• Anticoagulants are usually initiated in secondary care, a dedicated clinic in a hospital, or an outreach clinic in primary care.
• Where rapid anticoagulation is required:
• Warfarin is usually started with a loading dose of 10 mg.
• Subsequent doses depend up the prothrombin time reported as international normalized ratio (INR).
• For people older than 60 years of age, those with liver disease or cardiac failure, or those at high risk of bleeding, regimens that start with warfarin 5 mg doses, or a single 10 mg dose followed by 5 mg doses, may be preferable.
• It takes 48 to 72 hours for the anticoagulant effect of warfarin to fully develop.
• If an immediate effect is required (for example deep venous thrombosis or a pulmonary embolism) heparin is given concomitantly. This is done in secondary care.
• For people with with atrial fibrillation:
• There is no need to achieve anticoagulation rapidly; a slow loading regimen is safe and achieves therapeutic coagulation in the majority of people within 3–4 weeks.
• Warfarin 2 or 3 mg each day is generally an acceptable starting dose.
• A low starting dose is often more suitable for elderly people and people at high risk of bleeding.

• The maintenance dose of warfarin depends on the international normalized ratio (INR) during monitoring.
• A target INR of 2.5 is recommended for:
• Deep vein thrombosis.
• Pulmonary embolism (including those associated with antiphospholipid syndrome or for recurrence in people no longer receiving warfarin).
• 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).
• Dilated cardiomyopathy.
• Mural thrombus.
• Symptomatic inherited thrombophilia.
• Coronary artery thrombosis (if anticoagulated).
• Paroxysmal nocturnal haemoglobinuria.
• A target INR of 3.5 is recommended for:
• Recurrent deep-vein thrombosis.
• Pulmonary embolism in people currently receiving warfarin with INR above 2.
• Mechanical prosthetic heart valves:
• The recommended target INR depends on the type and location of the valve. A target INR of 3 is usually recommended for mechanical aortic valves, and 3.5 for mechanical mitral valves.
• Some people may be confused and have difficulty complying with treatment (for example, those with impaired cognition). If there are concerns about this, consider the use of support services (such as district nurse or health visitor), dosette compliance aids (for example, Medidose^®, or Manerex^®), or both. In the absence of such facilities, the risk of using warfarin may outweigh the benefits.
• The healthcare professional who monitors the INR and warfarin dosing for people who use compliance aids should inform the dispensing pharmacist of the warfarin dosage directions after each patient consultation. In general it is recommended that the prescription should:
• Use the fewest number of tablets each day.
• Use constant daily dosing (not alternate-day dosing).
• Avoid the use of half tablets — people find it difficult to break tablets in half and would rather use 0.5 mg tablets.

• For people with deep vein thrombosis (DVT) and pulmonary embolism:
• Duration of treatment for deep vein thrombosis (DVT) will vary for each individual, 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 distal DVT (calf vein thrombosis).
• Three months in people with proximal DVT or pulmonary embolism where there are known temporary risk factors and there is considered to be a low risk of recurrence.
• Six months in people with proximal DVT due to an unknown cause (idiopathic).
• Long-term if there have been recurrent DVTs or pulmonary embolism.
• 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, treatment with warfarin is usually 3 weeks before 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 therapy. 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.

• 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.
• The INR should be measured:
• Daily, or on alternate days, until it is within the therapeutic range (usually between 2.0 and 3.0, ideally 2.5) on two consecutive occasions. Note: although the INR may be measured each day after starting warfarin, a meaningful INR can only be obtained 3–4 days after starting treatment.
• Then, twice weekly for 1–2 weeks, followed by weekly measurements until the INR is stable within the therapeutic range.
• Thereafter, depending on the stability of the INR, at longer intervals (for example, up to every 12 weeks, if agreed locally). Once a stable warfarin dose that controls the INR has been established, changes in dose are seldom required.
• More frequent monitoring of the INR is recommended if the person:
• Has an increased risk of over coagulation: people with severe hypertension, liver disease (including alcoholic liver disease) or renal failure.
• Is at increased risk of bleeding: people on high intensity anticoagulation (INR > 4.0); age 65 years or over; highly variable INRs; history of gastrointestinal bleeding; uncontrolled hypertension; cerebrovascular disease; serious heart disease; risk of falling; thrombocytopenia, anaemia, or coagulation disorders; malignancy; trauma, renal insufficiency; morbidity changes (such as intercurrent illness, or exacerbations of chronic conditions); or has changed their medication (for example, when starting or stopping prescribed or over-the-counter medicines).
• May find adherence difficult.
• Warfarin metabolism can be affected by:
• Thyroid status. People with hypothyroidism or hyperthyroidism should be closely monitored on starting warfarin therapy.
• Genetic variability. If the person or another family member is known to have polymorphisms of CYP2CP or VKORC1, extra care is warranted.

• If the international normalized ratio (INR) is outside the therapeutic range, ask the person about any changes, including:
• Their routine for taking warfarin.
• Other medicines prescribed and purchased.
• Use of alcohol.
• General health. (Weight loss, acute illness, and smoking cessation can increase the effect of warfarin. Weight gain, diarrhoea, and vomiting can reduce the effect of warfarin.)
• If the INR is high:
• Ask the person if they have any signs of bleeding (see Information and advice). If they have significant bleeding, refer urgently for intravenous treatment with phytomenadione (vitamin K₁).
• Depending on the INR, the warfarin dose may need to be reduced and/or one or two doses may need to be omitted — the INR should then be measured 2 or 3 days later to ensure that it is falling.
• INR > 8.0 and no bleeding or minor bleeding — stop warfarin and refer urgently for intravenous or oral phytomenadione. For further information on phytomenadione dosage see the warfarin summary of product characteristics (www.emc.medicines.org.uk).
• INR 6.0 to 8.0 and no bleeding or minor bleeding — stop warfarin. Restart when INR < 5.0.
• INR < 6.0 but more than 0.5 units above target value — reduce dose or stop warfarin. Restart when INR < 5.0.
• If the INR is low:
• Ask the person if they have missed any doses.
• Depending on the INR, the warfarin dose may need to be (temporarily) increased, and sometimes a booster dose may be required — the INR should then be measured 2 or 3 days later to ensure that it is increasing.

• Advise the person taking warfarin that:
• It is very important to have their blood tested regularly (preferably in a warfarin clinic). However, ongoing prescriptions for warfarin tablets should be obtained from their GP.
• They should take the 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 healthcare 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).
• They should always carry their yellow anticoagulant treatment booklet or anticoagulant alert card (issued in hospital) with them.
• Advise the person to inform a healthcare professional (including anticoagulant clinic staff, their GP, dentist, pharmacist, and medical or nursing staff) of changes to their lifestyle, for instance if:
• They are pregnant or planning a pregnancy — they will need to stop taking warfarin (as it is dangerous to the fetus and pregnant women) and to start taking low molecular weight heparin.
• They start, stop, or change the dose of other medicines. Other medicines include not only prescribed drugs, but also products that may be bought without prescription, such as aspirin and medicines containing aspirin, vitamins, food supplements, and herbal or homoeopathic remedies.
• They require surgery or any other invasive procedure, as they may need to temporarily stop taking warfarin.
• For surgery where there is no risk of severe bleeding, surgery can be performed with an INR of < 2.5.
• For surgery where there is a risk of severe bleeding, warfarin should be stopped 72 hours prior to surgery. If it is necessary to continue anticoagulation because the person is at high risk of venous thromboembolism, (such as within the first 6 weeks after a deep vein thrombosis) the INR should be reduced to < 2.5 and heparin therapy should be started. (The risk for recurrent venous thromboembolism is high immediately after the initial deep vein thrombosis and declines over the subsequent period.)
• Outpatient dental surgery (including extractions) can usually be undertaken without temporarily stopping or reducing the dose of warfarin. It is recommended that the INR is checked 72 hours before dental surgery. The risk of significant bleeding in people with a stable INR within the range 2 to 4 is very small, but the risk of thrombosis may be increased if oral anticoagulants are temporarily discontinued.
• Advise the person to be aware of the adverse effects of warfarin and 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, and blood in the urine or stools.
• They get sudden severe back pain (may indicate spontaneous retroperitoneal bleeding).
• They experience difficulty breathing, increased breathing rate, or chest pain (symptoms of pulmonary embolism).
• Give the person general lifestyle information and advise that they should:
• Seek medical advice before undertaking any major changes in diet, especially if their diet is rich in vitamin K (such as broccoli, lettuce, or spinach) — this can potentially affect control of anticoagulation.
• Limit the amount of alcohol to a maximum of one or two drinks a day, and never binge drink.
• Avoid activities which could cause abrasion, bruising, or cuts (for example, contact sports, gardening, sewing), or at least use protection.
• Take extra care when brushing teeth or shaving, and consider using a soft toothbrush and an electric razor.
• Avoid insect bites where possible and consider use of an insect repellent, as appropriate.

Contraindications or cautions for the use of warfarin include:

• Haemorrhagic stroke.
• Bleeding disorders, such as:
• Uncorrected major bleeding — avoid using warfarin until the bleeding has stopped and the cause healed.
• Uncorrected major bleeding disorder — for example, thrombocytopenia, haemophilia, liver failure, renal failure.
• Potential bleeding lesions — for example; active peptic ulcer; oesophageal varices; aneurysm; proliferative retinopathy; recent organ biopsy; recent trauma or surgery to head, orbit, or spine; recent stroke; confirmed intracranial or intraspinal bleed; or within 72 hours of major surgery with risk of severe bleeding, or within 48 hours postpartum.
• Uncontrolled severe hypertension — for example, systolic blood pressure greater than 200 mmHg or diastolic pressure greater than 120 mmHg.
• Pregnancy — due to the risk of teratogenicity with warfarin.
• The person is uncooperative or unreliable — as there may be compliance and follow-up issues.
• The person is prone to repeated falls or unstable gait — since there is an increased chance of injury and head trauma.
• Concomitant use of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, selective serotonin-reuptake inhibitors (SSRIs), venlafaxine, or duloxetine — there is an increased risk of gastrointestinal bleeding (see Drug interactions).
• Protein C deficiency — a risk of skin necrosis on initiation of warfarin requires caution.

Interactions that may enhance the effect of warfarin

• 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 concomitant treatment.
• Alcohol — the person should avoid binge drinking. Heavy drinkers or people with liver disease should avoid alcohol or should not take warfarin.
• Amiodarone — from amiodarone loading onwards, a pragmatic approach is to reduce the warfarin dose by 50%, monitor weekly, and tailor the dose to achieve the target international normalized ratio (INR). This interaction persists for a month or more after amiodarone is withdrawn.
• Antidepressants — selective serotonin reuptake inhibitors (SSRIs) and venlafaxine should be avoided where possible, because of their antiplatelet effect. Duloxetine should also be avoided because it works in a similar way to venlafaxine. Tricyclic antidepressants and mirtazapine should also be avoided due to an enhanced anticoagulant effect. Consider offering trazodone instead.
• Aspirin or aspirin-containing products — (for example, cold and influenza preparations, and topical salicylates) should be avoided unless they are clinically recommended.
• Azoles (in particular fluconazole, miconazole, and voriconazole) — the warfarin dosage should be reduced as necessary. Monitoring is also recommended in people using intravaginal or topical miconazole.
• Clopidogrel or dipyridamole — should be avoided, unless it is clinically recommended.
• Corticosteroids (for example, high-dose prednisolone) — the warfarin dosage should be reduced as necessary.
• Co-trimoxazole — consider whether trimethoprim can be used instead, or reduce warfarin dosage.
• Cranberry juice or cranberry-containing products — the person should avoid cranberry juice and products unless the health benefits outweigh any risks.
• Fibrates — should be avoided if possible, or reduce warfarin dosage by one third to one half.
• Glucosamine — should be avoided.
• Metronidazole — the warfarin dosage should be reduced as necessary.
• Nonsteroidal anti-inflammatory drugs (including topical formulations) — should be avoided, or warfarin reduced as necessary.
• Tamoxifen — should be avoided if possible, or reduce warfarin dosage by one half to two thirds.
• Thyroxine — the warfarin dosage should be reduced as necessary. Consider weekly monitoring whilst the thyroxine dose is being titrated.

Interactions that may reduce the effect of warfarin

• 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 concomitant treatment.
• Tricyclic antidepressants — avoid; they can enhance or reduce the anticoagulant effect. Consider offering trazodone instead.
• St John's wort — stop St John's wort, monitor the INR, and then adjust the warfarin dosage as necessary. St John's wort can cause a moderate clinical reduction in the anticoagulant effect.
• Carbamazepine — the warfarin dosage may need to be doubled if its anticoagulant effect is markedly reduced.
• Griseofulvin — the warfarin dosage should be increased as necessary.
• Oral contraceptives — the warfarin dosage should be increased as necessary. The INR should also be monitored after emergency oral contraception.
• Phenobarbital or primidone — a reduced effect may be seen within 2 to 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. Dose increases of between 30 to 60% are likely to be needed.
• Phenytoin — the warfarin dosage should be increased as necessary. After stopping phenytoin, the INR may continue to be affected for up to 6 weeks.
• Rifampicin — a marked reduction occurs within 5 to 7 days of starting rifampicin, persisting for up to 5 weeks after the rifampicin is stopped. The warfarin dosage may need to be at least doubled.
• Vitamin K-containing vitamin complexes, mineral supplements, and green vegetables (as well as over-the-counter chilblain products) — the warfarin dosage should be increased, or the intake of vitamin K reduced. Vitamin K-rich diets should not be changed without at the same time reducing the warfarin dosage, because excessive anticoagulation and bleeding may occur.
• In addition, it is also be prudent to monitor the INR when warfarin is used concomitantly with the following drugs, especially in older people, as interactions have been documented:
• Allopurinol.
• Azathioprine.
• Grapefruit juice (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).
• Propafenone.
• Proton pump inhibitors.
• Quinolone antibiotics.
• Macrolide antibiotics.
• Statins (particularly fluvastatin or rosuvastatin; not pravastatin).
• Stopping smoking (it takes about 1 week for enzyme induction due to smoking to wear off).
• Zafirlukast.

• Self-testing is where the person tests their own 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).
• Three self-testing devices are available for use by patients in the UK: CoaguChek XS^®, INRatio^®, and Protime 3^®.
• The test strips and lancets can be prescribed on an FP10.
• However, the devices themselves cost from £400 to £800 and are not reimbursable on the NHS.
• The availability of training and support for self-testing or self-management varies across the UK.
• Training and on-going review and support is best managed through specialist anticoagulant services (based in primary or secondary care).
• People should only consider purchasing a self-testing device after discussing the following with their GP or with their anticoagulant service doctor, nurse, or pharmacist:
• Whether self-testing or self-management services (such as training, support, and specialist review) are available in their area.
• Their suitability for self-testing or self-management.

• For selected and successfully trained people, self-testing or self-management are as effective and safe as usual care for long-term oral anticoagulation therapy.
• However, in the UK, self-testing is unlikely to be more cost-effective than usual care, because of the increased frequency of testing.

• People who require long-term anticoagulation can be considered for warfarin self-testing or self management.
• Those who may benefit most are those who are frequently away from home, are in employment or in education, or find it difficult to travel to clinics.
• Previous stability of INR is not a prerequisite to home testing as people with an unstable INR may benefit from the possibility of increased frequency of testing.
• The following criteria should be met before self-testing is considered:
• The person is both physically and cognitively able to perform the self-monitoring test or a designated carer is able to do so.
• An adequate supportive educational programme is in place to train the person and/or carers.
• The person's ability to self-test of self-manage can be regularly reviewed.
• The person will have access to appropriately trained healthcare professionals for ongoing advice and support (including if they plan to travel abroad).
• The following additional criterion should also be met before self-managing is considered:
• The person is cognitively able to follow an individualized algorithm to adjust their own dose of warfarin, or a designated carer is able to do so.
• The following people are not suitable for self-testing or self-management:
• Those who fail to attend clinic appointments (unless work, school, or access make it hard to attend clinic, in which case self-testing or self-managing may be helpful).
• Those who do not adhere to their dosage instructions.
• Those who do not wish to do so.

• The person must:
• Give informed consent to self-testing or self-management, including agreement to record results accurately and participate in a quality assurance scheme for the device.
• Be trained to perform an INR test correctly.
• If self-testing, understand who to contact with their INR result, and how they will be informed of their new warfarin dose.
• If self-managing, be trained to adjust the dose of warfarin correctly based on the INR result, using an individualized patient algorithm.
• Once training has been completed, the person must:
• Be reviewed at least every 6 months by the responsible clinician.
• Have access to an appropriately trained healthcare professional for advice when needed (by telephone or in person).
• Participate in a scheme to check the device is working correctly:
• Either by participating in a formal external quality assurance programme such as UKNEQAS.
• Or by regularly attending clinic (such as every 6 months) to take a venous sample for comparison, or to use the clinic point of care device for comparison.
• Check that each batch of test strips is working correctly.
• Some strips come with a built-in internal quality assurance facility.
• For others, the manufacturers supply samples of known INR to be used for quality assurance testing.