Biography - Eamonn Brady MPSI is the owner of Whelehans Pharmacy in Mullingar. He graduated from the Robert Gordon University in Aberdeen in 2000 with a Masters in Pharmacy. He worked for Boots in the UK before moving back to Ireland in 2002. He bought Whelehans Pharmacy in Mullingar in 2005. He undertakes clinical training for nurses in the midlands.

CPD 13: WARFARIN

Warfarin

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How it works?

Warfarin is described as a blood thinner; however, this is not an accurate description. Warfarin does not actually thin the blood or make it less viscous. The blood needs vitamin K to be able to clot. Vitamin K is absorbed from the intestinal tract and it is then absorbed by and stored in the liver. Subsequently, vitamin K is used during the production of clotting Factors II, VII, IX, X, the anticoagulant protein C and its cofactor protein S. Warfarin acts by reducing the absorption of vitamin K in the liver. Warfarin indirectly prevents the production of Factors VII, IX, X, and II by the liver as these factors need vitamin K to be produced by the liver. Warfarin effectively competes for the same absorption sites within the liver needed for vitamin K uptake. Thus the levels of vitamin K within the liver are reduced. Reduced amounts of clotting factors VII, IX, X, and II are produced, and the clotting action of the blood is progressively impaired.

It works indirectly so has no effect on clots already formed. It is used to prevent rather than treat clots. Therefore, it is ineffective in treating myocardial infarction and strokes because the clots have already formed. It takes about 24 hours to exert its effect and has a half life of 36 hours. Its peak effect can take up to 3 days and may last up to 5 days.

Vitamin K is given for warfarin overdose as it reverses the effect of warfarin.

60 Second Summary

Warfarin is an oral anticoagu-lant. Its role is to prevent blood clots. Its main use is to prevent clots with atrial fibrillation (a type of cardiac arrhythmia that can lead to blood clots), artificial heart valves, deep vein thrombosis, pulmonary embolism and strokes.

Warfarin is sometimes used post myocardial infarction. However warfarin is not as effective as antiplatelet drugs at preventing or treating clots in coronary arteries. Hence, antiplatelet drugs, such as clopidogrel or aspirin are more often used after myocardial infarction.

Nearly 40,000 people in Ireland use warfarin1 and this number is likely to rise in the coming years as the population becomes older and there are better screening techniques.2

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Contraindications

Warfarin should not be used during pregnancy (can cause foetal haemorrhage, particularly in the first and third trimesters), severe hypertension, renal impairment (avoid if creatinine clearance is less than 10ml/minute) and in patients with peptic ulcers.3

Checking warfarin level

The narrow therapeutic index of warfarin and number of factors that influence INR make choosing the optimal dose challenging. The dose of warfarin that should be taken is determined by measurement of the International Normalised Ratio (INR). This is a ratio of the patient's prothrombin time to an international standard. Put simply, this test measures the clotting tendency of blood as compared to an international

standard. INR became the internationally recognised standard to measure the activity of warfarin in the 1980s. Up until then there was no internationally recognised standard to measure activity of warfarin due to variations of prothrombin time assays in different areas. This lead to problems as the rate of globalisation increased and people became more inclined to cross borders. INR became recognised by the World Health Organisation as the international standard of warfarin activity in the 1980s.

Many factors influence how the body responds to warfarin, therefore INR needs to be checked regularly. Patient factors that influence dose response include age, body weight, nutritional status, acute and chronic disease states, and changes in concomitant drug therapy and diet.

CPD 13: WARFARIN

The INR is normally checked at least once a month but more frequent checking may be needed, depending on the patient’s condition and factors such as diet, other medication and other illness. The INR level required varies depending on the condition but a level of between 2 and 3 is normally required. The risk of bleeding increases greatly with an INR of above 5.

The optimal INR is uncertain, but there are some general guidelines depending on the condition warfarin is being used for. An INR of between 2 and 2.5 is recommended for prevention of deep vein thrombosis, including surgery in high risk patients, while a level of between 2 and 3 is recommended for prevention of clots during hip surgery and fractured femur operations. An INR between 2 and 3 is recommended for atrial fibrillation, artificial heart valves made from tissue (usually using a valve of an animal like a pig)*, deep vein thrombosis, pulmonary embolism, transient ischaemic attacks and strokes. An INR of between 3 and 4.5 is needed in some situations because of the increased risk of clot. This includes recurrent deep vein thrombosis and pulmonary embolism, arterial disease including myocardial infarction and mechanical prosthetic heart valves*.

*An artificial valve is a device implanted into the heart when a patient’s heart valves are damaged, known as heart valve disease. There are many causes of heart valve damage, including hypertension and myocardial infarction. Heart valve disease disrupts the flow of blood through the heart and leads to symptoms, such as shortness of breath and weakness. There are two types of artificial valves used to substitute damaged valves, a mechanical valve, which

is made from metal or a tissue valve, which is when the valve of an animal (eg. pig). The

mechanical valve has the advantage that it can last indefinitely, however

it damages red blood cells which can lead to clots, hence the

need for long term warfarin. The tissue valve has the advantage that there is less risk of clot, which means that patients often do not need to take warfarin after getting one inserted. However, the major disadvantage of a tissue valve is that it doesn’t last as long as mechanical

valves, often needing to be replaced after 15 years.

How often should INR be checked?

INR should be checked daily or on alternate days after starting warfarin. After the patient leaves hospital; weekly INR checks are recommended for 4 to 6 weeks. After this, INR checks can be extended to once every 8 weeks if the patient is showing good control.4 Changes in the patient's medical condition such as heart disease, liver disease, thyroid status or change in drug therapy may alter anticoagulant control and will mean more frequent INR checks are needed.5

Indications

There are many indications for warfarin. The most common indications are the treatment and prevention of deep vein thrombosis and pulmonary embolism, prevention of clots with mechanical heart valves and atrial fibrillation.

Warfarin for Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF occurs when the atria do not contract simultaneously. This means that blood flow through the atria is not as constant thus increasing the likelihood of clots. AF is frequently caused by cardiac problems such as hypertension, heart valve disease, left ventricular hypertrophy, coronary heart disease, cardiomyopathy or pericarditis. It may also be triggered by non-cardiac problems including hyperthyroidism, alcohol abuse, pneumonia and pulmonary embolism. Because AF is often asymptomatic, it frequently goes unrecognised and untreated. However the likelihood of stroke in patients with AF is approximately five times higher than that of the general population. The prevalence of AF in the population doubles with each advancing decade of age, from 0.5% at age 50-59 years to almost 9% at age 80-89 years.

The attributable annual risk for stroke associated with AF increases steeply from 1.5% at age 50-59 years to 23.5% at age 80-89 years. Warfarin can reduce the risk of stroke by 60 to 70 per cent.

Dose of warfarin

The usual starting dose is 10mg for 2 days. A prothrombin time should be measured prior to commencement of warfarin to assess liver function. The dose should be taken at the same time each day, usually between 5-7 pm, and the INR measured 16 hours later, i.e. between 9 and 11am the next morning.7

The starting dose should be lower in the following situations: prolonged prothrombin time, abnormal liver function tests, congestive heart failure, parental feeding, underweight patients (BMI less than 18), medication that increase the affect of warfarin and in the elderly (over 80 years). For most patients, the daily dose of warfarin tends to fall between 3mg and 9mg. However responses can vary widely between patients and in the same patient over a period of treatment. Rarely a patient may have a hereditary resistance to warfarin and require large doses of warfarin or may respond more effectively to a different type of oral anticoagulant.8 In the UK and Ireland, warfarin tablets come in three strengths and each has a universally agreed colour to distinguish strengths. Warfarin 1mg are a brown colour, warfarin 3mg are a blue colour and warfarin 5mg are a red colour.

Changing brands of warfarin

It is not good practice to swap brands of warfarin due to potential difference in bioavailabilities between different brands. There have been reports of clinically significant variations in INR when brands of warfarin were changed and the dose remained the same. If a brand must be changed for a patient, due to a shortage of one brand, it is good practice for the patient to get their INR checked 5 to 7 days after changing the brand. The patient should be counselled about the change and potential issues and given a patient information sheet.

Side effects

Bleeding is the most important complication of warfarin. Other possible side effects include nausea, vomiting, diarrhoea, rash and skin necrosis (usually occurs on days 3 to 8 of therapy). Skin necrosis is an extremely rare side effect of warfarin. However, if it does occur treatment must be obtained immediately. Skin necrosis is basically death of skin tissue and usually starts with red skin. Other possible side effects include alopecia (hair loss) and purple toe syndrome. Purple toe syndrome is a rare condition that

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CPD 13: WARFARIN

can occur in the first few weeks of warfarin treatment. It is caused by deposits of cholesterol collecting in the toes. Usually the big toe only is affected and it is characterised by a blue or purple colour and, sometimes pain. Warfarin may need to be stopped if it occurs. Jaundice is a sign of liver problems so must be investigated immediately if taking warfarin. There is some evidence of a link between warfarin and osteoporosis.

Precautions

Warfarin should be taken at the same time each day. This ensures accuracy of INR results. A missed dose must be recorded. A missed dose should be taken within 12 hours and the normal dosing schedule resumed the next day. Never double up the next day if a dose is missed. Over the counter (OTC) drugs should be used in caution. Aspirin and NSAIDs should be avoided as they increase risk of bleeding. Paracetamol is safe to take as a painkiller while taking warfarin. The IMB has said that currently available evidence, as reflected in the product information, suggests that occasional doses of oral paracetamol have no significant impact on the anti-coagulant effect of warfarin however, prolonged regular use may potentiate its effect. Significant changes in intake of food high in Vitamin K (e.g. liver, green leafy vegetables) affects the action of warfarin and more frequent monitoring may be required. Alcohol consumption below 2 units per day (one drink per day) has no effect on the INR but going above this level can affect INR. Weight reducing diets can affect INR level so rapid weight loss should be avoided. A patient must be monitored more closely if they are losing weight. Avoid drinking cranberry juice as it can affect warfarin levels.

Bleeding is the most common side effect of warfarin. It more often occurs in the first month of treatment and is more common in patients over 65.9 Signs of bleeding to watch out for include excessive bruising, bleeding gums, nose bleeds, blood in urine, blood in stools (can be characterised by red or black stools), coughing up blood, excessively heavy periods and severe headaches. Patients must get immediate medical attention if they are unable to stop bleeding, are involved in an accident or get a significant blow to the head. If a patient has a nose bleed while taking warfarin, they should lean their head forward and pinch below the bridge of the nose firmly for ten minutes. If a nose bleed lasts for more than 15 minutes or the patient is having regular nose bleeds, they should get immediate medical attention. Patients should carry anticoagulant booklets for the recording of INR results and anticoagulation dose. Contact sport, such as Gaelic football or rugby is best avoided when taking warfarin. Use a soft tooth brush to avoid bleeding of the gums. Take extra care

when shaving, an electric razor is preferable when taking warfarin.

Recommendations for bleeds

Checking the INR and omitting doses when appropriate is essential if bleeding occurs. The INR should be checked 2 to 3 days after omitting doses to ensure INR is falling.

The British Society for Haemotology guidelines10 for bleeding while taking warfarin are based on the result of INR and whether there is a major or minor bleed. The recommendation for major bleed is to stop warfarin; give phytomenadione (vitamin k) 5-10mg by slow intravenous injection. Give dried prothrombin complex (factors II, VII, IX, X) at a dose of 30-50 units/kg or fresh frozen plasma 15ml/kg if dried prothrombin complex not available.

If INR is greater than 8 and there is no sign of bleeding, stop warfarin and re-start when INR is less than 5. If there are other risk factors for bleeding, give phytomenadione (vitamin k) 500mcg by slow intravenous injection or 5mg by mouth. For partial reversal of anticoagulation (eg. High risk of clots) give

smaller doses of phytomenadione (0.5-2.5mg) using the intravenous preparation orally. Repeat dose of phytomenadione after 24 hours if INR if still high.

If INR is between 6 and 8 and there is no sign of bleeding, stop warfarin and re-start when INR is less than 5. If INR is less than 6 but more than 0.5 units above target value and there is no sign of bleeding, reduce dose or stop warfarin and re-start when INR is less than 5. If there is unexpected bleeding at therapeutic levels, always investigate the possibility of an underlying cause such as illness or drug interaction.

Interactions

Warfarin interacts with more medication and foods than most drugs. Many drugs increase the effect of warfarin, thus increasing the risk of bleeds. These include antifungal medication, such as fluconazole and itraconazole and antibiotics, such as clarithromycin, erythromycin, metronidazole, ciprofloxacin and tetracycline. Other drugs which increase the effect of warfarin include NSAIDs, amiodarone, cimetidine,

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CPD 13: WARFARIN

omeprazole, phenytoin, simvastatin, tamoxifen and thyroxine. Some herbs increase the effect of warfarin including gingko biloba and devil’s claw. Some drugs reduce the effect of warfarin including some sedatives, carbamazipine and trazodone. Herbs that reduce the effect of warfarin include ginseng and green tea.

How long does warfarin need to be taken for?

The length of time that warfarin should be taken depends on many factors. It can vary from a few days to prevent a clot after a hip replacement to lifetime treatment for somebody treated with a mechanical heart valve. Every case is different, so how long warfarin needs to be taken is determined on a case by case basis. For example, someone who has a long term risk of clots such as atrial fibrillation will need to take it for at least six months.

Surgery

To reduce the risk of bleeding during surgery, warfarin is sometimes discontinued for a few days before surgery. The European Society of Cardiology recommends that for major surgical procedures an INR of 2.0 or below is required.

This may require discontinuation of warfarin for several days with the patient changed to heparin instead before and after elective surgery as heparin does not have a risk of bleeds. Generally, for patients with a low risk of clot, warfarin will be stopped 5 days prior to surgery. For patients with a high risk of clot, warfarin will be stopped 4 days before surgery and substituted with heparin. In both cases, warfarin is usually restarted as soon as oral fluids are tolerated by the patient after surgery.

Warfarin for elderly patients

There are often concerns about commencing warfarin in elderly patients where monitoring INR may be logistically difficult and there may be concern about the risk of bleeding, especially in a patient at risk of falls. However, these concerns lead to less people receiving the most effective treatment since elderly patients are at highest risk and, therefore have most to gain from anticoagulation. A 2007 study showed that warfarin is as effective in preventing strokes in AF patients over the age of 75 as it is in younger patients.11 The annual risk of extracranial bleeding in patients taking warfarin was 1.4% compared to 1.6% in those treated with aspirin and there was no increased risk of intracranial bleeding in those taking warfarin.

Summary of pharmacist counselling points

Discuss with the patient the reason warfarin is being taken, interactions and side-effects.Include information on:

• over the counter (OTC) drugs especially aspirin and NSAIDs

• significant changes in intake of food high in Vitamin K (e.g. liver, green leafy vegetables) affects the action of warfarin

• alcohol consumption

• signs of over anticoagulation e.g. excessive bruising, bleeding gums, severe headache, blood in urine, coughing up blood, excessive menstrual bleeding, etc

Warfarin should be taken at the same time daily to facilitate interpretation of INR results.

A missed dose must be recorded. It should be taken within 12 hours and the normal dosing schedule resumed the next day. Patients must immediately inform their GP if they have excessive or prolonged bleeding. Patients should carry anticoagulant booklets for the recording of INR results and anticoagulation dose.

References

1. Garcia-Alamino JM, Ward AM, Alonso- Coello P, Perera R, Bankhead C, Fitzmaurice D, Heneghan CJ. Self- monitoring and self-management of oral anticoagulation. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD003839. DOI: 10.1002/14651858.CD003839. Publication 2.

2. Fitzmurray DA, Murray DT, McCahon D, Holden R, Raferty JP, Hussain S, et al. Self management of oral anticoagulation: randomised trial. BMJ 2005 Nov 5; 331 (7524):1057-1059.

3. Joint Formulary Committee. British National Formulary 2011. 61st Edition.

4. Drug Therapeutic Bulletin 1992: 30; 77 – 80

5. Journal of Clinical Pathology 1990: Vol 43; 177 - 183.

6. Beglan TP, Keelan DM, Watson HG. Guidelines on warfarin oral anticoagulation (warfarin). Third Edition-2005 Update.

7. Guidelines and protocols advisory committee- British Columbia Health Services. Initiation and maintenance of warfarin. 2004.

8. Arch. Intern Med. 1985: 145; 499 – 501

9. Lancet 1996; volume 346: 423 – 428

10. Guidelines on Oral Anticoagulation (warfarin): third edition (2005 update). British Journal of Haematology 2005; 132: 277-285

11. Mant J, Hobbs FD, FletcherK, Roalfe A, Fitzmaurice D, Lip GY, Murray E; BAFTA Investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503

Disclaimer: The information expressed in this CPD article is that of the author and is independent of Pfizer Healthcare Ltd. and/or IPN Communications Ltd.

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