MHRA advice (October 2020): Warfarin and other anticoagulants – monitoring of patients during the COVID-19 pandemic

There have been concerns over an apparent increase in the number of patients taking warfarin found to have elevated international normalised ratio (INR) values. Continued INR monitoring is important in patients taking warfarin or other vitamin K antagonists (VKA) if they have suspected or confirmed COVID-19 infection.

Some patients taking warfarin may have been switched to DOACs during the pandemic to avoid regular blood tests for INR monitoring.

Healthcare professionals are therefore reminded:

• that acute illness may exaggerate the effect of warfarin tablets and necessitate a dose reduction
• of the potential for drug-drug interactions between oral anticoagulants (i.e. VKA or DOACs) and certain antibiotics and antivirals and are advised to follow existing advice in product information
• that warfarin treatment should be stopped before DOACs are started.

Further information regarding the monitoring of patients taking warfarin and other anticoagulants (from the MHRA) during the Coronavirus (COVID-19) pandemic can be found here; including advice to give to patients.

NHS England: specific information regarding the management of anticoagulant services (from NHS England (NHSE) during the Coronavirus (COVID-19) pandemic. Please see here.

NICE COVID-19 rapid guideline: managing COVID-19 (NG191). This guideline includes pharmacological prophylaxis of venous thromboembolism (VTE) for patients with COVID-19 managed in hospital or in hospital-led acute care in the community (see here).

For women with COVID-19 who are pregnant or have given birth within the past 6 weeks, the recommendation is to follow the advice on VTE prevention in the Royal College of Obstetricians and Gynaecologists guidance on coronavirus (COVID-19) in pregnancy

NICE COVID-19 rapid guideline NG200: vaccine-induced thrombocytopenia and thrombosis (VITT) (29 July 2021). This is an evolving area, check the NICE website for the latest guidance. Treatment is on the recommendation of a specialist involving a clinical haematologist. Warfarin should be avoided in some circumstances. If treatment with a direct-acting oral anticoagulant is considered, see the guidance for advice on dabigatran and edoxaban. Please see here.

Coumarins and phenindione

Warfarin

• Tablets 1mg, 3mg, 5mg (and 500micrograms, see note 5 below)

Notes

1. See Anticoagulation Guidance for information on
   1. Indications
   2. Target INR
   3. Induction regimens
   4. Monitoring
   5. Adverse effects
2. The yellow NPSA Oral Anticoagulant Therapy information pack may be used to support patient education in patients prescribed warfarin.
3. Warfarin should be used in accordance with the requirements of the NPSA alert. The key points are:
   1. Patients should receive appropriate verbal and written information at the start of therapy and when necessary throughout the course of treatment. Supply each patient with an anticoagulation book and ensure they fully understand the contents.
   2. Before issuing a repeat prescription, check that the patient's INR is being monitored regularly, that it is at a safe level for the prescription to be issued and that the patient understands the dose.
   3. Warfarin has many clinically important drug interactions, see BNF for details. If a patient is co-prescribed a clinically important drug, make arrangements for additional INR blood tests.
   4. For warfarin regimens, ensure that:
      • The least number of tablets each day are used
      • Doses are expressed in mg and not number of tablets
      • NPSA recommend constant daily dosing and not alternate day dosing
      • Do not use tablets that need to be halved; use 0.5mg (white) tablets instead if necessary.
4. Warfarin dose should be taken at 6pm to obtain correct INR value with blood tests taken in the morning.
5. Potentially serious errors can occur if patients confuse the 500microgram and 5mg tablets. Prescribers should ensure that prescriptions are written clearly and patients are thoroughly counselled if they are given the 500microgram strength tablets.
6. For monitoring and adverse events please refer to anticoagulation prescribing guidance.

Phenindione

• Tablets 10mg, 25mg (£2,628.00 = 100mg daily)

Direct-acting oral anticoagulants (DOACs):

MHRA Drug Safety Update (October 2013, September 2016) New oral anticoagulants apixaban, dabigatran and rivaroxaban: risk of serious haemorrhage. See anticoagulation prescribing guidance for further prescribing information.

MHRA Drug Safety Update (June 2019): Direct-acting oral anticoagulants (DOACs): increased risk of recurrent thrombotic events in patients with antiphospholipid syndrome.

• direct-acting oral anticoagulants (DOACs) are not recommended in patients with antiphospholipid syndrome, particularly high-risk patients (those who test positive for all 3 antiphospholipid tests — lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2 glycoprotein I antibodies)
• review whether continued treatment with a DOAC is appropriate for patients diagnosed with antiphospholipid syndrome, particularly high-risk patients, and consider switching to a vitamin K antagonist such as warfarin

MHRA Drug Safety Update (October 2019): Using the appropriate estimate of renal function to avoid the risk of adverse drug reactions

MHRA Drug Safety Update (June 2020): Direct-acting oral anticoagulants (DOACs): reminder of bleeding risk, including availability of reversal agents

MHRA Drug Safety Update (May 2023): Direct-acting oral anticoagulants (DOACs): paediatric formulations; reminder of dose adjustments in patients with renal impairment

National Patient Safety Alert (14 July 2021): Inappropriate anticoagulation of patients with a mechanical heart valve: All patients with prosthetic mechanical heart valves require life-long oral anticoagulation with a vitamin K antagonist (VKA), usually warfarin, and should not be switched to an alternative anticoagulant (e.g. low molecular weight heparin or DOAC)

NHS England: Management of anticoagulant services during the Coronavirus (COVID-19) pandemic: page 4 includes patient groups who should not be considered for switching from warfarin to DOACs

NHS England National Procurement of DOACs:

Commissioning recommendations for national procurement for DOACs (January 2024):

For patients commencing treatment for AF: subject to the criteria specified in the relevant NICE technology appraisal guidance, clinicians should use the best value DOAC that is clinically appropriate for the patient.

If the highest ranked best value DOAC (generic apixaban, twice a day treatment) is contraindicated or not clinically appropriate for the specific patient then, subject to the criteria specified in the relevant NICE technology appraisal guidance, clinicians should then consider edoxaban where this is clinically appropriate (see edoxaban entry note 1b), then rivaroxaban, then dabigatran, then branded apixaban (Eliquis) until an appropriate treatment is identified.

Apixaban

• Tablets 2.5mg, 5mg (£2.15 = 5mg twice daily)

Indications and dose

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and at least one risk factor listed in NICE TA275 (see note 1 and note 6 below)
  • Adult: 5mg twice daily, reduce dose to 2.5mg twice daily in patients with at least two of the following characteristics:
    • age 80 years and over, body weight less than 61kg, or serum creatinine 133 micromol/litre and over
  • Patients with creatinine clearance 15-29mL/min: 2.5mg twice daily
• Treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE)
  • Adult: Initially 10mg twice a day for 7 days, then maintenance 5mg twice a day for at least 3 months
• Prophylaxis of recurrent DVT and PE
  • Adult: 2.5mg twice daily, following completion of 6 months anticoagulant treatment
• Prophylaxis of venous thromboembolism following knee replacement surgery (to be supplied by hospital)
  • Adult: 2.5mg twice daily for 10–14 days, to be started 12–24 hours after surgery
• Prophylaxis of venous thromboembolism following hip replacement surgery (to be supplied by hospital)
  • Adult: 2.5mg twice daily for 32–38 days, to be started 12–24 hours after surgery

Notes

1. For patients commencing treatment for AF, in line with NHS England Commissioning recommendations for national procurement for DOACs (see above), consider generic apixaban first where this is clinically appropriate.
2. In patients with creatinine clearance <15ml/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended
3. Use with caution if creatinine clearance 15–29 ml/minute
4. When used for the treatment and prevention of DVT or PE, duration of therapy should be individualised after careful assessment of the treatment benefit and risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE
5. NICE TA245: Apixaban (Eliquis) is recommended as an option for the prevention of venous thromboembolism in adults after elective knee or hip surgery (January 2012)
6. NICE TA275: Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation (February 2013)
   1. Apixaban (Eliquis) is recommended as an option for preventing stroke and systemic embolism within its marketing authorisation, in people with non-valvular atrial fibrillation with 1 or more risk factors such as:
      • prior stroke or transient ischaemic attack
      • age 75 years or older
      • hypertension
      • diabetes mellitus
      • symptomatic heart failure
   2. The risks and benefits of apixaban compared to warfarin, dabigatran etexilate, and rivaroxaban should be discussed with the patient
      • Consider apixaban in preference to warfarin in people with a confirmed eGFR of 30–50 ml/minute/1.73m2 and NVAF who have 1 or more risk factors
7. NICE TA341: Apixaban (Eliquis) is recommended, within its marketing authorisation, as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults (June 2015)

Edoxaban

• Film-coated tablets 15mg, 30mg, 60mg (£49.00 = 60mg daily)

Indications and dose

• Prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and at least one risk factor listed in NICE TA355 (see note 1 and note 5 below)
  • Adult (body weight 61 kg and above): 60mg once daily
  • Adult (body weight up to 61kg): 30mg once daily
  • Patients with creatinine clearance 15-50ml/min: 30 mg once daily
  • Concomitant treatment with ciclosporin, dronedarone, erythromycin, or ketoconazole: 30mg once daily
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prophylaxis of recurrent DVT and PE, following at least 5 days treatment with a parenteral anticoagulant (see note 2)
  • Adult (body weight 61 kg and above): 60mg once daily
  • Adult (body weight up to 61kg): 30mg once daily
  • Patients with creatinine clearance 15-50ml/min: 30 mg once daily
  • Concomitant treatment with ciclosporin, dronedarone, erythromycin, or ketoconazole: 30mg once daily

Notes

1. Atrial fibrillation
   1. For patients commencing treatment for AF, consider generic apixaban first, then edoxaban where this is clinically appropriate (see note 1b), before considering rivaroxaban, then dabigatran, then branded apixaban (Eliquis). as per the NHS England Commissioning recommendations for national procurement for DOACs (see above).
      
   2. In patients with creatinine clearance greater than 80ml/min, edoxaban should only be considered for AF after a careful evaluation of the thromboembolic and bleeding risk (MHRA). A trend towards decreasing efficacy with increasing creatinine clearance was observed for edoxaban compared to well-managed warfarin in a trial for AF (SmPC). Consider whether an alternative DOAC may be more appropriate; if generic apixaban is not appropriate, consider rivaroxaban.
2. DVT and PE
   1. Treatment of DVT and PE requires initial treatment for at least 5 days with a parenteral anticoagulant. Edoxaban and initial parenteral anticoagulant should not be administered simultaneously. See SmPC for further information.
   2. When used for the treatment and prevention of DVT or PE, duration of therapy should be individualised after careful assessment of the treatment benefit and risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE
3. In patients with creatinine clearance <15ml/min, or in patients undergoing dialysis, edoxaban is not recommended
4. NICE TA354: Edoxaban (Lixiana) is recommended, within its marketing authorisation, as an option for treating and for preventing deep vein thrombosis and pulmonary embolism in adults (August 2015)
5. NICE TA355: Edoxaban (Lixiana) is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation with one or more risk factors (September 2015); including:
   1. congestive heart failure
   2. hypertension
   3. diabetes
   4. prior stroke or transient ischaemic attack
   5. age 75 years or older

Rivaroxaban

• Tablets 15mg, 20mg (£6.75 = 20mg daily)
• Tablets 2.5mg, 10mg (£9.12 = 10mg daily)

Indications and dose

• Prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) with at least one of the risk factors listed in NICE TA256 (see note 1 and note 6 below)
  • Adult: 20mg once daily
  • Renal impairment: Manufacturer advises reduce dose to 15mg once daily if creatinine clearance 15–49ml/minute
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
  • Adult: Initially 15mg twice daily for 21 days, then maintenance 20 mg once daily
  • Renal impairment: Following the first 21 days of treatment, the usual dose of 20mg once daily can be given, but manufacturer advises consider reducing to 15mg once daily if creatinine clearance 15–49ml/minute and the risk of bleeding outweighs the risk of recurrent DVT or PE
• Prophylaxis of recurrent DVT and PE
  • Adult: Following completion of at least 6 months of anticoagulant treatment, 10mg or 20mg once daily following specialist advice
  • Renal impairment: When the recommended dose is 20mg once daily, manufacturer advises consider reducing to 15mg once daily if creatinine clearance 15–49ml/minute and the risk of bleeding outweighs the risk of recurrent DVT or PE
• Prophylaxis of atherothrombotic events following an acute coronary syndrome (ACS) with elevated cardiac biomarkers
  • Adult: 2.5mg twice daily, co-administered with aspirin alone, or with aspirin plus clopidogrel or ticlopidine (see NICE TA335)
• Prophylaxis of atherothrombotic events in adult patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events listed in NICE TA607 (see note 10 below)
  • Adult: 2.5mg twice daily in combination with a daily dose of 75mg to 100mg aspirin (see NICE TA607)
• Prophylaxis of venous thromboembolism following knee replacement surgery (to be supplied by hospital)
  • Adult: 10 mg once daily for 2 weeks, to be started 6–10 hours after surgery
• Prophylaxis of venous thromboembolism following hip replacement surgery (to be supplied by hospital)
  • Adult: 10 mg once daily for 5 weeks, to be started 6–10 hours after surgery

Notes

1. For patients commencing treatment for AF, consider generic apixaban first, then edoxaban where this is clinically appropriate (see edoxaban entry note 1b), before considering rivaroxaban, then dabigatran, then branded apixaban (Eliquis), as per the NHS England Commissioning recommendations for national procurement for DOACs (see above).
   
2. In patients with creatinine clearance <15ml/min, rivaroxaban is not recommended, use with caution if creatinine clearance 15–29 ml/minute
3. When used for the treatment and prevention of DVT or PE, duration of therapy should be individualised after careful assessment of the treatment benefit and risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE
4. The routine commissioning of 10mg rivaroxaban is accepted in Devon for the prevention of recurrent deep vein thrombosis and pulmonary embolism (see Commissioning Policy for more details)
5. NICE TA170: Rivaroxaban (Xarelto), within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery (April 2009)
6. NICE TA256: Rivaroxaban (Xarelto) is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with non-valvular atrial fibrillation (May 2012), with one or more risk factors such as:
   1. congestive heart failure
   2. hypertension
   3. age 75 years or older
   4. diabetes mellitus
   5. prior stroke or transient ischaemic attack
7. NICE TA261: Rivaroxaban (Xarelto) is recommended as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults (July 2012)
8. NICE TA287: Rivaroxaban (Xarelto) is recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults (June 2013)
9. NICE TA335: Rivaroxaban (Xarelto) is recommended as an option within its marketing authorisation, in combination with aspirin plus clopidogrel or aspirin alone, for preventing atherothrombotic events in people who have had an acute coronary syndrome with elevated cardiac biomarkers (March 2015)
10. NICE TA607: Rivaroxaban (Xarelto) plus aspirin is recommended within its marketing authorisation, as an option for preventing atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease who are at high risk of ischaemic events (October 2019). High risk of ischaemic events is defined as:
    1. aged 65 or over, or
    2. atherosclerosis in at least 2 vascular territories (such as coronary, cerebrovascular, or peripheral arteries), or
    3. 2 or more of the following risk factors: current smoking, diabetes, kidney dysfunction with an estimated glomerular filtration rate (eGFR) of less than 60 ml/min (note that rivaroxaban is contraindicated if the eGFR is less than 15 ml/min), heart failure, previous non-lacunar ischaemic stroke
11. MHRA Drug Safety Update (October 2018). Rivaroxaban (Xarelto) after transcatheter aortic valve replacement (TAVR): increase in all-cause mortality, thromboembolic and bleeding events in a clinical trial.
    1. Preliminary analysis of a phase 3 clinical trial show risks of all-cause death and bleeding post-TAVR were approximately doubled in patients assigned to a rivaroxaban-based anticoagulation strategy compared with those assigned to receive an antiplatelet-based strategy (clopidogrel and aspirin)
    2. Rivaroxaban is not authorised for thromboprophylaxis in patients with prosthetic heart valves, including patients who have undergone TAVR, and should not be used in such patients
    3. Rivaroxaban treatment in patients who undergo TAVR should be stopped and switched to standard of care
    4. The direct-acting oral anticoagulants apixaban and edoxaban have not been studied in patients with prosthetic heart valves and their use is also not recommended in these patients; the use of dabigatran is contraindicated in patients with prosthetic heart valves requiring anticoagulant treatment
    5. Prescribers should refer to the MHRA Drug Safety Update for further details
12. MHRA Drug Safety Update (July 2019): Rivaroxaban (Xarelto): reminder that 15mg and 20mg tablets should be taken with food
    1. MHRA has received a small number of reports suggesting lack of efficacy (thromboembolic events) in patients taking 15 mg or 20 mg rivaroxaban on an empty stomach

Dabigatran etexilate

• Capsules 110mg, 150mg (£47.60 = 150mg twice daily)
• Capsules 75mg (hospital only)

Indications

• Primary prevention of VTE in orthopaedic surgery (to be supplied by hospital)
• Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors
• Treatment of DVT and PE and prevention of recurrent DVT and PE in adults

Dose

• See tables below

Notes

1. Atrial fibrillation
   1. For patients commencing treatment for AF, consider generic apixaban first, then edoxaban where this is clinically appropriate (see edoxaban entry note 1b), before considering rivaroxaban, then dabigatran, then branded apixaban (Eliquis), as per the NHS England Commissioning recommendations for national procurement for DOACs (see above).
      
2. DVT and PE
   1. Treatment of DVT and PE requires initial treatment for at least 5 days with a parenteral anticoagulant. Dabigatran and initial parenteral anticoagulant should not be administered simultaneously. See SmPC for further information.
   2. When used for the treatment and prevention of DVT or PE, duration of therapy should be individualised after careful assessment of the treatment benefit and risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE
3. In patients with creatinine clearance <30ml/min, dabigatran is contraindicated,
4. Dabigatran is not suitable for use with a compliance aid (e.g. blister pack) as the capsules are moisture sensitive and should not be stored outside their packaging
5. NICE TA157: Dabigatran etexilate (Pradaxa), within its marketing authorisation, is recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or knee replacement surgery (September 2008)
6. NICE TA249: Dabigatran etexilate (Pradaxa) is recommended as an option for the prevention of stroke and systemic embolism within its marketing authorisation, in people with nonvalvular atrial fibrillation (March 2012) with one or more of the following risk factors:
   1. previous stroke, transient ischaemic attack or systemic embolism
   2. left ventricular ejection fraction below 40%
   3. symptomatic heart failure of New York Heart Association (NYHA) class 2 or above
   4. age 75 years or older
   5. age 65 years or older with one of the following: diabetes mellitus, coronary artery disease or hypertension
7. NICE TA327: Dabigatran etexilate (Pradaxa) is recommended, within its marketing authorisation, as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults (November 2014)
8. MHRA Drug Safety Update (December 2014): Dabigatran (Pradaxa): contraindicated in patients with prosthetic heart valve(s) requiring anti-coagulant treatment
   1. Dabigatran is now contraindicated in patients with prosthetic heart valve(s) requiring anticoagulant treatment related to their valve surgery, regardless of the length of time elapsed since valve replacement took place.

Dabigatran dose recommendations for NVAF, DVT and PE

Dabigatran dose recommendations for primary prevention of VTE in orthopaedic surgery

Rapid reversal of dabigatran

Idarucizumab

• Solution for infusion vials 2.5g/50ml

Reversal of apixaban or rivaroxaban

Andexanet Alfa

• Powder for solution for infusion vials 200mg

Notes

1. NICE TA697: Andexanet alfa (Ondexxya) is recommended as an option for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding (May 2021), only if:
   1. the bleed is in the gastrointestinal tract, and
   2. the company provides andexanet alfa according to the commercial arrangement
2. Andexanet alfa is recommended only in research for reversing anticoagulation from apixaban or rivaroxaban in adults with life-threatening or uncontrolled bleeding in the skull (intracranial haemorrhage; ICH), in the form of an ongoing randomised trial mandated by the regulator