Original Research

Development of a Self-Assessment Instrument to Determine Daily Intake and Variability of Dietary Vitamin K R. Rebecca Couris, PhD, RPh, Gary R. Tataronis, MS, Sarah L. Booth, PhD, Gerard E. Dallal, PhD, Jeffrey B. Blumberg, PhD, FACN, and Johanna T. Dwyer, DSc Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (R.R.C., S.L.B., G.E.D., J.B.B., J.T.D.), Massachusetts College of Pharmacy and Health Sciences (R.R.C., G.R.T.), Boston, Massachusetts Key words: vitamin K, diet records, assessment tools, anticoagulation therapy Objective: To develop and validate a brief, self-assessment instrument (K-Card) to determine daily variations in dietary vitamin K1 (phylloquinone) intake for use in patients receiving oral warfarin anticoagulant therapy. Methods: The K-Card was designed to include a checklist of selected common foods and beverages providing ⱖ 5 ␮g vitamin K per serving in American diets and items with lower vitamin K content typically consumed in quantities which contribute significantly to total vitamin K intake. The K-Card was validated against records of weighed food intake from thirty-six healthy volunteers, 20 to 40 and 60 to 80 years of age, whose phylloquinone intakes and plasma concentrations had been previously measured by the Metabolic Research Unit, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA USA. Future use of the K-Card by patients was simulated by a single investigator using 108 one-day weighed food records to estimate phylloquinone intakes. Dietary phylloquinone calculated from the K-Card was compared to the values of phylloquinone intake from the diet records collected on the same days, and to fasting plasma phylloquinone concentrations obtained from the same individuals on the following day. Results: The mean dietary phylloquinone intake (⫾ SEM) was 138.8 ⫾ 15.7 ␮g for the K-Cards compared to 136.0 ⫾ 15.8 ␮g for the diet records (p ⫽ 0.067). Bland-Altman limits of agreement between quantities of dietary phylloquinone calculated from the K-Card and values obtained from the weighed food records were ⫾ 38 ␮g. Conclusion: In this simulation, the K-Card provided an accurate estimate of dietary phylloquinone intake and therefore deserves further testing for use by patients receiving coumarin-based anticoagulant therapy to determine whether variability in dietary patterns contributes to disruptions in anticoagulant drug efficacy and safety.

INTRODUCTION

form of vitamin K, which is involved in the post-translational modification of these coagulation factors, and thus antagonize the vitamin’s action [7]. Warfarin, a coumarin-based anticoagulant, has been used in human anticoagulant therapy since the 1940s and today is one of the primary oral anticoagulants for thromboembolic disease and related disorders [8 –10]. Warfarin’s anticoagulant effects can be disrupted by variations in dietary phylloquinone (vitamin K1) intake [11, 12] that may result in serious, life-threatening consequences [13–18]. Therefore, clinicians often recommend that patients who are receiving warfarin therapy limit their daily variations in

Vitamin K (phylloquinone) is involved in blood coagulation through its generation of the active cofactor required for the gamma-carboxylation of glutamic acid (Gla) which is a critical post-translational step in the synthesis of six vitamin K-dependent coagulation proteins: prothrombin, factors VII, IX, and X, and proteins C and S [1–5]. The synthesis of Gla residues in these proteins permits their binding to calcium and subsequent participation in the clotting cascade [4 – 6]. Oral anticoagulants, such as warfarin, act to create a partial deficiency in the active

Address reprint requests to: R. Rebecca Couris, Ph.D., R.Ph., Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, MA 02115. E-mail: [email protected]

Journal of the American College of Nutrition, Vol. 19, No. 6, 801–806 (2000) Published by the American College of Nutrition 801

Self-Assessment of Vitamin K Intake and Variability vitamin K consumption to no more than 250 to 500 ␮g from baseline intakes [16, 19]. When the intake of vitamin K remains constant, regardless of its absolute dietary level, no adverse drug-nutrient interaction that affects anticoagulant outcomes is evident [20]. However, when variations in vitamin K intake exceed these levels, disruptions can occur in the new homeostatic balance that has been achieved with anticoagulant drugs. Among patients who are anticoagulated with a constant dose of warfarin, increases in phylloquinone intake have been associated with abnormal and excessive blood clotting or warfarinresistant anticoagulation, necessitating increases in warfarin dose [13–16]. For example, warfarin resistance has been documented among patients consuming large amounts of broccoli, which contains 113 ␮g phylloquinone per 100 g serving [13]. Walker [14] found that patients taking anticoagulants on weight reduction diets who consumed large amounts of green leafy vegetables, which are typically rich in phylloquinone, had a greater incidence of myocardial infarctions associated with warfarin resistance than did their peers with lower intakes. Although 500 ␮g of phylloquinone has been demonstrated to overcome the disruption of vitamin K metabolism associated with warfarin [21], enteral products containing as little as 25 to 115 ␮g of phylloquinone per 100 mL have also been reported to create a dietary-induced warfarin resistance [22, 23]. Consistent with these observations, Oversen et al. [15] and Pedersen et al. [16] noted that patients taking anticoagulants who consumed vegetables that were poor sources of phylloquinone rarely reported adverse reactions. In contrast, decreases in phylloquinone intake among patients taking anticoagulants can result in abnormal bleeding or warfarin-potentiated anticoagulation [17, 18]. Chow et al. [18] reported hemorrhagic complications in two patients on longterm anticoagulant therapy due to dietary modifications that drastically lowered their intakes of phylloquinone. Furthermore, fluctuations in phylloquinone intake may prolong the interval necessary to reach a stable dosing regimen with anticoagulant therapy, a circumstance which may result in adverse hemorrhagic and thrombotic events. Therefore, the National Stroke Association and pharmaceutical manufacturers of anticoagulants recommend that dietary intakes of phylloquinone remain constant in patients receiving oral anticoagulant therapy [24, 25]. Constant dietary intakes of phylloquinone are especially important for patients receiving acenocoumarol, a drug that has an even shorter half-life than warfarin and is potentially affected even more dramatically by dietary phylloquinone fluctuations. A consistent phylloquinone intake that meets the current Recommended Dietary Allowance of 65 to 80 ␮g/day would therefore be prudent patient advice [26, 27]. The recent availability of food composition data for vitamin K makes it possible to identify foods that may potentially interfere with the efficacy of warfarin anticoagulant therapy. However, an efficient and inexpensive method for measuring dietary phylloquinone intake and variability in a clinical setting has not been available. Thus, we developed a short, practical

802

dietary self-monitoring tool, called the K-Card. The K-Card was then validated to determine deviations from a standard to quantitatively assess day-to-day and week-to-week variability in dietary phylloquinone intake which could be used by patients receiving coumarin-based anticoagulant therapy.

METHODS K-Card Development The items selected for inclusion on the K-Card represent foods and beverages determined in previous studies to provide ⱖ 5 ␮g vitamin K per serving [28 –30]. In addition, lower phylloquinone content foods eaten frequently or in quantities that contribute significantly to vitamin K intake were also included. Common supplements and products providing vitamin K were also incorporated into the K-Card. Fifty-five items are listed on one double-sided page of thick stock paper and categorized by color coding as follows: vegetables (green), meat/poultry/fish (yellow), mixed dishes (blue), fats/oils/salad dressings (yellow), snacks (green), desserts (purple), beverages (pink), and dietary supplements (lavender). Each side of the K-Card is presented in Tables 1 and 2, respectively. Foods and food groups that appear on the K-Card include those from the U.S. Food and Drug Administration Total Diet Study which provides the phylloquinone content of commonly consumed foods and beverages in the American diet [29]. These sources were supplemented by provisional tables listing the phylloquinone content of common foods and beverages and additional items from the vitamin K nutrient database at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University [28 –30].

K-Card Validation Utilizing Previous Metabolic Balance Study Diet Record Information We employed the information from a previously conducted metabolic balance study on vitamin K to validate the K-Card. Specifically, we used lists of foods documented from records of weighed food intake of 36 volunteers whose phylloquinone intakes and corresponding fasting plasma phylloquinone concentrations were previously collected [30]. In this previous metabolic balance study, subjects were stratified into four groups (nine individuals per group) and categorized by age (20 to 40 years and 60 to 80 years) and gender. The subjects were instructed not to use antibiotics or supplements for at least four weeks prior to and during the study. Each participant completed three sets of four consecutive day-weighed diet records of all foods, beverages and other ingredients that they consumed while living at home on their usual diets. Food portion sizes were estimated with dietary scales, rulers and household measures. There was a minimum of six weeks between each diet record period so that all months of the year were represented in

VOL. 19, NO. 6

Self-Assessment of Vitamin K Intake and Variability Table 1. K-Card (Check which foods you eat at each meal everyday. If you eat more or less than one serving indicate how much.)

the data for each subject. To determine vitamin K status, fasting plasma was drawn on the last day after each of the three diet record periods. Fasting plasma phylloquinone concentrations were then used to determine the diet-plasma relationship for

JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION

vitamin K [30]. The results of this metabolic balance study provided the best available standard for phylloquinone intake as it relates to diet records and fasting plasma phylloquinone concentrations.

803

Self-Assessment of Vitamin K Intake and Variability Table 2. K-Card (Check which foods you eat at each meal everyday. If you eat more or less than one serving indicate how much.)

Sampling of Diet Records for K-Card Validation In this study, one of us (R.R.C.) recorded lists of foods onto the K-Card using the diet records from the previous metabolic balance study [30]. The investigator was blinded to all identifying information for each record and also to calculation of dietary phylloquinone intake. The dietary record selected for this simulation study was taken from each of the three sets of four consecutive day-weighed diet records and corresponded to

804

the day prior to the 8:00 am fasting blood sample (12 to 14 hours postprandial) with plasma phylloquinone concentrations determined by HPLC according to Booth et al. [30]. A total of 108 one-day weighed diet records were sampled, representing three reporting periods for each of the 36 volunteers. Validation of the K-Card was accomplished by comparing phylloquinone intakes from the K-Cards to the completed diet records of the previous study [30]. Recorded food intakes on the K-Card were translated into quantities (␮g) of phylloquinone per serving and

VOL. 19, NO. 6

Self-Assessment of Vitamin K Intake and Variability used to determine amounts of phylloquinone consumed. In subsequent analyses these amounts were compared to those obtained from calculation of phylloquinone intakes assessed from the previous study’s diet records on the same days using the Tufts University vitamin K database.

Statistical Analysis Pearson correlation coefficients were used to compare the quantity of dietary phylloquinone from the K-Card against that from weighed food records obtained from Booth et al. [30]. Because strong correlations between two assessment methods do not account for bias between the two instruments and do not necessarily indicate agreement, limits of agreement between the quantity of dietary phylloquinone calculated from the KCard and that obtained from the diet records were derived according to the method of Bland and Altman [31]. Scatterplots were displayed to compare plasma phylloquinone concentrations (nmol/L) against vitamin K intake (␮g) from both the K-Card and the weighed diet records for each visit. A logarithmic transformation of the data was used because this data were skewed to the right. The quantity of vitamin K intake (␮g) from the K-Card and the diet records was also compared. Repeated measures ANOVA was used to compare mean differences between intake as measured by diet records and K-Cards.

RESULTS Fig. 1 depicts the differences in the quantities of dietary phylloquinone as determined from each of the three sets of 36 one-day weighed food records and the quantities of dietary phylloquinone assessed using the K-Card. The day-to-day variability was assessed by examining differences from one clinic visit to another within patients. A repeated measures analysis of variance comparing differences between visits revealed no statistical significance between the mean differences due to the visits (p ⫽ 0.578). The mean dietary vitamin K intake (⫾ SEM) was 138.8 ⫾ 15.7 ␮g for the K-Cards compared to 136.0 ⫾ 15.8 ␮g for the diet records (p ⫽ 0.067, repeated measures ANOVA). Pearson correlation coefficients were used to examine the association between the quantities of phylloquinone intake assessed by the K-Card and those from the diet records for each visit as follows: visit 1 (r ⫽ 0.995, p ⬍ 0.05), visit 2 (r ⫽ 0.998, p ⬍ 0.05) and visit 3 (r ⫽ 0.989, p ⬍ 0.05). As noted above, strong correlations between the assessment methods may not imply agreement. Therefore, the limits of agreement were determined between the quantities of dietary phylloquinone calculated from the K-Card and those obtained from the weighed diet records according to the method of Bland and Altman [31]. In advance of the analysis, ⱕ 50 ␮g of dietary phylloquinone was defined as an acceptable limit of variation between the two assessment methods. This value represents a more stringent

JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION

criterion for variability compared to the amounts documented in clinical studies that indicate variations of 250 ␮g/day in dietary phylloquinone have a significant effect on warfarin anticoagulant therapy [16, 19]. A plot of the differences in dietary phylloquinone intake between the two assessment tools against their mean for each individual is presented for all three visits (Fig. 2).

DISCUSSION In a simulation model, calculating dietary phylloquinone intake using the K-Card provided essentially identical values to those obtained by independent assessment from the same records of weighed food intake. These quantities were generally within 38 ␮g, substantially less than the 50 ␮g pre-defined acceptable limit of variation. The accuracy of the K-Card derives, in part, from its inclusion of all food items containing ⱖ 5 ␮g vitamin K per serving. Furthermore, food items with lower phylloquinone content but that were typically consumed in quantities which contribute significantly to total phylloquinone intake and dietary supplements containing vitamin K were also included in the K-Card. The K-Card is an easy-to-use self-assessment tool that provides an accurate estimate of dietary phylloquinone intake in this simulation exercise. Further assessment will be conducted to determine its accuracy when used by actual patients. The K-Card food checklist permits patients to record their daily diet in fewer than 15 minutes. Quick and simple tabulations of items contributing to phylloquinone intake from the K-Card can be performed by either the patient or trained personnel. In contrast, completion of multiple diet records is time-consuming for the patients and requires trained personnel to code and subsequently analyze record entries. The K-Card has been tested in a prospective clinical trial to determine the effect of phylloquinone intake on the stability of warfarin therapy (unpublished data). Variability in phylloquinone intake may underlie the discrepancies noted in patients with fluctuating responses to coumarin-based anticoagulant therapy from prolonged bleeding time to clotting. Dietary intakes of phylloquinone have greater within-to-between person variability than other fat-soluble vitamins, which may have detrimental effects on the stability of oral anticoagulant therapy [30]. Thus, when further validated, the K-Card could prove useful in monitoring serial daily phylloquinone intakes to establish day-to-day and week-to-week variability. Measuring variability in phylloquinone intake with a short and easy-to-use instrument like the K-Card may be beneficial in education programs for patients receiving coumarin-based anticoagulant therapy. The K-Card could also provide primary healthcare providers with information that could impact on patient counseling and education to encourage compliance to a stable phylloquinone intake among patients receiving anticoagulant therapy.

805

Self-Assessment of Vitamin K Intake and Variability

Fig. 1. Differences between dietary phylloquinone intake by patients as assessed using weighed diet records and the K-Card.

Fig. 2. Differences against means for dietary phylloquinone intake assessed from the K-Card and diet records.

806

VOL. 19, NO. 6

Self-Assessment of Vitamin K Intake and Variability

ACKNOWLEDGEMENTS The authors would like to thank Barbara Furie for critical evaluation of the study design and analysis, Nicola McKeown and Katherine Tucker for assessment of phylloquinone from the diet records, Ken Davidson for technical assistance and the volunteers who participated in this study. This study was supported by the School of Nutrition Science and Policy, Frances Stern Nutrition Center, and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA through Cooperative Agreement No. 58-1950-9-001 with the U.S. Department of Agriculture. Note: The K-Card, vitamin K intake assessment card, is trademarked and copyrighted by Tufts University. Any use or other infringement is prohibited. Contact the Associate Dean for Administration and Finance at the Tufts University School of Nutrition Science and Policy for information.

REFERENCES 1. Suttie JW, Mammah-Schendel LL, Shah DV, Lyle BJ, Greger JL: Vitamin K deficiency from dietary vitamin K restriction in humans. Am J Clin Nutr 47:475–480, 1988. 2. Suttie JW: “Current Advances in Vitamin K Research.” Amsterdam: Elsevier, 1988. 3. Suttie JW: Vitamin K and human nutrition. J Am Diet Assoc 92:585–590, 1992. 4. Furie BC, Furie B: Vitamin K-dependent blood coagulation proteins. In Arias IM, Boyer JL, Fausto N, Jakoby WB, Schacter DA, Shafritz DA (eds): “The Liver: Biology and Pathobiology,” 3rd ed. New York, NY: Raven Press, pp 1217–1225, 1994. 5. Furie BC, Furie B: Structure and mechanism of action of the vitamin K-dependent gamma-glutamyl carboxylase: recent advances from mutagenesis studies. Thromb Haemost 78:595–598, 1997. 6. Sadowski JA, Bovill EG, Mann KG: Warfarin and the metabolism and function of vitamin K. In Poller L (ed): “Recent Advances in Blood Coagulation.” London: Churchill, Edinburgh, Livingstone, pp 93–118, 1991. 7. Majerus PW, Broze GJ, Miletech JP, Tollefsen DM: Anticoagulant, thrombolytic, and antiplatelet drugs. In Gilman AG, Rall TW, Nies AS, Taylor P (eds): “The Pharmacological Basis of Therapeutics,” 8th ed. New York: Pergaman Press, pp 1311–1331, 1990. 8. Owen Jr CA, Bowie EJW: The history of the development of oral anticoagulant drugs. In Poller L, Hirsh J (eds): “Oral Anticoagulants.” New York: Arnold. 1996. 9. Hirsh J, Poller L, Deykin D, Levine M, Dalen JE: Optimal therapeutic range for oral anticoagulants. Chest 95 Suppl:5S–11S, 1989. 10. Hirsh J: Oral anticoagulants. N Engl J Med 324:1865–1875, 1991. 11. Udall JA: Human sources and absorption of vitamin K in relation to anticoagulation stability. JAMA 194:127–129, 1965. 12. Udall JA: Vitamin K and coumarin drug interrelationships in man. Curr Ther Res 8:627–631, 1966.

JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION

13. Kempin SJ: Warfarin resistance caused by broccoli. N Engl J Med 39:1229–1230, 1983. 14. Walker FB: Myocardial infarction after diet-induced warfarin resistance. Arch Intern Med 144:2089–2090, 1984. 15. Oversen L, Lyduch S, Idorn ML: The effect of a diet rich in brussel sprouts on warfarin pharmacokinetics. Eur J Clin Pharmacol 33: 521–523, 1991. 16. Pedersen FM, Hamberg O, Hess K, Ovesen L: The effect of dietary vitamin K on warfarin-induced anticoagulation. J Int Med 229: 517–520, 1991. 17. Colvin BT, Lloyd MJ: Severe coagulation defect due to a dietary deficiency of vitamin K. J Clin Pathol 30:1147–1148, 1977. 18. Chow WH, Chow TC, Tse TM, Tai YT, Lee WT: Anticoagulation instability with life-threatening complication after dietary modification. Postgrad Med J 66:855–857, 1990. 19. Karlson S, Leijd B, Hellstrom K: On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment. Acta Med Scand 220:347–350, 1986. 20. Harris JE: Interactions of dietary factors with oral anticoagulants: review and applications. J Am Diet Assoc 95:580–584, 1995. 21. Shetty HGM, Backhouse G, Bentley DP, Routledge PA: Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1. Thromb Haemost 647:13–15, 1993. 22. Howard PA, Hannaman KN: Warfarin resistance linked to enteral nutritional products. J Am Diet Assoc 85:713–715, 1985. 23. Martin JE, Lutomski DM: Warfarin resistance and enteral feedings. JPEN 13:206–208, 1989. 24. American Heart Association/National Stroke Association: Fighting heart disease and stroke. 70th Scientific Session Abstract Status Report, 1997. 25. DuPont Pharma: “A Patient’s Guide to Using Coumadin威 at Home.” Wilmington, DE: DuPont, 1996. 26. Booth SL, Charnley JM, Sadowski JA, Saltzman E, Bovill E, Cushman M: Dietary vitamin K1 and stability of oral anticoagulation: proposal of a diet with constant vitamin K1 content. Thromb Haemost 77:504–509, 1997. 27. Booth SL, Tucker KL, McKeown NM, Davidson KW, Dallal GE, Sadowski JA: Relationships between dietary intakes and fasting plasma concentrations of fat-soluble vitamins in humans. J Nutr 127:587–592, 1997. 28. Booth SL, Sadowski JA, Weihrauch JL, Ferland G: Vitamin K1 (phylloquinone) content of foods: a provisional table. J Food Comp Anal 6:109–120, 1993. 29. Booth SL, Sadowski JA, Pennington JAT: The phylloquinone (vitamin K1) content of foods in the US-FDA Total Diet Study. J Agric Food Chem 43:1574–1579, 1995. 30. Booth SL, Pennington JAT, Sadowski JA: Food sources and dietary intakes of vitamin K1 (phylloquinone) in the American diet: data from the FDA Total Diet Study. J Am Diet Assoc 96:149–154, 1996. 31. Bland JM, Altman DG: Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 2:307–310, 1986.

Received August 4, 1999; revision accepted August 31, 2000.

807