Vitamin K Antagonists

Vitamin K antagonists inhibit vitamin K epoxide reductase (VKORC1), preventing recycling of vitamin K and the gamma-carboxylation of factors II, VII, IX and X and of proteins C and S. Warfarin is the main drug worldwide. Therapy is cheap and reversible, but it needs INR monitoring and has many interactions.

Members. Warfarin, acenocoumarol (short acting), phenprocoumon (long acting, some regions), and phenindione (rarely used because of hypersensitivity).

Mechanism. The anticoagulant effect appears when circulating clotting factors with different half-lives (factor VII 6 hours, factor II 60 hours) have fallen, so full effect needs 5 to 7 days. Early protein C depletion can cause transient hypercoagulability and warfarin skin necrosis, which is why heparin overlap is used at initiation.

Pharmacokinetics. Warfarin is a racemic mixture with S-warfarin (CYP2C9, 3 to 5 times more potent) and R-warfarin (CYP1A2 and CYP3A4). Half-life is 36 to 42 hours, protein binding 99%. CYP2C9 and VKORC1 variants lower dose requirement. Dose needs vary by ancestry.

• Warfarin: the reference drug.
• Acenocoumarol: shorter half-life, faster INR changes, used in several regions.
• Phenprocoumon: longer half-life, more stable INR.

• Indications: mechanical heart valves, atrial fibrillation with moderate to severe rheumatic mitral stenosis, antiphospholipid syndrome, left ventricular thrombus, venous thromboembolism (when direct oral anticoagulants are not suitable), and atrial fibrillation where direct oral anticoagulants are not available.
• INR target: 2.5 (range 2.0 to 3.0) for most indications; 3.0 (range 2.5 to 3.5) for mechanical mitral valves and some high-risk mechanical aortic valves.
• Initiation: 5 mg daily for 2 days (2 to 3 mg in older adults, low body weight, liver disease, heart failure or interacting drugs), with INR on day 3 and then adjustment. Overlap with heparin until INR is therapeutic for 2 consecutive days in venous thromboembolism.
• Maintenance: typical 3 to 9 mg daily, adjusted by 5% to 20% of weekly dose to INR.
• Monitoring interval: daily to every few days at start, weekly until stable, then every 4 to 12 weeks. Check INR within 3 to 5 days after any interacting drug starts or stops.
• Quality: aim for time in therapeutic range over 65% to 70%. Poor control suggests adherence, diet, interaction or alcohol problems.
• Mechanical valves in pregnancy: specialist decision between warfarin (lowest embolism risk to mother, with teratogenic risk in weeks 6 to 12 and bleeding risk at delivery) and heparin strategies.
• Selection: warfarin where a direct oral anticoagulant is contraindicated, unaffordable or unavailable.

Contraindications. Pregnancy (except mechanical valves with specialist plan), active bleeding, severe uncontrolled hypertension, recent neurosurgery, and inability to monitor INR.

Adverse effects. Bleeding, skin necrosis (protein C deficiency), purple toe syndrome, warfarin embryopathy (nasal hypoplasia, stippled epiphyses) and central nervous system defects, hair loss, and calciphylaxis in kidney failure.

Interactions. Raise INR: amiodarone, azole antifungals, metronidazole, cotrimoxazole, ciprofloxacin, macrolides, fluoxetine, allopurinol, paracetamol at regular high dose, alcohol binge, acute illness and heart failure. Lower INR: rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort, high vitamin K intake (leafy greens such as sukuma wiki and managu, and liver), and enteral feeds. Aspirin and NSAIDs add bleeding without changing INR.

Reversal.

• INR 5 to 8 without bleeding: omit 1 to 2 doses and restart at lower dose.
• INR over 8 without bleeding: omit and give vitamin K 1 to 5 mg orally.
• Minor bleeding: vitamin K 1 to 3 mg intravenously.
• Major bleeding: stop warfarin, vitamin K 5 to 10 mg intravenously, and four-factor prothrombin complex concentrate 25 to 50 units/kg (fresh frozen plasma 15 mL/kg if concentrate unavailable).

Monitoring. INR, full blood count, and liver function. Point-of-care INR meters extend monitoring to peripheral facilities, with venous confirmation if results are extreme.

Patient counselling. Take at the same time each evening, keep diet consistent rather than avoiding greens, limit alcohol, report bleeding or falls, carry an anticoagulation card, and check before any new medicine or herbal remedy.

Referral and escalation. Major bleeding, INR repeatedly out of range, or planned surgery needs specialist advice.

Special groups. Breastfeeding: compatible. Older adults: lower doses. Children: specialist dosing. Liver disease: baseline INR is already raised, so use cautious dosing.