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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.

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          Most cited references 14

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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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            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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              Patient-specific factors predictive of warfarin dosage requirements.

              To identify patient-specific factors predictive of maintenance warfarin dosage requirements >5 mg/d. One hundred forty-six adults taking warfarin were identified from a community hospital and an outpatient anticoagulation clinic. Patient demographics and data on warfarin doses, laboratory results, and medication use were obtained by abstracting patient records. Estimates of vitamin K intake were obtained using a questionnaire and structured interview. Multiple logistic regression was used to identify patient characteristics independently predictive of warfarin maintenance requirements >5 mg/d. An assessment tool for estimating an individual patient's likelihood of requiring warfarin maintenance doses >5 mg/d was derived from the logistic regression model and was assessed in both the study cohort and a separate historical validation cohort of 125 patients. Five factors were independently associated with warfarin requirements >5 mg/d: age 400 micro g/d, and body weight >or=91 kg. The assessment tool derived from these factors correctly classified semiquantitative warfarin requirements as non-high-dose in 84 of 93 study cohort patients and 71 of 78 validation cohort patients, and correctly classified requirements as high-dose in 10 of 13 study cohort patients and 11 of 15 validation cohort patients. African American ethnicity is a newly identified predictor of warfarin requirements >5 mg/d and is independent of dietary vitamin K intake. An assessment tool incorporating this and other predictors can estimate a patient's likelihood of requiring such dosages.
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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
                © 2007 Dove Medical Press Limited. All rights reserved
                Categories
                Original Research

                Medicine

                survey, vitamin k, anticoagulation, cyp450 inducers, warfarin

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