Warfarin

Anticoagulants – vitamin K antagonists

ATC code: B01AA03 (Warfarin)

Mechanism of action

Inhibits vitamin K epoxide reductase (VKORC1) in the liver, impairing carboxylation and activation of clotting factors II, VII, IX, and X, as well as proteins C and S. Anticoagulant effect develops over 48–72 hours as circulating factors are depleted. Narrow therapeutic index – dose is guided by INR.

Indications

Atrial fibrillation

First line

Warfarin reduces stroke risk in atrial fibrillation by 64 % compared to placebo. Target INR 2.0–3.0. Direct oral anticoagulants (DOACs) have largely replaced warfarin as first choice in non-valvular AF. Warfarin remains first-line in valvular AF, particularly with mitral stenosis or mechanical valves.

Mechanical heart valve

First line

Warfarin is the only approved anticoagulant for mechanical heart valve prostheses. DOACs are contraindicated – the RE-ALIGN trial (dabigatran) was stopped early due to increased thromboembolism and bleeding. Target INR depends on valve type and position: 2.5–3.5 for mitral and older aortic valves, 2.0–3.0 for modern bileaflet aortic valves.

Venous thromboembolism

First line

Warfarin is a well-established anticoagulant for treatment and secondary prevention of DVT and PE. Target INR 2.0–3.0. Duration depends on context: 3 months for provoked VTE, indefinitely for unprovoked or recurrent. DOACs are the preferred alternative, but warfarin remains an option in antiphospholipid syndrome and when DOACs are unavailable.

Practical notes

Timing and administration

Take once daily, preferably at the same time each day. Most clinics recommend evening dosing so that the dose can be adjusted the same day after receiving the INR result. Foods high in vitamin K (dark leafy greens – spinach, broccoli, kale) are not prohibited, but intake should be consistent from day to day.

Monitoring

INR is checked every 1–3 days during dose titration, then every 1–4 weeks on stable therapy. If INR exceeds 4.5 without bleeding, hold one dose and reduce maintenance. If INR exceeds 9, consider oral vitamin K (1–2.5 mg). For active bleeding, IV vitamin K and prothrombin complex concentrate.

Safety

Contraindications

Active bleeding
Pregnancy (teratogenic – category X)
Severe uncontrolled hypertension
Recent CNS or ophthalmic surgery
Inability to monitor INR regularly
Severe hepatic failure

Serious adverse effects

Major bleeding – GI, intracranial, retroperitoneal
Warfarin-induced skin necrosis (rare, in the first days of therapy, more common with protein C deficiency)
Soft tissue calcification with prolonged use (calciphylaxis, rare)

Common adverse effects

Bleeding (epistaxis, gingival bleeding, ecchymoses, hematuria)
Dose sensitivity to dietary and drug interactions

PregnancyFDA X

FDA category X. Warfarin crosses the placenta and causes warfarin embryopathy: nasal hypoplasia, stippled chondral calcification, CNS abnormalities. Particularly dangerous at weeks 6–12. If anticoagulation is needed during pregnancy, switch to low-molecular-weight heparin.

Breastfeeding

Warfarin is excreted in breast milk in negligible amounts. Per AAP, breastfeeding is compatible with warfarin use. Infant INR monitoring is recommended in the first weeks.