Warfarin and liquid meal replacement products

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Warfarin is a widely used oral anticoagulant that acts by inhibiting factors II, VII, IX, and X (vitamin K–dependent clotting factors) and the anticoagulant proteins C and S. The manufacturers’ information does not specify whether warfarin should be taken with or without food; thus, many patients will take warfarin with a meal to improve adherence. Although warfarin is associated with many food interactions, these are typically related to the vitamin K content and not to proximity of warfarin and food ingestion. One exception may be liquid meal replacement products that were initially designed for tube feeding but have become popular as supplemental nutrition.

Protein binding and warfarin loss

In vitro models have been used to study the warfarin interaction with enteral formulas because of ethical reasons and difficulty in controlling confounding factors in human participants. Kuhn et al.1 mixed warfarin with an intact (“whole”) protein formula or water, filtered the mixture, and determined warfarin concentration in the initial mixture versus filtrate using high-performance liquid chromatography (HPLC). The concentration of warfarin was no different before and after filtration in the water mixture but was significantly less after filtration with the intact protein formula. Various concentrations of the formula then were tested. A higher percentage of warfarin was recovered when the formula was diluted with water compared with undiluted formula. The authors suggested warfarin binding to a component within the enteral formula.

Penrod et al.2 conducted a similar study, mixing 5 mg warfarin with 150 mL of two intact protein formulas and one hydrolyzed protein (peptide–amino acid) formula, then filtering the mixture. Warfarin recovery from filtrates of the intact protein formulas, as determined by HPLC, was approximately one-half the concentration compared with that of the control (warfarin mixed in water). About two-thirds of warfarin was recovered in the hydrolyzed formula filtrate, demonstrating less warfarin loss when proteins were no longer intact. The authors concluded that warfarin likely binds with the protein component of enteral formulas.

Formulas sold as liquid meal replacement products for oral consumption are typically very similar in composition to the intact protein formulas used in these studies. The above data suggest that ingestion of a liquid meal replacement product may cause warfarin resistance if taken at the same time as warfarin.

Recent study: Effect of tube feeding

A more recent study, however, questions whether protein binding is the problem with liquid meals and warfarin resistance. Klang et al.3 concluded that the tube itself binds warfarin rather than protein. In a two-part in vitro study, gastric dissolution was first tested for warfarin compared with warfarin intact protein enteral formula, and no significant difference was found. The effect of feeding tube material then was tested and found to reduce warfarin recovery significantly. Increasing the amount of warfarin in the test could not overcome the effect of feeding tube binding. In contrast to the previous two studies, the study by Klang et al. suggested that no interaction exists between warfarin and liquid diets unless a feeding tube is used for administration.

Conclusion

Although the study by Klang et al. provides good in vitro evidence of significant warfarin binding to feeding tube material, it does not fully explain the results of the other studies, particularly the difference in warfarin loss between intact and hydrolyzed protein formula noted in the study by Penrod et al. Until more definitive data on the interaction are available, warfarin should be separated by at least 1 hour before or after ingestion of such liquid meals. If a patient chooses to take warfarin with a liquid meal replacement product, closer monitoring of warfarin response should be recommended until the potential interaction can be evaluated.

References

  1. Kuhn TA, Garnett WR, Wells BK, Karnes HT. Recovery of warfarin from an enteral nutrient formula. Am J Hosp Pharm. 1989;46(7):1395–9.
  2. Penrod LE, Allen JB, Cabacungan LR. Warfarin resistance and enteral feedings: 2 case reports and a supporting in vitro study. Arch Phys Med Rehabil. 2001;82(9):1270–3.
  3. Klang M, Graham D, McLymont V. Warfarin bioavailability with feeding tubes and enteral formula. JPEN J Parenter Enteral Nutr. 2010;34(3):300–4.