A Review of Warfarin Dosing and Monitoring

The goal of anticoagulant therapy with warfarin is to administer the lowest effective dose of the drug to maintain the target international normalized ratio (INR). Warfarin, a vitamin K antagonist, is an oral anticoagulant indicated for the prevention and treatment of venous thrombosis and its extension and the prevention and treatment of the thromboembolic complications associated with atrial fibrillation. Warfarin has also been used to prevent recurrent transient ischemic attacks and to reduce the risk of recurrent myocardial infarction, but data supporting these indications are inconclusive at this time (1). Warfarin inhibits the synthesis of clotting factors II, VII, IX, and X, as well as the naturally occurring endogenous anticoagulant proteins C and S (2). The anticoagulant and antithrombotic activity of warfarin depends on the clearance of functional clotting factors from the systemic circulation once the drug is administered (2, 3). The earliest changes in INR are typically seen 24 to 36 hours after administration of the dose. The antithrombotic effect of warfarin is not present until approximately the fifth day of therapy, which is dependent on the clearance of prothrombin (1, 2). Initiation of warfarin therapy is challenging, since the pharmacodynamic response is delayed and difficult to predict. Because prothrombin has a half-life of around 50 hours, loading doses of warfarin are of limited value (4). In clinical practice, loading doses (e.g., 7.5 mg or more per day) of warfarin may increase the patient's risk of bleeding complications early in therapy by eliminating the production of functional factor VII (2, 5). Administration of loading doses may place a patient in a hypercoagulable state due to a severe depletion of protein C (2). The administration of a loading dose is a possible source of prolonged hospitalization secondary to dramatic rises in the INR value that may necessitate the administration of vitamin K (5). If a rapid anticoagulant effect is required, an initial dose of heparin or a low molecular-weight heparin should be used and overlapped with warfarin for approximately 4 to 5 days. Once the INR is therapeutic for at least 2 days, the supplemental anticoagulation treatment may be discontinued (1, 4, 5). The safety and efficacy of warfarin therapy are dependent on maintaining the INR within the target range for the indication (Table ​(Table11). When a patient is started on an oral anticoagulant, INR monitoring should be performed daily until the INR is within the therapeutic range for at least 2 consecutive days. Unexpected fluctuations in the INR in an otherwise stable patient could be due to a change in diet, poor compliance, undisclosed drug use, alcohol consumption, or self-medication (2). Lab error should also be considered for unexpected values. Table 1 Recommended therapeutic range for oral anticoagulant therapy* One of the major risks of warfarin therapy is bleeding, which correlates well with INR values. The Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy has published guidelines on the management of patients with high INR values with or without bleeding (Table ​(Table22). Table 2 Management of supratherapeutic INR values*