ADD-ONS / MEDICATION / ANTICOAGULANT THERAPY
Warfarin
Created 07/11/2022, last revision 03/08/2023
- vitamin K antagonists (VKAs) are indirect oral anticoagulants that have been available in clinical practice since the 1950s and were commonly used for VTE prophylaxis and cardioembolic stroke prevention
- nowadays, wherever possible, VKAs are replaced by DOACs
Mechanism of action
- warfarin is an indirect oral anticoagulant drug and belongs to vitamin K antagonist (VKA), also called coumarins
- warfarin inhibits vitamin K epoxide reductase complex 1(VKORC1) ⇒ depletion of reduced vitamin K (KH2) ⇒ the liver cells produce hypofunctional (non-carboxylated) clotting factors II, VII, IX, and X (vitamin K-dependent clotting factors) and the regulatory proteins C and S
- the coagulation factors are activated via carboxylation
- vitamin K1 in food can reverse the effects of coumarins because it is reduced to vitamin KH2 by a warfarin-insensitive vitamin K reductase

Direct anticoagulants They inactivate the clotting factors present in the plasma |
Indirect anticoagulants They affect clotting factors by reducing their liver production |
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Direct thrombin/factor Xa inhibitors These drugs bind to thrombin/factor Xa and thereby block their function |
Indirect thrombin/factor Xa inhibitors These drugs activate antithrombin |
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Indications
Main indications (in most of them, warfarin was replaced by DOACs):
- prevention of cardioembolic stroke
- in uncomplicated NVAF prefer DOACs
- use warfarin if direct oral anticoagulants (DOACs) are contraindicated or not recommended
- therapy and prevention of cerebral venous thrombosis
- dabigatran can be used instead of warfarin
- warfarin should be used in patients with a major hypercoagulable state
- dissection
- VTE prophylaxis and treatment (venous thrombosis/pulmonary embolism)
- warfarin is preferred to DOACs in patients with hypercoagulable state or if DOACs are contraindicated
- warfarin is preferred to DOACs in patients with hypercoagulable state or if DOACs are contraindicated
- according to meta-analyses, warfarin reduces the annual risk of stroke in Afib patients by 64% compared to placebo and by 39-46% compared to aspirin
[Hart, 2007] [Walraven, 2002]
- according to the above-stated meta-analysis, the absolute increase in major bleeding was approximately 0.9-1.5%/year
- warfarin is also more effective than dual antiplatelet (ASA+CLP) (ACTIVE W trial)
- the SPAF III (Stroke Prevention in Atrial Fibrillation) trial did not show superior efficacy of low-dose warfarin (INR 1.2-1.5) in combination with ASA compared to full-dose warfarin (with INR 2-3)
- the combination of warfarin + ASA is generally not recommended in Afib
- according to meta-analyses, it leads to a reduction of ischemic stroke only in patients with mechanical valves
- can be administered in patients with additional risk factors (e.g., CAD, ACS, etc.)
Contraindications
- conditions with a high risk of bleeding
- pregnancy and puerperium (switch to LMWH is required) because warfarin crosses the placenta, which may result in:
- fetal embryopathy (nasal hypoplasia and epiphyseal damage), which is greatest between 8-12 weeks gestation
- neurotoxicity
- the risk of bleeding
- warfarin can be used during breastfeeding as it does not pass into breast milk
Pharmacokinetics and pharmacodynamics
- rapid and complete absorption from the gut (food prolongs the absorption time but does not reduce the absorption rate)
- the onset of action is typically 24-72 hours; a peak therapeutic effect is seen 5-7 days after initiation
- duration of action: 2-5 days
- the relatively long elimination half-life
- 20-60 hours; mean 40 hours
- highly variable among individuals
- circulates in the blood bound to plasma proteins (mainly albumin – 90%) and accumulates in the liver, where its isomers are metabolized
- only free, unbound VKA is biologically active
- warfarin is administered as a racemic mixture of R and S enantiomers
- S-warfarin has a shorter half-life (approx. 33 hours) but is 4-5x more effective (70% effect) than the R-isomer (half-life approx. 45 hours)
- S-warfarin concentration has a more significant effect on the efficacy of anticoagulation
- metabolism: hepatic metabolism, primarily through the CYP2C9 enzyme; other minor enzymatic pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4
- excretion: as metabolites by the kidney (92% via urine)
- there are large interindividual differences in the pharmacokinetics and pharmacodynamics of warfarin ⇒ the dose should be strictly individualized
- interindividual variability leads to a large variance in effective doses
- slow metabolizers (warfarin sensitive) need a dose of around 1 mg per day
- fast metabolizers (warfarin resistant) need a dose above 10 mg per day
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Interactions
- warfarin has interactions with vitamin K-containing foods (leafy vegetables) and drugs
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Dietary precautions during warfarinization
- warfarin has interactions with vitamin K-containing foods (leafy vegetables)
- the aim is not to exclude vegetables and fruit from the diet but to maintain a stable, healthy diet without large fluctuations
- vitamin K is also present in meat; its content depends on how the animal is fed. In summer, animals contain more vitamin K in their meat than in winter
- substances used in alternative medicine can affect warfarin levels
- St. John’s wort, ginseng, and garlic can reduce warfarin concentrations
- ginkgo leads to an increase in levels
- patients should be warned that anticoagulation levels should be checked more frequently when a major long-term change in a diet high in leafy vegetables is made
Low content (< 10 μg/100 mg)
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Medium content (10-40 μg/100 g)
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high content ( > 40 μg/100 g)
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Dosing and monitoring
- usually start with a dose of 1.5-5 mg/day (most commonly with LMWH bridging), allowing the gradual onset of the effect
- do not begin with high doses as they can lead to a rapid decline in protein C and S ⇒ ↑ risk of hypercoagulable state and warfarin-induced skin necrosis
- a higher dose increases the risk of INR overshoot (especially in CYP2C9 and VKORC1 variants) ⇒ ↑ risk of hemorrhage
- the dose can be quite precisely calculated and adjusted according to pharmacogenetics (which, however, is usually not available)
- stop LMWHs, once INR is > 2
- timing
- once-daily oral medication
- it is recommended to administer warfarin in the afternoon or evening (it enables to individualize the patient’s warfarin dose the same day based on the current lab values)
- frequency of INR checks
- initially check INR every day (every other day during the next week)
- then once a week until dose stabilization (3 consecutive INR 2-3)
- long term monitoring with stabilized INR: once per month (self-monitoring is beneficial)
- the usual maintenance dose is 1.5-10 mg/d
- prefer stable daily dose or alternation with only minimal day-to-day dose variation
- significant alternate dosing leads to INR fluctuations, especially in borderline situations (infection, dietary error, etc.)
- educate patients about the need for earlier monitoring in high-risk situations:
- concurrent diseases
- change in medication (check interactions!)
- increase in minor bleeding
- difficulty in maintaining the therapeutic INR range is most often caused by:
- warfarin food and drug interactions (broccoli, spinach, kale, etc.)
- genetics
- poor adherence to treatment
- starvation (low albumin)/reduction diets, alcoholic excesses
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Long-term monitoring
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Warfarin and renal insufficiency
- think about the renal risks of VKA treatment and specific complications in patients with more advanced chronic kidney disease (CKD)
- patients with CKD are at higher risk of drug-drug interactions and are at higher risk of warfarin-related nephropathy (WRN), i.e., sudden progression of renal insufficiency characterized by glomerular vascularisation and the presence of erythrocyte cylinders in the renal tubules
- it is more common in patients with renal dysfunction but has also been described in patients with normal renal function
- other specific complications of warfarinization in patients with CKD include the effect on bone metabolism – calcification in large arteries and valves, but also in other locations, which may prevent later renal transplantation in patients with more advanced renal disease
- CKD patients treated with warfarin are also at risk of coumarin-induced skin necrosis (CISN) and calcific uremic arteriolopathy (CUA) or calciphylaxis, a disease with a high mortality rate that is unfortunately often not correctly recognized and treated
- in dialysis patients, warfarin administration leads to the worsening of adynamic bone disease
- on the other hand, warfarin is still the only option for oral anticoagulation in patients with glomerular filtration rate < 15 ml/min/1.73 m2 (0.25 ml/s/1.73 m2), i.e., in CKD stage 5
- LMWHs are an alternative – their advantage is a well-predictable effect and relatively high safety; the disadvantage is the need for parenteral administration
Adverse events
- bleeding is the most common complication (5-10%) of warfarin therapy; the risk is individual → risk and prevention of bleeding in anticoagulant therapy
- risk is higher in patients with renal insufficiency and hepatopathy
- according to studies, the majority of bleeding occurs with INR in the therapeutic range (EHRA 2018)
- it is necessary to distinguish between major and minor bleeding
- major bleeding is generally considered intracranial bleeding, retroperitoneal bleeding, and bleeding that has forced the transfer of ≥ 2 blood transfusions
- the most common cause of fatal bleeding is ICH
- mild/minor bleeding encompasses epistaxis, skin hematomas, suffusions, and micro/macroscopic hematuria
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