FDA-approved Clinical Uses for Warfarin:
Off-Label Clinical Uses of Warfarin include:
Warfarin competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1), which is an essential enzyme for activating the vitamin K available in the body. Through this mechanism, warfarin can deplete functional vitamin K reserves and therefore reduce the synthesis of active clotting factors. The hepatic synthesis of coagulation factors II, VII, IX, and X as well as regulatory factors protein C and protein S require the presence of vitamin K. Vitamin K is an essential cofactor for the synthesis of all of these vitamin K-dependent clotting factors.
Warfarin is a once-daily oral medication. Warfarin can be taken at any time during the day but is often recommended to be taken in the afternoon or evening. By instructing patients to take warfarin later in the day, healthcare providers can have the opportunity to individualize a patient's warfarin dose the same day based on their most current lab values. The dose-response of warfarin among patients is highly variable and depends on interpatient differences. Patient-specific factors such as drug metabolism, the presence of a vitamin K enriched diet, genetics, quantity of vitamin K-dependent clotting factors, concurrent disease states, binding proteins, concomitant drug interactions, laboratory testing, and medication adherence should be assessed when dosing warfarin.
Route of Administration: Oral
Drug Composition: Warfarin is a racemic mixture composed of R and S enantiomers of the drug. Each enantiomer is metabolized through unique pathways, and the S-enantiomer is approximately three to five times more potent that than the R-enantiomer.
Absorption: Rapid and complete absorption
The onset of action: The onset of action is typically 24 to 72 hours. A peak therapeutic effect is seen 5 to 7 days after initiation. However, the patient’s international normalized ratio (INR) may increase within 36 to 72 hours after initiating treatment.
Duration of Action: 2 to 5 days
Distribution: Small volume of distribution (0.14 L/kg)
Protein Binding: 99%
Metabolism: Hepatic metabolism, primarily through the CYP2C9 enzyme. Other minor enzymatic pathways for metabolism include CYP2C8, 2C18, 2C19, 1A2, and 3A4.
Genomic Variants: Genetic variations in CYP2C9 have been shown to affect an individual’s clearance of warfarin. Patients who are heterozygous for the 2C9 (*1/*2 or *1/*3) can experience an approximately 37% reduction in clearance of S-warfarin. Patients who are homozygous for reduced function alleles (*2/*2, *2/*3, or *3/*3) may experience a nearly 70% reduction in clearance of S-warfarin.
Elimination Half-life: The half-life of warfarin is generally 20 to 60 hours (mean: 40 hours). However, it is highly variable among individuals.
Time to peak (plasma concentration): approximately 4 hours
Excretion: Warfarin is primarily eliminated as metabolites by glomerular filtration in the kidney (92% via urine).
Serious adverse effects of warfarin include bleeding and major hemorrhage. A major hemorrhage (e.g., intracranial hemorrhage, gastrointestinal (GI) bleed, hematemesis, intraocular bleeding, hemarthrosis) can occur at virtually any site on the body. Patients should thoroughly be educated about the easy bleeding or bruising that is a common adverse effect. A physician should also counsel patients about the proper management of cuts, bruises, and nosebleeds. The risk of bleeding and hemorrhage is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility. Individuals should be assessed for their risk and adjustments to their treatment plan should be made accordingly.
Other adverse effects include nausea, vomiting, abdominal pain, bloating, flatulence, and altered sense of taste.
Rare cases of purple toe syndrome, warfarin-induced skin necrosis, and calciphylaxis have been reported with warfarin therapy. Purple toe syndrome is complication characterized by cholesterol microembolization that causes purple lesions to develop on the toes and sides of the feet. Purple toe syndrome usually develops 3 to 8 weeks after the initiation of warfarin therapy. Warfarin-induced skin necrosis is a serious condition in which the subcutaneous tissue necrosis occurs due to an acquired protein C deficiency following treatment with warfarin. The risk of necrosis is increased in patients with protein C or protein S deficiency. The skin necrosis usually occurs within the first week of therapy and management strategies including discontinuing treatment with warfarin, administering fresh frozen plasma and vitamin K, and initiating anticoagulation therapy with either unfractionated heparin or a low molecular weight heparin. Calciphylaxis or calcium uremic arteriolopathy is another rare adverse effect that can occur in patients with or without end-stage renal disease.
Warfarin is contraindicated in patients with:
Elderly patients are at an increased risk of bleeding complications secondary to falls, concomitant drug interactions, cognitive status, and living situation. The risk of bleeding complications has been associated with increased age. These patients need to be monitored closely and may require a more conservative dosage regimen.
Warfarin has two different pregnancy categories depending on the presence of a mechanical heart valve. Warfarin is currently listed as a Category D drug for pregnant women with a mechanical heart valve and Category X for all other indications in pregnant women. Warfarin crosses the placental barrier, causing fetal plasma levels similar to maternal values. Warfarin can cause bleeding in the fetus, and use during pregnancy is commonly associated with spontaneous abortion, stillbirth, preterm birth, and neonatal death. In pregnant women with high-risk for thromboembolism from mechanical heart valves, the benefits and risks of warfarin therapy should be evaluated. Some experts recommend avoiding warfarin use during the first trimester and close to delivery.
Warfarin is not excreted in breast milk. Therefore, breastfeeding women may be treated with warfarin. However, the drug manufacturer recommends close monitoring of breastfeeding infants for bruising or bleeding.
A reduced renal function can cause warfarin to accumulate in the body, thereby increasing the risk of bleeding. However, dosing adjustments are not necessary for renal impairment. Close monitoring of the patient’s INR is recommended. It is also important to note that warfarin is not dialyzable through hemodialysis.
According to the manufacturer’s drug labeling, there are no dosage adjustments necessary for hepatic impairment. However, the response to oral anticoagulants may be enhanced in patients with obstructive jaundice, hepatitis, and cirrhosis. The INR should be closely monitored in these patients.
While there is no specific diet recommended for patients on warfarin, certain foods and beverages can either limit or enhance the anticoagulant effect of warfarin. Vitamin K decreases the effectiveness of warfarin in the body. Therefore, the patient should be educated on maintaining a consistent dietary intake of vitamin K containing foods. Examples of foods that are high in vitamin K include kale, green tea leaves, Brussel sprouts, and spinach. Other dietary recommendations include limiting consumption of cranberry juice and alcohol while on warfarin therapy. Grapefruit juice and alcohol can enhance the anticoagulant effect of warfarin, thereby leading to increased bleeding complications.
Warfarin has numerous drug interactions that can either increase the risk of adverse effects or decrease the anticoagulant effect of warfarin. Therefore dosing adjustments, close monitoring, and use of alternative agents should be considered when combining warfarin with certain medications. Caution is advised when administering warfarin with antiplatelet agents, fibrinolytics, nonsteroidal anti-inflammatory agents (NSAIDs), antimicrobials, anti-arrhythmic medications, and other anticoagulant agents. It should be noted that the S-enantiomer of warfarin is approximately three to five times more potent that than the R-enantiomer. Thus, drug interactions involving the inhibition of the S-enantiomer are considered more severe and may require pre-emptive dose adjustments or therapeutic interchange of alternative anticoagulants. A comprehensive drug interaction database should be referenced when necessary.
Patients receiving treatment with warfarin should be closely monitored to ensure safety and efficacy of the medication. Periodic blood testing is recommended to assess the patient’s prothrombin time (PT) and the international normalized ratio (INR).
The laboratory parameter utilized to monitor warfarin therapy is the PT/INR. The PT is the number of seconds it takes the blood to clot, and the INR allows for the standardization of the PT measurement depending on the thromboplastin reagent used by a laboratory. Therefore monitoring a patient’s INR while on warfarin is strongly preferred over PT because it allows for a standardized measurement without variations due to different laboratory sites. Routine assessment of INR is essential in the management of patients receiving warfarin therapy. The INR of a patient who is not on anticoagulation therapy is approximately 1.0. If a patient has an INR of 2.0 or 3.0, that would indicate that it takes two or three times longer for that individual’s blood to clot than someone who is not taking any anticoagulants The therapeutic INR goal for patients on warfarin therapy is dependent on the indication, but may vary based on the patient’s clinical presentation and provider preference. Most patients on warfarin have an INR goal of 2 to 3. However, certain indications such as a mechanical mitral valve require an INR goal of 2.5 to 3.5.
Close monitoring of a patient’s INR is strongly recommended when initiating warfarin. The INR should be monitored more frequently when initiating warfarin. For hospitalized patients, INR is commonly monitored on a daily basis. Once a patient has reached the maintenance phase of therapy, the INR is typically assessed at least every four weeks. More frequent monitoring is necessary for patients with supratherapeutic or subtherapeutic INR in order to assess safety and efficacy. In addition, the INR may be assessed when initiating, discontinuing, or changing doses of medications that are known to interact with warfarin.
Patients should also be closely monitored for signs and symptoms of active bleeding throughout their treatment. Close monitoring for signs and symptoms of bleeding such as dark tarry stools, nosebleeds, and hematomas is necessary. The patient’s hemoglobin and hematocrit level should be assessed before initiating warfarin and approximately every six months while on therapy. Other laboratory tests may be recommended based on the patient’s clinical presentation and INR result. Monitoring liver function, renal function, and occult blood may be indicated in certain patient populations.
Warfarin toxicity can be assessed through signs and symptoms of bleeding as well as the determination of a supratherapeutic INR level. The risk of bleeding is significantly greater with increased INR, especially above 5.0. When managing warfarin toxicity, the initial step would be to discontinue warfarin and then administer vitamin K (phytonadione). The vitamin K may be administered either the oral, intravenous, or subcutaneous route. However, initial administration of oral vitamin K is often preferred in patients without major bleeding or extremely elevated INR. A reduction in INR is expected to occur within 24 hours of administration. After that, intravenous vitamin K administration is recommended if necessary. Subcutaneous vitamin K is often not recommended for warfarin toxicity or reversal due to erratic and unpredictable absorption. Administering agents like prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), and activated Factor VII may be considered for cases of major bleeding.
All healthcare workers including the primary care provider, nurse practitioner and emergency department physician need to know how to manage bleeding associated with warfarin. Once warfarin is prescribed, patients need to be educated about the importance of regular follow up, foods that can interact with warfarin and when to seek medical help. More important, healthcare workers need to be aware that today there are other options instead of warfarin, including the novel oral anticoagulant drugs, which are deemed to be safer and require less intense monitoring. (Level V)