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      Effect of patient-specific factors on weekly warfarin dose

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          Abstract

          Objective

          To determine the influence of various patient-specific factors, use of concomitant medications, and weekly vitamin K intake on total weekly warfarin maintenance dose (TWD).

          Methods

          Information collected, via retrospective chart review, included TWD, general demographics, vitamin K consumption, target INR range, use of alcohol, tobacco, and cytochrome P450 (CYP)-inducing medications, and concomitant medications and diseases.

          Results

          The majority of patients (n = 131) were Caucasian (71%), with more females (55%) than males. Use of CYP-inducing medications resulted in the largest correlation coefficient (r = 0.30). The sample was divided into high warfarin dose (TWD ≥ 50 mg) and low warfarin dose (TWD ≤ 25 mg) patient populations to discern areas where the two populations differed. Age and amiodarone use were the only statistically significant differences between the two groups, with high dose patients tending to be younger and to use less amiodarone. Age and CYP-inducing medications were found to be the only statistically significant predictors of TWD in the regression analysis. The TWD was 2.4 mg less for each additional decade of patient age. The coefficient on CYP-inducing medications indicates that the concomitant use of a CYP inducer is associated with an increase in TWD of 17.2 additional milligrams, adjusting for all other variables in the model.

          Conclusion

          We found concomitant use of CYP inducer, age, height, and ethnicity to have the greatest influence on TWD. Positive relationships were found between TWD and the use of CYP450 inducer, height, and African American ethnicity. Although it did appear that women required a lower TWD than men, this factor contributed mildly. Further studies with a greater sample size may more precisely predict the effect of patient-specific factors on TWD, thus uncovering additional relationships.

          Most cited references19

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          The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.

          Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.
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            Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

            The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level. Copyright 2005 Massachusetts Medical Society.
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              Aging and the anticoagulant response to warfarin therapy.

              To assess the effect of aging on the anticoagulant response to warfarin. Retrospective cohort study. A university hospital outpatient anticoagulation clinic. All patients (n = 530) monitored in the anticoagulation clinic over a 10-year period (1980 to 1990). The 530 study patients had a mean age of 61.5 (+/- 14.7) years (age range, 12 to 90 years). The patients were stratified into four age groups: younger than 50 years (n = 97); 50 to 59 years (n = 107); 60 to 69 years (n = 149); and 70 years or older (n = 177). For each patient, a dose-adjusted mean prothrombin time ratio was calculated by dividing the mean prothrombin time ratio by the mean daily warfarin dose. Older patients were more likely to be female (P less than 0.001), to have more medical problems (P less than 0.001), to be taking more medications (P less than 0.001), and to weigh less than younger patients (P less than 0.001). Across age groups, there were no significant differences in the use of medications that potentiated or inhibited the anticoagulant effects of warfarin. The prothrombin time ratio, when adjusted for dose, was significantly increased in older patients (P less than 0.001). The increased anticoagulant response to warfarin seen with increasing patient age persisted even after simultaneously controlling for relevant demographic and clinical variables in a multivariate model. Other factors significantly associated with an increased sensitivity to warfarin included use of a medication with a potentiating interactive effect with warfarin, female gender, and overall medication use. Increased body weight and duration of warfarin use exceeding 6 months were found to be inversely related to anticoagulant response. The anticoagulant response to warfarin is exaggerated with advancing age. This finding emphasizes the need for close monitoring of older patients treated with warfarin therapy.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                June 2007
                June 2007
                : 3
                : 3
                : 499-504
                Affiliations
                [1 ]Auburn University Harrison School of Pharmacy, Department of Pharmacy Practice and The University of Alabama School of Medicine, Tuscaloosa, Department of Community and Rural Medicine Tuscaloosa, AL USA
                [2 ]South Carolina College of Pharmacy, Department of Pharmacy and Clinical Sciences Charleston, SC USA
                [3 ]Medical University of South Carolina, College of Medicine Charleston, SC USA
                Author notes
                Correspondence: Heather P Whitley Clinical Assistant Professor, The University of Alabama School of Medicine, Tuscaloosa, Rural Health Institute for Clinical and Translational Research, Box 870326, Tuscaloosa, AL 35487-0326, USA Tel +1 205 348 1333 Fax +1 205 348 9417 Email whitlhp@ 123456auburn.edu
                Article
                2386352
                18488070
                b73a42fa-e9c8-45ee-b569-e5e2aa642cf2
                © 2007 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Original Research

                Medicine
                warfarin,cyp450 inducers,anticoagulation,vitamin k,survey
                Medicine
                warfarin, cyp450 inducers, anticoagulation, vitamin k, survey

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