Dietary advice in connection with warfarin treatment.

Fråga: Dietary advice in connection with warfarin treatment.

Sammanfattning: Dietary vitamin K should be regarded as an important environmental factor contributing to unwanted disturbances in warfarin-induced anticoagulation. Patients on oral anticoagulants should avoid major changes in diet, especially food rich in vitamin K. However, warfarin requirements should not change if patients are consistent in their intake of these foods.

There is no good reason to forbid occasional intake of moderate amounts of alcohol in warfarin-treated patients with normal liver function. However the effects on clotting mechanisms of more regular drinking, even in moderate amounts, can result from changes in the metabolism of the drug. Variable drinking habits are also thought to be dangerous in connection with oral anticoagulants.

Patients on oral anticoagulation with extensive changes in dietary habits require frequent monitoring of the prothrombin time, with appropriate adjustment of the warfarin dosage, to avoid important changes in the level of intensity of treatment.

Svar: Dietary modification has been reported to affect anticoagulation therapy (1). Ingestion of large amounts of foods rich in vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants (7). Vitamin K is an essential dietary factor which controls the synthesis of prothrombin (coagulation factor II) and blood coagulation factors VII, IX and X (3). It occurs in two forms; vitamin K1 (phylloquinone) and vitamin K2 (menaquinones). Phylloquinone is found to be the nutritionally important compound. Menaquinones are produced in the lower bowel by bacteria (3). Phylloquinone is found in green plants e.g. sauerkraut (15 mg/kg), parsley (8 mg/kg), spinach (6 mg/kg), chives (3 mg/kg), broccoli, brussels sprouts, cabbage (2.5 mg/kg) and liver (0.5 mg/kg) (8), but also in asparagus, lettuce, turnip greens, watercress and tomato (7). Small but significant amounts (0.05-0.5 mg/kg) are also present in milk and dairy products, meat, eggs, cereals, fruits, and other vegetables (1).

Warfarin is a coumarin-type anticoagulant which inhibits the vitamin K-dependent synthesis of clotting factors II, VII, IX and X in the liver and vitamin K antagonizes the inhibitory effects of warfarin (9). The absorption of vitamin K1 is reported to be very effective (4). Since meals do not appear to affect total absorption of warfarin, timing of administration with regard to meals does not seem necessary (7).

Concerning the interaction between warfarin and alcohol, it has been reported that the half-life of warfarin in alcoholic patients is significantly lower than in control subjects (6). Alcohol may stimulate the activity of hepatic enzymes responsible for inactivation of coumarins, but the consequences of alcohol consumption may be variable and unpredictable (4). Heavy regular drinkers may experience a diminished effect of warfarin. Acute ingestion of alcohol has been shown to enhance the effect of warfarin. However, a moderate alcohol intake is not considered to cause problems (9,10). A daily consumption of ethanol for a period of 3 weeks in the form of wine taken with meals in moderate (28.2 gram daily) or even in liberal quantities (56.4 gram daily) has been shown to have no effect on the hypoprothrombinemia induced by warfarin (11).

Although anticoagulants are commonly used in routine care, there seems to be a lack of studies indicating how to advise patients with regard to intake of alcohol and vitamin K-rich food. Studies indicate that a single intake of vitamin K1-rich vegetables has no major effect on prothrombin values. In one study of 21 patients stabilized on warfarin, ingestion of 250 gram spinach or 250 gram broccoli for one day resulted in a small, transient reduction in hypoprothrombinemia, but daily ingestion for 7 days markedly reduced the effect of warfarin (7). Another study (2), however, suggests that even a single day´s increase of one mg of dietary vitamin K can cause an undesirable increase in plasma coagulant activity. This is accentuated by continuous daily intake, and lasts for several days after resumption of the patient´s normal diet. The lower limit, according to this source, for daily variation in dietary vitamin K intake should not exceed 0.25-0.5 mg (2). The dangers of dietary modification in patients on long term oral anticoagulants are less often considered. A severe coagulation defect has occurred with dietary vitamin K deficiency and life-threatening bleeding tendency was observed in one patient on warfarin anticoagulation after he had given up his former long- standing dietary habit of ingesting porcine liver (approximately one kg/week) (1). Dietary modification resulting in a higher intake of vitamin K, on the other hand, would be expected to cause warfarin resistance (1). Consequently, an irregular intake of food rich in vitamin K may modify the effect of anticoagulant therapy (1,5).

The hypoprothrombinemic response should also be carefully monitored, if a patient on oral anticoagulant drugs is treated with very high doses of vitamin E, which may increase the hypoprothrombinemic response to warfarin. The mechanism is not established, but some have proposed that vitamin E may interfere with the effect of vitamin K in the production of clotting factors. The effect has been demonstrated with very high doses of vitamin E (over 100 IU) to a regimen of warfarin anticoagulation (12,13). Although the incidence of this interaction in patients receiving the combination is not known, very high doses of vitamin E should be avoided in patients treated with anticoagulant drugs, if there is not a justifiable need for vitamin E. 1 Chow WH, Chow TC, Tse TM, Tai YT, Lee WT: Anticoagulation instability with life-threatening complication after dietary modification. Postgrad Med 1990; 66: 855-857 2 Pedersen FM, Hamberg O, Hess GK, Ovesen L: The effect of dietary vitamin K on warfarin-induced anticoagulation. J Intern Med 1991; 229: 517-520 3 Suttie JW: Warfarin and vitamin K. Clin Cardiol 1990; 13: VI-16-18 4 Karlsson B, Leijd B, Hellström K: On the influence of vitamin K- rich vegetables and wine on the effectiveness of warfarin treatment. Acta Med Scand 1986; 220: 347-350 5 Ovesen L, Lyduch S, Idorn ML: The effect of a diet rich in brussels sprouts on warfarin pharmacokinetics. Eur J Clin Pharmacol 1988; 33: 521-523 6 Kater RMH, Roggin G, Tobon F, Zieve P, Iber FL: Increased rate of clearance of drugs from the circulation of alcoholics. Am J Med Sci 1969; 258: 35-39

7 Hansten, Horn, Drug interactions & Updates, 1971-
8 Johnsson H: Antikoagulantiabehandling. Läkemedelsboken 91/92. Apoteksbolaget 1991; sid 139-146
9 Martindale, The extra pharmacopoeia, 1989; 29th ed: 344-349
10 Goodman and Gilman, The pharmacological basis of therapeutics. 1990; 8th ed: 1317-1322
11 Meyler´s, Side effects of drugs. Ed by MNG Dukes. Elsevier, Amsterdam. 1988; 11th ed: 752-753
12 Megavitamin E supplementation and vitamin K-dependent carboxylation. Nutr Rev 1983; 41: 268-270

13 Vitamin K, vitamin E and the coumarin drugs. Nutr Rev 1982; 40: 180-182