3mg (blue), 5mg (pink) and 1mg (brown) warfarin tablets (UK colours)

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Warfarin

Warfarin (also known under the brand names of Coumadin® and Marevan®) is an anticoagulant medication that is administered orally. It is used for the prophylaxis of thrombosis and embolism in many disorders. Its activity has to be monitored by frequent blood testing for the international normalized ratio (INR). It is named for the Wisconsin Alumni Research Foundation. more...

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Warfarin was originally developed as a rat poison, and is still widely used as such, although warfarin-resistant rats are becoming more common.

Mechanism of action

Normally, vitamin K is converted to vitamin K epoxide in the liver. This epoxide is then reduced by the enzyme epoxide reductase. The reduced form of vitamin K epoxide is necessary for the synthesis of many coagulation factors (II, VII, IX and X, as well as protein C and protein S). Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting coagulation.

Uses

Medical use

Warfarin is given to people with an excessive tendency for thrombosis. This can prevent growth or embolism (spread) of a thrombus. Common indications for warfarin use are atrial fibrillation, artificial heart valves, deep venous thrombosis and pulmonary embolism.

Therapeutic drug monitoring is required, as warfarin has a very narrow therapeutic index, which means the levels in the blood that are effective are close to the levels that cause bleeding. Dosing of warfarin is further complicated by the fact that it is known to interact with many other medications and other chemicals which may be present in appreciable quantities in food (including caffeine and ascorbic acid). These interactions range from enhancing warfarin's anticoagulation effect to reducing the effect of warfarin.

As a result, it is easy to over- or under-coagulate the patient. Warfarin's effects must be closely monitored: this is done by using the INR. Initially, checking may be as often as twice a week; the intervals can be lengthened if the patient manages stable therapeutic INR levels on a stable warfarin dose.

When initiating warfarin therapy ("warfarinisation"), the doctor will generally decide how strong the anticoagulant therapy needs to be. A common target INR level is 2.0-3.0, though it varies from case to case.

The new oral anticoagulant ximelagatran (Exanta®) does not require INR monitoring, and was expected to replace warfarin to a large degree when introduced; however, it has run into approval problems and currently (2005) it is not clear if or when it will ever become available for general use.

Pesticide use

Warfarin is used as a rodenticide for controlling rats and mice in residential, industrial, and agricultural areas. It is both odorless and tasteless. It is effective when mixed with food bait, because the rodents will return to the bait and continue to feed over a period of days, until a lethal dose is accumulated (considered to be 1 mg/Kg/day over four to five days). It may also be mixed with talc and used as a tracking powder, which accumulates on the animal's skin and fur, and is subsequently consumed during grooming. The use as rat poison is now declining because many rat populations have developed resistance to warfarin.

Read more at Wikipedia.org

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Warfarin use in patients with atrial fibrillation
From American Family Physician, 10/1/05 by Karl E. Miller

Two percent of adults 65 to 75 years of age will develop atrial fibrillation, and the risk for developing this cardiac irregularity increases with age. Studies have shown that warfarin (Coumadin) therapy in patients with atrial fibrillation reduces the concomitant risk of stroke. Warfarin therapy presents challenges because of its narrow therapeutic window and its risk of overcoagulation, which increases the risk for hemorrhage. Maintaining warfarin therapy so that the international normalized ratio (INR) is between 2 and 3 is the most effective and safe level. Reynolds and colleagues performed a systematic review and meta-analysis on the safety and efficacy of warfarin therapy in nonvalvular atrial fibrillation. They assessed the risk for bleeding associated with overcoagulation (INR greater than 3) and the risk of stroke and other thromboembolic events with undercoagulation (INR less than 2).

A systematic review of the literature was performed using all relevant studies published in English between January 1, 1985, and October 30, 2002. In addition, the authors searched the reference lists of the retrieved articles to identify other relevant studies. Studies were included if they enrolled patients with nonvalvular atrial fibrillation who were receiving warfarin therapy. The studies also must have reported stroke or bleeding events based on the therapeutic INR range or time spent above, at, or below the INR therapeutic range. Studies that used combination therapy were not included in the analysis. Data extracted from the studies included patient and treatment characteristics, INR information, and number of patients with adverse events of interest by INR level.

There were 21 studies that met the inclusion criteria, with a total of 6,248 patients enrolled. The meta-analysis of the studies comparing ischemic events when the INR was less than 2, compared with when it was 2 or greater, showed an increase in the odds ratio of 5.07 (95% confidence interval [CI], 2.92 to 8.80). If the INR was greater than 3, the odds ratio for bleeding events was 3.21 (95% CI, 1.24 to 8.28) when compared with an INR of 3 or less. Four studies reported time spent in therapeutic range. The results showed an INR between 2 and 3 was maintained 61 percent of the time, exceeded the range 13 percent of the time, and was below the range 26 percent of the time.

The authors conclude that the risk for ischemic stroke in patients receiving warfarin therapy for nonvalvular atrial fibrillation is significantly higher in patients who are receiving insufficient anticoagulation (i.e., INR less than 2). They also note that the risk for adverse events is higher in patients who are overcoagulated (i.e., INR greater than 3). The authors note that the published data on this issue are sparse, heterogeneous, and primarily reported from clinical trials.

KARL E. MILLER, M.D.

Reynolds MW, et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation. A systematic review and metaanalysis. Chest December 2004;126:1938-45.

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