2.8.2 Oral anticoagulants

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.

Patients with COVID-19 may be treated with antibiotics in line with NICE guidance and may also be treated with antivirals.

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 (NG186): reducing the risk of venous thromboembolism in over 16s with Covid-19. This guideline covers pharmacological venous thromboembolism prophylaxis for all patients being treated for COVID-19 pneumonia. It includes patients receiving treatment in hospital or in a community setting with input from hospital clinicians such as a 'hospital at home' service or COVID-19 'virtual ward'. Specific guidance is referenced for women who are pregnant or have given birth within the last 6 weeks. Please see here

Coumarins and phenindione

Warfarin
  • Tablets 500 micrograms, 1mg, 3mg, 5mg

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, and is at a safe level, 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 drug which may affect INR, 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 milligrams 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 500 microgram and 5mg tablets. Prescribers should ensure that prescriptions are written clearly and patients are thoroughly counselled if they are given the 500 microgram strength tablets.
  6. The following recommendations are based on those of the British Committee for Standards in Haematology (2011) and current edition of BNF, and apply to patients taking warfarin:
    1. Vitamin K is very well absorbed orally.
    2. When partial correction is required it may be necessary to give intravenous vitamin K or alternatively give the intravenous preparation orally (Konakion® MM Paediatric 10mg/ml 0.2ml amp).
    3. Vitamin K will usually lower the INR within 12 to 24 hours. Repeat doses may be needed after 24 hours if the INR is still too high.
  7. For monitoring and adverse events, refer to Anticoagulation guidance
Phenindione
  • Tablets 10mg, 25mg (£2,400.00 = 100mg daily)

Dose

  • 200mg on day 1; 100mg on day 2, then adjusted according to response; maintenance dose usually 50–150mg 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

Apixaban
  • Tablets 2.5mg, 5mg (£53.20 = 2.5mg twice daily)

Indications and dose

  • Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF): 5mg twice daily. Some patients require a lower dose - refer to the BNF or SPC before prescribing
  • Treatment of acute DVT and PE: 10mg twice a day for 7 days, then 5mg twice a day for at least 3 months. Some patients require a lower dose - refer to the BNF or SPC before prescribing
    • Short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation)
  • Prevention of recurrent DVT and PE: 2.5mg twice daily, following 6 months of 5mg twice daily. Some patients require a lower dose - refer to the BNF or SPC before prescribing

Notes

  1. NICE Chronic Kidney Disease guideline (CG182): Consider apixaban in preference to warfarin in people with a confirmed eGFR of 30–50 ml/min/1.73 m2 and NVAF who have 1 or more risk factors.
  2. NICE TA245 Apixaban is recommended as an option for the prevention of venous thromboembolism after total hip or knee replacement in adults (January 2012)
  3. NICE TA275 Apixaban is recommended as an option for preventing stroke and systemic embolism in people with NVAF (February 2013)
  4. NICE TA341 Apixaban is recommended as an option for the treatment and secondary prevention of DVT and/or PE (June 2015)
Dabigatran etexilate
  • Capsules 110mg, 150mg (£47.60 = 150mg twice daily)
  • Capsules 75mg (hospital only)

Indications and dose

  • Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors: 150mg twice daily. Some patients require a lower dose - refer to the BNF or SPC before prescribing
  • Treatment of DVT and PE, and prevention of recurrent DVT, and PE in adults: 150 mg twice daily following treatment with a parenteral anticoagulant for at least 5 days. Some patients require a lower dose - refer to the BNF or SPC before prescribing
    • The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation); longer durations should be based on permanent risk factors or idiopathic DVT or PE.

Notes

  1. 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.
  2. NICE TA157 Dabigatran etexilate is recommended as a possible treatment for the prevention of venous thromboembolism after hip or knee replacement surgery in adults (Sept 2008)
  3. NICE TA249 Dabigatran etexilate is recommended as a possible treatment for the prevention of stroke and systemic embolism in AF (March 2012)
  4. NICE TA327 Dabigatran etexilate is recommended as a possible treatment for the treatment and secondary prevention of DVT and/or PE (November 2014)
  5. MHRA Drug Safety Update: (December 2014) Dabigatran (Pradaxa): contraindicated in patients with prosthetic heart valve(s) requiring anticoagulant treatment
    1. Dabigatrin 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
Edoxaban
  • Film-coated tablets 15mg, 30mg, 60mg (£49.00 = 60mg daily)

Indications and dose

  • Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors: 60mg once daily. Some patients require a lower dose - refer to the BNF or SPC before prescribing
  • Treatment of DVT and PE; prevention of recurrent DVT and PE: 60mg once daily following at least 5 days of parenteral anticoagulant. Some patients require a lower dose - refer to the BNF or SPC before prescribing
    • Edoxaban and initial parenteral anticoagulant should not be administered simultaneously
    • Assess benefit vs bleeding risk to determine treatment duration. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, or immobilisation). Longer duration should be based on permanent risk factors or idiopathic DVT or PE.

Notes

  1. NICE TA354 Edoxaban is recommended as an option for treating and for preventing deep vein thrombosis and pulmonary embolism in adults (August 2015)
  2. NICE TA355 Edoxaban is recommended as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation with one or more risk factors (September 2015)
Rivaroxaban
  • Tablets 15mg, 20mg (£50.40 = 20mg daily)
  • Tablets 2.5mg, 10mg (£50.40)

Indications and dose

  • Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors: 20mg once daily. For patients with renal impairment, refer to the BNF or SPC before prescribing
  • Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: 15mg twice daily for the first three weeks followed by 20mg once daily for continued treatment and prevention of recurrence. Following 6 months of treatment the dose may be maintained at 20mg once daily or reduced to 10mg once daily following specialist advice. For patients with renal impairment, refer to the BNF or SPC before prescribing
    • 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
  • Prevention of atherothrombotic events in people who have had an acute coronary syndrome (ACS) with elevated cardiac biomarkers: 2.5mg twice daily, co-administered with aspirin alone, or with aspirin plus clopidogrel or ticlopidine (see TA335). For patients with renal impairment - refer to the BNF or SPC before prescribing
  • Prevention of atherothrombotic events in adult patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events: 2.5mg twice daily in combination with a daily dose of 75 to 100 mg aspirin (see TA607). For patients with renal impairment - refer to the BNF or SPC before prescribing
  • Prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery: Secondary care only

Notes

  1. NICE TA170: Rivaroxaban ( Xarelto) 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)
  2. NICE TA256: Rivaroxaban ( Xarelto) is recommended as an option for the prevention of stroke and systemic embolism in people with atrial fibrillation with one or more risk factors (May 2012)
  3. 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)
  4. NICE TA287: Rivaroxaban ( Xarelto) is recommended as an option for treating pulmonary embolism and preventing recurrent venous thromboembolism in adults (June 2013)
  5. NICE TA335: Rivaroxaban ( Xarelto) is recommended as an option 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)
  6. NICE TA607: Rivaroxaban (Xarelto) plus aspirin is recommended 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)
  7. 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.
  8. 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 15mg or 20mg rivaroxaban on an empty stomach
  9. 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)

Rapid reversal of dabigatran

Idarucizumab
  • Solution for injection/ infusion 2.5g in 50ml
Last updated: 24-11-2020

 

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