Guidance for starting and maintaining adult patients on warfarin

• Background
• Treatment/management
  1. Starting warfarin therapy - rapid anticoagulation (DVT and PE)
  2. Starting warfarin therapy - slow induction of anticoagulation (AF - in patients not requiring heparinisation)
  3. Managing patients re-starting oral anticoagulation (warfarin) therapy
• Appendix 1 - See - Indication for Anticoagulation (for all other indications contact Haematology) 
• Appendix 2 - Clinically significant drug interactions involving warfarin
• Drug interactions
• Discharge arrangements
• Discontinuation of anticoagulation

Aims

This guideline has been developed to promote a safe and consistent approach to achieving therapeutic anticoagulation in adults with the vitamin K antagonist, warfarin.  It addresses starting treatment, cautions and contra-indications and drug interactions.  The guideline also covers the safe and appropriate management of patients at discharge.  It aims to provide a practical guide for medical and other healthcare professionals involved in starting and maintaining patients on warfarin.

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Background

Warfarin is the most frequently prescribed oral vitamin K antagonist anticoagulant in the UK. Acenocoumarol may be used in some patients who experience problems with hair loss, headache, or rash on warfarin.  Both drugs require regular monitoring and in some patients frequent dose adjustment to maintain the desired therapeutic action (measured by the international normalized ratio INR) and minimise adverse bleeding events. The National Patient Safety Agency (NPSA) issued a patient safety alert in March 2007 on actions that can make anticoagulant therapy safer.  Anticoagulants are one of the classes of medicines most frequently identified as causing preventable harm and admission to hospital.  Managing the risks associated with anticoagulants can reduce the chance of patients being harmed in the future.  This guideline will in part address some of the actions listed in the alert.
The use of the direct oral anticoagulants (DOACs) will not be covered in this guideline. Advice on the use of DOACS can be found in http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?id=3365 and
http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?id=3974

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Treatment / Management

Indications for anticoagulation

The table below shows the indications for oral anticoagulation and the target INR for a vitamin K antagonist.

Recommended target INRs for mechanical heart valves
(reproduced from BCSH Guidelines 2011 ³ )

 
*  Patient-related risk factors for thrombosis: mitral, tricuspid or pulmonary position; previous arterial thromboembolism; atrial fibrillation; left atrium diameter >50mm; mitral stenosis of any degree; left ventricle ejection fraction <35%; left atrial dense spontaneous echo contrast.
Note that new On-X type valves often require a lower target of 2 for aortic position after first 3 months. On-X in the mitral position require an INR target of 3.

**  Target INR was 4.0 one study.

Contra-indications

• Hypersensitivity to the active substance
• Haemorrhagic stroke
• Clinically significant bleeding
• Within 72 hours of major surgery with risk of severe bleeding
• Within 48 hours postpartum.
• Pregnancy (first and third trimesters)
• Drugs where interactions may lead to a significantly increased risk of bleeding
• Uncontrolled hypertension

Cautions

• risk of serious haemorrhage (e.g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal bleeding
• Patients with protein C deficiency are at risk of developing skin necrosis when starting warfarin treatment. In patients with protein C deficiency, therapy should be introduced without a loading dose of warfarin even if heparin is given. Patients with protein S deficiency may also be at risk and it is advisable to introduce warfarin therapy slowly in these circumstances.

Before commencing anticoagulant therapy

Check baseline coagulation screen (INR, PT (prothrombin time), APTT (activated partial thromboplastin time)), full blood count, U&Es and liver function tests.

Ensure INR is <1.3 before treatment.  If INR 1.3 or more consider reasons for raised INR and consider if warfarin is definitely indicated. Repeat and if still raised discuss with haemostasis/thrombosis haematology team

Choose appropriate loading regimen

A) Starting warfarin therapy - rapid anticoagulation (DVT and PE)
B) Starting warfarin therapy - slow induction of anticoagulation (AF - in patients not requiring heparinisation)
C) Managing patients re-starting oral anticoagulation (warfarin) therapy

A)  Starting warfarin therapy - rapid anticoagulation

Rapid anticoagulation is used where patients need to achieve their target INR as quickly as possible.  It takes five to ten days for the full effects of warfarin to be seen and in the early stages of treatment with warfarin a hypercoagulable state may be induced due to the rapid depletion of natural anticoagulant protein C.  Rapid anticoagulation is achieved using heparin; enoxaparin is the low molecular weight heparin of choice at Leeds Teaching Hospitals NHS Trust for this indication. Low molecular weight heparin should be continued for at least 5 days and until the INR is ≥2 for at least 24 hours, whichever is the longest.

The standard warfarin loading dose regimen (Appendix 1) is suitable for younger patients. 

Some patients are likely to be sensitive to warfarin*:

• Age over 65 years
• Prolonged baseline INR
• Cardiac failure
• Liver disease
• Abnormal renal function - often have lower dose requirements and labile INR’s. Often adopt a more cautious approach to prevent over anti-coagulation in this group of patients. Patients with an eGFR of 30–59 mL/min/1.73 m2 tend to need a 10% lower maintenance dose, while those with levels of eGFR <30 mL/min/1.73 m2 a 20% lower dose. This is probably related to the down-regulation of cytochrome P450 in chronic kidney disease.
• Nutritional deficiencies (hypoalbuminaemia, reduced intake or absorption of vitamin K)
• Body weight < 60kg
• Concomitant therapy with a drug known to potentiate warfarin (see BNF appendix 1) 
• acute illness or immediately post cardiac surgery
• treated with drugs which potentiate warfarin e.g. amiodarone, antibiotics, antifungals (see BNF appendix 1)

In these patients, please refer to Appendix 1 for the alternative regimen to use in patients likely to be sensitive *.
If patients are very elderly, very low body weight or very poor renal function consider a lower loading dose of 3mg and discuss with ward pharmacist

1) Prescribing warfarin
 
Patients requiring rapid anticoagulation should follow the warfarin loading dose regimen as shown above

Refer to Appendix 1 for Standard and sensitive warfarin loading dose regimen

If at day 4, patients are requiring greater than warfarin 10mg daily, consult a senior clinician or specialist anticoagulation pharmacist for advice on subsequent dosing.

2)  Commencing heparin as part of the rapid anticoagulation process

Rapid warfarin loading should be initiated in conjunction with therapeutic dose parenteral heparin.  Parenteral anticoagulation should continue for at least 5 days and until the INR is ≥2 for at least 24 hours, whichever is the longest.  Enoxaparin 1.5mg/kg by subcutaneous injection  is the low molecular weight heparin (LMWH) of choice for venous thromboembolism.

If creatinine clearance (CrCl) < or equal to 30mL/min (severe renal impairment) use enoxaparin 1mg/kg once daily Unfractionated heparin can be used if enoxaparin not appropriate.

It is not necessary to routinely monitor anti-factor-Xa activity in patients receiving LMWH. In patients with severe renal impairment, anti-factor Xa levels can be monitored and dose adjustments made accordingly. Seek advice from haematology.

Treatment with UFH is monitored using the APTT ratio, where the target range is 1.5-2.5.  Please refer to the heparin prescription chart for dosing and monitoring.

B)  Starting warfarin therapy - slow induction of anticoagulation (Atrial Fibrillation and stroke - in patients not requiring heparinisation)

Patients with atrial fibrillation are at an increased risk of thromboembolism and stroke.  Slow induction of anticoagulation is suitable in these patients (Janes et al 2004).  This regimen takes longer to achieve a stable INR but it avoids the potential hypercoagulability seen with rapid anticoagulation and results in fewer episodes of over anticoagulation.  These patients do not require additional anticoagulation with either UFH or LMWH until therapeutic and slow induction is usually carried out in an outpatient setting. It can take 3-4 weeks before therapeutic anticoagulation is achieved.

1) Prescribing warfarin

Usual slow induction regimen:  
2mg or lower daily dose - for patients with any of the cautionary risk factors listed below. Dose continued for 7 days, then check the INR on day 8.  An earlier INR check may be arranged if the patient has several (4 or more) of the cautionary risk factors listed below.

3mg daily (standard dose) - continue dose for 7 days, then check INR on day 8.

4mg daily- continue for 7 days, then check INR on day 8 may be used for larger patients with no cautionary risk factors). 

C) Managing patients re-starting oral anticoagulation (warfarin) therapy

Where warfarin therapy has been omitted for a period of time, all these patients should have a baseline INR checked before re-commencing warfarin therapy.  If a patient’s warfarin was stopped due to over-anticoagulation or bleeding, it is not appropriate to restart the patient’s usual maintenance dose. 

Metallic valve replacements, acute venous thromboembolism in the last 4 weeks, AF related stroke in last 4 weeks or clinical need for immediate rapid anticoagulation

If the baseline INR is therapeutic, re-commence warfarin at the patient’s usual maintenance dose.

If the baseline INR is below 1.8, the patient should re-commence anticoagulation with warfarin, usually using normal dose + 50% for 2 days then back on usual dose (if no risk factors listed above) and either LMWH or UFH; once the INR has been therapeutic for two consecutive days, discontinue LMWH or UFH.

Chronic venous thromboembolism (> 4 weeks since acute event)

Recommence warfarin at the same dose as prior to admission (as long as admission not related to over-anticoagulation or adverse events such as bleeding). Ensure the patient is on prophylactic LMWH for VTE prevention

Atrial fibrillation (no previous stroke or TIA)

Recommence warfarin at the same dose as prior to admission (as long as admission not related to over-anticoagulation or adverse events such as bleeding).  In cases where the reason for the patient’s admission was related to over-anticoagulation or bleeding, reassess the choice of anticoagulant and consider re-loading with slow induction regimen using lower dose than on admission if warfarin to continue.

Patients with Atrial fibrillation AND previous stroke or TIA or multiple other risk factors

Consider clinical need for immediate rapid anticoagulant (see above)

Target INRs and loading schedules

The target INR range, indication and duration of anticoagulation should be indicated on the patients Electronic Discharge Advice Note (EDAN) , anticoagulant referral letter and on Emeds.

Continued anticoagulation beyond the initial period of 3 months

• Long-term anticoagulant therapy is NOT recommended in patients with VTE provoked by surgery
• Long-term anticoagulant therapy is NOT recommended in patients with VTE provoked by non-surgical transient trigger factors
• Patients 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 the individual patient
• Long-term anticoagulant therapy is NOT recommended in patients with VTE confined to the calf (i.e. not extending into the popliteal vein)

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Drug Interactions

Many drugs and herbal medicines interact with warfarin.

Please refer to Appendix 2 for a list of clinically significant interactions with warfarin.

This list is not exhaustive, please consult the BNF, your ward pharmacist or Medicines Information (Ext 65377) for further information/advice

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Discharge arrangements

Warfarin Patient Information Checklist

The NPSA Patient Safety Alert issued in March 2007 on actions to make anticoagulants safer requires that all patients prescribed anticoagulants should receive appropriate written and verbal information at the start of therapy, at hospital discharge , on the first anticoagulant clinic appointment and when necessary throughout the course of their treatment.

At LTHT, all patients prescribed warfarin should receive a yellow anticoagulant book and verbal reinforcement of the messages conveyed in this booklet.  Yellow Anticoagulant Books are supplied directly from the ward (NOT Pharmacy).

The following points must be discussed with the patient when they are being given information on warfarin.

• Indication for warfarin
• Duration of treatment
• Need for blood tests and keeping appointments
• Target INR range and what INR means
• If unexpected bruising or bleeding occurs, consult GP
• If they have any dark tar like stools, attend A&E
• If trauma, head injury, thunder-clap type headache or severe bleeding, attend A&E
• Dose of warfarin and colour of tablets
• Take warfarin at the same time each day
• What to do if doses are missed
• What to do if doubled up on doses
• Further supplies of warfarin to be obtained from GP
• Avoid aspirin and NSAIDs, unless prescribed intentionally
• If any new medications are started or stopped, inform anticoagulation service
• Avoid sudden changes in diet.  No crash dieting or binge eating.
• Women and Men may drink within the national advised alcohol limits (14 units per week), providing their alcohol consumption is spread evenly over the whole week.  No binge drinking.
• Avoid saving units of alcohol for one night later in the week
• Take precautions to prevent pregnancy (if applicable)

Responsibility for ensuring patients have received appropriate warfarin patient information

An explanation of warfarin treatment to the patient may be undertaken by any suitably qualified pharmacist, pharmacy technician (having successfully completed the necessary training accreditation) nurse or doctor. 

For wards with no Pharmacist cover or discharge out of hours, the responsibility of warfarin counselling falls to the doctor prescribing the discharge prescription.

 Anticoagulation Clinic Referrals

All patients discharged on warfarin should be referred to the Leeds Oral Anticoagulant Service. 

If the patient is not monitored by Leeds please refer to their original clinic - see details of other Yorkshire and Humber clinics on the LHP anticoagulation pages.

All referrals should be completed online Via Patient Pass under Haematology (Anticoagulation).

See link to complete referral forms for new or existing patients on warfarin. http://lthweb.leedsth.nhs.uk/sites/clinical-haematology/haemostasis-and-thrombosis/anticoagulation-1/anticoagulation/warfarin-e-referrals

If the patient requires any form of hospital transport, it is the responsibility of the discharging ward to arrange this.

Referrals should NEVER delay discharge. A member of the anticoagulation team will be in touch with the patient or the ward to inform them of an appointment time.

Discharge Actions

Actions for the prescriber:

• Complete the Electronic Discharge Advice Note - EDAN (discharge prescription) with details of the indication for warfarin, dose on discharge and intended duration of treatment.
• Complete all sections of the yellow anticoagulant book, including the dose on discharge.
• Give the patient an explanation of their warfarin treatment (where this has not already been completed by the Pharmacist/Pharmacy Technician)
• Inform the patient if they are to be monitored by Leeds the anticoagulant service will be in touch

Actions for the pharmacist/pharmacy technician

• Check that the yellow anticoagulant book has been completed correctly with the information above
• Give the patient an explanation of their warfarin treatment

Actions for the Nurse responsible for discharging the patient
Ensure that all patients discharged on warfarin have:

• A yellow anticoagulant book
• Received written and verbal information on their warfarin treatment
• Sufficient supplies of the correct strengths of warfarin
• A fully completed yellow anticoagulant book with a written dose of warfarin until their next anticoagulant clinic appointment
• Date and time of anticoagulant clinic appointment

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Discontinuation of anticoagulation

The duration of anticoagulation treatment should always be stated when starting treatment based on the clinical indication for anticoagulation, and other risk factors the patient may have.  Where the duration of treatment is a deviation from the recommendations made, the reason for this should be stated in the medical notes, on the discharge prescription and on the anticoagulant referral letter.

The current recommendations are that oral anticoagulant therapy can be discontinued abruptly when the duration of therapy is complete.
Please remember to let the anticoagulant office know if a patient’s warfarin is discontinued.

You can send an email to inform them: Leedsth-tr.leedsacsreferral@nhs.net.

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Appendix 2

Clinically significant drug interactions involving warfarin

This list is not exhaustive, please consult the BNF, your ward pharmacist or Medicines Information (Ext 65377) for further information/advice