Warfarin Resistance and Unstable INRS

Two common problems complicate warfarin therapy. One is the patient who requires large doses of warfarin and the other is the patient with erratic INRs.

Rarely, the clinician is faced with a patient in whom massive doses of warfarin are required for anticoagulation or, more disturbingly, the patient who seems to be resistant to even large doses of warfarin. A careful evaluation of such a patient is needed to determine the cause of the warfarin resistance.

True genetic warfarin resistance is extremely rare, with only four affected kindreds reported. These patients are always difficult to anticoagulate and may only respond to very large doses (i.e., 150 milligrams) of warfarin. More common is acquired resistance to warfarin. The three major causes of acquired resistance are medications, ingestion of vitamin K, and non-compliance.

It is less common for medicines to inhibit the action of warfarin than to potentiate it. Common drugs which inhibit warfarin action are barbiturates, rifampin, and nafcillin. Patients on these medications may require 20 mg of warfarin per day to maintain a therapeutic INR. Since most drug-warfarin interactions are mediated through induction of liver enzymes, it may take several days for the warfarin resistance to be noticed after starting the drug and several days for the effect to wear off after stopping the drug. Cholestyramine uniquely interferes with warfarin absorption.

Vitamin K is found in several nutritional supplements and often in generic multivitamins, and use of these products can result in warfarin resistance. For example, Ensure contains 80 ^g of vitamin K per 1000 kcal and Sustacal 230 ^g/1000 kcal. In patients who depend solely on these products for nutrition large doses of warfarin or anticoagulation with heparin may be required. If a patient changes supplements or starts ingesting regular food, the warfarin requirement will change dramatically. Patients may also be ingesting large amounts of vitamin K-containing food that can induce warfarin resistance. Even one or two days of high intake of vitamin K-rich food can dramatically lower INRs.

Some patients who present with warfarin resistance are simply not taking the medicine as prescribed. These patients initially require the usual doses of warfarin therapy but then present with normal INRs despite massive warfarin doses. Measur

ing serum warfarin levels are useful in patients suspected of non-compliance. Patients with undetectable warfarin levels despite allegedly taking large doses of warfarin are most likely not taking the drug. In the patient who has a non-detectable warfarin level, a level should be repeated after the patient is witnessed taking the drug to ensure that the patient is not suffering from rare malabsorption of warfarin. One case has been described of a patient who could not absorb warfarin but could absorb phenindione, a non-coumarin vitamin K inhibitor. Curiously, this malabsorption occurred after two years of stable warfarin therapy.

Patients with erratic INRs are at greater risk for both bleeding and thrombosis. Patients need to be questioned about use of all other medications including "natural" remedies and over- the-counter medicines. A good dietary history as well as a frank discussion about compliance should be performed. Adding vegetables and other sources of vitamin K to the diet will stabilize the INR in some patients.

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