Warfarin and Direct Oral Anticoagulants (DOACs) in Adult Patients Undergoing Surgery or Invasive Procedures

The decision about whether to continue or interrupt anticoagulation depends on the risk of bleeding associated with the planned procedure, and the patient’s underlying thrombotic risk.  See Figure 1.

^* Additional risk factors in bileaflet mechanical aortic valve: AF, prior stroke or TIA, hypertension, diabetes mellitus, heart failure or left ventricular dysfunction, age >75 years. Consider bridging in these patients depending on the bleeding risk; refer to consultant anaesthetist/surgeon.

^**Low risk thrombophilia: Heterozygous Factor V Leiden or prothrombin gene mutation.

^**** High risk thrombophilia: Protein C or S deficiency, antithrombin deficiency, antiphospholipid syndrome, homozygous Factor V Leiden or homozygous prothrombin gene mutation, or combinations.

Atrial Fibrillation (AF)

Clinical trials have shown that bridging for AF does not reduce the risk of ischaemic/embolic events and increases bleeding.  It is therefore recommended that AF is not bridged peri-operatively. 

• If patients present to pre-assessment on warfarin for AF (without mitral stenosis), they should be referred back to their GP for consideration of switching to a DOAC pre-operatively, if there is sufficient time before surgery. DOACs are associated with a reduced bleeding risk and a briefer interruption of therapy peri-operatively will be required.
• Warfarin has a half-life of 36 hours and should be stopped 5 days pre-operatively.
• The INR should be checked on the day before surgery. If INR ≥5 administration of 1 to 2mg of oral vitamin K (Konakion MM Paediatric®) should be considered, bearing in mind it may take longer for the INR to return to therapeutic range because of the ongoing effects of Vitamin K.  Inform Consultant Anaesthetist and Surgeon.
• Patients with impaired renal function should ideally have their creatinine clearance calculated using the Cockcroft-Gault equation and using ideal body weight (see online calculator).

• Refer to Appendix 2 for guidance on management of patients requiring neuroaxial anaesthesia, to minimise the risk of spinal haematoma associated with anticoagulation.
• The recommended doses of enoxaparin to be used for prophylaxis and bridging therapy (i.e. therapeutic dose) are outlined below in Table 1.

Table 1: Recommended enoxaparin doses for prophylaxis and treatment, including renal impairment and extremes of body weight

• There are three different schedules for stopping warfarin and bridging with enoxaparin peri-operatively, depending on indication for warfarin (thrombosis risk) and renal function. Please refer to the appropriate schedule below.
• For patients on warfarin not requiring bridging, warfarin should be stopped 5 days pre-op and be given prophylactic enoxaparin post-op until warfarin resumed and INR therapeutic. INR should be checked within 1 week of resuming warfarin therapy, to ensure it is back in therapeutic range.

Bridging Schedule 1: Adult patients on warfarin requiring bridging for any indication excluding mechanical heart valves with normal renal function [CrCl≥30ml/min]

Bridging Schedule 2: Adult patients on warfarin for a mechanical heart valve or bileaflet mechanical aortic valve with additional risk factors with normal renal function [CrCl≥30ml/min]

Bridging Schedule 3: Adult patients on warfarin for any indication with impaired renal function [CrCl<30ml/min^*]

^*If creatinine clearance is less than 15ml/min please discuss with haematology or renal consultant.

Anti-factor Xa levels should be monitored in patients with renal impairment who receive LMWH for 3 or more days.  Use a citrate (green) tube and take samples 4 hours post injection.

Therapeutic range: 1.0 to 2.0 IU/ml (24 hourly injections).  Prophylactic range: 0.1 to 0.4 IU/ml.

• Resume normal warfarin and treatment enoxaparin dose post-operatively according to the schedules above, in general:
  • Low bleeding risk - wait 24 hours
  • High bleeding risk and after major surgery - wait at least 48 hours

• In some circumstances, e.g. where it is likely that a patient may return to the operating theatre, it may be necessary to withhold restarting enoxaparin and usual warfarin for longer than outlined in the schedule. Cardiology must be informed if the patient has a mechanical valve so that a heparin infusion can be considered. Haematology must be consulted if the patient is considered high risk as per Figure 1 above (VTE within 3 months, prior recurrent VTE with target INR of 3.5 or high risk thrombophilia).
• Treatment enoxaparin must be continued as per schedules above until the INR is therapeutic for patients who require bridging therapy. In patients who remain nil-by-mouth for a prolonged period post-operatively, it will be necessary to continue treatment enoxaparin until oral anticoagulation can be re-established.
• In patients with AF and no additional risk factors who were not switched to a DOAC pre-operatively, consideration should be made to switch to a DOAC post-operatively to reduce long-term bleeding risk and achieve prompt therapeutic anticoagulation sooner. Patients discharged on warfarin for AF should be referred back to their GP for this to be reviewed in the community, if not reviewed in hospital.
• For patients undergoing surgery with a very high bleeding risk, a heparin infusion can be considered, however managing heparin infusions is labour-intensive and requires frequent blood tests and a continuous intravenous infusion. Ensure nurses are familiar with heparin infusions and staffing levels are adequate before prescribing.  A high dependency area may be more suitable for nursing patients requiring a heparin infusion peri-operatively. Heparin charts are available on wards.
• In patients who were not bridged but where usual warfarin cannot be resumed within 48 to 72 hours post-operatively (e.g. prolonged ileus), treatment dose enoxaparin should be considered (see Table 1 for dosing) in patients with a high thromboembolic risk, if bleeding risk acceptable. However the majority of warfarin patients with high thromboembolic risk should have received peri-operative bridging therapy.

• Anticoagulation Warfarin guidance on TAM
• Check INR; if ≥5 give 5mg vitamin K by slow intravenous injection. It takes 6 to 8 hours for onset of effect, and 24 hours for the full effect to be seen.
• If there is insufficient time, reverse with Prothrombin Complex Concentrate (PCC, Beriplex®), 25 to 50 units/kg (see Table 2). Approval must be obtained from a Consultant Haematologist.  Syringe pumps for Beriplex administration are situated in A&E and ICU in Raigmore (standard syringe pumps will not permit the required rate in ml/hour to be administered).  Further advice on Beriplex reconstitution and administration is available here: http://intranet.nhsh.scot.nhs.uk/Org/DHS/SSU/MedicalDir/EmergencyDepartmentNEW/MASTER%20LIBRARY/02%20Emergency%20drugs%20sedation%20anaesthesia%20Guidance/Anticoagulant%20Reversal%20in%20ED.pdf#search=beriplex.

Table 2: Beriplex® (PCC) dosing                                     

• Recheck INR and give further Beriplex (PCC) if needed. The maximum single dose is 5000 units.
• Correction of the INR persists for approximately 6 to 8 hours with PCC. Simultaneous administration of vitamin K with PCC should mean that repeated administration is not required.
• Post-operatively, patients can be managed in the same way as elective patients (see tables above), bearing in mind it may take longer for the INR to return to therapeutic range because of the ongoing effects of Vitamin K
• If patients with a metal valve do not commence treatment dose LMWH by 48 hours post-op due to high bleeding risk, surgical complications etc., this must be discussed with a cardiologist as a heparin infusion may be required.

Pre-operative management of patients on DOACs

• DOACs have an almost immediate onset of action (peak levels are achieved within 2 to 4 hours of a dose) and they do not usually require any routine monitoring.
• The last dose of DOAC should be timed to achieve normal coagulation status by the time of surgery. See table 3. The timing of the last dose depends on the patient’s renal function, the half-life of the DOAC and the risk of bleeding associated with the surgery or procedure. DOACs do not require pre-operative bridging with treatment doses of LMWH.
• Patients with impaired renal function should ideally have their creatinine clearance calculated using the Cockcroft-Gault equation and using ideal body weight (see online calculator).

Dabigatran

• Dabigatran is a direct thrombin inhibitor with a half-life of 13 hours in normal renal function.
• A normal APTT excludes excess levels of dabigatran but there may still be anticoagulant activity

Rivaroxaban, Apixaban and Edoxaban

• Rivaroxaban, apixaban and edoxaban are direct Factor Xa inhibitors.
• In normal renal function, the rivaroxaban half-life is 5 to 9 hours; apixaban is 12 hours and edoxaban is 10 to 14 hours.
• Anti-Xa assay specific to these drugs is unavailable in NHS Highland at present.
• A normal coagulation screen does not exclude the presence of significant concentrations of the circulating drug.

Low-dose rivaroxaban

• Rivaroxaban 2.5mg in combination with aspirin is licensed for the prophylaxis of atherothrombotic events in patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events.
• Pre-operative cessation of low-dose rivaroxaban has not been studied.  Stop low-dose rivaroxaban pre-surgery as per table 3.  Bridging is not required; restart when bleeding risk is acceptable. 

Management of DOACs peri-operatively

^* Prophylactic doses of enoxaparin can be considered in the post-operative period until normal DOAC is resumed.  Should surgery be delayed for any reason, commence prophylactic enoxaparin from the evening of the planned day of surgery until surgery has taken place and DOAC is resumed.  If surgery to be rescheduled for a later date, resume DOAC and follow advice above prior to rescheduled procedure.

⁺ For patients undergoing a minor procedure with a low bleeding risk (see Appendix 1), the DOAC may be able to be restarted 6 to 12 hours after the procedure.  Seek physician’s advice.

Post-operative management of patients admitted on DOACs

• For patients undergoing surgery with a high bleeding risk or where even minimal blood loss is unacceptable, the DOAC should be restarted 48 hours post-operatively or when the bleeding risk is acceptable.
• If DOACs cannot be resumed within 48 to 72 hours post-operatively (e.g. prolonged ileus), treatment dose enoxaparin should be considered (see table 1 for dosing) in patients with a high thromboembolic risk, if bleeding risk acceptable.

Peri-operative management of patients on DOACs undergoing emergency surgery

• Management of Major Haemorrhage and Emergency Invasive Procedures in Patients on Direct Oral Anticoagulants (Dabigatran, Apixaban, Edoxaban and Rivaroxaban): http://intranet.nhsh.scot.nhs.uk/Org/DHS/SSU/MedicalDir/EmergencyDepartmentNEW/MASTER%20LIBRARY/02%20Emergency%20drugs%20sedation%20anaesthesia%20Guidance/Anticoagulant%20Reversal%20in%20ED.pdf#search=beriplex.
• 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 indication.  However it may be considered off-licence for edoxaban after careful discussion with consultant haematologist.

It is advisable to avoid epidural analgesia in patients requiring bridging anticoagulation, particularly in patients with renal impairment.

AF – atrial fibrillation

APTT – activated partial thromboplastin time

CrCl – creatinine clearance

CVA – cerebrovascular accident

DOAC – direct oral anticoagulant

DVT – deep vein thrombosis

GFR – glomerular filtration rate

INR – international normalised ratio

IU – international units

PCC – prothrombin complex concentrate

PE – pulmonary embolism

PTT – partial thromboplastin time

TIA – transient ischaemic attack

VTE – venous thromboembolism

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