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      Warfarin Dosing and Time Required to Reach Therapeutic International Normalized Ratio in Patients with Hypercoagulable Conditions Translated title: Hiperkoagülabilite Durumları Olan Hastalarda Terapötik Uluslararası Düzeltme Oranına Ulaşmak için Gerekli Warfarin Doz ve Süresi

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          Abstract

          Objective:

          The purpose of this study was to analyze the difference in duration of anticoagulation and dose of warfarin required to reach a therapeutic international normalized ratio [(INR) of 2 to 3] in patients with hypercoagulable conditions as compared to controls. To our knowledge, this study is the first in the literature to delineate such a difference.

          Materials and Methods:

          A retrospective chart review was performed in a tertiary care hospital. The total study population was 622. Cases (n=125) were patients with a diagnosis of a hypercoagulable syndrome who developed venous thromboembolism. Controls (n=497) were patients with a diagnosis of venous thromboembolism in the absence of a hypercoagulable syndrome and were matched for age, sex, and race.

          Results:

          The total dose of warfarin required to reach therapeutic INR in cases was higher (50.7±17.6 mg) as compared to controls (41.2±17.7 mg). The total number of days required to reach therapeutic INR in cases was 8.9±3.5 days as compared to controls (6.8±2.9 days). Both of these differences were statistically significant (p<0.001).

          Conclusion:

          Patients with hypercoagulable conditions require approximately 10 mg of additional total warfarin dose and also require, on average, 2 extra days to reach therapeutic INR as compared to controls.

          Translated abstract

          Amaç:

          Bu çalışmanın amacı kontrollerle karşılaştırıldığında hiperkoagülabilite durumları olan hastalarda terapötik uluslararası düzeltme oranında (INR) 2 ile 3 aralığına ulaşmak için gerekli warfarin doz ve antikoagülan süresindeki farklılığı analiz etmektir. Bildiğimiz kadarıyla; bu farklılığı tarifleyen literatürdeki ilk çalışmadır.

          Gereç ve Yöntemler:

          Retrospektif dosya taraması 3. basamak hastanede yapıldı. Toplam çalışmaya alınan hasta sayısı 622 idi. Venöz tromboembolizmi olan bu hastalardan 125’inin hiperkoagülabilite sendromu olup yaş, cins ve etnik kökeni aynı 497 kontrol hastasında hiperkoagülabilite sendromu yoktu.

          Bulgular:

          Hastalarda terapötik INR’ye ulaşmak için gerekli total warfarin dozu (50,7±17,6 mg) kontrollerin dozu (41,2±17,7 mg) ile karşılaştırıldığında yüksekti. Terapötik INR’ye ulaşmak için gerekli total gün sayısı hastalarda 8,9±3,5 gün olup kontrollerde 6,8±2,9 gün idi. Her iki karşılaştırmada da istatistiksel farklılık anlamlı bulundu (p<0,001).

          Sonuç:

          Hiperkoagülabilite durumları olan hastalarda terapötik INR’ye ulaşmak için kontrollere göre yaklaşık 10 mg ek total warfarin dozu ve ortalama 2 ek gün gereklidir.

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          Most cited references15

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          Systematic overview of warfarin and its drug and food interactions.

          Warfarin is a highly efficacious oral anticoagulant, but its use is limited by a well-founded fear of bleeding. Drug and food interactions are frequently cited as causes of adverse events with warfarin. We provide an updated systematic overview of the quality, clinical effect, and importance of these reported interactions. MEDLINE, TOXLINE, IPA, and EMBASE databases from October 1993 to March 2004. Database searches combined the keyword warfarin with drug interactions, herbal medicines, Chinese herbal drugs, and food-drug interactions. Eligible articles contained original reports of warfarin drug or food interactions in human subjects. Non-English articles were included if sufficient information could be abstracted. Reports were rated independently by 2 investigators for interaction direction, clinical severity, and quality of evidence. Quality of evidence was based on previously validated causation criteria and study design. Of 642 citations retrieved, 181 eligible articles contained original reports on 120 drugs or foods. Inter-rater agreement was excellent, with weighted kappa values of 0.84 to 1.00. Of all reports, 72% described a potentiation of warfarin's effect and 84% were of poor quality, 86% of which were single case reports. The 31 incidents of clinically significant bleeding were all single case reports. Newly reported interactions included celecoxib, rofecoxib, and herbal substances, such as green tea and danshen. The number of drugs reported to interact with warfarin continues to expand. While most reports are of poor quality and present potentially misleading conclusions, the consistency of reports of interactions with azole antibiotics, macrolides, quinolones, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, selective serotonin reuptake inhibitors, omeprazole, lipid-lowering agents, amiodarone, and fluorouracil, suggests that coadministration with warfarin should be avoided or closely monitored. More systematic study of warfarin drug interactions in patients is urgently needed.
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            Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

            Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established. To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy. Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash. Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included. Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events. Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, chi(2)(5) = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P =.004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86). The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.
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              Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition.

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                Author and article information

                Journal
                Turk J Haematol
                Turk J Haematol
                TJH
                Turkish Journal of Hematology
                Galenos Publishing
                1300-7777
                1308-5263
                December 2016
                1 December 2016
                : 33
                : 4
                : 299-303
                Affiliations
                [1 ] Wayne State University, Henry Ford Health System, Clinic of Internal Medicine, Detroit, USA
                [2 ] Weill Cornell University, Hamad Medical Corporation, Clinic of Internal Medicine, Doha, Qatar
                [3 ] Nishtar Hospital, University of Health Science, Multan, Pakistan
                [4 ] Wayne State University, Henry Ford Health System, Clinic of Hematology-Oncology, Detroit, USA
                Author notes
                * Address for Correspondence: Wayne State University, Henry Ford Health System, Clinic of Internal Medicine, Detroit, USA Phone: +1-313-482-8768 E-mail: shahzaib.nabi@ 123456ucdenver.edu
                Article
                1846
                10.4274/tjh.2015.0271
                5204184
                27093959
                c53909cb-b8b0-4866-b93a-62161e9f1d72
                © Turkish Journal of Hematology, Published by Galenos Publishing.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 July 2015
                : 6 October 2015
                Categories
                Research Article

                international normalized ratio,warfarin,hypercoagulable conditions,venous thromboembolism

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