ANTICOAGULANT THERAPY

Discussion
Oral anticoagulants are used to create a partial deficiency of the active form of vitamin K, which is responsible for maintaining normal blood coagulation.  By inhibiting the action of vitamin K, there is a reduced risk of abnormal blood clotting.

Indications
Oral anticoagulants are typically prescribed for the primary and secondary prevention of the following conditions:

• venous thrombosis
• pulmonary embolism
• myocardial infarction

Persons with prosthetic heart valves, atrial fibrillation with embolization, or heredity disorders that result in a hypercoagulant state may be treated with anticoagulants indefinitely (1,2).

A major complication of anticoagulant therapy is hemorrhage.  The therapeutic index and safety of anticoagulation therapy is assessed through the measurement of the prothrombin time (PT), which is expressed as the international normalized ratio (INR) (2).  An INR of 2.0 to 3.0 is generally considered in the therapeutic range, and the risk of bleeding increases when the INR exceeds 4.0 (2). 

Nutrition Implications of Anticoagulant Therapy
The goal of medical nutrition therapy for persons receiving anticoagulant therapy is to provide a consistent intake of vitamin K.  The Daily Value for vitamin K is 80 mcg for adults (3).  The Daily Value can be used as an appropriate goal for persons on anticoagulant therapy (3,4).  The average dietary intake of vitamin K for adults in the United States is estimated to be 90 to 118 mcg/day (5-7).  Although most patients’ intake will fall into this acceptable range, all patients should have their diets assessed for typical sources and patterns of foods containing vitamin K.  Persons who receive anticoagulant therapy should limit their consumption of foods that have a high level of vitamin K.    

   The list of drugs that interact with vitamin K antagonists is constantly expanding (7).  Drug-drug interactions that increase or decrease the effect of anticoagulant therapy should be evaluated before concluding that dietary intake is responsible for a change in the anticoagulant response (2,5,7). Drugs that increase the anticoagulant effect are agents for gout treatment, anabolic steroids, antiarrhythmic agents, antibiotics, antifungal agents, antihyperlipidemic agents, cimetidine, disulfiram, isoniazid, omeprazole, sulfonylureas, and tamoxifen citrate.  Drugs that decrease the anticoagulant effect are anticonvulsant agents, cholestyramine, griseofulvin, oral contraceptives, rifampin, sucralfate, and vitamin K (5,8).    

Nutrition Assessment and Diagnosis
The oral anticoagulant dose should be established based on the patient’s normal vitamin K intake.  After the dose is established, a reasonable goal is to maintain the daily vitamin K intake within 250 mcg of baseline (1,9). If major changes in food intake occur, the anticoagulant level may need to be reestablished.  Vitamin K intake may increase when a patient starts a weight-reduction diet and includes a greater number of vegetables that are high in vitamin K or begins a high-protein, low-carbohydrate diet (see discussion below).  Other reasons for an increased vitamin K intake may include an adjustment in diet because of hospitalization or a change in seasonal eating patterns (1).  Unlike other fat-soluble vitamins, stores of vitamin K are rapidly depleted if intake is deficient (1).  This information should be considered when assessing the vitamin K level of a patient who has had a low intake of food for a week or longer, as may occur in the hospital setting.

Nutrition Intervention and Monitoring
Patients should be educated about the dietary changes that impact anticoagulant therapy.  They also should be informed of foods that are high in vitamin K (Tables 1.1 and 1.2).  A limited intake of foods that provide more than 60% of the Daily Value (80 mcg) for vitamin K can help keep the INR/PT in the desired range (9).  Patients should be encouraged to keep their diet consistent with their present pattern.  However, if there is a change in diet that includes vitamin K–rich foods, patients should contact their physician and have their INR/PT monitored.

Table 1.1: Foods Moderately High in Vitamin K (60% to 199% of Daily Value) (9)

a Recommended not to consume more than three servings per day
Adapted from: Drug-Nutrient Interactions: Coumadin and Vitamin K. Bethesda, Md: Warren Grant Magnuson Clinical Center, National Institutes of Health; 2003.

Table 1.2: Foods High in Vitamin K (≥ 200% of Daily Value) (9)

a Recommended not to consume more than one serving per day
Adapted from: Drug-Nutrient Interactions: Coumadin and Vitamin K. Bethesda, Md: Warren Grant Magnuson Clinical Center, National Institutes of Health; 2003.

Some evidence suggests that cranberry products interact with anticoagulants to increase their effects (10).  However, a prospective randomized study of patients taking warfarin demonstrated that their INR levels were not adversely affected by consumption of 1 cup of cranberry juice daily (11).  Until further evidence is available on a variety of cranberry products, patients consuming cranberry juice or products should be educated, and their INR/PT should be monitored for the potential interaction.   Although iceberg lettuce, red cabbage, asparagus, cauliflower, and soybean oil are often reported as being high in vitamin K, these foods contain much smaller amounts of vitamin K than the foods listed in Tables 1.1 and 1.2.  Therefore, these foods and other foods and beverages not listed (including coffee and tea) may be consumed as desired (9). 

Special Considerations
Alcohol:  Alcohol has shown to adversely affect the PT/INR ratio (5).  Consuming more than 3 servings of alcoholic beverages per day can increase the effect of warfarin (9).  Limiting or avoiding alcohol may be advised, and persons who do consume alcohol should consult with their physician.

High-protein, low-carbohydrate diets:  A high-protein, low-carbohydrate diet pattern decreases the INR/PT ratio (12).  Case reports have demonstrated a decrease in the INR/PT ratio after initiation of a high-protein, low-carbohydrate diet (12).  The INR/PT ratio returned to a normal level after the diet was stopped and the warfarin dose was decreased to the original dose.  High-protein diets rapidly increase serum albumin levels.  This increase may result in more warfarin binding to serum albumin, thereby decreasing the anticoagulant effect of warfarin (12).  Patients receiving warfarin therapy should be monitored and educated about the potential interaction that occurs with warfarin and high-protein, low-carbohydrate diets (12).

Dietary and herbal supplements:  Several dietary and herbal supplements can interact with anticoagulants and alter the INR/PT ratio (9).  Dietary supplements that affect the INR/PT ratio include arnica, bilberry, butcher’s broom, cat’s claw, dong quai, feverfew, forskolin, garlic, ginger, ginkgo, ginseng, horse chestnut, inositol hexaphosphate, licorice, melilot (sweet clover), pau d’arco, red clover, St. John’s wort, sweet woodruff, turmeric, willow bark, and wheat grass (9).  In addition, persons who take vitamin and mineral supplements containing vitamin K should be monitored.   Vitamin and mineral supplements that are taken consistently pose less of a problem than supplements that are taken sporadically (9).  Vitamin E intakes greater than 1,000 International Units (IU) may increase the risk of excess bleeding.  Research suggests that doses up to 800 IU may be safe for individuals taking warfarin, but the evidence is not conclusive (9).  Persons taking or considering taking vitamin E supplements should consult with their physician.

Enteral nutrition: Patients who are receiving enteral nutrition support while on anticoagulant therapy should be monitored closely.  Significant vitamin K intake from enteral formulas can antagonize the effect of the anticoagulant drug warfarin and result in treatment failure (6).  Most enteral formulations contain modest amounts of vitamin K and provide daily vitamin K intake similar to the average dietary intake from foods (6).  Consistent intake of an enteral formulation containing less than 100 mcg of vitamin K per 1,000 kcal is not expected to cause warfarin resistance (6,8).  However, warfarin resistance can occur in patients on enteral nutrition support whose intake of vitamin K is substantially low (13).  This resistance may occur as a result of warfarin binding to protein contained in the enteral formula; however, this mechanism has not been substantiated by clinical data (13,14).  A reasonable approach to treating warfarin resistance associated with a low vitamin K intake is to initiate a trial of holding the enteral nutrition regimen for at least 1 hour before and after the warfarin dose (13,14). 

References

1. Harris J. Interaction of dietary factors with oral anticoagulants: review and applications. J Am Diet Assoc. 1995; 95:580-584.
2. Levine MN, Raskob G, Landfeld S, Kearon C.  Hemorrhagic complications of anticoagulant treatment.  Chest.  2001; 119 (suppl 1):108S-121S.
3. Reference values for nutrition labeling. In: A Food Labeling Guide.  US Food and Drug Administration Center for Food Safety and Applied Nutrition; 1994 (Editorial revisions, 1999).  Available at: www.cfsan.fda.gov/~dms/flg-7a.html. Accessed October 8, 2007.
4. Booth SL, Centurelli MA.  Vitamin K: a practical guide to the dietary management of patients on warfarin.  Nutr Rev.  1999; 57(9 pt 1):288-296.
5. Coumadin [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2006.
6. Rollins CJ.  Drug-Nutrient interactions.  In: Gottschlich MM, ed.  The A.S.P.E.N. Nutrition Support Core Curriculum.  Silver Spring, Md: American Society for Parenteral and Enteral Nutrition; 2007.
7. Vitamin K intake in micrograms by sex, age, and race/ethnicity: United States, 1988–94. In: Dietary Intake of Macronutrients, Micronutrients, and Other Dietary Constituents: United States, 1988–94.  National Center for Health Statistics. Vital Health Stat. 2002; 11(245):102. Available at: www.cdc.gov/nchs/data/series/sr_11/sr11/245.pdf. Accessed October 7, 2007.
8. Schulman S. Care of patients receiving long-term anticoagulant therapy.  N Engl J Med.  2003; 349:675-683.
9. Drug-Nutrient Interactions: Coumadin and Vitamin K.  Bethesda, Md: Warren Grant Magnuson Clinical Center, National Institutes of Health; 2003.  Available at: http://dietary-supplements.info.nih.gov/factsheets/cc/coumadin1.pdf.  Accessed October 2007.
10. Committee on Safety of Medicine and the Medicines and Healthcare Products Regulatory Agency.  Possible interaction between warfarin and cranberry juice.  Curr Probl Pharmacovigilance.  2003; 29:8.
11. Li Z, Seeram NP, Carpenter CL, Thames G, Minutti C, Bowerman S.  Cranberry does not affect prothrombin time in male subjects on warfarin.  J Am Diet Assoc.  2006; 106:2057-2061.
12. Beatty SJ, Mehta BH, Rodis JL.  Decreased warfarin effect after initiation of high-protein, low-carbohydrate diets.  Ann Pharmacother.  2005; 39: 744-777.
13. Petretich DA.  Reversal of osmolite-warfarin interaction by changing warfarin administration time.  Clin Pharm.  1990; 9:93.  Letter.
14. Penrod LE, Allen JB, Cabacungan LR.  Warfarin resistance and enteral feedings:  two case reports and a supporting in vitro study.  Arch Phys Med Rehabil.  2001; 82:1270-1273.

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