Advice on Oral Anticoagulation for Non-valvular Atrial Fibrillation

Overview

This Guidelines summary of the All Wales Medicines Strategy Group's Advice on oral anticoagulation for non-valvular atrial fibrillation (NVAF) outlines key recommendations for primary care settings. Refer to the full guideline for the complete set of recommendations.

Reflecting on Your Learnings

Reflection is important for continuous learning and development, and a critical part of the revalidation process for UK healthcare professionals. Click here to access the Guidelines Reflection Record.

Identification

• Non-valvular atrial fibrillation (NVAF) refers to atrial fibrillation (AF) in the absence of a mechanical prosthetic heart valve or moderate-to-severe mitral stenosis (usually of rheumatic origin)
• Perform manual pulse palpation to assess for the presence of an irregular pulse that may indicate underlying NVAF in people presenting with any of the following:
  • breathlessness/dyspnoea
  • palpitations
  • syncope/dizziness
  • chest discomfort
  • stroke/transient ischaemic attack
• Perform an electrocardiogram (ECG) in all people, whether symptomatic or not, in whom AF is suspected because an irregular pulse has been detected
• In people with suspected paroxysmal AF undetected by 12-lead ECG recording:
  • use an ambulatory ECG monitor, event recorder, or other ECG technology for a period appropriate to detect AF if symptomatic episodes are more than 24 hours
  • use a 24-hour ambulatory ECG monitor if asymptomatic episodes are suspected or symptomatic episodes are less than 24 hours apart.

Initial Assessment

• People with NVAF should have a documented:
  • stroke and bleeding risk assessment (including pre-treatment blood tests: full blood count [FBC], urea and electrolytes, liver function tests, coagulation screen, and international normalised ratio [INR]);
  • discussion with the clinician about the risks and benefits of treatment (consider NICE recommendations on shared decision-making)
• When a person is initiated on oral anticoagulants in one care setting, the documented baseline assessment should be transferred with the prescribing responsibility
• The focus of NVAF management should be to identify affected people and undertake a stroke risk assessment using the CHA₂ DS₂ -VASc risk assessment tool. Bleeding risk should also be assessed using an appropriate tool, such as the ORBIT bleeding risk score, and modifiable risk factors should be addressed. See the full guideline for AWMSG risk/benefit assessment tool for oral anticoagulant treatment in people with NVAF. This tool supports a consistent approach for people with AF and incorporates the CHA₂ DS₂ -VASc risk assessment tool and the ORBIT bleeding risk score
• Offer anticoagulation to people with a CHA₂ DS₂ -VASc score of 2 or above, taking bleeding risk into account
• Discuss the results of the assessments of stroke and bleeding risk with the person. Offer monitoring and support to modify risk factors for bleeding such as uncontrolled hypertension, concurrent medication (for example, antiplatelets), harmful alcohol consumption, and reversible causes of anaemia
• Consider anticoagulation for men with a CHA₂ DS₂ -VASc score of 1. Take the bleeding risk into account.

Choice of Agent

• Do not offer aspirin monotherapy solely for stroke prevention to people with NVAF
• Anticoagulation may be with a direct acting oral anticoagulant (DOAC) (apixaban, dabigatran etexilate, edoxaban, or rivaroxaban▼) or warfarin. Discuss the options for anticoagulation with the person and base the choice on their clinical features and preferences
• See Appendix 1 in the full guideline to compare information on warfarin and available DOACs
• Discuss the fact that for most people the benefit of anticoagulation outweighs the bleeding risk, but for people with an increased risk of bleeding that balance may differ or may require additional monitoring
• Consider using a patient decision aid (such as the Anticoagulation Decision Support Tool). This helps people reach a decision about whether to take an oral anticoagulant to reduce the risk of stroke
• If no anticoagulation preference exists, anticoagulation should be initiated with a DOAC. Take into account any contraindications for each DOAC and follow the guidance in the British National Formulary (BNF), summary of product characteristics (SPC), and the MHRA advice on DOACs, in particular for advice on dosages in people with renal impairment, reversal agents, and monitoring (See Appendix 1 in the full guideline)
• Warfarin can be used as an alternative if DOACs are contraindicated, not tolerated, or not suitable
• DOACs should not be used in patients with a mechanical heart valve associated with AF—see MHRA advice on inappropriate anticoagulation of patients with a mechanical heart valve
• The decision about whether to start treatment with warfarin or a DOAC should be made after an informed discussion between the clinician and the person about the risks and benefits
• In selecting the specific anticoagulant to use for the prevention of stroke and systemic embolism in people with NVAF, consider:
• Initiation of warfarin and DOACs:
  • warfarin may be initiated in primary care for NVAF using a slow-loading regimen. A slow-loading regimen is appropriate for patients who do not require rapid anticoagulation for NVAF. Refer to Directed enhanced service: oral anticoagulation with warfarin for further information
  • for DOACs, refer to Appendix 1 of the full guideline and manufacturer’s full prescribing information for standard doses and dosage reductions to account for renal impairment, age, and body weight.
• Monitoring of effects of warfarin and DOACs:
  • warfarin has a narrow therapeutic index and a long half-life (40 hours), as well as significant interpatient variability; therefore, regular INR blood monitoring tests are required to guide dosing. The British Society for Haematology recommend a target INR of 2.5 for AF
  • INR testing should be frequent for the first few weeks or months then normally every 1–2 months in NVAF. This provides an opportunity to monitor adherence, effectiveness and safety
  • self-monitoring of warfarin is an option once the patient is receiving a stable dose
  • level of anticoagulation is never monitored with a DOAC—if monitoring does occur, this is for drug levels only^[A]
  • see the MHRA advice on warfarin and other anticoagulants—monitoring of patients during the COVID-19 pandemic
• Access to a licensed product for rapid reversal of the anticoagulant effect:
  • the anticoagulant effect of warfarin can be reversed using phytomenadione (vitamin K1)—refer to the All Wales Warfarin Chart for advice on how this should be performed
  • current options for rapid reversal of apixaban, dabigatran etexilate, edoxaban, and rivaroxaban are detailed in the full guideline
• Experience: warfarin has been used for more than 60 years, its short and long‑term side-effect profiles are well-described
• Renal function in NVAF:
  • edoxaban is associated with decreasing efficacy with increasing creatinine clearance (CrCl). The summary of product characteristics (SPC) advises edoxaban should only be used in patients with NVAF and high CrCl after a careful evaluation of the individual thromboembolic and bleeding risk
• For information on renal impairment, extremes of BMI, and risk of haemorrhage, refer to the full guideline
• Interactions:
  • warfarin has many listed interactions. Careful INR monitoring can often pre-empt over- or under-coagulation. Advise people to minimise major changes in paracetamol use and not to use any over-the-counter medications or dietary supplements without checking with the healthcare team first
  • DOACs have a number of listed interactions for which the advice is to avoid concomitant use (see BNF and SPCs). Patients co-administered medication that may inhibit metabolism and potentiate bleeding risk with DOACs are managed more safely on warfarin, as the INR may be adjusted accordingly
• Time in therapeutic range: DOACs are likely to be more beneficial in patients whose INR on warfarin is regularly outside the therapeutic range despite good medication adherence
• Adherence:
  • warfarin is long-acting and is taken once daily
  • it is important to take a DOAC as recommended. For NVAF, this is once a day (edoxaban or rivaroxaban) or twice a day (apixaban or dabigatran etexilate) (see Appendix 1 in the full guideline). The protective effect of the DOAC on the risk of stroke may fade 12–24 hours after a dose
• Monitored dosage systems: dabigatran etexilate is not suitable for use in a monitored dosage system^[B]
• Switching from warfarin: the potential benefits of DOACs should be considered against their potential risks, taking into account the person’s level of INR control
  • according to the individual SPCs, warfarin should be discontinued and DOAC should be started when INR ≤2 (apixaban, dabigatran etexilate), INR ≤2.5 (edoxaban), INR ≤3 (rivaroxaban). All prescribing choices should be made according to the relevant SPC
• Diet:
  • rivaroxaban should be taken with food
  • warfarin:
    • advise people that consumption of alcohol should be limited to only within the recommended limits
    • certain foods such as liver, broccoli, Brussels sprouts and green leafy vegetables contain large amounts of vitamin K. Sudden changes in diet, including cranberry juice, grapefruit juice, can potentially affect control of anticoagulation
• Cancer patients requiring anticoagulation: if patients develop cancer, their risk of thromboembolism and bleeding will change. Given the heterogonous nature of patients with cancer, their risks and benefits for continued anticoagulation should be assessed individually and reviewed periodically. The International Society on Thrombosis and Haemostasis has developed guidance on the anticoagulation of patients with cancer and non-valvular atrial fibrillation receiving chemotherapy
• Risk of recurrent thrombotic events in patients with antiphospholipid syndrome: the MHRA advises DOACs are not recommended in patients with antiphospholipid syndrome, particularly high-risk patients (those who test positive for all three antiphospholipid tests—lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2 glycoprotein I antibodies). Consider a vitamin K antagonist such as warfarin
• Those initiating warfarin or DOACs should have access to local resources on the use of these medicines, for example:
  • see the full guideline for AWMSG risk/benefit assessment tool for oral anticoagulant treatment in people with NVAF
  • atrial fibrillation decision support tool (www.anticoagulation-dst.co.uk)^[C]
  • CKS summary: anticoagulation—oral
• The prescriber should make efforts to understand and address the reasons for non-adherence before switching to an alternative medicine
• Poor adherence to any oral anticoagulant regimen is likely to be associated with increased risk of thrombosis or bleeding
• If poor anticoagulation control cannot be improved, evaluate the risks and benefits of alternative stroke prevention strategies and discuss these with the person
• Ensure that people prescribed anticoagulants receive appropriate verbal and written information when necessary throughout the course of their treatment and are advised to carry an alert card with them at all times
• People initiated on warfarin should be issued the information (yellow) booklet
• People initiated on a DOAC should be provided with written information, an alert card, and a monitoring booklet, for example, the European Heart Rhythm Association Atrial fibrillation on oral anticoagulation card
• In people with NVAF (and in the absence of other clinical conditions such as recent acute coronary syndrome) the combination of aspirin and warfarin is not recommended
• If warfarin is indicated for moderate- or high-risk NVAF it should be used alone, even in the presence of concomitant stable cardiovascular disease
• Combination therapy of warfarin and antiplatelet may be advised by cardiologists, normally for a limited period, for patients who have coronary artery stents or cardiology intervention in the previous year. Clarification should be sought from the patient’s interventional cardiologist if there is any doubt.

Review

• Where warfarin is prescribed, there should be a documented process to systematically assess the time in therapeutic range (TTR) for each person. See also NICE QS93 Statement 4 for suggested measures
• Discuss the option of switching treatment to a DOAC at next routine appointment, taking into account the TTR for the patient
• Where DOACs are prescribed, there should be a documented process to systematically assess treatment (see Specialist Pharmacy Service Monitoring DOACs )
• For people who are taking an anticoagulant, review the need for anticoagulation and the quality of anticoagulation at least annually, or more frequently if clinically relevant events occur affecting anticoagulation or bleeding risk (see the full guideline for AWMSG risk/benefit assessment tool for oral anticoagulant treatment in people with NVAF)
• Undertake FBC and renal and liver function tests at least annually for people taking any anticoagulant. More frequent monitoring is advised if baseline tests are abnormal or there is intercurrent illness that may impact renal or hepatic function
• The European Heart Rhythm Association suggests that if the CrCl is ≤60 ml/minute, the frequency of monitoring (in months) can be guided by the CrCl divided by 10. For example, if the CrCl is 30 ml/minute then the renal function (and the prescribed dose) should be reassessed every 3 months
• Reassess anticoagulation (see later) for a person with poor anticoagulation control shown by a TTR of <65% over 6 months
• Consider also using the following as indicators of poor anticoagulation control:
  • two INR values >5 or one INR value >8 within the past 6 months
  • two INR values <1.5 within the past 6 months
• When reassessing anticoagulation, take into account and—if possible—address the following factors that may contribute to poor anticoagulation control, using national or locally agreed tools:
  • cognitive function
  • adherence to prescribed therapy
  • new diagnoses, for example cancer
  • interacting drug therapy, for example over-the-counter therapies, frequent antibiotics
  • lifestyle factors including diet and alcohol consumption
• Do not withhold anticoagulation solely because the person is at risk of having a fall
• For people with AF who are not taking an anticoagulant, review stroke risk when they reach 65 years of age or if they develop any of the following at any age:
  • diabetes
  • heart failure
  • hypertension
  • peripheral arterial disease
  • coronary heart disease
  • stroke, transient ischaemic attack or systemic thromboembolism
• For people with AF who are not taking an anticoagulant because of bleeding risk or other factors, review stroke and bleeding risks annually, and ensure that all reviews and decisions are documented.

Prescribing Responsibility

• People with a new diagnosis of NVAF should normally have the initial assessment and discussion regarding anticoagulation in the setting (hospital, GP practice) in which the diagnosis was made
• When a decision to initiate anticoagulation has been made, prompt initiation and stabilisation^[D] should normally be undertaken in the setting in which the decision was made
• If a primary care team does not have appropriate expertise to initiate warfarin or a DOAC a baseline assessment should be sent to the oral anticoagulant clinic. The clinic will provide patient education and counselling but will not advise on the decision to initiate treatment
• When a person is identified as having poor anticoagulation control, the reassessment of anticoagulation should be undertaken through discussion with the patient, by the healthcare professional providing dosing
• Anticoagulant clinics may need to liaise with the general practice following a reassessment of poor anticoagulant control to identify further possible causes
• If poor anticoagulation control cannot be improved as a result of this reassessment, the risks and benefits of alternative stroke prevention strategies should be evaluated and discussed with the person
• It may be appropriate for GP practices, particularly those that provide warfarin dosing services, to make the decision to start a DOAC depending on health board service models
• The cause of a raised INR (INR >8 or repeated INR of 6 or 7) should be investigated. This should normally be undertaken by the team requesting the INR.

Monitoring of INR Control (Warfarin Only)

• When calculating TTR:
  • use a validated method of measurement such as the Rosendaal method for computer-assisted dosing, or proportion of tests in range for manual dosing
  • exclude measurements taken during the first 6 weeks of treatment
  • calculate TTR over a maintenance period of at least 6 months
• Warfarin dosing:
  • providers should normally use computer dosing software systems
  • computer dosing should be interpreted and actioned by non‑administrative professionals, who are trained, accredited and competent to manage warfarin therapy
  • avoid overreliance on computer-generated dosing and use clinical expertise to interpret dosing advice
• Self-monitoring of coagulation status in adults and children on long-term vitamin K antagonist therapy should be in accordance with NICE DG14: if 'the person prefers this form of testing, and the person or their carer is both physically and cognitively able to self-monitor effectively'.

Management of Supratherapeutic INRs (Warfarin Only)

• People with mechanical valves with INR over 8 should be managed according to specialist advice. Please refer to health board specific guidelines
• It is appropriate to administer oral phytomenadione (vitamin K1) in general practice as well as in the hospital setting for people with INR >8, with no bleeding where the perceived risk of bleeding is high. Exceptions: people with mechanical valves with INR over 8
• Give phytomenadione (vitamin K1) 1–5 mg by mouth using the intravenous preparation orally (unlicensed use); repeat dose of phytomenadione if INR still too high after 24 hours; restart warfarin when INR <5
• Expert opinion suggests that 2 mg is an adequate dose
• Access to vitamin K—practices, community pharmacists and out-of-hours providers may wish to stock phytomenadione or agree local arrangements to ensure prompt access to therapy.

Use of Low Molecular Weight Heparin (LMWH) for Subtherapeutic INR (Warfarin Only)

• Selected patients on warfarin who are at high risk of thromboembolism (for example, patients with mechanical valves or recurrent deep vein thrombosis/pulmonary embolism and those identified by the haematologist or cardiac surgeon) should be co-prescribed low-molecular-weight heparin (LMWH) if the INR becomes subtherapeutic (unlicensed indication)
• LMWH prescribing in these circumstances should be undertaken by the department responsible for dosing warfarin.

Reporting

• Due to newer licensed indication(s), edoxaban and rivaroxaban are currently under ‘Additional Monitoring’ by the European Medicines Agency and all suspected adverse drug reactions (ADRs) should be reported, as well as all serious ADRs (see yellowcard.mhra.gov.uk for definition of serious) to apixaban, dabigatran etexilate, and warfarin. ADRs should be reported directly to the MHRA through the Yellow Card Scheme using the electronic form at yellowcard.mhra.gov.uk or cards available at the back of the BNF.

Footnotes

[A] With certain reagents, prolongation of the prothrombin time/activated partial thromboplastin time can be seen but this cannot be used to calibrate activity. For dabigatran etexilate, the thrombin clotting time is also a useful test. Apixaban, edoxaban, and rivaroxaban▼ levels can be measured with a calibrated quantitative anti-factor Xa assay

[B] Not suitable for standard monitored dosage systems; a specific dabigatran etexilate adherence aid can be provided

[C] At the time of writing (September 2021) the Atrial Fibrillation Decision Support Tool does not reflect the latest NICE guidance (NG196). However, updates to the tool are under consideration.

[D] Stabilisation: Two INR readings in range with confirmation that INR/dosing interval at least 7 days