Oral Anticoagulants

The oral anticoagulants available in the UK are warfarin, acenocoumarol (nicoumalone) and phenindione.

• Warfarin is the drug of choice for oral anti-thrombotic therapy - the other alternatives are seldom required.
• Warfarin antagonises vitamin K (needed for the synthesis of clotting factors) and takes 2-3 days to exert its full effect.
• For immediate effect heparin must be given with it.

Note that warfarin is inferior to low molecular weight heparin for treating thromboses in patients with solid tumours.

When to use aspirin plus warfarin

Aspirin in combination with warfarin was used quite frequently in patients after a myocardial infarction before the use of stenting. Patients with high thrombotic risk and low bleeding tendency may still benefit from this combination, but stenting has largely obviated its use in most patients.¹ There is evidence that in patients undergoing heart valve replacement, the aspirin should be continued when warfarin is commenced.²

• Known bleeding tendency
• Liver disease
• Platelets <80x10⁹/l.
• Haemorrhagic stroke
• Uncontrolled severe hypertension
• Continuing alcohol abuse
• Non-compliant patients
• Active peptic ulcer
• Pregnancy: oral anticoagulants are teratogenic (from week 6) and cross the placenta in late pregnancy and at delivery with risk of placental or fetal haemorrhage. Pregnant women with heart valves or recurrent venous thrombosis must discuss the relative risks of stopping or continuing warfarin.
• Breastfeeding - not contra-indicated

Ideally the baseline prothrombin time should be used to assess dosage, but if the clinical situation requires it, initiation should not be delayed.
When initiating an oral anticoagulant, consider the existence of co-morbidity or therapy likely to increase the risk of bleeding , e.g.:

• Hypertension
• Renal impairment
• Abnormal liver function tests
• Cardiac failure
• Low body weight
• Acute illness
• Vit. K deficiency
• Drugs likely to potentiate the effect of anticoagulation
• Advanced age

For most patients in an outpatient setting, warfarin can be initiated gradually, starting with 5 mg or 10 mg and followed by 5 mg doses. This achieves anticoagulation within 3-4 weeks and reduces the risk of bleeding secondary to overdosage. If rapid anticoagulation is required, a loading dose of 10 mg daily for 2 days is normally given, but for patients with a high risk of bleeding 5 mg daily should be considered.

There are some indications (e.g. the elderly) when a slower increase in dose may be appropriate, particularly in the outpatient setting where blood test monitoring may be difficult. There are many regimes available; one suggests a starting dose of 5 mg daily for five days, with further dose increases depending on the INR results at day 8.⁴

Maintenance dose is usually 3 to 9 mg daily (taken at the same time each day) depending on INR. Anticoagulant treatment booklets should be issued to patients (available from Primary Care Organisations).

People on oral anticoagulants need regular monitoring of INR. INR is checked daily until in the therapeutic range for 2 consecutive days, then twice a week for 1-2 weeks, then weekly until stable, then every 6-12 weeks.
Change in a patient's condition, e.g. liver disease, intercurrent illness, new drug started necessitates more frequent testing.

Near-patient testing (NPT) and patient self-management (PSM)

INR monitoring is normally managed by local anticoagulant clinics, but with appropriate training self-management using a portable coagulation monitor (e.g. CoagucheckS®) 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 patient self-management was as clinically effective as conventional care.⁵
It may improve control for some - although not all patients want to self-monitor.⁶

• Patients should conduct NPT, with or without PSM, within a managed anticoagulation clinic programme.¹
• The programme should aim for the same standards of care as 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 regularly audited for comparison with lab 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

The main adverse effect of warfarin is haemorrhage.
The Scottish Intercollegiate Network (SIGN) have issued the following guidance:³

• Life threatening bleeding (e.g. intracranial or major gastrointestinal bleed) requires urgent admission
• Less severe bleeding (e.g. haematuria, epistaxis): stop the warfarin and reverse the effect with phytomenadione (vitamin K1) 5-10 mg by slow intravenous injection. (The British Committee for Standards in Haematology previously recommended either oral or intravenous vitamin K, but are now in agreement that intravenous vitamin K should be used.)
• Prothrombin complex concentrate (factors II, VII, IX and X) 30-50 units/kg should also be given, or if this is not available, fresh frozen plasma 15 ml/kg.

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

Managing a high INR

• INR above 8 - stop warfarin, measure INR 2 days later to ensure that it is falling; restart when INR < 5.0.
  If there are risk factors for bleeding give vitamin K 5 mg orally or intravenously, and repeat it if INR remains high after 24 hours.
• INR of 6-8 stop warfarin, restart when INR in therapeutic range.⁷ If INR is 0.5 units above target value - reduce dose or stop warfarin, restart when INR < 5.0.

A high INR is often due to a drug interaction⁸ (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).

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 abruptly once therapy has been completed without any associated clinical risk.¹

• 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 complimentary remedies should not be forgotten.⁹
• Many drugs have a variable effect, meaning they can enhance or inhibit, including anti-epileptics and anti-fungals.
• Non-prescription products which enhance the effect of warfarin are those containing:⁷
  • Alcohol, aspirin or paracetamol
  • Cranberry or grapefruit juice
  • Glucosamine¹⁰
• 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 1 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.

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 difficulty in accessing veins.¹¹

Cancer patients with venous thromboembolism

Low molecular weight heparin gives a better risk/benefit profile (recurrent thromboembolism vs bleeding) than warfarin, and should be considered first line in these patients.¹²

Managing anticoagulation prior to surgery

Anticoagulants should be stopped prior to surgery unless there is a very high risk of thromboembolism. Heparin or low molecular weight heparin should be considered for patients at high risk. Low dose vitamin K has also been tried in this scenario.¹³ For dental surgery, anticoagulants can be continued providing the INR is in the therapeutic range (<3).¹⁴ Guidelines have recently been produced by the British Committee for Standards in Haematology.¹⁵