A practical guide to anticoagulation

Once the preserve of secondary care, anticoagulation – initiation and monitoring – is firmly established in general practice. Our guide examines the indications for anticlotting regimes and the therapeutic options

Atrial fibrillation (AF) is the commonest heart rhythm abnormality found in the UK, with nearly 50,000 new cases being diagnosed each year.^1,2 The main causes are ischaemia, hypertension, mitral stenosis and hyperthyroidism.² The prevalence rises with age and so is 0.5% at 50-59 years, but 9% at 80-89 years.³ It is commoner in men.⁴ People with AF have a five-fold increased risk of stroke and thromboembolism⁵ (relative risk: whatever the baseline risk of stroke for an individual, the risk is raised five-fold by the presence of atrial fibrillation). In people with AF who have never had a stroke or transient ischaemic attack (TIA), and do not take warfarin, the risk of stroke is about 4% a year (absolute risk): this risk is reduced to less than 1.5% if warfarin is taken. Another way of expressing these statistics is that, if 1,000 people with AF take warfarin for a year, then 25 strokes (half of which would have been disabling or fatal) would be avoided.⁶

As the prevalence of AF is dependent on age, and as the age of our patient list is getting greater, treating with warfarin is a common occurrence for UK general practice teams.

Historically warfarin treatment has been typically initiated in a secondary care setting, but more and more general practices are now starting warfarin in-house. The monitoring of warfarin treatment is now largely a general practice task, incentivised either locally or nationally by financial payments (it is cheaper to monitor warfarin in the community than to have people attending hospital outpatient clinics on a regular basis, especially as the people who need warfarin tend to be older and have more disability than the general population). It is important to get warfarin treatment right, and there is money involved, so practices want to be sure that their anticoagulant clinic is run properly and efficiently.

Not everyone with atrial fibrillation benefits from taking warfarin. For some the baseline risk is so low that the gains from taking warfarin are trivial. To work out which patients benefit, NICE recommends the use of the CHADS2 score. (Table 1) A score of 0 or 1 means that aspirin is sufficient protection: if the score is 2 or more then warfarin is recommended.⁵

WARFARIN

Warfarin is a coumarin anticoagulant – there are others, but warfarin is the preferred drug.⁷ It works by blocking the effects of Vitamin K, a vitamin important to blood clot formation. Indications for use include deep vein thrombosis (DVT), pulmonary embolism (PE), AF, and following the fitting of a mechanical heart valve.

Warfarin was initially produced in 1948 as a pesticide against mice and rats. It was found in the early 1950s to prevent thrombosis in humans and so was introduced for medical use in 1954. It is taken as a tablet or tablets one dose a day. The dose should be adjusted according to effect. There is a relatively small ‘therapeutic window’. If too little is used, then the warfarin will not do the job properly. If too much is used, then there is a tendency towards excessive bleeding, which can be serious especially if it leads to gastro-intestinal or intra-cerebral bleeding. So a target for treatment is set for all people taking warfarin, based on the International Normalised Ratio (INR). The INR sounds complicated and scientific, but the reality is a little more down to earth: if a blood sample takes twice as long to form a clot when compared with normal blood, then the INR is 2.

MONITORING

A target INR of 2.5 is suggested for most of the warfarin situations seen in general practice including DVT/PE and atrial fibrillation. Sometimes a higher target is specified (e.g. 3.5), but such cases will invariably be being seen in secondary care, so specialists will advise. A target of 2.5 means that the INR should be kept between 2 and 3 giving a margin for treatment of 0.5 each side of target.⁷ An INR can be obtained by sending a specimen up to the local laboratory. More commonly general practices are using sticks containing chemical reagents onto which a pinprick specimen of patient blood is dropped. The stick is then inserted into a machine to be read: this is not as accurate as using a laboratory, but sufficient for most practical purposes.

INTERACTIONS

If you look in the British National Formulary (BNF) you will find that the list of drug interactions for coumarin anticoagulants runs to a page and a half, greater than any other type of medication. However, in most cases the interactions are not dangerous, they just increase or decrease the effectiveness of the anticoagulant, i.e. they alter the INR. This is not a problem for drugs used in regular doses as the dose of warfarin is simply adjusted according to the INR. There is more of a problem when drugs are started and stopped, and when short courses of drugs are used, for instance with antibiotics. The BNF reports that the trials done with warfarin and antibiotics fail to reach statistical significance, but most workers in anticoagulation clinics would confirm that many of the antibiotics in regular use in primary care do in fact push up the INR in some people, occasionally to dangerous levels. It is wise to check the INR during or on completion of a course of antibiotics. Your patient may also be taking other medicines bought over-the-counter: you and your prescribing software may be unaware of this, and so cannot advise appropriately. Medicines available over-the-counter which may interfere with warfarin include lactulose, glucosamine and orlistat. When an unexpected INR occurs or there is evidence of excessive bleeding, ask about over-the-counter drugs.

Other drugs, such as aspirin and anti-inflammatory drugs (which are also available over-the-counter) can cause gastro-intestinal bleeding and so should be avoided when warfarin is being taken. Rarely a patient is taking aspirin or clopidogrel with warfarin as part of their treatment, but in such cases they will also be followed up by a specialist.

NHS Choices publishes a useful summary for patients on warfarin, available on-line.⁸ Foods such as spinach and broccoli can affect warfarin, as can cranberry juice. Small regular quantities are not a problem as they can be adjusted for, but non-continuous large doses can pose a problem. Alcohol is another substance that interacts with warfarin by sending up the INR, and which in some people, is drunk in binges. If your patient on warfarin fancies a drink, encourage a moderate steady consumption rather than occasional heavy drinking.

BLEEDING COMPLICATIONS

People taking warfarin should take their dose at the same time each day and not alter the dose without letting a healthcare professional know. Pregnancy will prompt a re-evaluation of the treatment. For surgery or dental treatment there will have to be a temporary halt to warfarin to reduce bleeding complications. Any evidence of extra bleeding should be reported, for instance nosebleeds, bleeding gums, prolonged bleeding after cuts, or blood in the stool or urine. This may indicate that the INR is too high and treatment is needed. And people on warfarin need to be sensible: playing rugby, or boxing, is not advisable, and keep in mind other situations where cuts and bruises are more common, such as gardening.

If a patient on warfarin reports possible excess bleeding, then do an INR. Sometimes an abnormal INR will turn up on routine surveillance measurement. If the level is on target or not too errant, then the software will advise suitable adjustments in drug dose. Where the INR is under 6 but more than 0.5 above target, then as long as there is no evidence of excessive bleeding, warfarin dose adjustment is appropriate. If it is 6 to 8 with no extra bleeding, it is probably better to stop the warfarin and then restart when the INR is under 5. If the INR is 8 or over, particularly if there is excess bleeding, then the risk of harm is significant and such people probably need hospital admission.⁷

The typical dose of warfarin maintenance is 3 to 9 mg a day, but there will be some who need more or less. Warfarin takes 48 to 72 hours to reach its full effect. When starting, it is seldom necessary to build up the anticoagulant effect quickly, so this can be done over 2 or 3 weeks starting with 2 or 3 mg a day, and then checking the INR every day of so until the desired level is achieved. Blood tests are more frequent (and so disruptive) in the early stages of treatment: later on, the intervals between testing can be extended to up to 12 weeks. Some people run a stormier course, sometimes due to inconsistencies in their eating habits, or sometimes just through bad luck.

The side effects of warfarin include bleeding, nausea, vomiting, diarrhoea, jaundice, pancreatitis, alopecia, rash and ‘purple toes’. It should not be used at all if kidney or liver function is severely impaired.⁷

ALTERNATIVES TO WARFARIN

Warfarin is by far the most commonly used anticoagulant in the UK. However, since March 2012, NICE has also approved the use of dabigatran (a direct thrombin inhibitor) to reduce the risk of cerebrovascular events in atrial fibrillation. At a dose of 150mg BD it is better than warfarin at reducing the risk of stroke with no excess of bleeding events. At 110mg BD it reduces strokes just as well as warfarin but fewer bleeding events.⁹

The other positive thing about dabigatran is that no INR monitoring blood tests are required. So why aren’t all our AF patients taking dabigatran? Well, there are side effects. It can’t be used in pregnancy, breast feeding, severe liver disease and if the eGFR is below 30mL/min/1.73m2 – indeed annual measures of eGFR are required.⁷ It too can cause nausea and diarrhoea, and also stomach ulcers and reflux. The other consideration is the cost, currently £75.60 a month at full dose.⁷ Warfarin is a cheaper drug, but then all the blood testing has to be factored in to the overall cost.

Even more recently approved is apixaban (Eliquis) which received a fast-tracked positive final appraisal determination from NICE towards the end of January. Apixaban is an oral anticoagulant, indicated for preventing stroke and systemic embolism in people with non-valvular AF and one or more risk factors (prior stroke or TIA; age 75 years or older; hypertension; diabetes; or symptomatic heart failure NYHA Class II or above). The recommended dose is 5mg, taken in divided doses twice daily, so the cost of a month’s treatment works out at £102.90, but like dabigatran it does not require routine monitoring.

ANTIPLATELET DRUGS

Platelets are the small blood cells that stick together to form clots. It follows that reducing platelet stickiness also reduces the chance of blood clots, which is exactly the required effect in someone with AF.

Aspirin

Acetylsalicylic acid (aspirin) was used for years as a pain killer and anti-pyretic before its use in reducing platelet stickiness was discovered. It is recommended for use in the secondary prevention (i.e. to prevent further episodes) of thrombotic cardiovascular or cerebrovascular disease, and after heart valve surgery, and for the primary prevention of thromboembolic episodes in AF. For these uses it is taken once a day, and comes in tablets (enteric coated and otherwise) and as a soluble (dispersible) preparation. The usual adult dose is 75mg, which ironically is the same as the old ‘Junior Aspirin’ used so widely in the UK before it was withdrawn because of the possibility of the very rare Reye’s syndrome. It should not be used in severe liver or kidney impairment, during breast feeding or the third trimester of pregnancy, or if there is a known significant allergy to either aspirin or to an NSAID drug. Aspirin can also cause bronchospasm (take care in people with asthma), and occasionally severe stomach irritation or bleeding: this latter may be ameliorated by taking after food or by co-prescribing a proton pump inhibitor (such as lansoprazole).⁷

Clopidogrel

Clopidogrel was introduced as a more gut-friendly antiplatelet agent than aspirin. In fact, looking at the risk of major gastrointestinal bleeding, clopidogrel has very little advantage over aspirin.¹⁰ Before the patent expired, clopidogrel was very expensive, and even now it costs more than aspirin. However, with NICE approval, it has found its place in the pantheon of cardiovascular protective agents. Clopidogrel can be used in peripheral vascular disease, after acute coronary syndromes (with or without ST elevation), and to prevent thrombotic episodes in people with AF. Unfortunately things are not that simple, and the BNF gives details of when clopidogrel should be used and in what combinations with other antiplatelet agents.⁷ Again it cannot be used in pregnancy, breast feeding and caution is needed in liver or kidney impairment. The more common side effects include dyspepsia, abdominal pain, diarrhoea and bleeding (including gastro-intestinal and intracerebral bleeding).

Dipyridamole

Another antiplatelet drug enjoying an Indian summer is dipyridamole. Originally it was introduced to help peripheral vascular disease, for which it was not very effective. Now it is used alone, or in combination with aspirin and/or clopidogrel after stroke or transient ischaemic attack. Details can be found in the BNF Section 2.9. Side effects include the usual gastrointestinal ones which appear unavoidable in this therapeutic area, but also some more novel items: dizziness, myalgia, throbbing headache, hypotension, hot flushes, racing heart. My own father, after a stroke, had to stop taking dipyridamole because of adverse effects. But it is not harmful in pregnancy.

CONCLUSION

Vascular disease in the UK is a big deal for hospitals, for general practice, and for undertakers. The use of drugs in primary and secondary prevention is well established, and research and guidance have rendered their use more rational. Warfarin has a particularly prominent role in some vascular disease categories, and much time and effort has gone in to providing anticoagulation services, usually run by practice nurses.

Time has brought new agents to the fore, some for the first time, some enjoying a renaissance. The very newest are the province of our hospital colleagues, and are universally expensive, but may in the fullness of time find their own place within primary care prescribing.

REFERENCES

1. BHF. Atrial fibrillation: an update. BHF Factfile 2004. British Heart Foundation. www.bhf.org.uk

2. Iqbal MB, Taneja AK, Lip GYH, et al. Recent developments in atrial fibrillation. BMJ 2005; 330(7485), 238-243.

3. National Collaborating Centre for Chronic Conditions. Atrial fibrillation. National clinical guideline for management in primary and secondary care (full NICE guideline). Royal College of Physicians (2006). www.nice.org.uk

4. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003;139(12), 1009-1017.

5. NICE Atrial fibrillation: the management of atrial fibrillation (NICE guideline, 2006). National Institute for Health and Clinical Excellence. www.nice.org.uk

6. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks (Cochrane Review). The Cochrane Library. 2005;3:CD001927 www.thecochranelibrary.com

7. British National Formulary No 64 (September 2012). London:BMA/RPS

8. Anticoagulants, warfarin – Interactions. http://www.nhs.uk/Conditions/Anticoagulants-warfarin-/Pages/Interactions---other-medicines.aspx

9. Connolly SJ, Ezekowitz MD, Yusuf S for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Eng J Med 2009;361:1139-1151

10. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006;119(8):624-638.