ADD-ONS  / MEDICATION / ANTICOAGULANT THERAPY

Warfarin

Created 07/11/2022, last revision 03/08/2023

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

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
    

→ see Anticoagulant therapy

→ see Anticoagulant therapy in cardioembolic stroke

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

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

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