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.

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Warfarin increases mortality in intracranial arterial stenosis
From American Family Physician, 8/15/05 by Mark Ebell

Clinical Question: Is warfarin (Coumadin) better than aspirin for the treatment of patients with intracranial arterial stenosis?

Setting: Outpatient (any)

Study Design: Randomized controlled trial (double-blinded)

Allocation: Concealed

Synopsis: Results of retrospective studies suggest that warfarin may be more effective than aspirin at preventing stroke in patients with intracranial arterial stenosis. However, these studies may be biased by poor ascertainment of outcomes and limited follow-up; that is, if patients who die because of warfarin complications are not identified, the drug may seem safer and more effective than it actually is. This study is the largest and best to date to address this question.

The investigators enrolled adults 40 years and older who had experienced a transient ischemic attack or nondisabling stroke in the previous 90 days and had a 50 to 99 percent stenosis of the internal carotid, middle cerebral, vertebral, or basilar arteries. They excluded patients with atrial fibrillation, major comorbidities, or significant stenosis of the extracranial carotid artery.

The mean age of participants was 63 years; 61 percent were men, and 58 percent were white. The most common lesion was middle cerebral (32 percent of all obstructions). Approximately 20 percent of patients had internal carotid, vertebral, or basilar artery lesions, and 6 percent had multiple lesions. One half of patients had a 50 to 69 percent stenosis and slightly more than one third had a 70 to 99 percent stenosis. Patients were assigned randomly to receive warfarin with a target International Normalized Ratio of 2.0 to 3.0 or aspirin in a dosage of 650 mg twice daily. If patients had dyspepsia, the dosage of aspirin could be lowered (minimum: 325 mg once daily). Groups were balanced at baseline, outcomes were assessed blindly, and analysis was by intention to treat.

Although investigators planned to follow patients for a mean of 36 months, the study was stopped prematurely by the safety committee. After a mean follow-up of 1.8 years, it was clear that patients receiving warfarin were more likely to die (9.7 versus 4.3 percent; P = .02; number needed to treat to harm [NNH] = 18 for 1.8 years; 95% confidence interval [CI], 10 to 84). There also were more major hemorrhages in the warfarin group (8.3 versus 3.2 percent; P = .01; NNH = 20 for 1.8 years; 95% CI 11 to 80).

Bottom Line: Warfarin instead of aspirin causes one extra death every two years for patients with intracranial arterial stenosis and a recent stroke or transient ischemic attack. Given the risk and cost of the imaging studies used to diagnose intracranial arterial stenosis, perhaps prescribing 650 mg of aspirin twice a day for these patients is the better option. (Level of Evidence: 1b)

MARK EBELL, M.D., M.S.

Study Reference: Chimowitz MI, et al., and the Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med March 31, 2005;352:1305-16.

Used with permission from Ebell M. Warfarin increases mortality in intracranial arterial stenosis. Accessed online June 1, 2005, at: http://www.InfoPOEMs.com.

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