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Plant Stanol Esters and Vitamin K

      To the Editor: Plant stanol esters (PSEs) are being developed as novel food ingredients that can substantially reduce serum total and low-density lipoprotein cholesterol concentrations. Because PSEs inhibit cholesterol absorption in the intestine, their potential effect on fat-soluble vitamins is of interest. Recent data have shown that PSEs do not significantly affect serum retinol, α- tocopherol, or 25-hydroxyvitamin D concentrations.
      • Hallikainen MA
      • Uusitupa MIJ
      Effects of 2 low-fat stanol ester-containingmargarineson serum cholesterolconcentrationsas partof a low-fat diet in hypercholesterolemic subjects.
      However, there are no data on PSE and vitamin K metabolism. More specifically, any potential interaction between PSEs and the anticoagulant warfarin would be of great clinical relevance.
      An 8-week open-label trial (Sistostanol Feasibility Study) of PSE-fortified margarinelike spread (4.5 g/d) was conducted in a community-dwelling population of 500 subjects in Olmsted County, Minnesota. Nine subjects (7 male and 2 female) underwent anticoagulation with warfarin before study entry. All the subjects received anticoagulant therapy for at least 3 months before enrollment in the study.
      Indications for anticoagulation in these patients included transient ischemic attack, recurrent deep venous thrombosis, and atrial fibrillation. Warfarin dose and baseline prothrombin time (PT) and international normalized ratio (INR) were recorded for each subject. Daily warfarin doses were titrated to achieve a target INR of 2.0 to 3.5.
      After 8 weeks of using PSE-fortified margarinelike spread, no subject experienced any adverse bleeding. There were no changes in warfarin dose related to PSE use. Subjects 1 through 8 consumed an average of 3 servings of PSE daily (total dose, 4.5 g) (Table 1). Subject 9 was noncompliant and consumed an average of 0.8 serving of PSE daily. In subject 5, the INR increased during the study because of an increased dose of warfarin prescribed by the primary care physician just before study entry to obtain an INR between 2.0 and 3.0. Baseline and end-of-study warfarin dosages, average PT, and average INR at baseline and during the 8-week study period, as well as the PT and INR values obtained at the end of the study for the 9 subjects who underwent anticoagulation with warfarin, are listed in Table 1. No baseline or end-of-study values are reported for subject 3 because he could not be reached to give consent for the release of his medical records.
      Table 1Baseline and End-of-Study Warfarin Doses and PT and INR Values
      INR = international normalized ratio; PSE = plant stanol ester; PT = prothrombin time. PT and INR values are averages of values over the 2 months prior to the study. In-study values are 8-week averages during PSE use.
      SubjectBaseline warfarin dose (mg/d)Baseline PT(s)Baseline INREnd warfarin dose (mg/d)In-study PT(s)In-study INRLast PT (s)Last INRDuration of PSE use at time of last test (wk)
      15282.85272.7272.78
      22.5202.02.5232.324.52.458
      35No valueNo value5No valueNo valueNo valueNo valueNo value
      42.5161.62.5181.8151.58
      58181.88292.926.72.678
      65182.5518.72.620.93.28
      73161.9317.92.417.32.27
      86272.76292.928.92.897
      95Tapering dose2.5Tapering doseTapering doseTapering doseTapering dose
      Average4.6720.42.194.3923.22.5122.92.527.7
      * INR = international normalized ratio; PSE = plant stanol ester; PT = prothrombin time. PT and INR values are averages of values over the 2 months prior to the study. In-study values are 8-week averages during PSE use.
      Patients receiving anticoagulant therapy, such as warfarin, are routinely monitored by determination of their INR and PT values. The effect of warfarin on INR and PT is influenced by the amount of dietary vitamin K. Body stores of fat-soluble vitamin K are limited (typically, 1-2 mg in adults), and in healthy persons who are receiving no anticoagulant therapy, a vitamin K–deficient diet can lead to a slight but statistically significant prolongation of the PT over a 3-week period.
      • Udall JA
      Human sources and absorptionof vitamin K in relation to anticoagulation stability.
      Thus, any meaningful decrease in the levels of vitamin K in subjects consuming PSE would result in an increase in INR and PT, particularly in this population. The results of this study indicate that the INR and PT were not meaningfully influenced by the concomitant use of in patients who previously underwent anticoagulation with warfarin. No changes in the dose of warfarin were necessary during the 8-week treatment period with PSE-fortified margarinelike spread. Although no data are available for a period longer than 2 months, these results suggest that PSEs do not substantially affect vitamin K-dependent hemostasis (as measured by INR) in patients receiving warfarin.

      References

        • Hallikainen MA
        • Uusitupa MIJ
        Effects of 2 low-fat stanol ester-containingmargarineson serum cholesterolconcentrationsas partof a low-fat diet in hypercholesterolemic subjects.
        Am 1 Clin Nutr. 1999; 69: 403-410
        • Udall JA
        Human sources and absorptionof vitamin K in relation to anticoagulation stability.
        JAMA. 1965; 194: 127-129