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      Clinical Application of Pharmacogenetic-Based Warfarin-Dosing Algorithm in Patients of Han Nationality after Rheumatic Valve Replacement: A Randomized and Controlled Trial

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          Abstract

          Background The polymorphisms of VKORC1 and CYP2C9 play increasingly important roles in the inter-individual variability in warfarin dose. This study aimed to evaluate the feasibility of clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality with rheumatic heart disease after valve replacement in a randomized and controlled trial. Methods One hundred and one consecutive patients of Han nationality with rheumatic heart disease undergoing valve surgery were enrolled and randomly assigned to an experimental group (n=50, based on CYP2C9 and VKORC1 genotypes, pharmacogenetic-based “predicted warfarin dose” for 3 days and then was adjusted to INR until stable warfarin maintenance dose) or a control group (n=51, 2.5mg/d for 3 days and then was adjusted to INR until stable warfarin maintenance dose). All included patients were followed for 50 days after initiation of warfarin therapy. The primary end-point was the time to reach a stable warfarin maintenance dose. Results During the follow-up, 84.0% patients in the experimental group and 58.8% patients in the control group received warfarin maintenance dose. Compared with control group, patients in the experimental group had shorter mean time elapse from initiation of warfarin therapy until warfarin maintenance dose (27.5±1.8 d versus 34.7±1.8 d, p<0.001). Cox regression revealed that group (HR for experimental versus control group: 1.568, 95%CI 1.103-3.284) and age were two significant variables related to the time elapse from initiation of warfarin therapy until warfarin maintenance dose. The predicted warfarin maintenance dose was prominently correlated with the actual warfarin maintenance dose (r=0.684, p<0.001). Conclusion: Based on CYP2C9 and VKORC1 genotypes, the pharmacogenetic-based warfarin-dosing algorithm may shorten the time elapse from initiation of warfarin therapy until warfarin maintenance dose. It is feasible for the clinical application of the pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality with rheumatic heart disease after valve replacement.

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          A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin.

          P. Perna, Giovanna D’Andrea, Vincenzo Brancaccio … (2005)
          Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability is largely genetically determined, and it can be only partly explained by genetic variability in the cytochrome CYP2C9 locus. In 147 patients followed from the start of anticoagulation with warfarin, we have investigated whether VKORC1 gene mutations have affected doses of drug prescribed to acquire the target anticoagulation intensity. Two synonymous mutations, 129C>T at Cys43 and 3462C>T at Leu120, and 2 missense mutations, Asp38Tyr and Arg151Gln, were identified. None of these mutations was found to affect the interindividual variability of warfarin prescribed. Finally, 2 common polymorphisms were found, 1173C>T in the intron 1 and 3730G>A transition in the 3' untranslated region (UTR). Regardless of the presence of confounding variables, the mean adjusted dose required of warfarin was higher (6.2 mg) among patients with the VKORC1 1173CC genotype than those of patients carrying the CT (4.8 mg; P = .002) or the TT genotype (3.5 mg; P < .001). In the present setting, VKORC1 and CYP2C9 genetic variants investigated accounted for about a third (r2, 0.353) of the interindividual variability. Genetic variants of the VKORC1 gene locus modulate the mean daily dose of drug prescribed to acquire the target anticoagulation intensity.
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            Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation.

            Jeffrey Anderson, Benjamin Horne, Scott Stevens … (2007)
            Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials. Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P or = 4 (P=0.03). An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.
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              Association of warfarin dose with genes involved in its action and metabolism

              Mia Wadelius, Leslie Chen, Niclas Eriksson … (2006)
              We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C9*2 and/or *3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin. Electronic supplementary material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00439-006-0260-8 and is accessible for authorized users.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Med Sci
                Journal ID (iso-abbrev): Int J Med Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Medical Sciences
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1449-1907
                Publication date Collection: 2012
                Publication date (Electronic): 10 August 2012
                Volume: 9
                Issue: 6
                Pages: 472-479
                Affiliations
                1. Department of Thoracic Cardiovascular Surgery, Xinhua Hospital of Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
                2. Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China.
                3. Department of Emergency Surgery, Ninth People's Hospital of Shanghai Jiaotong University School of Medicine, Shanghai 200072, P.R. China.
                4. Department of Thoracic Surgery, Pulmonary Hospital of Tongji University, Shanghai 200433, P.R. China.
                5. Department of Thoracic Cardiovascular Surgery, Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China.
                6. Department of Thoracic Cardiovascular Surgery, Tongji Hospital of Tongji University, Shanghai 200065, P.R. China.
                Author notes
                ✉ Corresponding author: Prof. ShiTao Cui, bojidefeiying@ 123456sohu.com , or Prof. Ke Fei, drfeike@ 123456yahoo.com.cn ; Dr. Qiang Ji, drjiqiang@ 123456tongji.edu.cn .

                # Contributed equally as the co-first author.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: ijmsv09p0472
                DOI: 10.7150/ijms.4637
                PMC ID: 3427951
                PubMed ID: 22927772
                SO-VID: f259be26-9716-4e63-a9be-0efb70e09235
                Copyright © © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                Date received : 23 May 2012
                Date accepted : 24 July 2012
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Medicine
                Keywords: trial.,pharmacogenetics,rheumatic valve surgery,individualized warfarin therapy
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: trial., pharmacogenetics, rheumatic valve surgery, individualized warfarin therapy

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