• 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
Vitamin K and warfarin
Direct anticoagulants
They inactivate the coagulation factors present in the plasma
Indirect anticoagulants
They affect coagulation factors by reducing their liver production
Direct thrombin/factor Xa inhibitors
These drugs are bound to thrombin/factor Xa and thereby block their function
Indirect thrombin/factor Xa inhibitors
These drugs act through the activation of antithrombin
  • vitamin K antagonists (VKAs)
    • warfarin (coumadin)
  • xabans (free and clot-bound factor Xa inhibitors)
    • apixaban
    • rivaroxaban
    • edoxaban
    • betrixaban
  • hirudin (direct thrombin inhibitor – DTI)

Indications

Main indications (in most of them, warfarin was replaced by DOACs):

  • prevention of cardioembolic stroke
  • 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
  • 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 Meta-analysis comparing warfarin and ASA in Afib patients (Walraven, 2002)  [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)

  • dairy products, cereals, bread, rice, meat, fish, eggs, fruit, sweets, ice cream, beverages including beer and wine (both less than 0.01 μg)
  • vegetables: tomatoes, radishes, corn, onions, potatoes fats – butter, sunflower oil
Medium content (10-40 μg/100 g)

  • vegetable juice, beans, cabbage, carrots, mixed vegetables, olive oil, mayonnaise
high content ( > 40 μg/100 g)
  • broccoli, spinach, lettuce, soybean oil, green tea, avocado

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
  • bleeding
  • purpura with increased capillary fragility
  • dermatitis
  • cutaneous or organ necrosis (mainly in the initial phases of treatment, especially with initial high-dose warfarin with rapid reduction of PC and PS levels)
  • hepatotoxicity
  • immune allergic reactions
  • complications in patients with advanced CKD
    • warfarin-related nephropathy (WRN)
    • coumarin induced skin necrosis (CISN)
    • calcific uremic arteriolopathy (CUA)
    • exacerbation of adynamic bone disease

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