Warfarin
Vitamin K antagonist for anticoagulation
Warfarin is an oral vitamin K antagonist of the coumarin class introduced into medicine in the 1950s; it is one of the most commonly prescribed anticoagulants worldwide. Brand names include Coumadin and Marevan. In Germany warfarin is used considerably less often than the structurally related phenprocoumon (Marcumar, Falithrom). In English speaking countries, North and South America and in parts of Asia, however, warfarin is the standard vitamin K antagonist.
Despite the growing use of direct oral anticoagulants (DOACs or NOACs such as apixaban, rivaroxaban, edoxaban, dabigatran), warfarin and phenprocoumon retain a firm place. They are still first line for mechanical heart valve replacement, severe antiphospholipid syndrome and severe renal impairment. Therapy requires regular coagulation monitoring (INR) and patient education, because the bleeding risk is substantial.
Mechanism of Action
Warfarin inhibits vitamin K epoxide reductase (VKORC1) in the liver. This enzyme recycles vitamin K to its reduced active form. The reduced form is a cofactor for γ carboxylation of clotting factors II, VII, IX and X as well as of the anticoagulant proteins C and S. Without γ carboxylation, these factors cannot bind calcium and lose their procoagulant or anticoagulant activity.
The effect sets in with delay because already synthesised factors have to be degraded according to their individual half lives. Factor VII has the shortest half life of about 6 hours, factor II (prothrombin) the longest at 60 hours. Full anticoagulant effect therefore develops over 5 to 7 days. In acute venous thromboembolism, overlapping therapy with heparin or low molecular weight heparin is used for at least 5 days until the INR has been in the target range on two occasions.
A further important aspect is the short half life of the anticoagulant proteins C and S. They are degraded faster than the procoagulant factors, so a transient procoagulant state can occur in the first days of warfarin therapy. The clinical consequence is the well known warfarin induced skin necrosis in patients with protein C or S deficiency.
Indications
- Atrial fibrillation for stroke prevention, alternative to DOACs
- Mechanical heart valve replacement as the sole standard therapy, DOACs are contraindicated here
- Rheumatic mitral stenosis with increased embolic risk
- Venous thromboembolism (DVT, pulmonary embolism) secondary prophylaxis, alternative to DOACs
- Antiphospholipid syndrome, particularly with triple positivity or venous thromboses, vitamin K antagonists are superior to DOACs
- Intracardiac thrombi in severe left ventricular dysfunction or after a large anterior infarct
- Long term prophylaxis after recurrent thromboembolism of unclear origin
Dosage and INR
The dose is individually titrated. A typical starting dose is 5 mg once daily for 2 days, followed by INR check. The INR target range depends on the indication. For most indications (atrial fibrillation, pulmonary embolism) the target is INR 2.0 to 3.0. For mechanical mitral or double valve prostheses the target is 2.5 to 3.5, in individual cases higher. For modern mechanical aortic valves the target is 2.0 to 3.0.
The maintenance dose is usually 2 to 10 mg per day, with wide interindividual variability. Polymorphisms in VKORC1 and CYP2C9 strongly affect the required dose. Take the drug at the same time each day, preferably in the evening. Missed doses may be taken later the same day; do not double the next dose.
Renal impairment: no formal dose adjustment, close INR monitoring. Hepatic impairment: caution advised, reduce dose because of lower synthesis of clotting factors and slower warfarin metabolism. The INR check interval depends on stability, from daily during titration to monthly in stable patients.
Side Effects
Common: bleeding at any site. Skin and mucosal bleeds (gums, nose, haematomas), heavier menstrual bleeding and minor gastrointestinal bleeds are frequent. The annual rate of major bleeding within therapeutic INR is about 1 to 3 percent.
Major bleeding (0.3 to 1 percent per year): intracranial haemorrhage, severe gastrointestinal bleeding, retroperitoneal bleeding. These are acutely life threatening and demand emergency treatment.
Specific adverse effects: warfarin induced skin necrosis during the first days of therapy (in protein C or S deficiency), purple toe syndrome (cholesterol embolism), alopecia, nausea, hepatotoxicity.
Pregnancy: warfarin is contraindicated in pregnancy, teratogenic in the first trimester (warfarin embryopathy with nasal hypoplasia and chondrodysplasia punctata), later fetal bleeding and CNS damage may occur. When pregnancy is planned, switch to low molecular weight heparin.
Interactions
- Antibiotics (ciprofloxacin, metronidazole, cotrimoxazole, macrolides, fluconazole): marked INR rise through CYP inhibition or vitamin K reduction
- Amiodarone: strong CYP2C9 inhibitor, INR rises, dose often halved
- NSAIDs, acetylsalicylic acid, clopidogrel, DOACs: additive bleeding risk
- SSRIs (fluoxetine, sertraline): bleeding risk rises, especially gastrointestinal
- Rifampicin, carbamazepine, phenytoin, St John's wort: CYP induction, loss of warfarin effect, INR falls
- Green leafy vegetables (rich in vitamin K): consistent intake allows smooth titration, large variations destabilise the INR
- Alcohol: acutely, alcohol can slow breakdown (INR rise); chronic alcohol intake induces enzymes (INR fall)
Special Notes
Emergency therapy of bleeding: in minor bleeding, pause therapy; in larger bleeding give intravenous vitamin K; in life threatening bleeding give prothrombin complex concentrate (PCC) and vitamin K. Fresh frozen plasma is second choice because of unfavourable volume loading.
Periprocedural management: for minor procedures (dental extraction, skin surgery) warfarin is usually continued. For major procedures stop 5 days beforehand, bridging with low molecular weight heparin according to thromboembolic risk. After surgery check INR and restart warfarin.
Breastfeeding: warfarin passes into breast milk in small amounts and is considered compatible with breastfeeding, as is phenprocoumon. Older patients: higher bleeding risk, lower maintenance dose, close INR monitoring.
Patient education: self management and self measurement of the INR can improve therapy outcomes. Carry an ID with current dose and INR target range. Provide counselling on diet, bleeding warning signs and behaviour after falls or injuries.
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Frequently Asked Questions
What is the difference between warfarin and DOACs?
DOACs act directly on single clotting factors (thrombin or factor Xa), require no INR monitoring and in many indications (atrial fibrillation, DVT) show similar or better efficacy with lower bleeding risk. Warfarin remains first choice in mechanical heart valves, severe antiphospholipid syndrome and severe renal impairment.
Can I eat leafy greens while on warfarin?
Yes. The key is a consistent amount of vitamin K in the diet. Daily portions of spinach, kale, broccoli or rocket are unproblematic when eaten regularly. Large fluctuations (for example, a sudden vitamin K restrictive diet) destabilise the INR; restrictive diets are unnecessary.
What does the INR value mean?
The International Normalized Ratio measures the speed of the extrinsic coagulation pathway in a standardised way. In healthy non anticoagulated people it is 1.0; under warfarin a value of 2.0 to 3.0 is typical and means that the blood takes two to three times as long to clot. What matters is not a single reading but the time spent in the therapeutic range.
How should I manage warfarin before surgery?
Inform your surgeon and anaesthetist about anticoagulation in good time. Depending on the procedure and thromboembolic risk, warfarin is paused 5 days before the appointment and, where appropriate, bridged with heparin. For dental extractions or minor skin procedures, surgery can often be performed without interruption. Never stop the drug on your own.
Sources
- EMA, European Medicines Agency
- AWMF, S2k Guideline on Atrial Fibrillation and Thromboembolism
- Gelbe Liste, Warfarin active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
Legal Notice and Disclaimer
The information provided on this page is for general informational purposes only and does not constitute medical advice, diagnosis or treatment recommendation. It does not replace consultation with a licensed physician or pharmacist. Medicines should only be taken on medical prescription or via a pharmacy. All information is based on product information and recognised scientific sources published at the time of creation; the manufacturer's current summary of product characteristics is always authoritative. Sanoliste assumes no liability for the completeness, timeliness or accuracy of the information presented. In a medical emergency, call the emergency number 112 (Europe).