Because warfarin is so commonly used and has a narrow therapeutic index and complex pharmacology that can cause multiple drug interactions, physicians should know how to manage patients receiving this drug. Gage and colleagues conducted a MEDLINE search to review the pharmacology, initiation and maintenance of warfarin treatment, as well as management of abnormal laboratory results and bleeding complications in persons taking warfarin.

Warfarin inhibits the formation of clotting factors II, VII, IX and X. The drug is highly protein-bound (99 percent bound to albumin). Because of this inverse relationship between the levels of albumin and free warfarin, acutely ill and postoperative patients may need lower dosages of warfarin. The International Normalized Ratio (INR) is the patient's prothrombin time divided by the mean of the normal prothrombin time, with this ratio raised to the international sensitivity index, a number that reflects characteristics of the thromboplastin reagent used.

After beginning warfarin therapy, a steady-state response is not achieved for about two weeks. A dosage of 4 to 5 mg per day is typical, although the needed dosage may be as low as 0.5 mg or as high as 50 mg per day. Elderly patients should start at a lower dosage. A loading dose of warfarin is unnecessary; in one study, patients who received an initial 5-mg dose achieved their goal INR earlier than patients who received an initial 10-mg dose.

Determining the ideal second dose of warfarin may be based on clinical experience, nomograms or computer programs. Checking the INR 15 to 24 hours after the first dose can help determine the second dose. If there has been a negligible rise in the INR (which is to be expected), a 5-mg dose on the second day should be safe. If an INR is not available on the day after the first dose, it can be obtained on days 2, 3 or 4. If the initial INR (on days 1 through 4) is high, the patient is probably sensitive to warfarin's effects; therefore, a lower dose should be prescribed. Patients who are resuming warfarin therapy after a time off of the drug can safely begin with their previous maintenance dose.

There are several schools of thought about when to change the dosage of warfarin. One set of experts recommends changing the dosage if two consecutive INR values are outside of the target range, whereas another group of experts recommends a change if two consecutive INR values are more than 0.3 outside of the target range. If the INR is moderately outside of the range, the standard adjustment is 5 to 20 percent of the total weekly dosage of warfarin. Dosage adjustments can be made empirically or with the help of computer-based decision support systems. Two well-designed studies have evaluated such proprietary systems and found that the percentage of time a patient spent with a normal INR and the level of INR control were as good or better when the computer-based system was used. However, the various systems and nomograms in use do not always agree with one another and are not patient-specific.

Experts at the College of American Pathologists recently recommended that the INR be checked at least four times during the first week of therapy. This frequency could then be gradually decreased, based on the stability of the INR. Because the risk of hemorrhage is highest in the first six to 12 weeks of treatment, checking the INR weekly may be reasonable during this time. The maximum interval between tests should be no more than four to six weeks.

If a patient's INR has been stable and then fluctuates by more than 0.2 below or 0.4 above the goal INR, the authors recommend evaluating the patient for the cause of the change. Leading causes would be laboratory error, noncompliance, use of a drug that interacts with warfarin (see accompanying table), dietary indiscretion or a change in the patient's health. If no reversible cause is found, a change in dosage may be made, with a review of the INR within two weeks. Close attention to the INR is needed because the patients who have the most variation in results are most likely to develop hemorrhage or thromboembolism.

In asymptomatic patients whose INR is elevated, temporary discontinuation of the drug is an option, but administration of vitamin K1 will shorten the time to return to the target INR. There is indirect evidence that use of vitamin K1 is associated with a lower incidence of hemorrhage. Oral vitamin K₁ is effective and may have fewer risks than the parenterally administered form. When a patient's INR is between 5 and 9, the American College of Chest Physicians recommends temporary discontinuation of warfarin therapy. If the patient is at risk for hemorrhage (e.g., is taking nonsteroidal anti-inflammatory agents), low-dose oral vitamin K₁ (1.0 to 2.5 mg) also should be given. However, the lowest dose available in tablet form is 5 mg, and often only 1 or 2 mg is needed. The parenteral form can be given orally and mixed in a flavored drink if needed. If the patient cannot be treated orally, 0.5 to 1.0 mg of intravenous vitamin K1 should be administered. For INRs of 9 or higher, vitamin K₁ also should be given, although at a higher dose (2.5 mg intravenously or 5 mg orally). A repeat INR should be obtained within 24 hours. Additional vitamin K₁ may be needed, depending on the result of the repeat INR.

If the INR is elevated and the patient is bleeding, fresh-frozen plasma or a concentrate of clotting factors will be required. A repeat INR should be obtained shortly after the fresh-frozen plasma is given. More fresh-frozen plasma may be needed because its effects are fairly short-lived. A large dose of vitamin K1 (10 mg) should also be given. Vitamin K1 will probably need to be readmin-istered because the half-life of warfarin is longer than the half-life of vitamin K1. Daily INR measurements will be needed.

Patients who are managed with anticoagulation-consultation services have fewer adverse events and lower rates of bleeding, although these services are not commonly employed. Future improvements to management of patients on warfarin therapy include the use of handheld devices that can measure the INR at a site remote from the physician's office or laboratory.