergency surgery1. It can be administered intravenously (IV) or orally (PO) (usual dose 1g three times a day).
  • Idarucizumab (Praxbind®) is licensed for rapid reversal of dabigatran in emergency surgery, urgent procedures and life threatening / uncontrolled bleeding8. A second dose may be required at 24 hours after the initial dose, particularly in patients with CrCl < 50ml/min (see current product literature)8. A Haematologist should be contacted to discuss patients who have a prolonged thrombin time and / or abnormal post-operative bleeding at 24 hours following the initial dose.
  • Prothrombin Complex Concentrate (PCC) can be considered for the reversal of apixaban, edoxaban or rivaroxaban in life-threatening or uncontrolled bleeding or prior to emergency surgery [unlicensed use]. Consultant Haematologist advice must be sought to approve use of PCC.
  • Andexanet alfa has recently been licensed in the UK for reversal of apixaban or rivaroxaban in life-threatening or uncontrolled bleeding. It has not been investigated when direct oral factor Xa inhibitors are administered before surgery or other invasive procedures; hence it is not currently licensed for this indication9. The current expected publication of NICE guidance on this agent is June 202010.


Perioperative Considerations

Neuraxial (Spinal / Epidural) Anaesthesia or Lumbar Punctures
In patients treated with DOACs who require neuraxial anaesthesia or lumbar puncture, there is a risk of developing an epidural or spinal haematoma that can result in long-term paralysis. The risk may be increased by post-operative use of indwelling epidural catheters or concomitant use of medications affecting haemostasis7, 11, 12.

Continuation of DOACs in patients who receive neuraxial anaesthesia is not recommended due to the risk of spinal haematoma13.

Indwelling Catheter Removal Advice
The following advice is taken from The Association of Anaesthetists of Great Britain and Ireland guidance on Regional Anaesthesia13 (NB: advice for edoxaban has been extrapolated from rivaroxaban since they have similar pharmacokinetic profiles).

Figure 3: Advice on timings of DOAC doses in relation to removal of an indwelling catheter13.

*It is recommended that in the event of traumatic puncture, the administration of rivaroxaban should be delayed for 24 hours3. Although not recommended by other DOAC manufacturers, consideration should be given to delaying administration of all DOACs by 24 hours in the event of traumatic puncture.

Post-operative Advice

NB: All DOACs are rapidly absorbed and have a rapid onset of action, with peak anticoagulant activity at approximately 2-3 hours after oral ingestion. Attention to post-operative haemostasis is clinically important since too early resumption of DOACs, especially within 24 hours of surgery, is associated with a two- to fourfold increased risk of major bleeding5.

Minor / Low Risk Procedures
Recommence 6 – 12 hours post-procedure if haemostasis has been fully secured5.

High Risk Procedures / Increased Bleeding Risk
Do not recommence at full-dose until at least 48 hours post-procedure5.

Consider prophylactic LMWH, commenced 6-12 hours post-op based on patient’s thromboembolic risk and bleeding risk.

LMWH should be discontinued immediately upon recommencing DOAC.

Patients Who Have Received Idarucizumab
Re-initiate DOAC a minimum of 24 hours (48 hours for high risk procedures / increased bleeding risk) after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved1, 8.

If necessary, alternative antithrombotic therapy (e.g. LMWH) can be started at any time, if the patient is clinically stable and adequate haemostasis has been achieved8. Alternative antithrombotic therapy should be immediately discontinued upon recommencing dabigatran.

Patients Who Have Received Andexanet Alfa
Re-initiate DOAC as soon as medically indicated if the patient is clinically stable and adequate haemostasis has been achieved14.


  Interaction(s) with Common Anaesthetic Agents

 

None relevant7, 11, 12, 15, 16, 17.


  Interaction(s) with other Common Medicines used in the Perioperative Period

 

Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

DOACs are predicted to increase the risk of bleeding when given with NSAIDs. Short-term post-operative use may be considered although caution is advised7, 11, 12, 15, 16, 17. Consider appropriate use of a gastroprotective agent (e.g. proton pump inhibitor).

Low Molecular Weight Heparin (LWMH) / Unfractionated Heparin (UFH)

DOACs and LMWH / UFH can increase the risk of bleeding15. Concomitant use is contraindicated unless under specific circumstances and advised by a specialist7, 11, 12, 16. Prophylactic LMWH should be discontinued immediately upon recommencing DOAC.

Antimicrobials

Erythromycin (via CYP3A4 and P-gp inhibition) increases the exposure to edoxaban – the manufacturer advises a reduction in the edoxaban dose (see current product literature)16, 17. Clarithromycin may increase the exposure to edoxaban. Consideration may be given to reducing the dose of edoxaban, although the manufacturer makes no specific recommendation17.

Erythromycin and clarithromycin may increase the exposure to apixaban and dabigatran7, 11, 17. The patient should be monitored for excessive bleeding if either erythromycin or clarithromycin are co-administered with a DOAC17.

It is recommended to monitor the patient for signs of excessive bleeding if co-administration of erythromycin or clarithromycin with a DOAC is necessary17.

Whilst single surgical prophylactic doses should not pose a problem for most antimicrobials, continued post-operative treatment may require close monitoring. Consult current product literature.


  Further Information


Rationale for Perioperative Advice

The Perioperative Management of Patients with Atrial Fibrillation receiving a Direct Oral Anticoagulant Evaluation (PAUSE), published in August 2019, supports the use of a standardised perioperative DOAC management protocol, without LWMH bridging or measurement of coagulation function. The study findings show that this approach was associated with low rates of major bleeding and arterial thromboembolism2.

Information for Patients

All patients (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 DOAC1. For an example patient information leaflet please click here.


  References


  1. Steffel J, Verhamme P, Potpara TS et al. European Society of Cardiology. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. European Heart Journal. 2018; 39:1330-1393
  2. Douketis JD, Spyropoulios AC, Carrier M et al. Perioperative Management of Patients with Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Internal Medicine. 2019. Available at www.jamanetwork.com [Accessed 31st October 2019]
  3. Summary of Product Characteristics – Xarelto® (rivaroxaban) 2.5 mg film-coated tablets. Bayer plc. Accessed via www.medicines.org.uk 20/06/2019 [date of revision of the text August 2018]
  4. Veitch, A Vanbiervliet G, Gershlick A et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Gut. 2016; 65:374-389
  5. 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; 175:602-612
  6. Levy JH, Ageno W, Chan NC et al. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost. 2016; 14(3):623-7
  7. Summary of Product Characteristics – Eliquis® (apixaban) 2.5mg film-coated tablets. Bristol-Myers Squibb-Pfizer. Accessed via www.medicines.org.uk 16/06/2019 [date of revision of the text June 2019]
  8. Summary of Product Characteristics – Praxbind® (idarucizumab) 2.5 g/50 mL solution for injection/infusion. Boehringer Ingelheim Limited. Accessed via www.medicines.org.uk 16/06/2019 [date of revision of the text August 2018]
  9. European Medicines Agency. Media and Public Relations. Press Release: First antidote for reversal of anticoagulation with factor Xa inhibitors apixaban and rivaroxaban. 01/03/2019. www.ema.europa.eu [Accessed 21/06/2019]
  10. National Institute for Health and Care Excellence (NICE): Andexanet alfa for reversing anticoagulation [ID1101]. In Development [GD-TA10440]. Available at www.nice.org.uk [Accessed 2/11/19]
  11. Summary of Product Characteristics – Pradaxa® (dabigatran) 110mg hard capsules. Boehringer Ingelheim Limited. Accessed via www.medicines.org.uk 16/06/2019 [date of revision of the text May 2019]
  12. Summary of Product Characteristics – Xarelto® (rivaroxaban) 15mg film-coated tablets. Bayer plc. Accessed via www.medicines.org.uk 16/06/2019 [date of revision of the text August 2018]
  13. The Association of Anaesthetists of Great Britain & Ireland, The Obstetric Anaesthetists’ Association and Regional Anaesthesia UK. Regional Anaesthesia and Patients with Abnormalities of Coagulation. Anaesthesia. 2013; 68:966 – 72
  14. Summary of Product Characteristics – Ondexxya® (andexanet alfa) 200 mg powder for solution for infusion. Portola Pharmaceuticals Inc. Accessed via www.ondexxya.eu 03/11/2019 [date of revision of the text April 2019]
  15. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 16th June 2019]
  16. Summary of Product Characteristics – Lixiana® (edoxaban) 60mg Film-Coated Tablets. Daiichi Sankyo UK Limited. Accessed via www.medicines.org.uk 30/10/2019 [date of revision of the text August 2018]
  17. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 9th September 2019]