Makindo Medical Notes

Related Subjects:Warfarin | Warfarin and Bleeding | Vitamin K (Phytomenadione) |

Warfarin prevents the production of Factors 2/7/9/10 and Protein C. Protein C is reduced first which can lead to clotting in small skin venules and skin necrosis and so Heparin is often given at the same time.

About: Always check BNF or equivalent for prescribing advice

• Used for the treatment and prevention of thrombotic disorders
• Warfarin is an acronym - Wisconsin Alumni Research Foundation + arin

Aetiology

• Clotting system contains factors II, VII, IX, X
• They are rich in glutamic acid residues
• These require gamma-carboxylation to maintain the tertiary structure
• The carboxylase enzyme requires Vitamin K as a cofactor
• To be active Vit K epoxide needs to be regenerated by the reductase enzyme
• Vitamin K epoxide reductase is inhibited by Warfarin

Indications

• Prosthetic metal heart valves
• DVT, PE, VTE
• Atrial fibrillation (Age >65 or other factors)
• Certain patients with Antiphospholipid syndrome
• Rheumatic heart disease
• Previous thrombosis

Warfarin tablets UK

• Brown 1 mg , Blue 3 mg , Pink 5 mg

Investigations

• INR - a ratio of tested and normal prothrombin times (extrinsic pathway)

Reversal of effect

• Oral Vitamin K + IV Vitamin K + Octaplex /Beriplex (Prothrombin factor concentrates)

Interactions Always check BNF : Drugs causing a Raised INR

• Cranberry juice (Vaccinium macrocarpon) is popular and is also used to prevent cystitis. Interaction with Warfarin is possible because cranberry juice contains antioxidants, including flavonoids, which are known to inhibit cytochrome P450 enzymes and Warfarin is predominantly metabolised by P450 CYP2C9.
• NSAIDs can displace Warfarin from protein binding sites and so potentiate its effect and they also inhibit platelet cyclooxygenase which can impair platelet function and worsen bleeding
• Ciprofloxacin and Amiodarone
• Liver disease - impaired synthesis of clotting factors and also cholestasis can impair Vitamin K absorption and lead to impaired production of Vitamin K dependent clotting factors
• Ginkgo biloba, ginseng, and cranberry products are associated most often with an INCREASE in the effects of COUMADIN. Coenzyme Q10 (ubidecarenone) and St. John's wort are associated most often with a DECREASE in the effects of COUMADIN.

BCSH Warfarin Guidelines

• First episodes of VTE should be treated with an INR target of 2.5
• Warfarin used for the treatment of VTE should be introduced along with parenteral anticoagulation which should continue for at least 5 d and until the INR is >= 2 for at least 24 h
• Recurrent VTE whilst anticoagulated and within the therapeutic range should be managed by increasing the INR target to 3.5
• The target INR should be 2.5 in patients with anti-phospholipid antibodies
• Patients undergoing elective cardioversion should be anticoagulated with Warfarin for at least 3 weeks prior to and 4 weeks post cardioversion with a target INR of 2.5. To minimize cardioversion cancellations due to low INRs on the day of the procedure a target INR of 3.0 can be used prior to the procedure.
• Patients with AF who require Warfarin for the prevention of cardioembolism, stroke should have an INR target of 2.5
• Patients with mitral stenosis or regurgitation who have AF or a history of systemic embolism or LA thrombus or an enlarged left atrium should receive Warfarin with an INR target of 2.5
• In situations where an embolic event occurs during anticoagulation within target, the elevation of the INR target or the addition of antiplatelet drugs should be considered
• Patients with a bioprosthesis in the mitral position should receive 3 months of anticoagulation with Warfarin with an INR target of 2.5
• Patients with a bioprosthetic valve and a history of systemic embolism should have at least 3 months of anticoagulation with Warfarin with an INR target of 2.5
• Patients with a bioprosthetic valve and left atrial thrombus at surgery should receive Warfarin until the clot has resolved with an INR target of 2.5
• Patients with bioprosthetic valves and other prothrombotic risk factors, such as atrial fibrillation and low ventricular ejection fraction, should receive Warfarin with an INR target of 2.5
• Patients with intermittent claudication should not routinely be treated with anticoagulants
• Patients who suffer acute arterial embolism and proceed to embolectomy should be considered for long-term anticoagulation with Warfarin with an INR target of 2.5
• When Warfarin is used following myocardial infarction, the INR target for anticoagulation is 2.5
• Patients with dilated cardiomyopathy who are anticoagulated to prevent systemic embolism should have an INR target of 2.5
• Patients with proximal DVT or PE should be treated for at least 3 months
• If a diagnostic strategy that identifies isolated calf vein DVT is employed, treatment of such clots can be restricted to 6 weeks
• Patients with cancer-associated VTE should initially be treated for 6 months with therapeutic dose LMWH rather than Warfarin
• Long-term anticoagulant therapy is not recommended in patients with VTE provoked by surgery or non-surgical transient trigger factors
• Patients with unprovoked proximal DVT or PE should be considered for long-term anticoagulation, after considering ongoing risks of VTE and bleeding
• Long-term anticoagulant therapy is not recommended in patients with VTE confined to the calf (i.e. not extending into the popliteal vein)
• Overall there is no evidence to suggest a 10 mg loading dose is superior to a 5 mg loading dose. However, in the elderly lower initiation doses or age-adjusted doses may be more appropriate as they lead to fewer high INRs
• For outpatients who do not require rapid anticoagulation a slow-loading regimen is safe and achieves therapeutic anticoagulation in the majority of patients within 3-4 weeks

Bridging

• Pre-operative bridging carries a low risk of bleeding but the use of post-operative bridging requires careful consideration due to the high risk of bleeding. We recommend that post-operative bridging should not be started until at least 48 h after high bleeding risk surgery
• Patients with VTE more than 3 months earlier can be given prophylactic dose LMWH (or a suitable alternative) rather than bridging therapy
• Patients with low-risk AF(no prior stroke or TIA)do not require bridging therapy
• Patients with a bileaflet aortic MHV with no other risk factors do not require bridging
• Patients with a VTE within the previous 3 months, patients with AF and previous stroke or TIA or multiple other risk factors, and patients with a mitral MHV should be considered for bridging therapy

Side effects

• Bleeding
• Pregnancy - Warfarin crosses the placenta and is contraindicated in the first trimester of pregnancy. Multiple Fetal defects, fetal anticoagulation at all stages of pregnancy and Chondromalacia punctata Warfarin may be used from weeks 12 to 36 weeks in those with metal prosthetic valves. Take specialist advice.

Cautions/Contraindications

• Pregnancy (usually)
• Homozygous protein C deficiency (risk of skin necrosis)
• History of Warfarin-related skin necrosis
• Uncooperative/unreliable patients (long-term therapy)
• Thrombocytopenia, haemophilias, liver failure, renal failure
• Systolic >200 mm Hg or diastolic >120 mm Hg
• Active peptic ulcer, oesophageal varices
• Aneurysm, proliferative retinopathy, recent organ biopsy
• Recent trauma or surgery to head, orbit, spine, recent stroke
• Confirmed intracranial or intraspinal bleed

Management

• I load slowly with Warfarin 3-5 mg day and give cover with LMWH or UFH where needed. Follow local guidance. I rarely give larger doses.
• Ensure referral to outpatient anticoagulation and a standard Warfarin book detailing changes in dose and other useful patient information. A Warfarin clinic will often give added advice about drugs to avoid.
• It is however the doctors job to explain the rationale behind treatment and get verbal consent from the patient after discussing risks and benefits.

Guidance on Dosing

• For patients on Warfarin, computer-assisted dosing is superior to manual dosing
• Self-Testing and self-management of Warfarin is associated with improved anticoagulant control but may not be suitable for most patients
• All patients on Warfarin must have a written record of their results and dose changes
• In individuals with an unstable INR, supplementing the diet with 100-150 mcg Vitamin K may improve anticoagulant control
• All patients on Warfarin who are prescribed a drug that may interact with it should have an INR performed after 3-5 d

References

• Guidelines on oral anticoagulation with Warfarin. British Committee for Standards in Haematology 2011