Warfarin Prescribing

Introduction

Warfarin has anticoagulant effects due to being an oral vitamin K antagonist. Despite the recent emergence of newer direct-acting oral anticoagulants (DOACs), warfarin remains the most widely used oral anticoagulant agent available on the market due to familiarity around its use, as well as the ability to directly monitor its effect and rapidly reverse its action with relative ease.¹

Whilst preference for warfarin is slowly diminishing due to its extensive drug and diet interactions, higher incidence of major bleeding, and need for laboratory monitoring compared to DOACs, an understanding of how to prescribe warfarin remains crucial for clinicians.¹

Warfarin is the anticoagulant of choice for preventing thromboembolic events in patients with mechanical heart valves and valvular atrial fibrillation and in patients with end-stage renal failure.¹

Safe warfarin prescribing requires understanding its mechanism of action, indications, contraindications, treatment targets, duration of treatment, dosing, international normalised ratio (INR) monitoring, reversal and interactions. 

Brand names

Several brands of warfarin exist, including Coumadin, Marevan, and many more internationally.²

Different brands of warfarin have differing bioavailability, resulting in variable absorption with an unpredictable response if brands are interchanged. Therefore, patients should always take the same brand of warfarin.²

Mechanism of action

Warfarin exerts its effect through antagonising vitamin K, which is responsible for synthesising vitamin K-dependent clotting factors II, VII, IX and X, as well as proteins C and S.^1,3

The mnemonic “2 + 7 = 9, not 10” can be used to remember the vitamin K-dependent clotting factors.⁴

DOACs, by contrast, directly inhibit a single blood clotting factor:¹

• Dabigatran inhibits thrombin
• Rivaroxaban, apixaban and edoxaban inhibit activated factor Xa

Indications & contraindications

Indications for warfarin include:^1,3

• Treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism)
• Atrial fibrillation: if anticoagulation is indicated for prophylaxis of systemic embolisation
• Rheumatic heart disease: for prophylaxis of systemic embolisation
• Mechanical heart valves: for prophylaxis of systemic embolisation and valve thrombosis
• Mitral valve disease, irrespective of valve replacement, for prophylaxis of systemic embolisation
• Inherited, symptomatic thrombophilia

Contraindications for warfarin include:^1,6

• Malignancy (heparin or a DOAC must be used in this instance)
• Known hypersensitivity to warfarin or its ingredients
• Haemorrhagic stroke
• Clinically significant bleeding
• Potential bleeding lesions (e.g. active peptic ulcer, oesophageal varices)
• Uncorrected major bleeding diathesis (e.g. haemophilia, chronic kidney disease)
• Pregnancy, due to the risk of congenital malformations and fetal death (breastfeeding is allowed)
• Within 72 hours of major surgery with the risk of severe bleeding
• Within 48 hours postpartum
• Uncontrolled severe hypertension
• Patient factors (e.g. uncooperative, unreliable and/or high risk of repeated falls)
• Drugs with which there is a significantly increased risk of bleeding (e.g. antiplatelet drugs*, non-steroidal anti-inflammatory drugs, and enzyme inhibitors)

*Concomitant use of aspirin and other antiplatelets with warfarin may be indicated in a small selection of patients, after careful instruction by their specialists with haematology input as appropriate (e.g. <12 months post-acute coronary syndrome after the insertion of a drug-eluting stent).^1,3 However, in most other circumstances, if warfarin therapy is indicated, aspirin is discontinued.¹

Warfarin therapy

Treatment targets

Treatment targets are referred to in terms of the international normalised ratio (INR). INR is a standardised version of the prothrombin time, the time for blood to clot via the extrinsic pathway. 

For more information on prothrombin time and interpreting a coagulation screen, see the Geeky Medics guide.

The treatment targets are usually as follows:¹

• INR 2 – 3: for treatment of venous thromboembolism, atrial fibrillation, mitral valve disease and inherited symptomatic thrombophilia
• INR 2.5 – 3.5: for mechanical heart valves

However, these are a guide only, and there is some variability in the target range. Higher targets may be required if patients have a recurrence of venous thromboembolism despite anticoagulation.¹

It is important to document the target range to avoid errors in prescribing.

Duration of treatment

Duration of treatment is usually lifelong for all indications of warfarin. The exception is the management of venous thromboembolism, which can be complex and depends on whether the patient had temporary risk factors before developing the clot.^1,5

In this instance, therapy is usually limited to three months (or six weeks if distal limb deep venous thrombosis), given the instigating risk factor is no longer present. Otherwise, warfarin therapy may be indicated for six months or longer if the risk factor is permanent or unknown.^1,5

Dosing and INR monitoring

It is important to follow local guidelines when initiating warfarin. Many institutions have specific protocols on commencing a patient on warfarin, considering their baseline INR, age and renal function.

These guidelines will recommend initial and subsequent doses, which will eventually decide the patient’s maintenance dose.^1,3

Regular INR monitoring ensures the patient’s maintenance dose is appropriate for their treatment targets.^1,3

Warfarin may take up to five days to achieve an INR within the therapeutic range.¹

Paradoxically, warfarin induces a hypercoagulable state because the suppression of protein C occurs much quicker than the coagulation factors due to protein C having a short half-life (approximately eight hours).⁸

To address this, if a patient develops an acute venous thromboembolism and is at high risk of further thrombosis, concurrent administration of heparin should be considered for at least five days until the INR is within the therapeutic range.^1,8

Side effects

The most common side effect of warfarin is haemorrhage.¹

This may manifest as easy bruising, epistaxis and bleeding for longer than expected with simple wounds.¹

Life-threatening bleeding can occur, including prolonged epistaxis, haematemesis, haematochezia, melaena, haemoptysis, haematuria and menorrhagia.^3,7 Additionally, intracranial haemorrhage must be excluded following a head injury.^3,7

Other side effects include hypersensitivity, rash and alopecia.^1,3

Warfarin reversal

An advantage of warfarin compared to DOACs is its ability to be rapidly reversed.^1,3,9

The decision to reverse warfarin is made if the patient’s INR is supratherapeutic, presenting with bleeding (either non-life threatening or life-threatening) and/or need to reverse before surgery.^1,3,9

Follow local guidelines regarding the reversal of warfarin therapy. Generic advice is available from the British National Formulary or on the iTransfuse app by the Australian Red Cross Lifeblood.¹⁰

Options available for warfarin reversal include the following, in ascending order of potency of reversal:

• Withholding warfarin
• Vitamin K, either orally or intravenously
• Prothrombin complex concentrate (PCC): contains vitamin-K dependent clotting factors; PCC containing factors II, VII, IX and X is known as 4-factor PCC whilst PCC without factor VII is known as 3-factor PCC.¹¹ If PCC unavailable, give fresh frozen plasma (FFP) which contains normal levels of all coagulation factors.^1,3,9

Often a mixture of the above reversal agents may be considered. The decision to treat with more potent agents (i.e. PCC or FFP) depends on how supratherapeutic the INR level is and, most importantly, the severity of the bleeding.^1,3,9

Interactions

Drug interactions

The cytochrome P450 system in the liver metabolises warfarin.³

As a result, its metabolism is subjected to an extensive list of drug interactions of enzyme inducers and enzyme inhibitors.

Enzyme inducers decrease the amount of active warfarin in the body and thus decrease its efficacy (decrease INR). These include St John’s wort, phenytoin and carbamazepine.⁷

Enzyme inhibitors increase the amount of active warfarin in the body and thus increase its potency (increase INR). These include amiodarone, metronidazole and clarithromycin.⁷

It is important to advise patients to check with their pharmacist before commencing any new medications, whether prescribed or over the counter.⁷ 

Many antibiotics interact with warfarin, and interactions should be checked before issuing an antibiotic prescription.¹ 

Diet interactions

As warfarin is an antagonist of vitamin K, consuming an excess of foods containing vitamin K may reduce warfarin’s efficacy and thus require higher doses to maintain therapeutic INR levels.

It is important to advise patients to maintain a regular, healthy diet, and aim for a consistent intake of foods with high vitamin K levels, such as green leafy vegetables.⁷

Other dietary interactions include cranberries and cranberry juice. Cranberries are an enzyme inhibitor for warfarin, which increases its potency.⁷

For more information on how to counsel a patient on warfarin, see the Geeky Medics guide to warfarin counselling. 

Peri-procedural management

Surgery and invasive procedures carry a risk of bleeding to all patients, with the risk being higher in patients on anticoagulants.

The need to withhold warfarin is determined by the bleeding risk that the procedure poses, as well as the techniques utilised and patient factors.^1,3,9,12,13

Ultimately, each proceduralist assesses and manages the bleeding risk following local guidelines and input from the haematology team if required. 

Withholding warfarin

Warfarin does not necessarily need to be withheld in all situations.^1,9,12

In certain circumstances, the risk of bleeding is low or can be mitigated through other means, such as applying direct pressure with a tourniquet. In this scenario, warfarin therapy can continue.^1,9,12

In other situations, the risk of bleeding is significant, and warfarin should be held, ideally for five days before the procedure, with an INR check the day before/on the day of surgery.^9,12 

Bridging therapy with heparin

Holding warfarin for any time pre-procedurally will increase the risk of thrombosis.^1,9,12,13

If this risk is unacceptable (based on their indication for warfarin and/or other comorbidities), low molecular weight heparin (LMWH) or unfractionated heparin (UFH) can be used to ‘bridge’ the gap in warfarin therapy.^9,12,13

LMWH is preferred due to ease of use (subcutaneous injection) and predictable pharmacokinetic properties.^{9,12,13,14,15}

UFH may be considered in severe renal impairment and patients at the extremes of weight due to its short activity and reversibility in case of bleeding.^9,14,15

Bridging usually commences three days before the procedure.^7,9,10

LMWH is usually discontinued one day before the procedure, and UFH is usually discontinued six hours before the procedure, due to its shorter half-life.^12,13,14,15

INR monitoring

Ideally, INR should be checked the day before the procedure to ensure it is within the required range.^9,13

Otherwise, warfarin may need to be corrected with the options for reversal outlined above.

Recommencing warfarin

Warfarin is usually recommenced once surgical haemostasis has been achieved, the patient can tolerate oral medications, and as instructed by the proceduralist.⁹

Owing to the initial hypercoagulable state warfarin induces during its initiation, bridging with heparin post-operatively may be required in patients at high risk of thromboembolism.⁹

Key points

• Warfarin is an oral vitamin K antagonist.
• Warfarin is the anticoagulant of choice for preventing thromboembolic events in patients with mechanical heart valves and valvular atrial fibrillation and for patients with end-stage renal failure.
• Different brands of warfarin have differing bioavailability, resulting in variable absorption with an unpredictable response if brands are interchanged.
• Warfarin exerts its effect through antagonising vitamin K, which is responsible for synthesising vitamin K-dependent clotting factors II, VII, IX and X, as well as proteins C and S.
• Treatment targets are referred to in terms of the international normalised ratio (INR).
• Many institutions have specific protocols on commencing a patient on warfarin, considering their baseline INR, age and renal function.
• The most common side effect of warfarin is haemorrhage which can be life-threatening (e.g. intracranial haemorrhage or gastrointestinal haemorrhage).
• The decision to reverse warfarin is made if the patient’s INR is supratherapeutic, presenting with bleeding (either non-life threatening or life-threatening) and/or need to reverse before surgery.
• The cytochrome P450 system in the liver metabolises warfarin. As a result, its metabolism is subjected to an extensive list of drug interactions of enzyme inducers and enzyme inhibitors.
• The need to withhold warfarin before an invasive procedure is determined by the bleeding risk that the procedure poses, the techniques utilised and patient factors.

Reviewer

Dr Andrew Vanlint

Haematology Registrar

Editor

Dr Chris Jefferies

References

1. Tidy, C. Oral Anticoagulants. 2015. Available from: [LINK]
2. Chen, F, Wang, I, Graudins, L & Hopper, I. 2016. Is switching anticoagulant brands safe – Coumadin and Marevan?. Available from: [LINK]
3. EMC. 2017. Warfarin 0.5mg Tablets. Available from: [LINK]
4. Amanda, B. Mnemonic for Vitamin K Dependent Clotting Factors 2 plus 7 is 9 NOT 10 | Medical education, Nursing students, Mnemonics. Available from: [LINK].
5. Swannell, C. 2019. New guidelines for venous thromboembolism. Available from: [LINK].
6. Mulder, FI, Bosch, FTM, Young, AM, Marshall, A, McBane, RD, Zemla, TJ, Carrier, M, Kamphuisen, PW, Bossuyt, PMM, Büller, HR, Weitz, JI, Middeldorp, S & van Es, N. 2020. Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis. Available from: [LINK].
7. EMC. 2017. Warfarin Anticoagulant Record. Available from: [LINK].
8. Kim, Y & Bang, OY. 2015. Paradoxical Procoagulant Effect of Early Doses of Warfarin: Possible Role of Non-Vitamin K Oral Anticoagulant in Patients with Atrial Fibrillation-Related Stroke. Available from: [LINK].
9. Douketis, JD & Lip, GY. 2020. Perioperative management of patients receiving anticoagulants. Available from: [LINK].
10. Australian Red Cross Lifeblood. iTransfuse App. Available from: [LINK].
11. Makris, M & van Veen, JJ. 2011. Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? Available from: [LINK].
12. McIlmoyle, K & Tran, H. 2018. Perioperative management of oral anticoagulation. Available from: [LINK].
13. Oxford University Hospitals NHS Foundation Trust. 2020. Anticoagulant protocols. Available from: [LINK].
14. Merli, GJ & Groce, JB. 2010. Pharmacological and Clinical Differences Between Low-Molecular-Weight Heparins. Available from: [LINK].
15. National Blood Clot Alliance. Unfractionated Heparin (UFH). Available from: [LINK].