The oral anticoagulants available in the UK are warfarin, acenocoumarol, phenindione, dabigatran etexilate and rivaroxaban.¹

• Warfarin is the drug of choice of oral antithrombotic therapy for most indications.
• Warfarin antagonises vitamin K (needed for the synthesis of clotting factors) and takes 2-3 days to exert its full effect.
• Heparin needs to be given for immediate anticoagulation, whilst waiting for the INR to get into the required range.

Indications and targets

Note that the use of warfarin to treat thromboses has more evidence base than the use of heparin.

When to use aspirin plus warfarin

The following is recommended:²

• Patients on an antiplatelet agent for primary prevention of cardiovascular disease (CVD) or peripheral artery disease or previous ischaemic stroke should have this stopped if they develop an indication for warfarin.
• Patients on aspirin or clopidogrel for secondary prevention of CVD with stable ischaemic heart disease (one definition being symptom-free >12 months following acute myocardial infarction) should also have this stopped if they develop an indication for warfarin.
• For patients who have had an acute coronary syndrome (ACS) within in the last year:
  • Those on a single antiplatelet agent should continue this even if they have to start oral anticoagulation. The antiplatelet agent should be stopped 12 months post-ACS.
  • Those on dual antiplatelets following ACS or insertion of drug-eluting stents, who then need to start oral anticoagulants, should be assessed with cardiological and haematological specialists and an attempt made to determine the risk versus benefits of triple therapy.
• If a patient on warfarin develops the need for a coronary artery stent then bare metal stents are preferred, as triple therapy will only be needed for four weeks, following which clopidogrel can be stopped (and aspirin can be stopped at 12 months provided the patient remains cardiovascularly stable).
• There is evidence that in patients undergoing heart valve replacement, aspirin should be continued when warfarin is commenced.³

Dabigatran etexilate and rivaroxaban^4,5

Dabigatran etexilate and rivaroxaban are both licensed for the prophylaxis of venous thromboembolism in adults after total hip replacement or total knee replacement surgery. Neither requires therapeutic drug monitoring.

Contra-indications⁶

The Medicines and Healthcare products Regulatory Agency (MHRA) revised its list of contra-indications in 2009 as a result of Yellow Card reports received over the years. The current list is as follows:

• Known hypersensitivity to warfarin or to any of the excipients.
• 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, can cause congenital malformations and fetal death).
• Drugs where interactions may lead to a significantly increased risk of bleeding, e.g. antiplatelet drugs, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), venlafaxine, or duloxetine.
• Uncorrected major bleeding disorder (e.g. haemophilia, renal failure).
• Potential bleeding lesions, e.g. active peptic ulcer, oesophageal varices.
• Uncontrolled severe hypertension.
• An unco-operative or unreliable patient.
• A patient at risk of repeated falls.
• Breast-feeding - not contra-indicated.

Initiation^1,2,7,8

Ideally, the baseline prothrombin time should be used to assess dosage but, if the clinical situation requires it, initiation should not be delayed.

The latest guidance for acute venous thromboembolism recommends that parenteral anticoagulation continue for at least five days and until the INR ≥2 (whichever is the longer).²If rapid anticoagulation is required, a loading dose of 5-10 mg should be given on the first day. The subsequent dosage regime depends on the prothrombin time expressed as the INR.

Computer-assisted dosing is superior to manual dosing - but not widely available at present.²
When initiating an oral anticoagulant, consider the existence of comorbidity or therapy likely to increase the risk of bleeding; for example:

• Hypertension.
• Renal impairment.
• Abnormal LFTs.
• Cardiac failure.
• Low bodyweight.
• Parenteral feeding.
• Acute illness.
• Vitamin K deficiency.
• Drugs likely to potentiate the effect of anticoagulation.
• Advanced age.

If any condition is present which is likely to potentiate the effect of warfarin, or if the baseline prothrombin time is prolonged, consider reducing the first loading dose.

Aim for an INR within 0.5 units of the target.

In atrial fibrillation there is no need to increase warfarin rapidly. An initial dose of 2-3 mg a day achieves therapeutic coagulation in most people in 3-4 weeks.

Thrombophilia

Patients with protein C deficiency are at risk of developing skin necrosis with warfarin. The loading dose should therefore be omitted at initiation. A similar cautious approach should be instigated in patients with protein S deficiency.

Monitoring⁶

People on oral anticoagulants need regular monitoring of INR. INR is checked daily until in the therapeutic range, twice a week for 1-2 weeks, weekly until stable, then every 6-12 weeks.

Change in a patient's condition, e.g. liver disease, intercurrent illness, a new drug started, necessitates more frequent testing.

Enhancement of warfarin effect can occur in:

• Loss of weight.
• Acute illness.
• Cessation of smoking.

Reduction of warfarin effect can occur in:

• Weight gain.
• Diarrhoea.
• Vomiting.

In patients with unstable INRs, supplementation of the diet with 100-150 micrograms vitamin K may improve anticoagulant control.²

Near-patient testing (NPT) and patient self-management (PSM)^2,7

INR monitoring is normally managed by local anticoagulant clinics but, with appropriate training, self-management using a portable coagulation monitor (e.g. CoaguChek® S system), can be safe and reliable and much more convenient for many patients. A worrying trend is for patients to buy monitors directly from the manufacturer and use them without proper training. It is hoped that the manufacturers can be engaged to encourage patients to discuss the options with their GP prior to purchase. A recent study found that PSM was as clinically effective as conventional care.⁹ It is not deemed cost-effective in the UK compared with usual care, due to the increased frequency of testing but it is recognised that it may improve quality of life in highly motivated individuals who do not have time to attend clinics.

• Patients should conduct NPT, with or without PSM, within a managed anticoagulation clinic programme.²
• The programme should aim for the same standards of care as a hospital clinic.
• Patients should be assessed for capability - only patients able to follow the same total quality management procedures as hospitals should undertake NPT ± PSM.
• Patients should be audited regularly for comparison with laboratory results, proportion of INRs in range and adverse events.

Patient advice

Patients should be advised to:

• Take the prescribed dose at the same time, daily.
• Report any bruising or bleeding immediately.
• Attend for blood tests as advised.
• Avoid pregnancy - ensure adequate contraception.
• Avoid aspirin - use paracetamol for pain.
• Avoid contact sports and activities carrying a risk of head injury.
• Remind medical and dental carers of anticoagulant use
• Avoid NSAIDS (diclofenac, meloxicam can be used with care).
• Keep the primary care organisation booklet up to date.

Complications and reasons to discontinue drug⁶

The main adverse effect of warfarin is haemorrhage. Risk factors for haemorrhage in patients taking warfarin include:

• High intensity of anticoagulation (INR >4.0).
• Age ≥65 years.
• Highly variable INRs.
• History of gastrointestinal bleeding.
• Uncontrolled hypertension.
• Cerebrovascular disease.
• Serious heart disease.
• Risk of falling.
• Anaemia.
• Malignancy.
• Trauma.
• Renal insufficiency.
• Concomitant drugs.

Other adverse effects include hypersensitivity, rash, alopecia, diarrhoea. See monograph for full list.

Managing haemorrhage and/or a high INR^1,7,8

If the patient has life-threatening bleeding (e.g. intracranial or gastrointestinal haemorrhage), hospital admission is indicated. Hospital management involves giving phytomenadione (vitamin K1) 5-10 mg by slow intravenous injection, together with dried prothrombin complex, (factors II, VII, IX and X) 30-50 units/kg. Fresh frozen plasma 15 mg/kg should be used if dried prothrombin complex cannot be obtained but is suboptimal.² In other cases, manage as below:

• INR above 8 without bleeding or with only a minor bleed (e.g. haematuria or epistaxis) - stop warfarin, administer vitamin K1, using the intravenous solution orally (unlicensed use) 2.5-5 mg by mouth, or 0.5-1 mg by intravenous injection slowly. Check INR again 24 hours later; if more than 0.5 above target value, give another dose of vitamin K1. Restart warfarin when INR <5.0.
• INR of 5-8, no bleeding - stop warfarin. If minor bleed, administer vitamin K1 1-2.5 mg by mouth, using intravenous preparation orally. In either case, warfarin can be started again when INR <5.0.

A high INR is often due to a drug interaction¹⁰ (see monograph for a full list).

If possible, prescribe drugs that do not interact with warfarin. Note that considerable variation exists between drugs in the same class (e.g. antibiotics).

If the haemorrhage occurred when the warfarin level was in the therapeutic range, consider an underlying cause such as unsuspected renal or gastrointestinal tract pathology.

Managing a low INR

• Ask the patient if they have missed any doses.
• Consider increasing the dose temporarily and adding a booster dose if necessary. Measure the INR again 2-3 days later.

Stopping anticoagulation²

There was initial concern that stopping anticoagulation abruptly would cause a rebound hypercoagulable state. This has not been confirmed by prospective trials and it is now known that warfarin can be stopped without any associated clinical risk, once therapy has been completed.²

Interactions⁷

• Warfarin is enhanced by: alcohol, allopurinol, paracetamol, SSRIs, lipid-regulating drugs, cranberry juice, influenza vaccine and many other drugs and is reduced by oral contraceptives and St John's wort. The effect of other herbal and complementary remedies should not be forgotten.¹¹
• Advise people on warfarin to check with their pharmacist that any new medicine they are prescribed or buy is OK to take with warfarin.
• Reassess the need for warfarin regularly; a person's cardiovascular risk and the risk of bleeding will change over time.

Managing unavoidable interactions

• If an interacting drug will be used for less than 5 days, often no dosage change is necessary. Omission of one full warfarin dosage may be prudent with known potentiating drugs.
• If an interacting drug will be used for more than 5 days, check the INR one week after starting therapy and adjust the warfarin dose accordingly. The INR should also be monitored when an interacting drug is stopped.
• During amiodarone loading, reduce warfarin by half and check INR weekly.
• Major changes in diet (especially involving salads and vegetables) consumption may affect warfarin control.

Special clinical scenarios⁶

• Ischaemic stroke in atrial fibrillation patients: the risk of early recurrent embolism of haemorrhagic stroke is small, so a break in treatment is justified in order to minimise the risk of secondary haemorrhage. The break should be for 2-14 days depending on the size of the infarct and the blood pressure.
• Intravenous drug users: thrombosis of the iliofemoral vein is common in this patient group. The use of low molecular weight heparin should be considered as an alternative to oral warfarin, particularly if monitoring is difficult because of the patient's lifestyle or there is difficulty in accessing veins.¹²
• Cancer patients with venous thromboembolism: low molecular weight heparin gives a better risk/benefit profile (recurrent thromboembolism versus bleeding) than warfarin and should be considered first-line in these patients.¹³
• Patients with peptic ulcers: patients with active peptic ulcers are at increased risk of bleeding when on warfarin, so should be reviewed regularly, advised how to recognise bleeding and informed what to do should bleeding occur.
• Head injuries: patients on warfarin are at an increased risk of intracranial bleed following a head injury and a low threshold to perform a CT head scan is needed. If there is a high suspicion of an intracranial bleed then the INR should be reversed without delay. There is also a risk of delayed intracranial bleed even if the initial CT scan was normal. Therefore, it is recommended that the INR be kept close to 2.0 for the first four weeks following a significant head injury.²
• Managing anticoagulation prior to surgery:
  • For surgery where there is no risk of severe bleeding, surgery can be performed with an INR of <2.5, unless there is a risk of life-threatening thromboembolism.
  • Where there is a risk of severe bleeding, warfarin should be stopped three days before surgery. If anticoagulation is deemed necessary, INR should be reduced to <2.5 and heparin started. If warfarin cannot be stopped beforehand, low-dose vitamin K should be used to reverse anticoagulation.
  • For dental surgery, anticoagulants can be continued, providing the INR is in the therapeutic range (<3).¹⁴
  The timing of re-introduction of warfarin depends on the risk of haemorrhage after surgery. In most cases this can occur as soon as the patient can take medication orally but, for any high bleeding risk surgery, it is recommended to wait at least 48 hours.²
• Thyroid disease: myxoedema and thyrotoxicosis can both affect warfarin levels and patients should be closely monitored at the time of initiation.

Improving compliance⁷

Compliance can be improved by:

• Prescribing the smallest number of tablets each day.
• Use of daily dosing rather than alternate day dosing if possible.
• Avoiding using half tablets, as patients may find it difficult to break tablets exactly in half.

Document references

1. British National Formulary
2. Guidelines on oral anticoagulation with warfarin, British Committee for Standards in Haematology (2011)
3. Larson RJ, Fisher ES; Should aspirin be continued in patients started on warfarin? J Gen Intern Med. 2004 Aug;19(8):879-86. [abstract]
4. Venous thromboembolism - dabigatran, NICE Technology Appraisal Guideline (September 2008); Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults
5. Venous thromboembolism - rivaroxaban, NICE Technology Appraisal Guidance (April 2009); Rivaroxaban for the prevention of venous thromboembolism
6. Medicines and Healthcare products Regulatory Agency; Warfarin: changes to safety information, 2009
7. Anticoagulation - oral, Prodigy (March 2009)
8. Antithrombotic Therapy, Scottish Intercollegiate Guidelines Newwork - SIGN (1999)
9. McCahon D, Murray ET, Jowett S, et al; Patient self management of oral anticoagulation in routine care in the UK. J Clin Pathol. 2007 Nov;60(11):1263-7. Epub 2007 Jan 26. [abstract]
10. Blann AD, Fitzmaurice DA, Lip GY; Anticoagulation in hospitals and general practice.; BMJ. 2003 Jan 18;326(7381):153-6.
11. Shalansky S, Lynd L, Richardson K, et al; Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy. 2007 Sep;27(9):1237-47. [abstract]
12. Mackenzie AR, Laing RB, Douglas JG, et al; High prevalence of iliofemoral venous thrombosis with severe groin infection among injecting drug users in North East Scotland: successful use of low molecular weight heparin with antibiotics. Postgrad Med J. 2000 Sep;76(899):561-5. [abstract]
13. Meyer G, Marjanovic Z, Valcke J, et al; Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. [abstract]
14. Dunn AS, Turpie AG; Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med. 2003 Apr 28;163(8):901-8. [abstract]

Internet and further reading

• Deep vein thrombosis, Prodigy (March 2009)
• Deep vein thrombosis - prevention for travellers, Prodigy (May 2009)
• Atrial fibrillation, Prodigy (August 2009)