Warfarin - Drug Monograph

Introduction

Warfarin is an oral anticoagulant medication that has been widely used for over 60 years to prevent and treat thromboembolic disorders. As a vitamin K antagonist, it remains a cornerstone therapy despite the introduction of newer direct oral anticoagulants. Warfarin requires careful dosing and monitoring due to its narrow therapeutic index and significant interpatient variability.

Mechanism of Action

Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase, an enzyme responsible for recycling oxidized vitamin K to its reduced form. Reduced vitamin K is essential for the γ-carboxylation of glutamate residues on vitamin K-dependent clotting factors II, VII, IX, and X. This carboxylation process is crucial for the biological activity of these clotting factors. By interfering with this process, warfarin ultimately decreases the production of functional clotting factors, resulting in anticoagulation.

Indications

• Prevention and treatment of venous thrombosis and pulmonary embolism
• Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement
• Reduction of risk of death, recurrent myocardial infarction, and thromboembolic events after myocardial infarction
• Secondary prevention after transient ischemic attack or stroke in high-risk patients

Dosage and Administration

• Elderly patients: Often require lower maintenance doses
• Hepatic impairment: Requires careful monitoring and potentially reduced dosing
• Renal impairment: No dosage adjustment typically needed (not renally excreted)

Pharmacokinetics

Contraindications

• Hemorrhagic tendencies or blood dyscrasias
• Recent or planned surgery of the eye, spinal cord, or brain
• Active bleeding or history of warfarin-induced necrosis
• Severe hypertension
• Unsupervised patients with conditions associated with high risk of hemorrhage
• Pregnancy (especially first trimester due to teratogenic effects)
• Hypersensitivity to warfarin or any component of the formulation

Warnings and Precautions

Additional precautions:

• Risk of tissue necrosis (typically occurs 3-8 days after initiation)
• Acute kidney injury secondary to anticoagulant-related nephropathy
• Elevated INR without bleeding may require dosage adjustment or vitamin K administration
• Many factors (diet, medications, illness) can alter warfarin response
• Perioperative management requires careful planning

Drug Interactions

• NSAIDs, antiplatelets, other anticoagulants: Increased bleeding risk
• CYP2C9 inhibitors (amiodarone, fluconazole, metronidazole): Increased warfarin effect
• CYP2C9 inducers (rifampin, carbamazepine): Decreased warfarin effect
• Vitamin K-containing products: Decreased warfarin effect
• Antibiotics: May alter gut flora and affect vitamin K production

• Herbal supplements (ginseng, St. John's wort, garlic, ginkgo)
• Cholestyramine may decrease warfarin absorption

Adverse Effects

• Bleeding (ecchymosis, epistaxis, gingival bleeding, hematuria)
• Gastrointestinal disturbances
• Elevated liver enzymes

• Major hemorrhage (GI bleeding, intracranial hemorrhage)
• Warfarin-induced skin necrosis (typically in patients with protein C or S deficiency)
• Purple toe syndrome (cholesterol microembolization)
• Systemic atheroemboli
• Hypersensitivity reactions
• Tracheobronchial calcification (with long-term use)

Monitoring Parameters

• INR: Target range typically 2.0-3.0 for most indications (2.5-3.5 for mechanical heart valves)
• Complete blood count with platelets
• Occult blood in stool
• Signs and symptoms of bleeding

• Liver function tests periodically
• Vitamin K status in malnourished patients
• Dietary vitamin K intake assessment
• Medication reconciliation at every visit

Patient Education

• Importance of regular INR monitoring and adherence to scheduled appointments
• Consistency in vitamin K-containing food intake (leafy greens, broccoli, etc.)
• Recognition of bleeding signs (unusual bruising, blood in urine/stool, prolonged bleeding from cuts)
• Need to inform all healthcare providers about warfarin therapy
• Avoidance of alcohol excess
• Use of soft-bristle toothbrush and electric razor to minimize bleeding risk
• Importance of avoiding NSAIDs and aspirin unless specifically approved by anticoagulation provider
• Carry medical identification indicating anticoagulant therapy
• Consultation before starting any new medications, including over-the-counter products and supplements

References

1. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S.

2. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-e184S.

3. Warfarin sodium prescribing information. FDA approved label. Revised 2021.

4. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S.

5. Nutescu EA, Shapiro NL, Ibrahim S, West P. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf. 2006;5(3):433-451.

6. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011;90(4):625-629.