Vitamin K antagonist anticoagulants
ATC code: B01AA03 (Warfarin)
Inhibits hepatic vitamin K epoxide reductase (VKORC1), impairing γ-carboxylation of clotting factors II, VII, IX, X and proteins C/S. Anticoagulant effect develops over 36–72 h. Narrow therapeutic window (INR 2.0–3.0 for most indications) demands routine laboratory monitoring. Metabolized by CYP2C9; CYP2C9 and VKORC1 polymorphisms account for substantial interindividual dose variability.
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.
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.
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.
INR effect is unpredictable: acute alcohol intoxication raises INR, chronic abuse via CYP induction lowers it. Binge drinking – high bleeding risk. Stable moderate intake acceptable with counseling.
Source: FDA: Coumadin (warfarin) prescribing information (2021)
Vitamin K is a warfarin antagonist: it restores synthesis of vitamin-K-dependent clotting factors (II, VII, IX, X). Sudden increases in dietary vitamin K (leafy greens) lower INR. Maintain stable intake without sharp variations.
Source: AHA/ACC: 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease (2020)
18 pairs found. Sorted from critical to minor.
Mechanism
Additive antithrombotic effect plus platelet aggregation inhibition. Sharply increased bleeding risk including GI and intracranial.
Management
Combine only when life-indicated (e.g. post-stenting). Monitor INR and bleeding. Prefer monotherapy when possible.
Sources
Mechanism
Additive antithrombotic effect at two levels: warfarin inhibits clotting factors while aspirin blocks platelet aggregation and simultaneously damages gastric mucosa (antiprostaglandin effect). Major GI bleeding and hemorrhagic stroke risk rise 2–3-fold.
Management
Routinely avoid the combination. It is justified only with clear indications: mechanical valve plus recent ACS, recent stenting in atrial fibrillation. In those cases, use aspirin 75–81 mg/day, add a PPI (pantoprazole, not omeprazole), and keep the INR at the lower end of the target range.
Sources
Mechanism
Amiodarone potently inhibits CYP2C9 (the main enzyme metabolizing S-warfarin) and, to a lesser extent, CYP3A4 (R-warfarin metabolism). Warfarin concentration rises, with INR doubling or tripling. The effect develops gradually over 1–7 weeks and persists for weeks after amiodarone discontinuation due to its long half-life.
Management
When starting amiodarone in a patient on warfarin, empirically reduce the warfarin dose by 30–50 %. Monitor INR weekly for the first 6–8 weeks, then every 2 weeks until stable. After amiodarone discontinuation, expect warfarin requirements to rise for several more months.
Mechanism
Broad-spectrum antibiotics eliminate gut flora that synthesize vitamin K2 – reducing vitamin K availability for hepatic γ-carboxylation. INR rises 3–7 days after antibiotic initiation. The effect is most pronounced in patients on a low-vitamin-K diet.
Management
Check INR on days 3 and 7 of the antibiotic course, and again 7–10 days after completion. For courses ≥ 7 days, pre-emptively reduce the warfarin dose by 10–20 % and titrate by INR.
Sources
Mechanism
Atorvastatin weakly inhibits CYP3A4 and CYP2C9. Clinically significant INR elevations are documented in a minority of cases, especially at 40–80 mg doses. The opposite – dose-dependent INR decrease – is also possible.
Management
Check INR 1–2 weeks after starting atorvastatin and after each dose change. Additional warfarin adjustment is usually not required but may be needed.
Sources
Mechanism
Карбамазепин – сильный индуктор CYP2C9 и CYP3A4, снижает концентрацию варфарина на 50–70% через 2–4 недели.
Management
При старте карбамазепина – еженедельный контроль МНО, постепенное повышение дозы варфарина. При отмене – обратное снижение.
Mechanism
Dual mechanism: 1) ciprofloxacin is a moderate CYP1A2 inhibitor and weak CYP3A4 inhibitor, raising R-warfarin concentration; 2) elimination of gut flora reduces vitamin K2 synthesis. INR rises 3–7 days after antibiotic initiation; in some patients by 1–2 units or more (Stockley's Drug Interactions; review by Glasheen et al., J Gen Intern Med, 2005).
Management
Check INR on days 3 and 7 of the course and again 7–10 days after completion. For courses ≥ 5 days, pre-emptively reduce the warfarin dose by 15–25 %. If feasible, choose an antibiotic with less INR impact (e.g. a cephalosporin where susceptibility allows).
Sources
Mechanism
Additive antithrombotic effect: warfarin in the coagulation cascade plus clopidogrel at the platelet P2Y12 receptor. Major bleeding risk rises 2.5–3-fold.
Management
Triple therapy (warfarin + aspirin + clopidogrel) after stenting in AF patients is limited to about 1 month, then transitioned to dual therapy (warfarin + clopidogrel or aspirin) for 6–12 months. After one year, warfarin alone. An alternative is the WOEST/PIONEER regimen with a DOAC (apixaban) + clopidogrel.
Sources
Mechanism
Аддитивный антитромботический эффект через разные механизмы (антиагрегация + антикоагуляция). Высокий риск кровотечений.
Management
Только по строгим показаниям (стент + фибрилляция предсердий) и на минимальный срок. Контроль МНО и признаков кровотечения.
Mechanism
Флуконазол ингибирует CYP2C9 – основной фермент метаболизма варфарина. МНО может удвоиться за 3–7 дней.
Management
Снизить дозу варфарина на 25–50% или временно отменить. Контроль МНО через 3 и 7 дней.
Mechanism
вытесняют варфарин из связи с альбумином и подавляют агрегацию тромбоцитов. Аддитивный риск кровотечения, особенно .
Management
Избегать. При необходимости анальгезии – парацетамол до 2 г/сут. Если без нельзя – минимальная доза, , контроль признаков кровотечения.
Sources
Mechanism
Thyroid hormones accelerate catabolism of vitamin K-dependent clotting factors. When levothyroxine is initiated or its dose is raised in a patient becoming euthyroid, warfarin effect increases – INR rises and the warfarin dose must be reduced. Conversely, hypothyroidism or a tyroxine dose reduction lowers INR.
Management
Check INR at 1, 2, and 4 weeks after starting or adjusting levothyroxine. A 10–25 % reduction in the warfarin dose is usually needed when the patient becomes euthyroid.
Sources
Mechanism
Метронидазол – мощный ингибитор CYP2C9, основного фермента метаболизма S-варфарина. МНО может удвоиться за 5–7 дней.
Management
Снизить дозу варфарина на 25–35% при старте курса метронидазола. МНО на 4-й и 7-й день.
Mechanism
Metronidazole stereospecifically inhibits CYP2C9, the enzyme that metabolizes S-warfarin (the more potent enantiomer). Warfarin concentration rises and INR climbs substantially (often by 2–4 units) as early as days 3–5 of the course. Cases of INR above 10 and major bleeding have been reported (Stockley's Drug Interactions; Drug Interaction Database).
Management
Pre-emptively reduce warfarin dose by 25–35 % before starting metronidazole. Check INR on days 3 and 7 of the course and again 7–10 days after completion. For high bleeding risk (age ≥ 75, ≥ 3, recent bleeding), choose an alternative antibiotic where possible or pre-transition to a DOAC.
Mechanism
Paracetamol above 2 g/day for more than 7 days raises INR by 1–3 units. The mechanism is not fully understood – the NAPQI metabolite probably inhibits vitamin K-dependent γ-carboxylation. A single 0.5–1 g dose is clinically insignificant. Occasional use up to 2 g/day for less than 7 days is safe.
Management
In warfarin-treated patients, paracetamol remains the preferred analgesic over NSAIDs. For courses longer than 7 days or doses above 2 g/day, check INR at 7 days. After the course ends, recheck INR in 7–10 days.
Sources
Mechanism
Индукция CYP2C9 рифампицином снижает концентрацию варфарина на 50–70% через 2–3 недели.
Management
Контроль МНО еженедельно после старта рифампицина с постепенным повышением дозы варфарина.
Mechanism
Dual mechanism: 1) sertraline inhibits serotonin reuptake in platelets, depleting platelet serotonin and reducing aggregation; 2) moderate CYP2C9 inhibition raises warfarin concentration and INR. GI bleeding risk roughly doubles.
Management
When starting sertraline in a warfarin-treated patient, check INR at 1, 2, and 4 weeks. Add a PPI (pantoprazole) if GI bleeding risk factors are present. Alternatives include mirtazapine (less serotonergic activity) or agomelatine.
Sources
Mechanism
Simvastatin inhibits CYP3A4 and to a lesser extent CYP2C9, raising warfarin concentration. Average INR rise is 0.5–1.5 units, with significantly larger increases in some patients.
Management
Check INR 1–2 weeks after starting simvastatin and after dose changes. In warfarin patients, statins with minimal interaction – pravastatin or rosuvastatin – are preferred.
Sources
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.
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.
warfarin is evaluated for the following indications with varying evidence strength: Venous thromboembolism (evidence tier A), Mechanical heart valve (evidence tier A), Atrial fibrillation (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of warfarin (≥ 1 in 100): Bleeding (epistaxis, gingival bleeding, ecchymoses, hematuria), Dose sensitivity to dietary and drug interactions. See the Safety section for uncommon and serious reactions.
FDA category 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.
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.
warfarin is contraindicated in: Active bleeding; Pregnancy (teratogenic – category X); Severe uncontrolled hypertension; Recent CNS or ophthalmic surgery; Inability to monitor INR regularly. Full list in the Safety section.