Warfarin

Warfarin is an oral vitamin K antagonist that lowers the levels of clotting factors II, VII, IX and X. It treats and prevents venous thromboembolism, prevents stroke in atrial fibrillation, and is the anticoagulant of choice for mechanical heart valves and for atrial fibrillation with moderate to severe rheumatic mitral stenosis, which is common in East Africa. It has a narrow therapeutic range, many drug and diet interactions, and needs regular INR tests. It is cheap and widely available.

Classification. Oral anticoagulant; vitamin K antagonist; coumarin.

Mechanism. Inhibits vitamin K epoxide reductase (VKORC1), blocking regeneration of reduced vitamin K needed to carboxylate clotting factors II, VII, IX, X and proteins C and S.

Pharmacodynamics. Anticoagulant effect appears after 2 to 3 days (as existing factors decay) and reaches full effect at 5 to 7 days. Early protein C fall can cause transient hypercoagulability. Effect lasts 2 to 5 days after stopping.

Pharmacokinetics. Bioavailability about 100%. Half life 36 to 42 hours. 99% protein bound. A racemic mixture: S warfarin (more potent) is metabolised by CYP2C9; R warfarin by CYP1A2 and CYP3A4. Variants in CYP2C9 and VKORC1 change dose needs.

Venous thromboembolism, treatment and prevention of recurrence, adult.

• Start 5 mg once daily in the evening for 2 days (2 to 3 mg in older adults, frailty, liver disease, heart failure, low body weight and with interacting drugs); then adjust by INR.

• Overlap with a parenteral anticoagulant for at least 5 days and until the INR is 2.0 or more for 24 hours.

• INR target 2.5 (range 2.0 to 3.0); treat for 3 months in provoked events and 6 months or longer in unprovoked events.

Non valvular atrial fibrillation and rheumatic mitral stenosis with atrial fibrillation, adult. INR target 2.5 (2.0 to 3.0). In moderate to severe rheumatic mitral stenosis or a mechanical valve, warfarin is preferred over direct oral anticoagulants.

Mechanical heart valves, adult. Aortic valve without risk factors: INR target 2.5 (2.0 to 3.0). Mechanical mitral valve, or aortic valve with atrial fibrillation, previous clots or poor left ventricular function: INR target 3.0 (2.5 to 3.5). Lifelong.

Bioprosthetic valve or mitral valve repair, adult. INR 2.5 (2.0 to 3.0) for 3 to 6 months.

Left ventricular thrombus, adult. INR 2.5 (2.0 to 3.0) for 3 to 6 months.

Dose adjustment. Weekly dose changes of about 5 to 20%, set by the INR.

• INR below 1.5: increase by 10 to 20%.
• 1.5 to 1.9: increase by 5 to 10%.
• 2.0 to 3.0: no change.
• 3.1 to 4.0: reduce by 5 to 10%.
• 4.1 to 4.9: hold one dose and reduce by 10 to 15%.
• 5.0 to 8.9 without bleeding: omit 1 to 2 doses, reduce by 10 to 20%, consider vitamin K 1 to 2.5 mg orally.
• 9.0 or more without bleeding: vitamin K 2.5 to 5 mg orally.

Children (specialist). 0.2 mg/kg loading dose (0.1 mg/kg with liver disease), then adjust to INR 2.0 to 3.0.

Contraindications. Pregnancy (first trimester embryopathy at weeks 6 to 12 and bleeding; avoid, especially in the first trimester); active major bleeding; recent haemorrhagic stroke; severe uncontrolled hypertension; severe liver disease with coagulopathy; non adherent patients who cannot be monitored; bacterial endocarditis; hypersensitivity.

Warnings. Bleeding (the main risk; intracranial haemorrhage); skin necrosis (rare; protein C deficiency); purple toe syndrome; interaction with antibiotics and herbal products; fluctuating dietary vitamin K intake; falls; alcohol; thyroid disease; fever and diarrhoea raise INR; calciphylaxis in kidney failure; use of enteric products.

Adverse effects. Bleeding, bruising, hair loss, rash, skin necrosis, nausea, raised liver enzymes, osteoporosis in long term use.

Interactions. Raise INR: amiodarone, azole antifungals (fluconazole), metronidazole, cotrimoxazole, macrolides, fluoroquinolones, isoniazid, cimetidine, aspirin and other non steroidal anti-inflammatory drugs (bleeding), paracetamol (regular high dose), simvastatin, acute alcohol, ethacrynic acid, many herbal products (ginkgo, garlic, ginger).

Lower INR: rifampicin (large effect; double or triple the dose may be needed), carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, St John's wort, high vitamin K foods (green leafy vegetables), chronic alcohol. Review the INR within 3 to 5 days after any new drug.

Reversal. INR 5 to 9 without bleeding: omit doses, vitamin K 1 to 2.5 mg orally. INR above 9 without bleeding: vitamin K 2.5 to 5 mg orally. Major bleeding: stop warfarin; vitamin K 5 to 10 mg slow IV, and prothrombin complex concentrate 25 to 50 units/kg (or fresh frozen plasma 15 mL/kg when concentrate is not available).

Special groups.

• Pregnancy: contraindicated; use low molecular weight heparin; warfarin only in selected women with mechanical valves and a low dose requirement, under specialist care after the first trimester.

• Breastfeeding: acceptable; does not enter milk in active form.

• Patients of African ancestry: dose requirement varies by CYP2C9 and VKORC1 genotype (often higher than in Asian patients); adjust the dose by the INR.

• Older adults: start 2 to 3 mg; higher bleeding risk.

• Kidney impairment: no starting adjustment; INR is more variable in advanced disease.

• Liver impairment: start at a lower dose; INR monitoring more often.

Formulations. Tablets 0.5, 1, 3, 5 mg (strengths and colours differ by manufacturer).

Administration. Oral once daily at the same time each evening, with or without food. Keep food intake and alcohol consistent. Check the strength and the tablet colour at each prescription.

Baseline. INR and prothrombin time, platelet count, haemoglobin, liver and kidney function, blood pressure, drug history, pregnancy status.

Monitoring. INR daily or on alternate days during start up until stable in range on 2 consecutive tests, then every 1 to 2 weeks, then every 4 weeks, then up to every 12 weeks when stable. After any new interacting drug, illness or dose change: recheck within 3 to 5 days. Haemoglobin if bleeding is suspected. Time in therapeutic range target above 65 to 70%.

Stopping. For elective surgery, stop 5 days before (INR 1.5 or less); bridge with low molecular weight heparin only for high risk patients (mechanical mitral valve, recent clot). Restart on the evening after surgery when bleeding is controlled.

Common prescribing errors.

• Loading with 10 mg doses.
• No parenteral overlap in acute venous thromboembolism.
• Failing to adjust after rifampicin, fluconazole or cotrimoxazole.
• Use of a direct oral anticoagulant in a mechanical valve or moderate to severe mitral stenosis.
• Omitting INR checks after an antibiotic course.
• Prescribing in pregnancy.
• Confusing tablet strengths.