Previous changes

June to August 2025 — reviewed. A literature search was conducted in May 2025 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. No major changes to clinical recommendations have been made.

May 2025 — minor update. QOF indicators updated in line with the NHS England Quality and Outcomes Framework guidance for 2025/26.

March 2025 — minor update. Added additional information about patients on warfarin who have an INR 5-8 and no bleeding (but are at high risk of bleeding) for clinicians to consider discussing the possibility of using oral vitamin K with a specialist. 

July 2024 — minor update. Monitoring guidance for NOACs has been updated from 6 monthly to 4 monthly for people 75 years or older or those who are frail. This aligns with recommendations from the European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (2021). 

April 2024 — minor update. Recommendations on management of pre-operative cessation of DOACs revised to include a recommendation to liaise with an interventional cardiologist about the risk/benefit in high-risk procedures where the person is at high thrombotic risk. We have also revised the wording for procedures with a high bleeding risk, where we advise that the last dose of rivaroxaban should be taken 3 days before the procedure. These changes are in line with the Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update [Veitch, 2021].

January 2024 — minor update. Adverse effect of anticoagulant-related nephropathy added to apixaban in line with an update to the manufacturer's summary of product characteristics. 

October 2023 — minor update. Adverse effect of nephropathy added to edoxaban in line with an update to the manufacturer's summary of product characteristics. 

August 2023 — minor update. Adverse effect of nephropathy added to rivaroxaban in line with an update to the manufacturer's summary of product characteristics. 

July 2023 — minor update. BNF link added to the dabigatran section on dosing recommendations. 

April 2023 — minor update. Recommendations on management of missed doses of DOACs has been updated in line with manufacturers' summaries of product characteristics. Typographical error corrected. 

November 2022 — minor update. Added a rare adverse effect of rivaroxaban of eosinophilic pneumonia in line with the manufacturer's SPC. 

June 2022 — minor update. A typographical error has been corrected. 

May 2022 — minor update. Additional adverse effect of cutaneous vasculitis related to apixaban aligned with an update in the manufacturer's summary of product characteristics. 

March 2022 — minor update. Recommendations on managing people who are undergoing dental treatment and taking DOAC anticoagulants have been added and recommendations on people taking warfarin have been updated in line with the NHS Education for Scotland guidance Management of dental patients taking anticoagulants or antiplatelet drugs.

August 2021 — minor update.  A minor typographical error has been corrected.

April 2021 — minor update. Information about reducing the dose of apixaban in renal impairment has been clarified. Erythema multiforme has also been added as an adverse effect of apixaban. A minor typographical error has also been corrected.

January 2021 — reviewed. A literature search was conducted in December 2020 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. No major changes to clinical recommendations have been made. However, sections on monitoring people taking anticoagulants during the COVID-19 pandemic has been included, based on the Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety Update Warfarin and other anticoagulants: monitoring of patients during the COVID-19 pandemic [MHRA, 2020].

September 2020 — minor update. Information on monitoring of people taking direct oral anticoagulants (DOACs) has been clarified. A link to a reference has also been updated. 

August 2020 — minor update. Dosage information for rivaroxaban has been clarified and angioedema added as an adverse effect of apixaban. 

July 2020 — minor update. Broken URL links updated.

July 2020 — minor update. Dabigatran adverse effects updated in line with revised manufacturer's Summary of Product Characteristics (SPC).

May 2020 — minor update. The section on Warfarin scenario has been updated to clarify that the target range for some conditions is 2.5.

January 2020 — minor update. Dose information for dabigatran was updated to clarify that treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults should be started following treatment with a parenteral anticoagulant for at least 5 days.

June 2019 — minor update. Apixaban is now known to be contraindicated in people with history of thrombosis diagnosed with antiphospholipid syndrome, especially in triple positive people, where use of DOACs could be associated with increased rates of recurrent thrombotic events.

November 2017 — minor update. Information added on concurrent use of apixaban with clarithromycin as per the updated manufacturer's SPC. 

July 2017 — minor update. Added additional adverse effects of rivaroxaban as per the updated manufacturer's SPC. 

January 2017 — minor update. Updated the topic in line with the Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety Update Direct-acting antivirals to treat chronic hepatitis C: risk of interaction with vitamin K antagonists and changes in INR.

October to November 2016 — reviewed. A literature search was conducted in October 2016 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. Information on edoxaban, a new DOAC, has been added to this topic. 

October 2015 — minor update. Angioedema, allergic oedema, cholestasis, hepatitis (including hepatocellular injury), and thrombocytopenia have been included as adverse effects of rivaroxaban as per the updated manufacturer's SPC.

August 2015 — minor update. The information in the section on Managing dosing errors for rivaroxaban has been clarified.

July 2015 — minor update. The dosing of apixaban and rivaroxaban for people with renal impairment has been changed to give creatinine clearance (CrCl) values (instead of estimated Glomerular Filtration Rates [eGFR]).

February 2015 — minor update. The dabigatran section regarding dosage adjustments required for elderly people (80 years or older) and people prescribed verapamil has been updated in line with the National Institute for Health and Care Excellence (NICE) technology appraisal Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism.

December 2014 — minor update. Prophylaxis of atherothrombotic events in adults with an acute coronary syndrome has been added as a licensed indication for rivaroxaban as per an update to the manufacturer's SPC.

September 2014 — minor update. Minor typographical error corrected.

August 2014 — minor update to the text to reflect the fact that apixaban is now licensed for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

July 2014 — minor update to the text to reflect the fact that dabigatran is now licensed for the treatment of DVT and PE, and prevention of recurrent DVT and PE in adults.

May 2014 — minor update to the text to remove lettuce as a food that is high in vitamin K and replaced with kale.

January 2014 — minor update. Minor typographical error regarding the ages in each of the scenarios has been fixed.

October 2013 — minor update. A Drug Safety Update issued by the MHRA has clarified that contraindications for dabigatran where the person is at significant risk of major bleeding have also been applied to apixaban and rivaroxaban.

May 2013 — reviewed. A literature search was conducted in March 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of the topic. Three new sections have been added to include the newer anticoagulants; apixaban, dabigatran, and rivaroxaban. Minor changes have been made to the recommendations for prescribing warfarin.

November 2012 — minor update. The links to the electronic Medicines Compendium (eMC) website (www.medicines.org.uk) have been updated.

May 2012 — minor typographical error corrected.

March 2012 — minor update. The 2012/2013 Quality and Outcomes Framework (QOF) indicators have been added to this topic.

December 2011 — minor update. Minor typographical error corrected. 

July 2011 — minor update. All references to the British Committee for Standards in Haematology (BCSH, 2011) guideline on oral anticoagulation with warfarin have been updated to reflect the latest guideline. Several sections within the topic have also been updated to reflect the guideline. 

April 2011 — minor update. Changes to text in line with College of Sexual and Reproductive Healthcare (CoSRH) guideline Drug interactions with hormonal contraception, which states that an interaction between warfarin and hormonal contraception is unlikely.

November 2010 — minor update. Advice regarding the effect of major changes in diet on anticoagulation has been reworded. 

January 2010 — minor update to include recent changes to warfarin safety information in the MHRA Public assessment report. Warfarin: changes to product safety information.

December 2009 — minor update. Advice on taking antidepressants in people receiving warfarin has been amended in the section on Drug interactions. Issued in December 2009.

August to September 2009 — updated to include recommendations and supporting evidence on the place of self-testing and self-management of warfarin. Advice on the management of the drug interaction between selective serotonin reuptake inhibitors (SSRIs) and warfarin has also been added. 

July 2009 — updated to include target international normalized ratio (INRs) and duration of treatment for all indications for warfarin. A change to the recommendation on management of potential drug interaction between warfarin and macrolide antibiotics has also been made. 

December 2008 to March 2009 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 May 2025.

HTAs (Health Technology Assessments)

No new HTAs published since 1 May 2025.

Economic appraisals

No new economic appraisals relevant to England since 1 May 2025.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion since 1 May 2025.

Primary evidence

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion since 1 May 2025.

New policies

No new national policies or guidelines since 1 May 2025.

New safety alerts

No new safety alerts since 1 May 2025.

Changes in product availability

Pradaxa® (dabigatran) 20mg, 30mg, 40mg, 50mg, 110mg and 150mg coated granules will be discontinued from the end of August 2026.

What are the licensed indications for apixaban?

• Apixaban is licensed for [EMC, 2024b; EMC, 2025a; BNF, 2025]:
  • Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more of the following risk factors [NICE, 2021b]:
    • Previous stroke or transient ischaemic attack.
    • Age 75 years or older.
    • Hypertension.
    • Diabetes mellitus. 
    • Symptomatic heart failure (New York Heart Association [NYHA] Class 2 or higher).
  • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) [NICE, 2015a].
  • Prevention of recurrent DVT and PE in adults [NICE, 2015a].
  • Prevention of venous thromboembolic events in adults who have undergone elective hip or knee replacement surgery [NICE, 2012a].

What are the licensed indications for dabigatran?

• Dabigatran is licensed for [EMC, 2024c; EMC, 2025b] :
  • Prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation (NVAF) with one or more of the following risk factors [NICE, 2021c]:
    • Previous stroke or transient ischemic attack.
    • Age 75 years and older
    • Hypertension.
    • Diabetes mellitus.
    • Symptomatic heart failure (New York Heart Association [NYHA] Class 2 or higher).
  • Prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or total knee replacement surgery [NICE, 2008].
  • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) [NICE, 2014].
  • Prevention of recurrent DVT and PE in adults [NICE, 2014].

What are the licensed indications for edoxaban?

• Edoxaban is licensed for [EMC, 2024a; EMC, 2024d; BNF, 2025]:  
  • Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation with one or more of the following risk factors [NICE, 2021d]:
    • Previous stroke or transient ischaemic attack.
    • Age greater than 75 years.
    • Hypertension. 
    • Diabetes mellitus. 
    • Congestive heart failure.
  • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults [NICE, 2015b].
  • Prevention of recurrent DVT and PE in adults [NICE, 2015b].

What are the licensed indications for rivaroxaban?

• Rivaroxaban is licensed for [EMC, 2025c; EMC, 2025e; EMC, 2025f; BNF, 2025]:
  • Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation with one or more of the following risk factors [NICE, 2021e]:
    • Previous stroke or transient ischaemic attack.
    • Age greater than 75 years.
    • Hypertension.
    • Diabetes mellitus.
    • Congestive heart failure.
  • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults [NICE, 2012b; NICE, 2013].
  • Prevention of recurrent DVT and PE in adults [NICE, 2012b; NICE, 2013].
  • Prevention of venous thromboembolism (VTE) in adults undergoing elective hip or knee replacement surgery [NICE, 2009].
  • Prevention of atherothrombotic events following an acute coronary syndrome with elevated cardiac biomarkers (in combination with aspirin alone or aspirin and clopidogrel) [NICE, 2015c].
  • Prevention of atherothrombotic events in people with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events (in combination with aspirin) [NICE, 2019].

What are the indications for warfarin?

• Warfarin is licensed for [EMC, 2025g; EMC, 2025d; BNF, 2025]:
  • Prophylaxis of systemic embolism in people with rheumatic heart disease and atrial fibrillation.
  • Prophylaxis after insertion of prosthetic heart valves.
  • Prophylaxis and treatment of venous thrombosis and pulmonary embolism.
  • Transient ischaemic attacks.

What is the recommended dose and duration of treatment for apixaban?

• For the prophylaxis of stroke and systemic embolism in adults with non-valvular atrial fibrillation and at least one risk factor, such as previous stroke or transient ischaemic attack, symptomatic heart failure, diabetes mellitus, hypertension, or age 75 years and over:
  • The recommended dose is 5 mg twice daily.
  • The dose should be reduced to 2.5 mg twice daily in people with:
    • At least two of the following characteristics: age 80 years or over, body weight 60 kg or less, or serum creatinine 133 micromol/L or over.
    • Creatinine clearance (CrCl) 15–29 mL/minute.
  • Treatment is usually long-term.
• For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE):
  • The recommended dose is 10 mg twice daily for the first 7 days, followed by 5 mg twice daily.
  • The duration of treatment should be based on the presence of transient risk factors (for example, recent surgery, trauma, and immobilization), but it should be for a minimum of 3 months.
• For the prophylaxis of recurrent DVT and PE in adults (following completion of 6 months of anticoagulation treatment):
  • The recommended dose is 2.5 mg twice daily.
  • The duration of treatment is based on an assessment of benefit against the risk of bleeding.
• For the prophylaxis of venous thromboembolism (VTE) in people who have undergone hip replacement surgery:
  • The recommended dose is 2.5 mg twice daily for 32–38 days, to be started 12–24 hours after surgery.
• For the prophylaxis of VTE in people who have undergone knee replacement surgery: 
  • The recommended dose is 2.5 mg twice daily for 10–14 days, to be started 12–24 hours after surgery.

What are the contraindications and cautions for apixaban?

• Apixaban is contraindicated in:
  • People with:
    • Creatinine clearance (CrCl) less than 15 mL/minute.
    • Liver disease associated with coagulopathy and clinically relevant bleeding risk.
    • A prosthetic heart valve — efficacy not established.
    • Antiphospholipid syndrome — increased risk of recurrent thrombotic events.
    • Active, clinically significant bleeding.
    • Concomitant use of any other anticoagulant (except under specific circumstances such as switching therapy).
  • People with a significant risk of major bleeding, such as:
    • Current or recent gastrointestinal ulcer.
    • Known or suspected oesophageal varices.
    • Recent brain or spinal injury.
    • Recent brain, spine, or ophthalmic surgery.
    • Recent intracranial haemorrhage.
    • Malignant neoplasm at high risk of bleeding.
    • Vascular aneurysm.
    • Arteriovenous malformations.
    • Major intraspinal or intracerebral vascular abnormalities.
  • Women who are pregnant or breastfeeding — the safety of apixaban has not been established in these groups.
• Apixaban should be prescribed with caution in the following groups:
  • Elderly people (age 80 years or older) — dose reduction may be required.
  • People with:
    • Body weight of 60 kg or less — dose reduction may be required (low body weight may increase plasma concentrations of apixaban).
    • Severe renal impairment (CrCl 15–29 mL/minute) — dose reduction is indicated (approximately 27% of apixaban is excreted renally).
    • Hepatic impairment — use with caution in mild or moderate hepatic impairment.
  • People on concurrent treatment with other drugs that can cause bleeding, such as nonsteroidal anti-inflammatory drugs (NSAIDs).
    • If concurrent treatment is unavoidable, close monitoring for signs of bleeding and anaemia is recommended.
    • See the section on Drug interactions for more information, and for information on other drug interactions of apixaban.

What are the adverse effects of apixaban?

• Bleeding is a common adverse effect of all anticoagulants, including apixaban, and it can occur in any part of the body.
  • Advise people taking apixaban to:
    • Carry an alert card and keep it with them at all times.
    • Seek immediate medical advice if spontaneous bleeding occurs and does not stop, or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • Seek medical advice if they get sudden, severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • Get advice from a doctor or pharmacist before taking other medications, including over-the-counter medicines (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with apixaban.
  • Andexanet alfa (Ondexxya®) is a specific reversal agent indicated for adults treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
• Other adverse effects of apixaban include:
  • Common — anaemia, bruising, nausea, and skin reactions.
  • Uncommon — hypersensitivity, anaphylaxis, erythema multiforme, pruritus, hypotension, post-procedural haematoma, thrombocytopenia, deranged liver function tests, and wound complications.
  • Unknown frequency — angioedema, cutaneous vasculitis and anti-coagulant-related nephropathy. 

What are the key drug interactions for apixaban?

• Key drug interactions with apixaban include:
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) — apixaban is predicted to increase the risk of bleeding events when given with NSAIDs (such as ibuprofen). 
    • The manufacturer of apixaban advises use with caution or avoid.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
  • Other anticoagulants, such as heparin, warfarin, rivaroxaban, or dabigatran — there is an increased risk of bleeding if other anticoagulants are given with apixaban.
    • Avoid concurrent use except in specific clinical situations such as switching treatment. See the section on Switching anticoagulants for more information.
  • Antiplatelets, such as aspirin, clopidogrel, and ticagrelor — apixaban is predicted to increase the risk of bleeding events when given with antiplatelet drugs. 
    • The manufacturer of apixaban advises using it with caution or avoid.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
  • Strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as itraconazole, ketoconazole, and HIV protease inhibitors (for example, ritonavir) — plasma concentration of apixaban is increased by these drugs.
    • The manufacturer of apixaban advises avoiding concurrent use with these drugs.
    • For drugs that are not considered strong inhibitors of both CYP3A4 and P-gp, such as amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, and verapamil, the plasma concentration of apixaban is increased to a lesser extent. No dose adjustment for apixaban is required with these drugs, but the person should be monitored for signs of bleeding or anaemia.
  • Strong inducers of both CYP3A4 and P-gp, such as carbamazepine, phenytoin, rifampicin, and St John's Wort — plasma concentration of apixaban may be reduced by these drugs.
    • For the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE), the person should be closely monitored for signs of thrombosis.
    • For the treatment of DVT and PE, apixaban should not be used since efficacy may be compromised.
  • Selective serotonin reuptake inhibitors (such as citalopram), serotonin norepinephrine re-uptake inhibitors (duloxetine), and venlafaxine — there is a possible increased risk of bleeding when apixaban is given with these antidepressants.
    
    • The manufacturer of apixaban advises to use with caution or avoid.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for other possible drug interactions with apixaban.

How should I switch a person to or from another anticoagulant?

• Switching from warfarin to apixaban:
  • Stop warfarin, and measure the international normalized ratio (INR):
    • If the INR is less than 2, start apixaban.
    • If the INR is between 2 and 2.5, start apixaban immediately or the next day.
    • If the INR is greater than 2.5, wait until the person's INR has dropped to less than 2 before starting apixaban.
  • The time taken for the person's INR to reach less than 2 will vary from person to person and will depend on what the person's initial INR level was.
• Switching from apixaban to warfarin:
  • Start warfarin, but do not stop apixaban. 
    • See the section on Starting warfarin treatment for information on how to initiate warfarin treatment.
    • The European Heart Rhythm Association advises that for the indication of atrial fibrillation, a loading dose of warfarin is not required when switching from apixaban to warfarin – follow local protocol and seek specialist advice if unsure.
  • After at least 2 days of concurrent treatment with warfarin and apixaban, measure the INR prior to the next scheduled dose of apixaban.
    • If the INR is in the target range, stop apixaban and continue with warfarin.
    • If the INR is not in the target range, continue warfarin and apixaban concurrently until the person's INR is in the target range, then stop apixaban. Warfarin has a slow onset of action, and it may take 5–10 days before the INR is within range. 
  • After treatment with apixaban has stopped:
    • Measure the INR after 24 hours to ensure adequate anticoagulation.
    • Monitor the person's INR closely (for example, once a week) in the first month of warfarin treatment until the person has three consecutive stable INR values (for example, between 2–3).
• Switching from apixaban to another direct-acting oral anticoagulant (DOAC):
  • Stop apixaban, and start the new DOAC (dabigatran, edoxaban, or rivaroxaban) when the next dose of apixaban is due.
• Switching from another DOAC to apixaban:
  • Stop the initial DOAC (dabigatran, edoxaban, or rivaroxaban), and start apixaban when the next dose of the initial DOAC (dabigatran, edoxaban, or rivaroxaban) is due.

Should apixaban be stopped if surgery or dental treatment is required?

• If the person needs to have surgery or any other invasive procedure, they may need to temporarily stop taking apixaban.
  • The decision to stop apixaban and when to stop it will depend on the individual's risk of having a thromboembolic event and the bleeding risk associated with the procedure. The interruption periods listed below may require adaptation based on the individual benefit/risk ratio and local guidance.

  • All patients undergoing a planned intervention, as well as caregivers (including primary care clinicians), should receive written information from the operating physician indicating the anticipated date and time of the intervention, as well as the date and time of the last DOAC intake.

  • If unsure about the risk/benefit of discontinuing, seek specialist advice from a consultant interventional cardiologist.

• For most minor surgical procedures and those associated with a minor bleeding risk, it is recommended not to interrupt oral anticoagulation.
  • In general, these procedures can be performed 12–24 hours after the last dose of apixaban is taken (at the 'trough level').
• For surgical procedures with a low bleeding risk, apixaban should be stopped at least 24 hours before the procedure.
  • If creatinine clearance (CrCl) is 15–29 mL/minute, apixaban should be stopped at least 36 hours before the procedure.
• For surgical procedures with a high bleeding risk, the last dose of apixaban should be taken at least 48–72 hours before the procedure.
• For people who require a dental procedure with a:
  • Low risk of bleeding complications, treat without interrupting apixaban treatment.
  • Higher risk of bleeding complications, advise them to miss their morning dose of apixaban on the day of their dental treatment.
    • The evening dose should be taken at the usual time, provided it is no earlier than 4 hours after haemostasis has been achieved.

How should I monitor a person taking apixaban?

There is no need to monitor the international normalized ratio (INR) in people taking apixaban; however, regular follow up and monitoring are recommended.

• At the start of treatment, baseline clotting screen, renal and liver function tests, and a full blood count should be performed.
• Once treatment has started, review the person on a regular basis and preferably after 1 month initially.
  
  • Follow-up intervals may be longer or shorter (for example, every month) depending on patient factors, such as bleeding risk factors, renal function (creatinine clearance less than 60ml/min), age, and comorbidities. 
• During a review:
  • Assess adherence to treatment.
  • Look for signs of bleeding or anaemia. 
  • Ask about other adverse effects of apixaban.
  • Assess for features of thromboembolic events, such as symptoms of stroke, or breathlessness (which may suggest a pulmonary embolism). See the CKS topics on Stroke and TIA and Pulmonary embolism for more information.
  • Ask about the use of other medications, including over-the-counter (OTC) products, to identify possible drug interactions with apixaban.
  • Assess and minimize modifiable risk factors for bleeding, such as uncontrolled hypertension, medication predisposing for bleeding (such as aspirin), excessive alcohol intake and falls.
  • Give appropriate information and advice on apixaban treatment. See the section on Advice for patients for more information.
• Repeat the full blood count and the renal and liver function tests yearly for most people.
  • If the person is frail or older than 75 years, repeat the blood tests every 4 months.
  • If the person has a creatinine clearance (CrCl) less than 60 mL/minute, the frequency of monitoring (in months) can be guided by the CrCl divided by 10. For example, every 3 months if CrCl is 30 mL/minute.
  • If the person has an intercurrent illness that may impact renal or hepatic function, repeat renal and liver function tests as needed.
• Manage any problems identified during a review or from blood test results. 
  • If renal function has declined, review treatment — apixaban may need to be stopped or a lower dose may be required. 
  • If there is an unexplained fall in haemoglobin and/or haematocrit, occult bleeding may be present (apixaban can cause bleeding from any site).
    • Consider the need for stopping treatment with apixaban — seek specialist advice and arrange further assessment to identify the underlying cause (with urgency depending on the specific clinical situation). 
• See the section on Monitoring during Covid-19 pandemic for more monitoring advice.

How should I monitor a person taking apixaban during the COVID-19 pandemic?

• When monitoring a person taking apixaban during the COVID-19 pandemic, remember that:
  
  • Direct-acting oral anticoagulants (DOACs), such as apixaban, may interact with other medicines, including antibacterials and antivirals. Follow the advice in the manufacturer's Summary of Product Characteristics (SPC), available on the electronic Medicines Compendium (eMC) website, to minimize the risk of potential interactions.
  • If switching from warfarin to apixaban, stop warfarin before starting apixaban, to reduce the risk of over-anticoagulation and bleeding. See the section on Switching anticoagulants for more information.

How should I manage dosing errors in a person taking apixaban?

• If the person has missed a dose of apixaban:
  • A missed morning dose should be taken immediately when it is noticed, and it may be taken together with the evening dose. A missed evening dose can only be taken during the same evening; the person should not take two doses the next morning. The person should continue with the intake of the regular dose twice daily as recommended on the following day.
• If the person has taken a double dose of apixaban, they should omit the next planned dose (that is, after 12 hours) and resume treatment as normal 24 hours after the double dose intake.
• If the person is uncertain whether they have taken their dose, it is generally advisable not to take another dose, but to continue with the next scheduled dose (that is, after 12 hours).

What advice should I give a person who is taking apixaban?

• Advise the person taking apixaban:
  • That although (unlike warfarin) there is no need to have regular blood tests to monitor the international normalized ratio (INR), they will still require regular monitoring, blood tests, and review of their treatment.
  • On the importance of a regular dosing schedule.
    • The anticoagulant effect of apixaban reduces 12–24 hours after the last dose is taken; therefore, it is important to take the medication as directed, or the person is at increased risk of a thromboembolic event.
    • They should not miss doses (or take additional doses) without advice from a healthcare professional.
  • That they should seek immediate medical advice:
    • If spontaneous bleeding occurs and does not stop or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • If they get sudden severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • If they experience difficulty breathing, increased breathing rate, or chest pain (which could be symptoms of pulmonary embolism).
  • That they should also seek medical advice:
    • If there has been a dosing error (such as a missed dose or if a double dose has been taken).
    • Before taking other medications, including over-the-counter drugs (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with apixaban. 
    • If they experience other adverse effects of apixaban.
  • That they may have to stop apixaban treatment temporarily for certain surgical and dental treatments.
  • To read the manufacturer's patient information leaflet, if they have not already.
  • To carry a Patient Alert Card at all times.
    • These are contained in each UK tablet pack and can also be printed off from the electronic Medicines Compendium (eMC) website (www.medicines.org.uk).

What is the recommended dose and duration of treatment for dabigatran?

• For the prophylaxis of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) and with one or more risk factors, such as previous stroke or transient ischaemic attack, symptomatic heart failure, age 75 years or older, diabetes mellitus, or hypertension:
  
  • The recommended dose is 150 mg twice a day.
  • A reduced dose of 110–150 mg twice daily is recommended if the person:
    • Is aged 75–79 years.
    • Has moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/minute), based on individual assessment of thromboembolic risk and risk of bleeding.
    • Is at increased risk of bleeding.
  • A reduced dose of 110 mg twice daily is recommended if the person:
    • Is aged 80 years or older.
    • Is receiving concurrent treatment with verapamil. See the section on Drug interactions for more information.
  • Treatment is usually long-term.
• For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and the prevention of recurrent DVT and PE, following initial use of parenteral anticoagulation for at least 5 days:
  • The recommended dose is 150 mg twice daily.
  • A reduced dose of 110–150 mg twice daily should be considered if the person:
    • Is aged 75–79 years. 
    • Has moderate renal impairment (CrCl 30–50 mL/minute), based on individual assessment of thromboembolic risk and risk of bleeding.
    • Is at increased risk of bleeding.
  • A reduced dose of 110 mg twice daily is recommended if the person:
    • Is aged 80 years or older. 
    • Is receiving concurrent treatment with verapamil. See the section on Drug interactions for more information.
  • The duration of treatment is based on an assessment of benefit against the risk for bleeding:
    • Short duration of treatment (at least 3 months) should be based on transient risk factors (for example, recent surgery, trauma, immobilization).
    • Longer durations of treatment should be based on permanent risk factors or idiopathic DVT or PE.
• For the prevention of venous thromboembolism (VTE) in people who have undergone knee replacement surgery: 
  • The recommended dose is 110 mg to be taken 1–4 hours after surgery, followed by 220 mg once daily for 10 days, to be taken on the first day after surgery.
  • A reduced dose of 75 mg taken 1–4 hours after surgery, followed by 150 mg once daily for 10 days, to be taken on the first day after surgery, is recommended if the person:
    
    • Is aged 75 years or older.
    • Is receiving concurrent treatment with amiodarone or verapamil. See the section on Drug interactions for more information.
    • Has moderate renal impairment (CrCl 30–50 mL/minute). 
• For the prevention of VTE in people who have undergone hip replacement surgery: 
  • The recommended dose is 110 mg to be taken 1–4 hours after surgery, followed by 220 mg once daily for 28–35 days, to be taken on the first day after surgery.
  • A reduced dose of 75 mg taken 1–4 hours after surgery, followed by 150 mg once daily for 28–35 days, to be taken on the first day after surgery, is recommended if the person:
    
    • Is aged 75 years or older.
    • Is receiving concurrent treatment with amiodarone or verapamil. See the section on Drug interactions for more information.
    • Has moderate renal impairment (CrCl 30–50 mL/minute). 

What are the contraindications and cautions for dabigatran?

• Dabigatran is contraindicated in:
  • People with:
    • Severe renal impairment (creatine clearance [CrCl] less than 30 mL/minute).
    • Active bleeding.
    • A prosthetic heart valve — increased risk of thromboembolic and bleeding events.
    • Antiphospholipid syndrome — increased risk of recurrent thrombotic events.
    • Severe hepatic impairment or liver disease expected to have any impact on life expectancy.
    • Elevated liver enzymes (if they are more than twice the upper limit of normal).
    • Concomitant treatment with any other anticoagulant except in specific clinical circumstances, such as when switching therapy.
    • Concomitant treatment with the following strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and the fixed-dose combination glecaprevir/pibrentasvir.
  • People with a significant risk of major bleeding, such as:
    • Current or recent gastrointestinal ulcer.
    • Known or suspected oesophageal varices.
    • Recent brain or spinal injury.
    • Recent brain, spine, or ophthalmic surgery.
    • Recent intracranial haemorrhage.
    • Malignant neoplasms at high risk of bleeding.
    • Arteriovenous malformations.
    • Vascular aneurysm.
  • Women who are pregnant or breastfeeding — the safety of dabigatran has not been established in these groups.
• Dabigatran should be used with caution in the following groups: 
  • Elderly people (aged 75 years and older) — dose reduction is indicated.
  • People with:
    • Moderate renal impairment (CrCl 30–50 mL/minute) — dose reduction is indicated (approximately 80% of dabigatran is excreted renally).
    • Body weight less than 50 kg — close monitoring for signs of bleeding and anaemia is recommended (low body weight may increase plasma concentrations of dabigatran). No dose adjustment is needed. 
    • Other risk factors for bleeding, such as gastritis, gastro-oesophageal reflux, oesophagitis, recent biopsy, recent major trauma, or thrombocytopenia — close monitoring for signs of bleeding and anaemia is recommended.
  • People taking certain drugs, including:
    • Verapamil, amiodarone, quinidine and ticagrelor — dose reduction is indicated (verapamil increases plasma concentrations of dabigatran).  
    • Other drugs that can cause bleeding, such as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, clopidogrel, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) — if concurrent treatment is unavoidable, close monitoring for signs of bleeding and anaemia is recommended. See the section on Drug interactions for more information, and for information on other drug interactions of dabigatran.

What are the adverse effects of dabigatran?

• Bleeding is a common adverse effect of all anticoagulants, including dabigatran, and it can occur in any part of the body.
  • Advise people taking dabigatran to:
    • Carry an alert card and keep it with them at all times. 
    • Seek immediate medical advice if spontaneous bleeding occurs and does not stop, or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • Seek medical advice if they get sudden, severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • Get advice from a doctor or pharmacist before taking other medications, including over-the-counter medicines (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with dabigatran.
  • Idarucizumab (Praxbind®) is a specific reversal agent indicated in adults treated with dabigatran when rapid reversal of its anticoagulant effects is required.
• Other adverse effects of dabigatran include:
  • Common — anaemia, diarrhoea, abnormal hepatic function, gastrointestinal discomfort, and nausea.
  • Uncommon — dysphagia, gastrointestinal disorders, hyperbilirubinaemia, post-procedural/wound complications, skin reactions, thrombocytopenia and vomiting.
  • Rare or very rare — angioedema, post-procedural drainage, and wound drainage.
  • Frequency unknown — agranulocytosis, neutropenia, alopecia and bronchospasm.

What are the key drug interactions for dabigatran?

• Key drug interactions with dabigatran include:
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) — dabigatran is predicted to increase the risk of bleeding events when given with NSAIDs (such as ibuprofen).
    • The manufacturer of dabigatran advises avoiding concurrent use unless the benefit outweighs the risk.
    • If concurrent use is indicated, monitor closely for signs of bleeding or anaemia.
  • Other anticoagulants, such as heparin, warfarin, dabigatran, edoxaban, and rivaroxaban — there is an increased risk of bleeding if other anticoagulants are given with dabigatran.
    • Avoid concurrent use except in specific clinical circumstances, such as when switching anticoagulant therapy. See the section on Switching anticoagulants for more information.
  • Antiplatelets, such as aspirin, clopidogrel, and ticagrelor — dabigatran is predicted to increase the risk of bleeding events when given with antiplatelet drugs. 
    • The manufacturer of dabigatran advises avoiding concurrent use unless the benefit outweighs the risk.
    • If concurrent use is indicated, monitor closely for signs of bleeding or anaemia.
  • Strong inhibitors of P-glycoprotein (P-gp), such as ciclosporin, dronedarone, itraconazole, and ketoconazole — plasma concentration of dabigatran is increased by these drugs (dabigatran is a substrate for P-gp).
    • The manufacturer of dabigatran advises avoiding concurrent use — contraindicated.
  • Mild to moderate P-gp inhibitors, such as amiodarone, verapamil, clarithromycin and quinidine — plasma concentration of dabigatran is increased by these drugs.
    
    • With verapamil, reduce the dose of dabigatran to 110 mg twice daily, and monitor for signs of bleeding.
    • With amiodarone and quinidine, the manufacturer of dabigatran advises that, depending on the indication, no dose adjustment may be necessary — the person should be monitored closely for signs of bleeding or anaemia.
  • Strong inducers of P-gp, such as carbamazepine, phenytoin, rifampicin, and St John's Wort — plasma concentration of dabigatran is reduced by these drugs.
    • The manufacturer of dabigatran advises avoiding concurrent use with these drugs.
  • Protease inhibitors, such as ritonavir, affect P-gp (either as an inhibitor or inducer).
    
    • The manufacturer advises avoiding concomitant use.
  • Selective serotonin reuptake inhibitors (such as citalopram), serotonin norepinephrine reuptake inhibitors (duloxetine), and venlafaxine — there is a possible increased risk of bleeding when dabigatran is given with these antidepressants.
    • The manufacturer of dabigatran advises avoiding concurrent use unless the benefit outweighs the risk.
    • If concurrent use is indicated, monitor closely for signs of bleeding or anaemia.
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for other possible drug interactions with dabigatran.

How should I switch a person to or from another anticoagulant?

• Switching from warfarin to dabigatran:
  • Stop warfarin, and measure the international normalized ratio (INR):
    • If the INR is less than 2, start dabigatran.
    • If the INR is between 2 and 2.5, start dabigatran immediately or the next day.
    • If the INR is greater than 2.5, wait until the person's INR has dropped to less than 2 before starting dabigatran.
  • The time taken for the person's INR to reach less than 2 will vary from person to person and will depend on what the person's initial INR level was.
• Switching from dabigatran to warfarin:
  • Start warfarin, but do not stop dabigatran. 
    • See the section on Starting warfarin treatment for information on how to initiate warfarin treatment.
    • The European Heart Rhythm Association advises that for the indication of atrial fibrillation, a loading dose of warfarin is not required when switching from dabigatran to warfarin – follow local protocol and seek specialist advice if unsure.
  • After at least 2 days of concurrent treatment with warfarin and dabigatran, measure the INR prior to the next scheduled dose of dabigatran.
    
    • If the INR is in the target range, stop dabigatran and continue with warfarin.
    • If the INR is not in the target range, continue warfarin and dabigatran concurrently until the person's INR is in the target range, then stop dabigatran. Warfarin has a slow onset of action, and it may take 5–10 days before the INR is within range. 
  • After treatment with dabigatran has stopped:
    • Measure the INR after 24 hours and again after 2-3 days (reflecting solely warfarin therapy) to ensure adequate anticoagulation.
    • Monitor the person's INR closely (for example, once a week) in the first month of warfarin treatment until the person has three consecutive stable INR values (for example, between 2–3).
• Switching from dabigatran to another direct-acting oral anticoagulant (DOAC):
  • Stop dabigatran, and start the new DOAC (apixaban, edoxaban, or rivaroxaban) when the next dose of dabigatran is due.
• Switching from another DOAC to dabigatran:
  • Stop the initial DOAC (apixaban, edoxaban, or rivaroxaban), and start dabigatran when the next dose of the initial DOAC (apixaban, edoxaban, or rivaroxaban) is due.

Should dabigatran be stopped if surgery or dental treatment is required?

• If the person needs to have surgery or any other invasive procedure, they may need to temporarily stop taking dabigatran.
  • The decision to stop dabigatran and when to stop it will depend on the person's risk of having a thromboembolic event and the bleeding risk associated with the procedure. The DOAC interruption periods listed below may require adaptation based on the individual benefit/risk ratio and local guidance.
  • All patients undergoing a planned intervention, as well as caregivers (including primary care clinicians), should receive written information from the operating physician indicating the anticipated date and time of the intervention, as well as the date and time of the last DOAC intake.
  • If unsure about the risk/benefit of discontinuing, seek specialist advice from a consultant interventional cardiologist.
• For most minor surgical procedures and those associated with a minor bleeding risk, it is recommended not to interrupt oral anticoagulation.
  • In general, these procedures can be performed 12–24 hours after the last dose of dabigatran is taken.
• For procedures with a low bleeding risk, dabigatran should be stopped at least 24 hours before the procedure.
  • If creatinine clearance (CrCl) is 50–79 mL/minute, dabigatran should be stopped at least 36 hours before the procedure.
  • If CrCl is 30–49 mL/minute, dabigatran should be stopped at least 48 hours before the procedure.
• For procedures with a high bleeding risk, the last dose of dabigatran should be taken 48-72 hours before the procedure.
  • If CrCl is 50–79 mL/minute, dabigatran should be stopped at least 72 hours before the procedure.
  • If CrCl is 30–49 mL/minute, dabigatran should be stopped at least 96 hours before the procedure.
• For people who require a dental procedure with a:
  • Low risk of bleeding complications, treat without interrupting dabigatran treatment.
  • Higher risk of bleeding complications, advise them to miss their morning dose of dabigatran on the day of their dental treatment.
    • The evening dose should be taken at the usual time, provided it is no earlier than 4 hours after haemostasis has been achieved.

How should I monitor a person taking dabigatran?

There is no need to monitor the international normalized ratio (INR) in people taking dabigatran; however, regular follow up and monitoring are recommended.

• At the start of treatment, baseline clotting screen, renal and liver function tests, and a full blood count should be performed.
• Once treatment has started, review the person on a regular basis, preferably after 1 month initially.
  • Follow-up intervals may be longer or shorter depending on patient factors, such as bleeding risk factors, renal function, age, and comorbidities.
• During a review:
  • Assess adherence to treatment.
  • Look for signs of bleeding or anaemia. 
  • Ask about other adverse effects of dabigatran.
  • Assess for the presence of thromboembolic events, such as symptoms of stroke, or breathlessness (which may suggest a pulmonary embolism). See the CKS topics on Stroke and TIA and Pulmonary embolism for more information.
  • Ask about the use of other medications, including over-the-counter (OTC) products, to identify possible drug interactions with dabigatran.
  • Assess and minimize modifiable risk factors for bleeding, such as uncontrolled hypertension, medication predisposing for bleeding (such as aspirin), excessive alcohol intake and falls.
  • Give appropriate information and advice on dabigatran treatment. See the section on Advice for patients for more information.
• Repeat the full blood count and the renal and liver function tests yearly for most people.
  • If the person is frail or older than 75 years, repeat the blood tests every 4 months.
  • If the person has a creatinine clearance (CrCl) less than 60 mL/minute, the frequency of monitoring (in months) can be guided by the CrCl divided by 10. For example, every 3 months, if CrCl is 30 mL/minute.
  • If the person has an intercurrent illness that may impact renal or hepatic function, repeat renal and liver function tests as needed.
• Manage any problems identified during a review or from blood test results. 
  • If renal function has declined, review treatment — dabigatran may need to be stopped or a lower dose may be required. 
  • If there is an unexplained fall in haemoglobin and/or haematocrit, occult bleeding may be present (dabigatran can cause bleeding from any site).
    • Consider the need for stopping treatment with dabigatran — seek specialist advice and arrange further assessment to identify the underlying cause (with urgency depending on the specific clinical situation).
• See the section on Monitoring during Covid-19 pandemic for more monitoring advice.

How should I monitor a person taking dabigatran during the COVID-19 pandemic?

• When monitoring a person taking dabigatran during the COVID-19 pandemic, remember that:
  
  • Direct-acting oral anticoagulants (DOACs), such as dabigatran, may interact with other medicines, including antibacterials and antivirals. Follow the advice in the manufacturer's Summary of Product Characteristics (SPC), available on the electronic Medicines Compendium (eMC) website, to minimize the risk of potential interactions.
  • If switching from warfarin to dabigatran, stop warfarin before starting dabigatran, to reduce the risk of over-anticoagulation and bleeding. See the section on Switching anticoagulants for more information.

How should I manage dosing errors in a person taking dabigatran?

• If the person has missed a dose of dabigatran, the forgotten dose may be taken up to 6 hours prior to the next scheduled dose.
  • If the next scheduled dose is due within 6 hours, the missed dose should be omitted. 
  • A double dose should not be taken to make up for a missed individual dose.
• If the person has taken a double dose of dabigatran:
  • For a twice-daily dosing regimen of dabigatran, they should omit the next planned dose (that is, after 12 hours) and resume treatment as normal 24 hours after the double dose intake.
  • For a once-daily dosing regimen of dabigatran, they should take the next dose as normal the following day.
• If the person is uncertain whether they have taken their dose:
  • For a twice-daily dosing regimen of dabigatran, it is generally advisable not to take another dose, but to continue with the next scheduled dose (that is, after 12 hours).
  • For once-daily dosing regimen of dabigatran, management will depend on the person's thrombotic risk:
    • If thrombotic risk is high (CHA2DS2-VASc score greater than 3), it may generally be advisable to take another dose and then continue the planned dose regimen.
    • If thrombotic risk is low (CHA2DS2-VASc score less than 2), it is recommended that they wait until the time of their next scheduled dose.

What advice should I give a person who is taking dabigatran?

• Advise the person taking dabigatran:
  • That although (unlike warfarin) there is no need to have regular blood tests to monitor the international normalized ratio (INR), they will still require regular monitoring, blood tests, and review of their treatment.
  • On the importance of a regular dosing schedule.
    • The anticoagulant effect of dabigatran reduces 12–24 hours after the last dose is taken; therefore, it is important to take dabigatran as directed in order to reduce the risk of a thromboembolic event.
    • They should not miss doses (or take additional doses) without advice from a healthcare professional.
  • That they should seek immediate medical advice:
    • If spontaneous bleeding occurs and does not stop or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • If they get sudden severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • If they experience difficulty breathing, increased breathing rate, or chest pain (which could be symptoms of pulmonary embolism).
  • That they should also seek medical advice:
    • If there has been a dosing error, for example, a missed dose or if a double dose has been taken.
    • Before taking other medications, including over-the-counter drugs (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with dabigatran.
    • If they experience other adverse effects of dabigatran.
  • That they may have to stop dabigatran treatment temporarily for certain surgical and dental treatments.
  • To read the manufacturer's patient information leaflet, if they have not already.
  • To carry a Patient Alert Card at all times. These are contained in each UK tablet pack and can also be printed off from the electronic Medicines Compendium (eMC) website (www.medicines.org.uk).

What is the recommended dose and duration of treatment for edoxaban?

• For the prevention of stroke and systemic embolism in non-valvular atrial fibrillation in people with at least one risk factor, such as congestive heart failure, hypertension, aged 75 years and over, diabetes mellitus, previous stroke or transient ischaemic attack:
  • The recommended dose is 60 mg once daily.
  • A reduced dose of 30 mg once daily is recommended if the person:
    • Weighs 60 kg or less.
    • Has moderate or severe renal impairment (creatinine clearance [CrCl] 15–50 mL/minute).
    • Is receiving concurrent treatment with any of the following P-glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole. See the section on Drug interactions for more information.
  • Treatment is usually long-term.
• For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrent DVT and PE:
  • The recommended dose is 60 mg once daily following initial use of parenteral anticoagulation for at least 5 days.
  • A reduced dose of 30 mg once daily is recommended if the person:
    • Weighs 60 kg or less.
    • Has moderate or severe renal impairment (CrCl 15–50 mL/minute).
    • Is receiving concurrent treatment with any of the following P-gp inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole. See the section on Drug interactions for more information.
  • The duration of treatment should be individualized after careful assessment of the treatment benefit against the risk for bleeding:
    • Short duration of treatment (at least 3 months) should be based on transient risk factors (for example, recent surgery, trauma, and immobilization), and longer durations should be based on permanent risk factors.

What are the contraindications and cautions for edoxaban?

•  Edoxaban is contraindicated in:
  • People with:
    • Creatinine clearance (CrCl) less than 15 mL/minute.
    • Active bleeding.
    • Antiphospholipid syndrome — increased risk of recurrent thrombotic events.
    • Prosthetic heart valve and moderate to severe mitral stenosis — safety and efficacy not established.
    • Arteriovenous malformations.
    • Major intraspinal or intracerebral vascular abnormalities.
    • Uncontrolled severe hypertension.
    • Liver disease associated with coagulopathy and clinically relevant bleeding risk.
    • Concurrent use of any other anticoagulants except in specific clinical situations, such as switching anticoagulant therapy.
  • People with a significant risk of major bleeding, such as:
    • Current or recent gastrointestinal ulcer.
    • Known or suspected oesophageal varices.
    • Recent brain or spinal injury.
    • Recent brain, spine, or ophthalmic surgery.
    • Recent intracranial haemorrhage.
    • Malignant neoplasm at high risk of bleeding.
    • Vascular aneurysm.
  • Women who are pregnant or breastfeeding — the safety of edoxaban has not been established in these groups.
• Edoxaban should be used with caution in the following groups:
  • People with:
    
    • Moderate to severe renal impairment (CrCl 15–50 mL/minute) — dose reduction is indicated (approximately 50% of edoxaban is excreted renally).
    • Body weight of 60 kg or less — dose reduction is indicated (low body weight may increase plasma concentrations of edoxaban).
    • Mild or moderate hepatic impairment.
    • Elevated liver enzymes (alanine aminotransferase (ALT) or aspartate transaminase (AST) more than twice the upper limit of normal (ULN)) or total bilirubin 1.5 or more times the ULN.
  •  People taking certain drugs, including:
    • Strong inhibitors of P-glycoprotein (P-gp), such as ciclosporin, dronedarone, erythromycin, or ketoconazole — dose reduction is indicated (plasma concentration of edoxaban is increased by these drugs).
    • Other drugs that can cause bleeding, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombotic agents, fibrinolytic therapy, selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors— if concurrent treatment is unavoidable, close monitoring for signs of bleeding and anaemia is recommended. See the section on Drug interactions for more information, and for information on other drug interactions of edoxaban.

What are the adverse effects of edoxaban?

• Bleeding is a common adverse effect of all anticoagulants, including edoxaban, and it can occur in any part of the body.
  • Advise people taking edoxaban to:
    • Carry an alert card and keep it with them at all times.
    • Seek immediate medical advice if spontaneous bleeding occurs and does not stop, or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • Seek medical advice if they get sudden, severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • Get advice from a doctor or pharmacist before taking other medications, including over-the-counter medicines (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with edoxaban.
  • There is currently no reversal agent for edoxaban.
• Other adverse effects of edoxaban include: 
  • Common — abdominal pain, anaemia, dizziness, gastrointestinal disorders, headache, pruritus, rash, nausea, and abnormal liver function tests.
  • Uncommon — thrombocytopenia, hypersensitivity, and urticaria. 
  • Rare — anaphylactic reaction and allergic oedema.
  • Frequency unknown — anticoagulant-related nephropathy.

What are the key drug interactions for edoxaban?

• Key drug interactions with edoxaban include:
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) — edoxaban is predicted to increase the risk of bleeding events when given with NSAIDs (such as ibuprofen).
    • The manufacturer of edoxaban advises avoiding chronic use of NSAIDs.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
  • Other anticoagulants, such as heparin, warfarin, apixaban, dabigatran, and rivaroxaban — there is an increased risk of bleeding if other anticoagulants are given with edoxaban.
    • Avoid concurrent use except under specific circumstances such as switching anticoagulant therapy. See the section on Switching anticoagulants for more information.
  • Antiplatelets, such as aspirin, clopidogrel, and ticagrelor — edoxaban is predicted to increase the risk of bleeding events when given with antiplatelet drugs. 
    • The manufacturer of edoxaban advises using concurrently with caution or avoiding.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
  • Strong inhibitors of P-glycoprotein (P-gp), such as ciclosporin, dronedarone, erythromycin, itraconazole, and ketoconazole — plasma concentration of edoxaban is increased by these drugs (edoxaban is a substrate for P-gp).
    • The manufacturer advises that the dose of edoxaban should be reduced to 30 mg daily during concurrent treatment with these drugs.
    • With mild to moderate P-gp inhibitors, such as quinidine, amiodarone, and verapamil, no dose reduction is required during concurrent treatment with edoxaban.
  • Strong inducers of P-gp, such as carbamazepine, phenytoin, rifampicin, and St John's Wort — plasma concentration of edoxaban may be reduced by these drugs.
    • The manufacturer of edoxaban advises avoiding or using with caution.
    • If concurrent use is indicated, monitor for signs of thrombosis.
  • Selective serotonin reuptake inhibitors (such as citalopram), serotonin norepinephrine reuptake inhibitors (duloxetine), and venlafaxine — there is a possible increased risk of bleeding when edoxaban is given with these antidepressants.
    • The manufacturer of edoxaban advises to avoid concurrent use. 
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for other possible drug interactions with edoxaban.

How should I switch a person to or from another anticoagulant?

• Switching from warfarin to edoxaban:
  • Stop warfarin, and measure the international normalized ratio (INR): 
    • If the INR is less than 2, start edoxaban.
    • If the INR is between 2 and 2.5, start edoxaban immediately or the next day.
    • If the INR is greater than 2.5, wait until the person's INR has dropped to less than 2.5 before starting edoxaban.
  • The time taken for the person's INR to reach less than 2.5 will vary from person to person and will depend on what the person's initial INR level was.
• Switching from edoxaban to warfarin:
  • Start warfarin, and reduce the dose of edoxaban:
    • For people taking 60 mg of edoxaban, prescribe 30 mg once daily with warfarin.
    • For people taking 30 mg of edoxaban, prescribe 15 mg once daily with warfarin.
    • See the section on Starting warfarin treatment for information on how to initiate warfarin treatment.
    • The European Heart Rhythm Association advises that for the indication of atrial fibrillation, a loading dose of warfarin is not required when switching from edoxaban to warfarin – follow local protocol and seek specialist advice if unsure.
  • Continue concurrent warfarin and edoxaban until the person's INR is at the target range (2 or more), then stop edoxaban.
    • Most people should be able to achieve an INR of 2 or more within 14 days of concurrent administration of edoxaban and warfarin. 
    • Measure the INR at least 3 times just prior to taking the daily dose of edoxaban during the first 14 days of concurrent treatment.
    • After 14 days, it is recommended that edoxaban be discontinued and warfarin continued to be titrated to achieve an INR between 2–3.
  • After treatment with edoxaban has stopped:
    • Measure the INR after 24 hours to ensure adequate anticoagulation.
    • Monitor the person's INR closely in the first month of warfarin treatment until the person has three consecutive stable INR values (for example, between 2–3).
• Switching from edoxaban to another direct-acting oral anticoagulant (DOAC):
  • Stop edoxaban, and start the new DOAC (apixaban, dabigatran, or rivaroxaban) when the next dose of edoxaban is due.
• Switching from another DOAC to edoxaban:
  • Stop the initial DOAC (apixaban, dabigatran, or rivaroxaban), and start edoxaban when the next dose of the initial DOAC (apixaban, dabigatran, or rivaroxaban) is due.

Should edoxaban be stopped if surgery or dental treatment is required?

• If the person needs to have surgery or any other invasive procedure, they may need to temporarily stop taking edoxaban.
  • The decision to stop edoxaban and when to stop it will depend on the person's risk of having a thromboembolic event and the bleeding risk associated with the procedure. As such, the DOAC interruption periods listed below may require adaptation based on the individual benefit/risk ratio and local guidance.
  • All patients undergoing a planned intervention, as well as caregivers (including primary care clinicians), should receive written information from the operating physician indicating the anticipated date and time of the intervention, as well as the date and time of the last DOAC intake.
  • If unsure about the risk/benefit of discontinuing, seek specialist advice from a consultant interventional cardiologist.
• For most minor surgical procedures and those associated with a minor bleeding risk, it is recommended not to interrupt oral anticoagulation.
  • In general, these procedures can be performed 12–24 hours after the last dose of edoxaban is taken.
• For surgical procedures with a low bleeding risk, edoxaban should be stopped at least 24 hours before the procedure.
  • If the person has a creatinine clearance (CrCl) between 15–29 mL/min, edoxaban should be stopped at least 36 hours before the procedure.
• For procedures with a high bleeding risk, the last dose of edoxaban should be taken 48 to 72 hours before the procedure.
• For people who require a dental procedure with a:
  • Low risk of bleeding complications, treat without interrupting edoxaban treatment.
  • Higher risk of bleeding complications, advise them to delay their morning dose of edoxaban on the day of their dental treatment.
    • The delayed morning dose should be taken 4 hours after haemostasis has been achieved, and the next dose should be taken as usual the following morning.
    • If the person normally takes edoxaban in the evening, they can take this at the usual time on the day of treatment, provided it is no earlier than 4 hours after haemostasis has been achieved.

How should I monitor a person taking edoxaban?

There is no need to monitor the international normalized ratio (INR) in people taking edoxaban; however, regular follow up and monitoring are recommended.

• • At the start of treatment, baseline clotting screen, renal and liver function tests, and a full blood count should be performed.
  • Once treatment has started, review the person on a regular basis, preferably after 1 month initially. 
    • Follow-up intervals may be longer or shorter depending on patient factors, such as bleeding risks, renal function, age, and comorbidities.
  • During a review:
    • Assess adherence to treatment.
    • Look for signs of bleeding or anaemia. 
    • Ask about other adverse effects of edoxaban.
    • Assess for features of thromboembolic events, such as symptoms of stroke, or breathlessness (which may suggest a pulmonary embolism). See the CKS topics on Stroke and TIA and Pulmonary embolism for more information.
    • Ask about the use of other medications, including over-the-counter (OTC) products, to identify possible drug interactions with edoxaban.
    • Assess and minimize modifiable risk factors for bleeding, such as uncontrolled hypertension, medication predisposing for bleeding (such as aspirin), excessive alcohol intake and falls.
    • Give appropriate information and advice on edoxaban treatment. See the section on Advice for patients for more information.
  • Repeat the renal and liver function tests and the full blood count yearly for most people.
    • If the person is frail or older than 75 years, repeat the blood tests every 4 months.
    • If the person has a creatinine clearance (CrCl) less than 60 mL/minute, the frequency of monitoring (in months) can be guided by the CrCl divided by 10. For example, every 3 months if CrCl is 30 mL/minute.
    • If the person has an intercurrent illness that may impact renal or hepatic function, repeat renal and liver function tests as needed.
  • Manage any problems identified during a review or from blood test results. 
    • If renal function has declined, review treatment — edoxaban may need to be stopped or a lower dose may be required. 
    • If there is an unexplained fall in haemoglobin and/or haematocrit, occult bleeding may be present (edoxaban can cause bleeding from any site).
      • Consider the need for stopping treatment with edoxaban — seek specialist advice and arrange further assessment to identify the underlying cause (with urgency depending on the specific clinical situation).
  • See the section on Monitoring during Covid-19 pandemic for more monitoring advice.

How should I monitor a person taking edoxaban during the COVID-19 pandemic?

• When monitoring a person taking edoxaban during the COVID-19 pandemic, remember that:
  
  • Direct-acting oral anticoagulants (DOACs), such as edoxaban, may interact with other medicines, including antibacterials and antivirals. Follow the advice in the manufacturer's Summary of Product Characteristics (SPC), available on the electronic Medicines Compendium (eMC) website, to minimize the risk of potential interactions.
  • If switching from warfarin to edoxaban, stop warfarin before starting edoxaban, to reduce the risk of over-anticoagulation and bleeding. See the section on Switching anticoagulants for more information.

How should I manage dosing errors in someone taking edoxaban?

• If the person has missed a dose of edoxaban, the forgotten dose should be taken immediately, and they should continue the following day with the once-daily dose as normal.
  • A double dose should not be taken on the same day to make up for a missed dose.
• If the person has taken a double dose of edoxaban, they should take the next dose as normal the following day.
• If the person is uncertain whether they have taken their dose, management will depend on their thrombotic risk:
  • If thrombotic risk is high (CHA2DS2-VASc score greater than 3), it may generally be advisable to take another dose and then continue the planned dose regimen.
  • If thrombotic risk is low (CHA2DS2-VASc score less than 2), it is recommended that they wait until the time of their next scheduled dose.

What advice should I give a person who is taking edoxaban?

• Advise the person taking edoxaban:
  • That although (unlike warfarin) there is no need to have regular blood tests to monitor the international normalized ratio (INR), they will still require regular monitoring, blood tests, and review of their treatment.
  • On the importance of a regular dosing schedule.
    • The anticoagulant effect of edoxaban reduces 12–24 hours after the last dose is taken; therefore, it is important to take edoxaban as directed or the person is at increased risk of a thromboembolic event.
    • They should not miss doses (or take additional doses) without advice from a healthcare professional.
  • That they should seek immediate medical advice:
    • If spontaneous bleeding occurs and does not stop or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • If they get sudden severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • If they experience difficulty breathing, increased breathing rate, or chest pain (which could be symptoms of pulmonary embolism).
  • That they should also seek medical advice:
    • If there have been dosing errors (for example, a missed dose or if a double dose has been taken).
    • Before taking other medications, including over-the-counter medicines (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with edoxaban.
    • If they experience other adverse effects of edoxaban.
  • That they may have to stop edoxaban treatment temporarily for certain surgical and dental treatments.
  • To read the manufacturer's patient information leaflet, if they have not already.
  • To carry a Patient Alert Card at all times. These are contained in each UK tablet pack and can also be printed off from the electronic Medicines Compendium (eMC) website (www.medicines.org.uk).

What is the recommended dose and treatment duration for rivaroxaban?

Rivaroxaban must be taken with food. In people who have difficulty swallowing, the tablets can be crushed and mixed with water or apple puree immediately before, and followed by food immediately after, ingestion.

• For the prophylaxis of stroke and systemic embolism in adults with non-valvular atrial fibrillation and at least one risk factor, such as congestive heart failure, hypertension, previous stroke or transient ischaemic attack, age 75 years or older, or diabetes mellitus:
  • The recommended dose is 20 mg once daily.
  • In people with moderate to severe renal impairment (creatinine clearance [CrCl] 15–49 mL/minute), the recommended dose is 15 mg once daily.
  • For this indication, treatment with rivaroxaban is usually long-term.
• For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE):
  • The recommended dose is 15 mg twice daily for the first 21 days, then 20 mg once daily thereafter.
  • In people with moderate to severe renal impairment (CrCl 15–49 mL/minute), following the first 21 days of treatment for DVT or PE:
    • A dose reduction from 20 mg once daily to 15 mg once daily should be considered if the risk of bleeding outweighs the risk of recurrent DVT or PE.
  • The duration of treatment will vary for each individual, depending on a variety of factors. The manufacturer recommends:
    • Short-term treatment (3 months) for people with transient risk factors, such as recent surgery and trauma.
    • Long-term treatment for people with permanent risk factors or idiopathic (unprovoked) DVT or PE.
• For the prophylaxis of recurrent DVT and PE in adults (following completion of at least 6 months of anticoagulant treatment):
  • The recommended dose is 10 mg once daily, increasing to 20 mg once daily in people considered to be at high risk of recurrence (such as with complicated comorbidities or previous recurrence with rivaroxaban 10 mg once daily).
  • In people with moderate to severe renal impairment (CrCl is 15–49 mL/minute):
    • When the recommended dose is 20 mg once daily, a dose reduction to 15 mg once daily should be considered if the risk of bleeding outweighs the risk of recurrent DVT or PE.
    • When the recommended dose is 10 mg once daily, no dose adjustment is needed.
• For the prophylaxis of venous thromboembolism (VTE) in people who have undergone hip replacement surgery:
  • The recommended dose is 10 mg once daily for 35 days, to be started 6–10 hours after surgery.
• For the prophylaxis of VTE in people who have undergone knee replacement surgery:
  • The recommended dose is 10 mg once daily for 14 days, to be started 6–10 hours after surgery.
• For the prophylaxis of atherothrombotic events following an acute coronary syndrome with elevated cardiac biomarkers (in combination with aspirin alone or aspirin and clopidogrel):
  • The recommended dose is 2.5 mg twice daily. 
  • The usual duration is 12 months.
• For the prophylaxis of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events (in combination with aspirin):
  
  • The recommended dose is 2.5 mg twice daily.

What are the contraindications and cautions for rivaroxaban?

• Rivaroxaban is contraindicated in:
  • People with:
    
    • Severe renal impairment (creatinine clearance [CrCl] less than 15 mL/minute).
    • Active bleeding.
    • Antiphospholipid syndrome — increased risk of recurrent thrombotic events.
    • A prosthetic heart valve — efficacy not established.
    • Liver disease associated with coagulopathy and clinically relevant bleeding risk, as well as people who have cirrhosis with Child-Pugh grade B (moderate impairment) or grade C (severe impairment).
    • Previous stroke — when used for prophylaxis of atherothrombotic events following an acute coronary syndrome (ACS), or prophylaxis of atherothrombotic events in people with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD).
    • Transient ischaemic attack — when used for prophylaxis of atherothrombotic events following an ACS.
  • People with a significant risk of major bleeding, such as:
    • Current or recent gastrointestinal ulcer.
      • Use of rivaroxaban is also not recommended in people with gastrointestinal disease without active ulceration that can potentially lead to bleeding complications, including inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease.
    • Known or suspected oesophageal varices.
    • Recent brain or spinal injury.
    • Recent brain, spine, or ophthalmic surgery.
    • Recent intracranial haemorrhage.
    • Malignant neoplasm at high risk of bleeding.
      • People with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in patients with active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumours located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding during rivaroxaban therapy.
    • Congenital or acquired bleeding disorders.
    • Uncontrolled severe arterial hypertension.
    • Arteriovenous malformation.
    • Major intraspinal or intracerebral vascular abnormalities.
    • Vascular aneurysm.
    • Vascular retinopathy.
    • Bronchiectasis or history of pulmonary bleeding.
    • Concomitant use with any other anticoagulants except in specific circumstances such as switching anticoagulant therapy.
  • Pregnant and breastfeeding women — the safety of rivaroxaban has not been established in these groups.
• Rivaroxaban should be used with caution in the following groups:
  • Elderly people — the benefits and risks of treatment should be individually assessed on a regular basis. Close monitoring for signs of bleeding and anaemia is recommended (increasing age may increase bleeding risk).
  • People with:
    • Moderate to severe renal impairment (CrCl 15–49 mL/minute) — dose reduction is indicated (approximately 35% of rivaroxaban is excreted renally).
  • People on concurrent treatment with other drugs that can cause bleeding, such as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, platelet aggregation inhibitors or selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.
    • If concurrent treatment is unavoidable, close monitoring for signs of bleeding and anaemia is recommended. See the section on Drug interactions for more information, and for information on other drug interactions of rivaroxaban.
• When used for prophylaxis of atherothrombotic events following an ACS, or prophylaxis of atherothrombotic events in people with CAD or symptomatic PAD, rivaroxaban should be used with caution in:
  
  • People with body weight less than 60 kg — close monitoring for signs of bleeding and anaemia is recommended (low body weight may increase plasma concentrations of rivaroxaban). No dose adjustment is needed.

What are the adverse effects of rivaroxaban?

• Bleeding is a common adverse effect of all anticoagulants, including rivaroxaban, and it can occur in any part of the body.
  • Advise people taking rivaroxaban to:
    
    • Carry an alert card and keep it with them at all times.
    • Seek immediate medical advice if spontaneous bleeding occurs and does not stop, or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • Seek medical advice if they get sudden, severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • Get advice from a doctor or pharmacist before taking other medications, including over-the-counter medicines (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with rivaroxaban.
  • Andexanet alfa (Ondexxya®) is a specific reversal agent indicated for adults treated with a direct factor Xa (FXa) inhibitor (rivaroxaban or apixaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
• Other adverse effects of rivaroxaban include:
  • Common or very common — anaemia, fatigue, asthenia, constipation, diarrhoea, dizziness, fever, gastrointestinal discomfort, dyspepsia, constipation, headache, hypotension, haematoma, menorrhagia, nausea, vomiting, oedema, pain in extremity, renal impairment, increase in transaminases, pruritus, and skin reactions.
  • Uncommon — angioedema and allergic oedema, allergic reaction, allergic dermatitis, dry mouth, feeling unwell, hepatic disorders, haemarthrosis, hypersensitivity, malaise, syncope, tachycardia, thrombocytopenia, thrombocytosis, and urticaria.
  • Rare or very rare — anaphylactic reactions (including anaphylactic shock), jaundice, cholestasis, hepatitis (including hepatocellular injury), Stevens-Johnson syndrome/toxic epidermal necrolysis, eosinophilic pneumonia, and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).
  • Frequency unknown — nephropathy, compartment syndrome secondary to bleeding, renal failure/acute renal failure secondary to bleeding sufficient to cause hypoperfusion.

What are the key drug interactions for rivaroxaban?

• Key drug interactions with rivaroxaban include:
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) — rivaroxaban is predicted to increase the risk of bleeding events when given with NSAIDs (such as ibuprofen). 
    • The manufacturer of rivaroxaban advises avoiding concurrent use or using with caution.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
  • Other anticoagulants, such as heparin, warfarin, apixaban, or dabigatran — there is an increased risk of bleeding if other anticoagulants are given with rivaroxaban.
    • Avoid concurrent use, except when switching anticoagulant therapy. See the section Switching anticoagulants for more information.
  • Antiplatelets, such as aspirin, clopidogrel, and ticagrelor — rivaroxaban is predicted to increase the risk of bleeding events when given with antiplatelet drugs. 
    • The manufacturer of rivaroxaban advises caution.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
  • Strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as itraconazole, ketoconazole, and HIV protease inhibitors (for example, ritonavir) — plasma concentration of rivaroxaban is increased by these drugs.
    • The manufacturer of rivaroxaban advises avoiding concurrent use with these drugs.
    • For drugs that are not considered strong inhibitors of both CYP3A4 and P-gp, such as clarithromycin, erythromycin, and fluconazole, the plasma concentration of rivaroxaban is increased to a lesser extent. The interaction with rivaroxaban is likely not clinically relevant in most people but can be potentially significant in high-risk people, for example, those with renal impairment.
  • Strong inducers of both CYP3A4 and P-gp, such as carbamazepine, phenytoin, rifampicin, and St John's Wort — plasma concentration of rivaroxaban may be reduced by these drugs.
    • The manufacturer of rivaroxaban advises avoiding.
    • If concurrent use is indicated, monitor for signs of thrombosis.
  • Selective serotonin reuptake inhibitors (such as citalopram), serotonin norepinephrine re-uptake inhibitors (duloxetine), and venlafaxine — there is a possible increased risk of bleeding when rivaroxaban is given with these antidepressants.
    
    • The manufacturer of rivaroxaban advises caution.
    • If concurrent use is indicated, monitor for signs of bleeding and anaemia.
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for other possible drug interactions with rivaroxaban.

How should I switch a person to or from another anticoagulant?

• Switching from warfarin to rivaroxaban:
  • Stop warfarin, and measure the international normalized ratio (INR):
    • For prevention of stroke and systemic embolism: warfarin treatment should be stopped and rivaroxaban therapy should be initiated when the INR is 3.0 or lower.
    • For the treatment of DVT, PE and prevention of recurrence, warfarin treatment should be stopped and rivaroxaban therapy should be initiated once the INR is 2.5 or lower.
  • The time taken for the person's INR to reach less than 2 will vary from person to person and will depend on what the person's initial INR level was.
• Switching from rivaroxaban to warfarin:
  • Start warfarin, but do not stop rivaroxaban.
    • See the section on Starting warfarin treatment for information on how to initiate warfarin treatment.
    • The European Heart Rhythm Association advises that for the indication of atrial fibrillation, a loading dose of warfarin is not required when switching from rivaroxaban to warfarin – follow local protocol and seek specialist advice if unsure.
  • Continue concurrent warfarin and rivaroxaban, and measure the INR just before the person takes their next dose of rivaroxaban.
    
    • If the INR is in the target range (2 or more), stop rivaroxaban and continue with warfarin.
    • If the INR is not in the target range, continue warfarin and rivaroxaban concurrently until the person's INR is in the target range. 
    • During concurrent treatment with warfarin and rivaroxaban, the INR should be measured just before the person takes their next dose of rivaroxaban.
    • Warfarin has a slow onset of action, and it may take 5–10 days before the INR is within range. 
  • After treatment with rivaroxaban has stopped:
    • Measure the person's INR after 24 hours to ensure adequate anticoagulation.
    • Monitor the person's INR closely in the first month of warfarin treatment until the person has three consecutive stable INR values (for example, between 2–3).
• Switching from rivaroxaban to another direct-acting oral anticoagulant (DOAC):
  • Stop rivaroxaban, and start the new DOAC (apixaban, dabigatran, or edoxaban) when the next dose of rivaroxaban is due.
• Switching from another DOAC to rivaroxaban:
  
  • Stop the initial DOAC (apixaban, dabigatran, or edoxaban), and start rivaroxaban when the next dose of the initial DOAC (apixaban, dabigatran, or edoxaban) is due.

Should rivaroxaban be stopped if surgery or dental treatment is required?

• If the person needs to have surgery or any other invasive procedure, they may need to temporarily stop taking rivaroxaban.
  • The decision to stop rivaroxaban and when to stop it will depend on the person's risk of having a thromboembolic event and the bleeding risk associated with the procedure. As such, the DOAC interruption periods listed below may require adaptation based on the individual benefit/risk ratio and local guidance.
  • All patients undergoing a planned intervention, as well as caregivers (including primary care clinicians) should receive written information from the operating physician indicating the anticipated date and time of the intervention,the as well as the date and time of last DOAC intake.
  • If unsure about the risk/benefit of discontinuing, seek specialist advice from a consultant interventional cardiologist.
• For most minor surgical procedures and those associated with a minor bleeding risk, it is recommended not to interrupt oral anticoagulation.
  • In general, these procedures can be performed 12–24 hours after the last dose of rivaroxaban is taken.
• For surgical procedures with a low bleeding risk, rivaroxaban should be stopped at least 24 hours before the procedure.
  • If the person has a creatinine clearance (CrCl) between 15–29 mL/minute, rivaroxaban should be stopped at least 36 hours before the procedure.
• For procedures with a high bleeding risk, the last dose of rivaroxaban should be taken 48 to 72 hours before the procedure. 
• For people who require a dental procedure with a:
  • Low risk of bleeding complications, treat without interrupting rivaroxaban treatment.
  • Higher risk of bleeding complications, advise them to delay their morning dose of rivaroxaban on the day of their dental treatment.
    • The delayed morning dose should be taken 4 hours after haemostasis has been achieved, and the next dose should be taken as usual the following morning.
    • If the person normally takes rivaroxaban in the evening, they can take this at the usual time on the day of treatment, provided it is no earlier than 4 hours after haemostasis has been achieved.

How should I monitor a person taking rivaroxaban?

There is no need to monitor the international normalized ratio (INR) in people taking rivaroxaban; however, regular follow up and monitoring is recommended.

• At the start of treatment, baseline clotting screen, renal and liver function tests, and a full blood count should be performed.
• Once treatment has started, review the person on a regular basis, preferably after 1 month initially.
  • Follow-up intervals may be longer or shorter depending on patient factors, such as bleeding risk, renal function, age, and comorbidities.
• During a review:
  • Assess adherence to treatment.
  • Look for signs of bleeding or anaemia.
  • Ask about other adverse effects of rivaroxaban.
  • Assess for features of thromboembolic events, such as symptoms of stroke, or breathlessness (which may suggest a pulmonary embolism). See the CKS topics on Stroke and TIA and Pulmonary embolism for more information.
  • Ask about the use of other medications, including over-the-counter (OTC) products, to identify possible drug interactions with rivaroxaban.
  • Assess and minimize modifiable risk factors for bleeding, such as uncontrolled hypertension, medication predisposing for bleeding (such as aspirin), excessive alcohol intake and falls.
  • Give appropriate information and advice on rivaroxaban treatment. See the section on Advice for patients for more information.
• Repeat the renal and liver function tests and the full blood count yearly for most people.
  • If the person is frail or older than 75 years, repeat the blood tests every 4 months.
  • If the person has a creatinine clearance (CrCl) less than 60 mL/minute, the frequency of monitoring (in months) can be guided by the CrCl divided by 10. For example, every 3 months if CrCl is 30 mL/minute.
  • If the person has an intercurrent illness that may impact renal or hepatic function, repeat renal and liver function tests as needed.
• Manage any problems identified during a review or from blood test results. 
  • If renal function has declined, review treatment — rivaroxaban may need to be stopped or a lower dose may be required. 
  • If there is an unexplained fall in haemoglobin and/or haematocrit, occult bleeding may be present (rivaroxaban can cause bleeding from any site).
    • Consider the need for stopping treatment with rivaroxaban — seek specialist advice and arrange further assessment to identify the underlying cause (with urgency depending on the specific clinical situation).
• See the section on Monitoring during Covid-19 pandemic for more monitoring advice.

How should I monitor a person taking rivaroxaban during the COVID-19 pandemic?

• When monitoring a person taking rivaroxaban during the COVID-19 pandemic, remember that:
  
  • Direct-acting oral anticoagulants (DOACs), such as rivaroxaban, may interact with other medicines, including antibacterials and antivirals. Follow the advice in the manufacturer's Summary of Product Characteristics (SPC), available on the electronic Medicines Compendium (eMC) website, to minimize the risk of potential interactions.
  • If switching from warfarin to rivaroxaban, stop warfarin before starting rivaroxaban, to reduce the risk of over-anticoagulation and bleeding. See the section on Switching anticoagulants for more information.

How should I manage dosing errors in a person taking rivaroxaban?

• If the person has missed a dose of rivaroxaban:   
  • During a 15 mg twice-daily dosing regimen of rivaroxaban (every 12 hours), the forgotten dose should be taken immediately (this may mean taking two tablets at the same time to ensure the full daily dose [30 mg] is taken). The normal twice-daily regimen should be continued the following day.
  • For a once-daily dosing regimen of rivaroxaban (every 24 hours), the forgotten dose should be taken immediately and continued as normal the following day. A double dose should not be taken on the same day to make up for a missed dose. 
  • For a 2.5 mg twice daily dosing regimen of rivaroxaban, the person should continue with the regular dose as recommended at the next scheduled time. The dose should not be doubled to make up for a missed dose.
• If the person has taken a double dose of rivaroxaban:
  • For a twice-daily dosing regimen of rivaroxaban, they should omit the next planned dose (that is, after 12 hours) and resume treatment as normal 24 hours after the double dose intake.
  • For a once-daily dosing regimen of rivaroxaban, they should take the next dose as normal the following day.
• If the person is uncertain whether they have taken their dose:
  • For a twice-daily dosing regimen of rivaroxaban, it is generally advisable not to take another dose, but to simply continue with the regular dose regimen (that is, starting with the next dose at the 12-hour interval).
  • For a once-daily dosing regimen of rivaroxaban, management will depend on the person's thrombotic and bleeding risk:
    • If thrombotic risk is high (CHA2DS2-VASc score greater than 3) and bleeding risk is low, it may generally be advisable to take another dose and then continue the planned dose regimen.
    • If thrombotic risk is low (CHA2DS2-VASc score less than 2) and bleeding risk is high, it is recommended to wait until the next scheduled dose.

What advice should I give a person who is taking rivaroxaban?

• Advise the person taking rivaroxaban:
  • That although (unlike warfarin) there is no need to have regular blood tests to monitor the international normalized ratio (INR), they will still require regular monitoring, blood tests, and review of their treatment.
  • On the importance of a regular dosing schedule.
    • The anticoagulant effect of rivaroxaban reduces 12–24 hours after the last dose is taken; therefore, it is important to take it as directed in order to reduce the risk of a thromboembolic event.
    • They should not miss doses (or take additional doses) without advice from a healthcare professional.
  • That rivaroxaban must be taken with food.
    • If the person has difficulty swallowing, the tablets can be crushed and mixed with water or apple puree immediately before, and followed by food immediately after ingestion.
  • That they should seek immediate medical advice:
    • If spontaneous bleeding occurs and does not stop, or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, haemoptysis, subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • If they get sudden severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • If they experience difficulty breathing, increased breathing rate, or chest pain (which could be symptoms of pulmonary embolism).
  • That they should also seek medical advice:
    • If there has been a dosing error (for example, a missed dose or if a double dose has been taken).
    • Before taking other medications, including over-the-counter medicines (such as nonsteroidal anti-inflammatory drugs) and herbal remedies, due to possible drug interactions with rivaroxaban.
    • If they experience other adverse effects of rivaroxaban.
  • That they may have to stop rivaroxaban treatment temporarily for certain surgical and dental treatments.
  • To read the manufacturer's patient information leaflet.
  • To carry a Patient Alert Card at all times. These are contained in each UK tablet pack and can also be printed off from the Electronic Medicines Compendium website (www.medicines.org.uk)

What is the starting dose when warfarin treatment is initiated?

• Baseline full blood count, liver function tests and coagulation screen, including prothrombin (PT) or international normalized ratio (INR) measurements, should be taken before starting treatment with warfarin.
  • The typical induction dose of warfarin is 10 mg daily for 2 days, but this should be tailored to individual requirements. 
    • A low starting dose is often more suitable for frail or elderly people, people with a low body weight, people with liver disease or cardiac failure, and people at high risk of bleeding. Subsequent doses depend on the PT, reported as an INR. 
    • The INR should be checked daily or on alternate days in the early days of treatment. Once the INR has stabilised in the target range, the INR can be monitored at longer intervals (depending on response and in line with local protocol).
      • INR should be monitored more frequently in people at an increased risk of overcoagulation (for example, those with liver or renal disease) and those for whom adherence may be difficult.
    • People with protein C deficiency are at increased risk of developing skin necrosis when starting warfarin treatment.
      • In people with protein C deficiency, therapy should be introduced without a loading dose of warfarin. People with protein S deficiency may also be at risk — slow introduction of warfarin is advised.
      • Seek specialist advice from the haematology or anti-coagulation team.
  • The daily maintenance dose of warfarin is usually 3–9 mg, taken at the same time each day.
    • The exact maintenance dose is dependent on the INR or other appropriate coagulation tests.
    • INR should be monitored at regular intervals, and the maintenance dose should be adjusted accordingly.
    • A maintenance dose can be omitted if the prothrombin time is excessively prolonged. 
  • Where an immediate effect is required (for example, in deep venous thrombosis or a pulmonary embolism), heparin or a low molecular weight heparin is given concurrently until adequate anti-coagulation is achieved.
    • Where there is less urgency, anticoagulant treatment may be initiated with warfarin alone.
  • For people with atrial fibrillation, there is generally no need to achieve anticoagulation rapidly; a slow-loading regimen is safe and achieves therapeutic anticoagulation in most people within 3–4 weeks — follow local protocol. 
  • Specialist advice should be sought if the person has a prolonged baseline prothrombin time.
    • Monitoring the person's INR may be problematic, and an alternative anticoagulant may be required. 

What is the duration of treatment with warfarin?

• For people with deep vein thrombosis (DVT) and pulmonary embolism (PE):
  • Duration of treatment will vary for each person, depending on a variety of factors.
  • Experts are not unanimous on the optimal duration of warfarin treatment, but usually it should be continued:
    • For at least six weeks in people with isolated distal DVT (calf vein thrombosis).
    • For at least three months in people with proximal DVT or PE where there are known temporary risk factors and there is considered to be a low risk of recurrence.
    • Long-term if there have been recurrent DVTs or PEs.
  • People with unprovoked proximal DVT or PE should be considered for long-term anticoagulation, taking into account information that may help predict risk of recurrence and risk of bleeding in each specific clinical situation.
  • Warfarin can be stopped abruptly without harm when the duration of treatment is completed.
• For people with atrial fibrillation (AF):
  • Warfarin treatment is usually long-term.
  • If the person is going to have cardioversion, the target international normalized ratio (INR) should be achieved at least 3 weeks before cardioversion and 4 weeks after (if normal sinus rhythm is maintained).
  • People who have undergone cardioversion and have a high risk of AF recurring also require long-term warfarin treatment. People at high risk of AF recurring include those with:
    • A history of failed attempts at cardioversion.
    • Structural heart disease (mitral valve disease, left ventricular dysfunction, or an enlarged left atrium).
    • A prolonged history of AF (greater than 12 months).
    • Previous recurrences of AF.
• For people with mechanical prosthetic heart valves, warfarin treatment is usually long-term.

What are the contraindications and cautions for warfarin?

• Warfarin is contraindicated:
• In people with:
• Haemorrhagic stroke.
• Clinically significant bleeding. 
• Severe hepatic impairment.
• Within 72 hours of major surgery with risk of severe bleeding.
• Within 48 hours postpartum.
• In pregnant women — due to the risk of teratogenicity.
• In people taking drugs where interactions lead to a significantly increased risk of bleeding.
• Warfarin should be used with caution in the following groups: 
• People aged 65 years or older.
• People with increased risk of bleeding — warfarin should be used with extreme caution if the benefit of anticoagulation outweighs the risk. Risk factors for bleeding include:
• History of gastrointestinal bleeding.
• History of peptic ulceration.
• Recent ischaemic stroke.
• Uncontrolled hypertension.
• Concurrent nonsteroidal anti-inflammatory (NSAID) use.
• Recent surgery.
• The postpartum period — should be delayed until the risk of bleeding is low, usually 5–7 days after delivery. 
• People with:
• Thrombophilia — warfarin should be introduced slowly due to the risk of skin necrosis.
• Thyroid disorders — the rate of warfarin metabolism depends on thyroid status. People with hyperthyroidism or hypothyroidism should be closely monitored.
• Risk factors for over coagulation, such as severe hypertension, or severe renal or hepatic impairment — international normalized ratio (INR) should be monitored more frequently.
• Mild to moderate hepatic or renal impairment.
• Bacterial endocarditis.
• Risk of falling.
• The following factors may exaggerate the effect of warfarin and necessitate a dose reduction:
• Weight loss.
• Acute illness
• Smoking cessation.
• The following factors may reduce the effect of warfarin and necessitate a dose increase:
• Weight gain.
• Diarrhoea.
• Vomiting.

What are the adverse effects of warfarin?

• Bleeding is a common adverse effect of all anticoagulants, including warfarin, and it can occur in any part of the body.
  
  • Advise the person taking warfarin to seek immediate medical advice if:
    • Spontaneous bleeding occurs whilst on warfarin and the bleeding does not stop, or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, coughing up blood, a subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • They get sudden severe back pain (which may indicate spontaneous retroperitoneal bleeding).
  •  Vitamin K1 (phytomenadione) is indicated as an antidote to coumarin anticoagulants (such as warfarin) in the treatment of haemorrhage or threatened haemorrhage, associated with a low blood level of prothrombin or factor VII.
• Other adverse effects of warfarin include:
  • Rare or very rare — alopecia, nausea, and vomiting.
  • Frequency unknown — blue toe syndrome, diarrhoea, fever, haemothorax, jaundice, pancreatitis, skin reactions, and abnormal hepatic function. 
• Skin necrosis and calciphylaxis are rare but serious adverse effects of warfarin.
  • Warfarin-related skin necrosis presents as painful, localized skin lesions (due to thrombosis of venules and capillaries) within subcutaneous fat.
    • It is associated with the use of high induction doses of warfarin and is more likely in people with protein C or protein S deficiency.
    • The lesions can occur in areas of fatty tissue, such as the breasts, abdomen, or extremities.
    • Treatment with warfarin should be stopped if warfarin-related skin necrosis is suspected.
  • Calciphylaxis is a rare syndrome of vascular calcification with cutaneous necrosis, associated with high mortality.
    • It mainly occurs in people with end-stage renal disease on dialysis or in people with known risk factors, such as protein C or S deficiency, hyperphosphataemia, hypercalcaemia, or hypoalbuminaemia.
    • Rare cases of calciphylaxis have been reported in people taking warfarin, also in the absence of renal disease.
    • Advise people taking warfarin to seek urgent medical advice if they develop a painful skin rash.
    • If diagnosed, appropriate treatment should be started and stopping warfarin treatment considered.

What are the key drug interactions with warfarin?

Warfarin has a narrow therapeutic range, and care is required with all concomitant therapy. If prescribing a drug that may interact, check the person’s international normalized ratio (INR) 3–5 days after starting treatment with the new drug.

• Concomitant use of the following should be avoided if possible:
  • Clopidogrel and dipyridamole. Low-dose aspirin with warfarin may have a role in some patients, but the risk of gastrointestinal bleeding is increased.
  • Non-steroidal anti-inflammatory drugs (NSAIDs).
  • Direct oral anticoagulants (DOACs), for example, dabigatran, rivaroxaban.
  • Unfractionated heparins and heparin derivatives, low molecular weight heparins. Warfarin may initially be given with a heparin in the initial treatment of thrombosis, until the INR is in the correct range.
  • Glycoprotein IIb/IIIa receptor antagonists such as tirofiban.
  • Selective serotonin reuptake inhibitor (SSRI) and serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants.
  • Azoles, including fluconazole and miconazole.
• The following interactions may enhance the effect of warfarin and are likely to need close monitoring and clinical intervention, especially when initiating, changing, and stopping concurrent treatment.
  • Alcohol — the person should avoid binge drinking. Heavy drinkers or people with liver disease should avoid alcohol or should not take warfarin.
  • Amiodarone — amiodarone increases the anticoagulant effect of warfarin, monitor INR closely during treatment and after amiodarone is stopped – the interaction between warfarin and amiodarone persists for a month or more after amiodarone is stopped.
  • Antibiotics — such as macrolide antibiotics and metronidazole. Monitor INR carefully and adjust warfarin dose.
  • Antidepressants — SSRIs and SNRIs should be avoided where possible there may be an increased risk of bleeding when taken concurrently with warfarin due to their antiplatelet effect. Consider increasing the frequency of INR monitoring. Some tricyclic antidepressants (TCAs) and mirtazapine should also be avoided due to an enhanced anticoagulant effect.
  • Aspirin or aspirin-containing products (for example, cold and influenza preparations, and topical salicylates) — avoid concurrent use unless clinically indicated. High-dose aspirin should be avoided. If low-dose aspirin is indicated, monitor for signs of bleeding and consider giving gastroprotection (for example, a proton pump inhibitor) to at-risk patients.
  • Azoles (in particular fluconazole, miconazole, and voriconazole) — monitor and adjust warfarin dose based on the INR. Monitoring is also recommended in people using intravaginal or topical miconazole.
    • Miconazole oral gel should be avoided. If concurrent use of miconazole and warfarin is necessary, the anticoagulant effect should be carefully monitored and, where indicated, the dose of warfarin reduced. Advise people to stop the miconazole and seek immediate medical attention if they experience any signs of bleeding (such as unexplained bruising, nose bleeds, or blood in their urine). Bleeding can take up to 15 days to develop.
  • Cranberry juice or cranberry-containing products — advise the person to avoid concurrent use; INRs greater than 8 have occurred.
  • Pomegranate juice — an increase in INR may occur.
  • Clopidogrel or dipyridamole — concurrent use should be avoided unless clinically indicated. Consider gastroprotection in people at risk of gastrointestinal bleeds.
  • Tramadol — there is a risk of increased INR when warfarin and tramadol are taken together, which can lead to potentially life-threatening bruising and bleeding.
  • Corticosteroids — corticosteroids have a variable effect on INR – monitor and adjust the dose of warfarin as needed.
  • Direct-acting antiviral medications for treatment of chronic hepatitis C — monitor INR closely, and adjust warfarin treatment if necessary. Changes in liver function, secondary to hepatitis C treatment with direct-acting antivirals, may affect the efficacy of warfarin because of possible changes in liver function during treatment.
  • Fibrates — avoid concurrent use if possible, or reduce the warfarin dose as necessary.
  • Glucosamine — avoid concurrent use.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), including topical formulations  — avoid concurrent use. If the person must take an oral NSAID, use with caution, monitor and counsel the person on signs of gastrointestinal bleeding.
  • Tamoxifen — avoid concurrent use, or reduce warfarin dose as necessary.
  • Thyroxine — the rate of warfarin metabolism depends on thyroid status. Monitor closely on starting and titrating warfarin therapy.
• The following interactions may reduce the effect of warfarin and are likely to need close monitoring and clinical intervention, especially when initiating, changing, and stopping concurrent treatment.
  
  • St John's Wort — stop St John's Wort, monitor the INR, and adjust warfarin dose as necessary. St John's wort can cause a moderate clinical reduction in the anticoagulant effect.
  • Griseofulvin — monitor the INR, and adjust warfarin dose as necessary.
  • Rifampicin — monitor the INR, and adjust warfarin dose as necessary.
  • Carbamazepine — monitor the INR, and adjust warfarin dose as necessary.
  • Phenobarbital or primidone — a reduced effect may be seen within 2–4 days (maximum effect by about 3 weeks) after starting phenobarbital and persisting for up to 6 weeks after phenobarbital is stopped. Monitor INR until stable. Increase warfarin dose as necessary.
  • Phenytoin — increase warfarin dose as necessary. After stopping phenytoin, the INR may continue to be affected for up to 6 weeks.
  • Vitamin K-containing vitamin complexes, including some enteral feeds (containing vitamin K), food supplements, and large amounts of green vegetables or green tea. Certain foods, such as liver, broccoli, brussels sprouts and green leafy vegetables, contain large amounts of vitamin K. Sudden changes in diet can potentially affect the control of anticoagulation. Patients should be informed of the need to seek medical advice before undertaking any major changes in diet. Monitor INR and adjust the dose of warfarin as necessary.
  • Chronic heavy alcohol use  — may induce the metabolism of warfarin.
• In addition, it is also prudent to monitor the INR when warfarin is used concurrently with the following drugs, especially in older people, as interactions have been documented:
  • Allopurinol.
  • Azathioprine.
  • Grapefruit juice (possible interaction; it may be easier to completely avoid this).
  • Influenza vaccine.
  • Methylphenidate.
  • Orlistat (may reduce the absorption of vitamin K).
  • Paracetamol or paracetamol-containing products (particularly if prolonged regular use).
  • Proton pump inhibitors.
  • Quinolone antibiotics.
  • Statins (particularly fluvastatin or rosuvastatin; not pravastatin).
  • Stopping smoking (it takes about 1 week for the enzyme induction due to smoking to wear off).
  • Zafirlukast.
• See the electronic Medicines Compendium (eMC) or the British National Formulary (BNF) for other possible drug interactions with warfarin.

Should warfarin be stopped before planned surgery or dental treatment?

• If the person needs to have surgery or any other invasive procedure, they may need to temporarily stop taking warfarin.
  • The decision to stop warfarin and when to stop it will depend on the person's risk of having a thromboembolic event and the bleeding risk associated with the procedure. As such, the warfarin interruption periods listed below may require adaptation based on the individual benefit/risk ratio and local guidance.
  • All patients undergoing a planned intervention, as well as caregivers (including primary care clinicians), should receive written information from the operating physician indicating the anticipated date and time of the intervention as well as the date and time of the last warfarin intake.
  • If unsure about the risk/benefit of discontinuing, seek specialist advice.
• Minor surgical procedures with low risk of bleeding can be performed in general with an international normalized ratio (INR) of less than 2.5. However, local recommendations should be considered. 
• For surgery or other surgical procedures where there is a risk of severe bleeding:
  • Warfarin should usually be stopped 3–5 days prior to the surgery or procedure.
    • People stopping warfarin prior to surgery who are considered to be at high risk of thromboembolism (such as those with a venous thromboembolic event within the last 3 months, atrial fibrillation with previous stroke or transient ischaemic attack, or mitral mechanical heart valve may require interim therapy (‘bridging’) with a low molecular weight heparin (full treatment dose).
    • People taking warfarin who require emergency surgery that can be delayed for 6–12 hours can be given intravenous phytomenadione (vitamin K1) to reverse the anticoagulant effect. If surgery cannot be delayed, dried prothrombin complex can be given in addition to intravenous phytomenadione, and the INR checked before surgery. 
  • Where it is necessary to continue anticoagulation, for example, with life-threatening thromboembolism, the INR should be reduced to less than 2.5, and heparin therapy should be started.
  • The timing for re-instating warfarin treatment depends on the risk of post-operative haemorrhage. In most instances, if there is adequate haemostasis, warfarin treatment can be restarted as soon as the person has an oral intake.
• For dental procedures:
  • In most cases, warfarin need not be stopped before routine dental surgery, for example, tooth extraction.
  • It is recommended that the INR be checked ideally no more than 24 hours before dental surgery — in people with a stable INR, checking it no more than 72 hours before surgery is acceptable.
    • If the INR is below 4, treatment can continue without interrupting anticoagulation.
    • If the INR is above 4, treatment should be delayed until the INR has been reduced to less than 4.  
  • The risk of significant bleeding in people with a stable INR within the range of 2–4 is very small, but the risk of thrombosis may be increased if oral anticoagulants are temporarily discontinued.

How should I monitor someone taking warfarin?

• The anticoagulant effect of warfarin is measured as the international normalized ratio (INR).
  • The INR calculation is based on the ratio between the prothrombin times of the test and control samples.
  • The INR is most accurately measured in venous blood samples, but many anticoagulation clinics use capillary blood samples because these are more convenient to obtain.
  • Intravenous drug users and people with hepatitis B, hepatitis C, or HIV may be referred to a specialist clinic. Capillary blood sampling in these populations may cause risk of transmission, and venous access is often difficult. Arrangements for monitoring the INR in such cases may vary with locality.
• Clinical guidance on warfarin induction and monitoring regimens varies — follow local protocol and if unsure seek advice from anticoagulation services.
  • Generally, when warfarin is started using a standard dosing regimen, the INR should be measured:
    • Daily or on alternate days in the early days of treatment.
    • Then at longer intervals (depending on response and the specific clinical situation). 
    • Thereafter, depending on the stability of the INR, at regular intervals (for example, up to every 12 weeks), if agreed locally.
• More frequent routine monitoring of the INR is recommended for people:
  • With risk factors for bleeding such as:
    • High intensity of anticoagulation (INR >4.0)
    • Age 65 years or older.
    • Highly variable INRs.
    • History of gastrointestinal bleeding.
    • Uncontrolled hypertension, cerebrovascular disease, or serious heart disease, including congestive cardiac failure.
    • Risk of falling.
    • Anaemia.
    • Malignancy.
    • Trauma.
    • Renal insufficiency.
    • Impaired hepatic function.
    • Haemorrhagic blood dyscrasias.
    • Hypermetabolic states (such as hyperthyroidism or acute illness).
    • Vitamin K deficiency.
    • Diarrhoea.
  • Taking other drugs that may interact with warfarin.
  • For whom adherence to treatment may be difficult.
• Regular monitoring of INR and appropriate dose adjustment of warfarin (according to local protocol) is essential — seek advice from local anticoagulation services if unsure.
  • If the INR is found to be too high, the dose of warfarin should be reduced or omitted.
  • Depending on the specific clinical situation, it may be necessary to reverse anticoagulation. 
  • INR should be checked within 2–3 days to ensure that it is falling.
• Reassess anticoagulation for a person with poor anticoagulation control, indicated by any of the following:
  • Two INR values higher than 5, or one INR value higher than 8, within the past 6 months. 
  • Two INR values less than 1.5 within the past 6 months.
  • Time in therapeutic range (TTR) is less than 65%. 
• Take into account and, if possible, address the following factors that may contribute to poor anticoagulation control:
  • Cognitive function.
  • Adherence to prescribed therapy.
  • Illness.
  • Interacting drug therapy.
  • Lifestyle factors, including diet and alcohol consumption.
• If poor anticoagulation control cannot be improved:
  • Evaluate the risks and benefits of alternative strategies and discuss these with the person — seek specialist advice if unsure.
• The person on warfarin should:
  • Have all their results recorded in their 'Yellow book', with their dose instructions and their next review appointment time.
  • Be aware of the reasons for anticoagulation, their target INR, and the duration of their treatment.
  • Receive appropriate information and advice on warfarin treatment.
• Be aware that warfarin metabolism can be affected by:
  • Thyroid status — people with hypothyroidism or hyperthyroidism should be closely monitored on starting warfarin treatment.
  • Genetic variability — if the person or a family member is known to have polymorphisms of CYP2C9 or VKORC1, extra care is warranted.

How should I monitor a person taking warfarin during the COVID-19 pandemic?

• When monitoring a person taking warfarin during the COVID-19 pandemic, remember that:
  • Acute illness (including COVID-19 infection) may exaggerate the effect of warfarin and necessitate a dose reduction.
  • Continued international normalized ratio (INR) monitoring is important in people taking warfarin if they have suspected or confirmed COVID-19 infection, so they can be clinically managed at an early stage to reduce the risk of bleeding.
  • Warfarin may interact with other medicines (including antibacterials and antivirals). Follow the advice in the manufacturer's Summary of Product Characteristics (SPC), available on the electronic Medicines Compendium (eMC) website, to minimize the risk of potential interactions.
  • If switching from warfarin to a direct-acting oral anticoagulant (DOAC), stop warfarin before starting the DOAC, to reduce the risk of over-anticoagulation and bleeding. See the sections on switching to Apixaban, Dabigatran, Edoxaban, and Rivaroxaban for more information.
• Remind the person to:
  • Carefully follow the instructions for the use of warfarin, including those in the patient information leaflet.
  • Notify the GP or healthcare team if they:
    • Have symptoms of, or confirmed, COVID-19 infection.
    • Are otherwise unwell with sickness or diarrhoea, or have lost their appetite.
    • Have changed their diet, smoking habits, or alcohol consumption.
    • Are taking any new medicines or supplements.
    • Are unable to attend their next scheduled blood test for any reason.

What is target international normalized ratio (INR) for warfarin treatment?

• The maintenance dose of warfarin depends on the international normalized ratio (INR) during monitoring.
  • The average daily maintenance dose of warfarin is usually 3 to 9 mg taken at the same time every day. However, there is wide variation from person-to-person and the daily dose may lie between 1–15 mg for some people.
  • An INR that is within 0.5 units of the target value is generally satisfactory; larger deviations require dosage adjustment. Target values (rather than ranges) are now recommended.
• A target INR of 2.5 is recommended for:
  • Treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), including those associated with antiphospholipid syndrome or for recurrence in people no longer receiving warfarin treatment.
  • Atrial fibrillation.
  • Cardioversion (higher target values, such as an INR of 3, can be used for up to 4 weeks before the procedure to avoid cancellations due to low INR).
  • Mitral stenosis or regurgitation with atrial fibrillation, history of systemic embolism, left atrial thrombus, or enlarged left atrium.
  • Bioprosthesis in the mitral position.
  • Bioprosthetic valve and history of systemic embolism.
  • Bioprosthetic valve and left atrial thrombus at surgery.
  • Bioprosthetic valves and other prothrombotic risk factors, such as atrial fibrillation and low ventricular ejection fraction.
  • Acute arterial embolism leading to embolectomy.
  • Dilated cardiomyopathy.
  • Post myocardial infarction.
• A target INR of 3.5 is recommended for:
  • Recurrent DVT or PE in people currently receiving anticoagulation and with an INR above 2.
• For mechanical prosthetic heart valves:
  • The recommended target INR depends on the type and location of the valve and patient-related risk factors. Increasing the INR target or adding an antiplatelet drug should be considered if an embolic event occurs whilst the person is anticoagulated at the target INR.
  • See Table 1 for the recommended target INRs for mechanical valves.

Table 1. Recommended target international normalized ratios (INRs) for mechanical valves.

How should I manage a person if their INR is not in the therapeutic range?

• If the international normalized ratio (INR) is outside the therapeutic range, ask the person about any changes in order to find the cause of the out-of-range result. For example, ask about:
  • Adherence to warfarin treatment, for example, if they have missed any doses or taken too much.
  • Use of other medications, including over-the-counter products, vitamins, and herbal or homoeopathic remedies.
  • Use of alcohol or illicit drugs.
  • Food and drink intake (for example, green vegetables and cranberry juice).
  • Their general health:
    • Weight loss, acute illness (such as gastroenteritis), and smoking cessation can increase the effect of warfarin.
    • Weight gain, diarrhoea, and vomiting can reduce the effect of warfarin.
• If the person has major bleeding, stop warfarin, and arrange immediate emergency admission for intravenous treatment with phytomenadione (vitamin K₁) and dried prothrombin complex concentrate (factors II, VII, IX, and X), or fresh frozen plasma if dried prothrombin complex is unavailable.
• If the INR is high and is:
  • Greater than 8 with minor bleeding — stop warfarin and arrange same-day hospital assessment for phytomenadione by slow intravenous injection. The dose of phytomenadione may be repeated after 24 hours if the INR is still too high.
    • Restart warfarin when the INR is less than 5.
  • Greater than 8 with no bleeding — stop warfarin and arrange same-day hospital assessment for phytomenadione. The dose of phytomenadione may be repeated after 24 hours if the INR is still too high.
    • Restart warfarin when the INR is less than 5.
  • Between 5–8 with minor bleeding — stop warfarin and arrange same-day hospital assessment for consideration of phytomenadione.
    • Restart warfarin when the INR is less than 5.
  • Between 5–8 with no bleeding — withhold 1 or 2 doses of warfarin, monitor INR closely and alter subsequent maintenance dose appropriately.
    • Consider discussing those patients with a high risk of bleeding (older age, uncontrolled hypertension, diabetes, renal or liver failure, previous gastrointestinal or cerebral bleeds) with a specialist as some may be appropriate for oral vitamin K. 
• If there is unexpected bleeding at therapeutic levels — always investigate possibility of underlying cause, such as unsuspected renal or gastrointestinal tract pathology.

What advice should I give to a person receiving warfarin?

• Advise the person taking warfarin that:
  • It is very important to have their blood tested regularly to check their international normalized ratio (INR), at intervals agreed with the anticoagulant clinic staff.
    • They should always take their anticoagulant treatment booklet ('Yellow book') when they go to the warfarin clinic to have their INR checked.
    • The 'Yellow book' includes advice for people taking anticoagulants, an alert card (which the person should carry at all times), and a section for recording the INR readings.
  • They should take their warfarin at the same time each day.
  • They should not miss doses or take additional doses without advice from a healthcare professional.
    • They must inform anticoagulant clinic staff if they think they have taken too much warfarin or have missed any doses.
    • If a dose is accidentally missed, they should continue with the regimen as prescribed, and never take a double dose (unless specifically advised).
  • Warfarin levels can be affected by diet, alcohol, acute illness, and other medications, including over-the-counter drugs, vitamins, food supplements, and herbal and homoeopathic remedies. They should:
    • Seek medical advice before undertaking any major changes in diet, especially if their diet is rich in vitamin K (such as broccoli, kale, or spinach) — this can potentially affect control of anticoagulation.
    • Limit alcohol intake to a maximum of one or two drinks a day, and never binge drink.
    • Inform the anticoagulant clinic staff and other healthcare professionals (their GP, dentist, pharmacist, and/or medical or nursing staff) of changes to their lifestyle, for example, if they start, stop, or change the dose of other medicines.
  • They should seek immediate medical advice if:
    
    • Spontaneous bleeding occurs whilst on warfarin and the bleeding does not stop, or recurs. This includes bruising, bleeding gums, nosebleeds, prolonged bleeding from cuts, blood in the urine or stools, coughing up blood, a subconjunctival haemorrhage, and vaginal bleeding in a postmenopausal woman.
    • They get sudden severe back pain (which may indicate spontaneous retroperitoneal bleeding).
    • They experience difficulty breathing, increased breathing rate, or chest pain (which could be symptoms of pulmonary embolism).
  • They should seek medical advice if they experience other adverse effects of warfarin. 
  • They may have to stop warfarin treatment temporarily for certain surgical and dental treatments.
  • They should:
    
    • Expect to bruise more easily.
    • Take extra care when brushing teeth or shaving and consider using a soft toothbrush and an electric razor.
• For women of childbearing potential, advise that:
  • They should use effective contraception during treatment because warfarin is a known teratogen.
    • Warfarin crosses the placenta with risk of congenital malformations, and placental, fetal, or neonatal haemorrhage, especially during the last few weeks of pregnancy and at delivery. Therefore, if at all possible, it should be avoided in pregnancy, especially in the first and third trimesters. 
    • Pre-pregnancy counselling is recommended for all women of reproductive age with a mechanical heart valve and should be delivered by a specialist multidisciplinary team (MDT).
• If pregnancy is confirmed in a woman taking warfarin, refer urgently (as soon as a pregnancy test is positive) to the specialist team (ideally to be seen before 6 weeks of gestation). 
  • Ongoing management should be in a designated specialist centre with an experienced MDT including obstetrics, cardiology, cardiac surgery, anaesthetics, neonatology and haematology. Complex decisions on optimal anticoagulation regimens and balancing competing risks will be required.

What is self-testing and self-management of warfarin?

• Self-testing is where a person tests their own international normalized ratio (INR) but contacts a healthcare professional for dose adjustment.
• Self-management is where the person tests their own INR and also adjusts the dose of warfarin themselves (based on an individualized algorithm).
• The availability of training and support for self-testing or self-management varies across the UK.
  • Training and ongoing review and support are best managed through specialist anticoagulant services (based in primary or secondary care).
  • People should only consider purchasing a self-testing device, such as the CoaguChek® INRange, after discussing the following with their GP or with the anticoagulant clinic staff:
    • Whether self-testing or self-management services (such as training and support, and specialist review) are available in their area.
    • Their suitability for self-testing or self-management.
  • Warfarin self-testing devices are not available on the NHS; however, some test strips and lancets are available on prescription.
• For selected and successfully trained people, self-testing or self-management is as effective and safe as usual care for long-term oral anticoagulation treatment and can improve the quality of oral anticoagulation treatment in this group of people. In the UK, however, self-testing is unlikely to be more cost-effective than usual care, because of the increased frequency of testing and the subsequent cost of test strips.