Continuing Education Activity

Warfarin is a medication used in the prophylaxis and treatment of venous thrombosis and thromboembolic events. It is in the anticoagulant class of drugs. This activity reviews the indications, action, and contraindications for warfarin as a valuable agent in the prophylaxis and treatment of myocardial infarction, deep vein thrombosis, pulmonary embolism, and atrial fibrillation. This activity will highlight the mechanism of action, adverse event profile, pharmacokinetics, and drug interactions pertinent for interprofessional team members to treat patients with venous thrombosis and thromboembolic events.

Objectives:

• Review the mechanism of action of warfarin.
• Describe the therapeutic uses of warfarin.
• Explain the side effects of warfarin.
• Outline how the importance of collaboration and coordination among the interprofessional team can enhance patient care when dosing and monitoring warfarin therapy.

Indications

Warfarin is an oral anticoagulant commonly used to treat and prevent blood clots. Warfarin has multiple FDA-approved and off-label clinical uses.

FDA-approved clinical uses for warfarin:

• Prophylaxis and treatment of venous thrombosis and arising pulmonary embolisms[1][2][1]
• Prophylaxis and treatment of thromboembolic complications from atrial fibrillation or cardiac valve replacement[1]
• Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events (e.g., stroke, systemic embolization) after myocardial infarction[3]

Off-Label clinical uses of warfarin include:

• Secondary prevention of recurrent stroke and transient ischemic attacks[4]

Mechanism of Action

Warfarin competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1), an essential enzyme for activating the vitamin K available in the body. Through this mechanism, warfarin can deplete functional vitamin K reserves and thereby reduce the synthesis of active clotting factors. The hepatic synthesis of coagulation factors II, VII, IX, and X, as well as coagulation 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.

Administration

Warfarin is a once-daily oral medication. Warfarin administration can be at any time during the day, but recommendations are for administration 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.[5] 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 requires assessment when dosing warfarin.[6][7]

Pharmacodynamics/Kinetics:

Route of Administration: Oral

Drug Composition: Warfarin is a racemic mixture composed of R and S enantiomers of the drug. Each enantiomer gets metabolized through unique pathways, and the S-enantiomer is approximately three to five times more potent 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: Research has shown that genetic variations in CYP2C9 affect an individual's warfarin clearance. Patients who are heterozygous for the 2C9 (*1/*2 or *1/*3) can experience an approximately 37% reduction in S-warfarin clearance. Patients who are homozygous for reduced function alleles (*2/*2, *2/*3, or *3/*3) may experience a nearly 70% reduction in clearing 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).

Adverse Effects

Serious adverse effects of warfarin include bleeding and significant hemorrhage. A significant hemorrhage (e.g., intracranial hemorrhage, gastrointestinal (GI) bleed, hematemesis, intraocular bleeding, hemarthrosis) can occur at virtually any site on the body. Patients should receive education about easy bleeding or bruising, which is a common adverse effect. A clinician 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 undergo an assessment for their risk, with appropriate adjustments to their treatment plan made accordingly.

Other adverse effects include nausea, vomiting, abdominal pain, bloating, flatulence, and an altered sense of taste.

Rare cases of purple toe syndrome, warfarin-induced skin necrosis, and there are reports of calciphylaxis with warfarin therapy.[8][9] Purple toe syndrome is a 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 subcutaneous tissue necrosis occurs due to an acquired protein C deficiency following treatment with warfarin. The risk of necrosis increases 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 low molecular weight heparin. Calciphylaxis or calcium uremic arteriolopathy is another rare adverse effect in patients with or without end-stage renal disease.

Contraindications

Warfarin has several contraindications and clinical considerations for its use.

Warfarin is contraindicated in patients with:

• Hypersensitivity to warfarin or any component of the formulation[10]
• Hemorrhagic tendencies (e.g., active GI ulceration, patients bleeding from the GI, respiratory, or GU tract; a cerebral aneurysm; central nervous system (CNS) hemorrhage; dissecting aortic aneurysm; spinal puncture and other diagnostic or therapeutic procedures with the potential for significant bleeding)[11]
• Recent or contemplated surgery of the eye, central nervous system, or traumatic surgery resulting in large open surfaces
• Bleeding tendencies associated with any of the following:
  • Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract
  • Central nervous system hemorrhage
  • Cerebral aneurysms, dissecting aorta
  • Pericarditis and pericardial effusions
  • Bacterial endocarditis
• Threatened abortion, eclampsia, or preeclampsia[12]
• Unsupervised patients with conditions associated with a high potential of non-adherence
• Spinal puncture and other diagnostic or therapeutic procedures with the potential for uncontrollable bleeding
• Major regional or lumbar block anesthesia
• Malignant hypertension
• Pregnancy (exception: women with mechanical heart valves at high risk for thromboembolism)

Clinical Considerations

Geriatric Considerations:

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 correlated with advanced age. These patients need to be monitored closely and may require a more conservative dosage regimen.

Pregnancy Considerations:

Warfarin has two different pregnancy categories depending on the presence of a mechanical heart valve. Warfarin was 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 a high risk for thromboembolism from mechanical heart valves, the benefits and risks of warfarin therapy should undergo careful evaluation. Some experts recommend avoiding warfarin use during the first trimester and close to delivery.[13]

Breastfeeding Considerations:

Warfarin is not excreted in breast milk. Therefore, breastfeeding women may receive treatment with warfarin. However, the drug manufacturer recommends closely monitoring breastfeeding infants for bruising or bleeding.

Renal Impairment:

A reduced renal function can cause warfarin to accumulate in the body, thereby increasing bleeding risk. However, dosing adjustments are not necessary for renal impairment. Close monitoring of the patient's INR is the recommended procedure. It is also important to note that warfarin is not dialyzable through hemodialysis.[14]

Hepatic Impairment:

According to the manufacturer's drug labeling, no dosage adjustments are necessary for hepatic impairment. However, the response to oral anticoagulants may become enhanced in patients with obstructive jaundice, hepatitis, and cirrhosis. The INR requires close monitoring in these patients.

Dietary Considerations:

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 receive education on maintaining a consistent dietary intake of vitamin K-containing foods.[15] Examples of high vitamin K foods include kale, green tea leaves, Brussel sprouts, and spinach. Other dietary recommendations include limiting the 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.[16][17][16]

Drug Interactions:

Warfarin has numerous drug interactions that can increase the risk of adverse effects or decrease warfarin's anticoagulant effect. Therefore dosing adjustments, close monitoring, and alternative agents should be considered when combining warfarin with certain medications. Caution is necessary when administering warfarin with antiplatelet agents, fibrinolytics, nonsteroidal anti-inflammatory agents (NSAIDs), antimicrobials, anti-arrhythmic drugs, and other anticoagulant agents. It is worth noting that the S-enantiomer of warfarin is approximately three to five times more potent 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. Clinicians should reference a comprehensive drug interaction database when necessary.[18]

Monitoring

Patients receiving treatment with warfarin should have close monitoring to ensure the 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).[19]

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 preferable to PT because it allows for a standardized measurement without variations due to different laboratory sites. Routine assessment of INR is essential in managing 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 does not take 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, specific indications, such as a mechanical mitral valve, require an INR goal of 2.5 to 3.5.[20]

Close monitoring of a patient's INR is a strong recommendation when initiating warfarin. The INR requires more frequent monitoring when starting warfarin. For hospitalized patients, INR monitoring commonly occurs daily. Once a patient has reached the maintenance phase of therapy, the INR assessment is typically at least every four weeks but up to the provider's discretion. More frequent monitoring is necessary for patients with supratherapeutic or subtherapeutic INR to evaluate safety and efficacy. Also, the INR requires assessment when initiating, discontinuing, or changing doses of medications known to interact with warfarin.

Patients also require close monitoring 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 specific patient populations.[21]

Toxicity

Warfarin toxicity is assessable 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 administration can be either via the oral, intravenous, or subcutaneous route. However, the initial administration of oral vitamin K is often preferable in patients without major bleeding or extremely elevated INR. A reduction in INR should occur within 24 hours of administration. After that, the recommendation is for intravenous vitamin K administration 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 significant bleeding.[2]

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team clinicians, including the primary care provider, mid-level practitioners (NP or PA), and emergency department physicians, need to know how to manage potential bleeding associated with warfarin. After prescribing warfarin, patients require education regarding the importance of regular follow-up, foods that can interact with warfarin, and when to seek medical help. The prescriber should enlist the services of a pharmacist to help "dial in" the warfarin dose, and inpatients often have their INR and dose adjustment handled by a pharmacist. Nurses must be aware of the signs of warfarin toxicity so that they can alert the attending/prescribing clinician. More importantly, interprofessional team members need to be mindful that there are other options today instead of warfarin, including the novel oral anticoagulant drugs, which are generally safer and require less intense monitoring. Given the potential severity of warfarin toxicity, there needs to be an interprofessional team approach to prescribing and managing warfarin, including clinicians, specialists, pharmacists, and nursing staff, so positive therapeutic benefit has the greatest chance with minimal adverse effects. [Level 5]