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Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients

2008; Elsevier BV; Volume: 6; Issue: 6 Linguagem: Inglês

10.1111/j.1538-7836.2008.02974.x

1538-7933

Ellen Hatch, Hilary Wynne, Peter Avery, Mia Wadelius, Farhad Kamali,

Hormonal Regulation and Hypertension

Journal of Thrombosis and HaemostasisVolume 6, Issue 6 p. 1038-1040 Free Access Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients E. HATCH, E. HATCH School of Clinical and Laboratory Sciences Institute for Ageing and HealthSearch for more papers by this authorH. WYNNE, H. WYNNE Institute for Ageing and Health School of Clinical Medical SciencesSearch for more papers by this authorP. AVERY, P. AVERY School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne, UKSearch for more papers by this authorM. WADELIUS, M. WADELIUS Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, SwedenSearch for more papers by this authorF. KAMALI, F. KAMALI School of Clinical and Laboratory Sciences Institute for Ageing and HealthSearch for more papers by this author E. HATCH, E. HATCH School of Clinical and Laboratory Sciences Institute for Ageing and HealthSearch for more papers by this authorH. WYNNE, H. WYNNE Institute for Ageing and Health School of Clinical Medical SciencesSearch for more papers by this authorP. AVERY, P. AVERY School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne, UKSearch for more papers by this authorM. WADELIUS, M. WADELIUS Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, SwedenSearch for more papers by this authorF. KAMALI, F. KAMALI School of Clinical and Laboratory Sciences Institute for Ageing and HealthSearch for more papers by this author First published: 14 April 2008 https://doi.org/10.1111/j.1538-7836.2008.02974.xCitations: 3 Farhad Kamali, Wolfson Unit of Clinical Pharmacology, Claremont Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.Tel.: +44 191 2228043; fax: +44 191 2225827.E-mail: farhad.kamali@ncl.ac.uk AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat The anticoagulation response to warfarin is influenced by a number of genetic and environmental factors. Two major genes affect warfarin dose requirements. The gene that encodes CYP2C9, the main enzyme responsible for S-warfarin metabolism, is highly polymorphic; two common allelic variants, CYP2C9*2 and CYP2C9*3, have been associated with low dose warfarin requirements and increased risk of bleeding [1]. Vitamin K epoxide reductase (VKOR) is the pharmacological target for warfarin. Polymorphisms in the VKOR complex subunit 1 (VKORC1) gene have been demonstrated to contribute to inter-individual differences in warfarin dose requirement, with (-1639) GG genotype patients requiring a significantly higher daily dose of warfarin than GA and AA genotypes to achieve the same target International Normalized Ratio (INR) [2]. We recently demonstrated that the factors of patient age, height, and CYP2C9 and VKORC1 genotypes account for over half the variability in warfarin dose requirement in a cohort of British Caucasian patients [2]. A dosing algorithm was developed based on the regression model containing these factors. In the search for a wider applicability of the dosing algorithm, we set out to test its accuracy in predicting warfarin dose requirements in a cohort of Swedish Caucasian patients. We also examined the influence of concomitant use of drugs known to influence warfarin dose requirement on the accuracy of the predicted dose. Data were obtained on CYP2C9 and VKORC1 polymorphisms, and demographic information relating to an anonymized cohort of Swedish Caucasian patients, with a target INR of 2–3 and with stable maintenance warfarin dose, attending the anticoagulation clinic at Uppsala University Hospital, Uppsala, Sweden. The genotype information on this group of patients was available as part of an earlier study [3, 4]. A patient was deemed as stable when his/her daily dose requirement had remained unchanged for at least the previous three visits to the clinic. Warfarin dose requirement for each patient was estimated using the published pharmacogenetic-based dosing algorithm [2]. Statistical analysis of data was performed using Minitab 14 (Coventry, UK). Regression analysis between actual and estimated warfarin dose was assessed for the cohort as a whole and for those patients taking no interacting drugs. Concurrent drug use was input in the multiple regression analysis. A P value of <0.05 was considered as statistically significant. Data were analyzed from 88 patients (65 males) on stable warfarin doses aged 48–86 years, with a mean ± SD height of 175.7 ± 77 cm and weight of 81.9 ± 13.8 kg. Eight of the patients were smokers. The primary indication for anticoagulation was atrial fibrillation in 68 patients, pulmonary embolism/deep vein thrombosis in five patients and other thromboembolic disorders in 15 patients. Twenty-seven (16 males) were taking drugs that have the potential to increase the action of warfarin. These included alloprurinol (four), aspirin (eight), amiodarone (four), atrovastatin (one), diclofenac (one), disopyramide (two), fluvastatin (six), naproxen (two), omeprazole (one), paracetamol (four), propafenone (one), simvastatin (11), and tolterodine (one). There were two patients taking carbamazepine, which is known to reduce the action of warfarin. There was a good relationship between the actual and the predicted warfarin dose in the 61 patients taking no interacting drugs (r2 = 53.3%; P < 0.05). The regression equation is daily dose = −0.228 + 1.16 × estimated dose. The r2 fell to 43.9% when all 88 patients were considered. In both cases, the intercept was not significantly different from 0, and the slope did not differ from 45°. There was no discernible pattern of dose requirement for those patients taking drugs that increase the action of warfarin (Fig. 1A). With the exception of amiodarone and carbamazepine, none of the interacting drugs made a significant impact on warfarin dose in the regression model. The data for those patients taking amiodarone lie below the regression line and the data for those taking carbamazepine lie above it. The inclusion of amiodarone in the regression model for dose significantly lowered the daily warfarin dose requirement by 0.38 mg (P = 0.03). Conversely, the inclusion of carbamazepine increased the dose requirement by 0.66 mg (P < 0.005). Smoking had no influence on warfarin dose in the regression model. The relationship between actual and predicted daily warfarin dose requirements in patients not taking drugs that interact with warfarin is shown in Fig. 1B. In this subset of patients, there were two outliers whose estimated daily warfarin doses of 6.3 and 6.5 mg were considerably lower than their respective actual daily maintenance doses of 11.0 and 10.5 mg. Figure 1Open in figure viewerPowerPoint (A) Daily dose requirement and estimated dose requirement for all patients. (B) Daily dose requirement and estimated dose requirement for patients not prescribed drugs known to interact with warfarin. We were the first to report on a pharmacogenetic-based warfarin dosing algorithm [2]. A number of similar dosing algorithms have since been reported [5-9]. Although our pharmacogenetic-based dosing algorithm was previously validated using an unrelated cohort of British Caucasian patients [2], its application to patient populations elsewhere and with similar ethnic origin had not been tested. The results of this study showed that our dosing algorithm could be used to predict warfarin daily maintenance dose requirement in an unrelated European Caucasian cohort with a fair degree of accuracy. Our algorithm was derived from data on patients with a stable maintenance dose and who were not taking drugs that interact with warfarin. Therefore, warfarin dose estimation did not allow for the concomitant use of interacting drugs. Predictably, there was some discordance between the actual and predicted doses in a small number of patients (n = 6) in the cohort who were taking drugs that affected warfarin anticoagulation response; the actual mean warfarin daily doses for patients taking amiodarone and carbamazepine were 3.5 ± 1.0 and 7.3 ± 2.3 mg, respectively, compared to their respective estimated mean daily doses of 5 ± 1.2 and 4.2 ± 0.1 mg. There were two outliers whose estimated warfarin dose, in the absence of interacting drugs, was considerably lower than their actual daily maintenance dose. Our dosing algorithm, which included factors of CYP2C9 and VKORC1 genotypes and patient age and height, explained about 55% of the inter-individual variability in warfarin dose requirements [2], with 45% of the variability remaining unexplained. Other factors could explain the discord between the estimated and actual warfarin doses for the two outliers, such as rare polymorphisms in CYP2C9, VKORC1, and the less prominent genes that mediate the action of warfarin [10, 11], as well as other novel genes and environmental factors, such as dietary vitamin K. The r2 value of 53.3% for the Swedish cohort is similar to the value of 55% derived in the British cohort, implying that the identified factors exert the same influence in both of these Caucasian populations. Although, as explained earlier, our dosing algorithm does not wholly explain the inter-individual differences in warfarin dose requirements, its use could improve the accuracy of dosing, and therefore reduce the uncertainty in anticoagulation response in patients with thromboembolic disorders. While the study results show that, in general, our pharmacogenetic-based dosing algorithm can reliably estimate warfarin maintenance dose for a Swedish Caucasian population, its wider applicability to other non-Caucasian patient populations is uncertain. Currently, the International Warfarin Pharmacogenetics Consortium (IWPC), representing an international collaboration between PharmGKB and 21 research groups across four continents, is creating a repository of warfarin pharmacogenetics data, including data on CYP2C9 and VKORC1 polymorphisms in 5700 patients. This will help to define a clinically useful dosing algorithm that is relevant across different populations and ethnicities. An individualized pharmacogenetic approach toward the initiation of anticoagulation could offer the possibility of safer treatment by achieving target INR in a shorter time period. This would avoid the underdosing and overdosing, which are so common in current practise [12], and reduce the need for current intensive monitoring within the early stages of therapy. Prospective studies investigating the safety, cost-effectiveness, and utility of a pharmacogenomic approach towards the initiation of anticoagulation therapy are warranted. Acknowledgements E. Hatch was funded by a grant from the UK Department of Health, as part of the prospective study analyzing genetic and environmental factors involved in warfarin dosage requirements. We would like to thank P. Deloukas and L. Y. Chen at the Sanger Institute, Cambridge, UK, for the VKORC1 genotyping of blood samples from Swedish patients. Disclosure of Conflict of Interests The authors state that they have no conflict of interest. References 1 Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717– 9. CrossrefCASPubMedWeb of Science®Google Scholar 2 Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329– 33. CrossrefCASPubMedWeb of Science®Google Scholar 3 Wadelius M, Sorlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, Wadelius C, Melhus H. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 2004; 4: 40– 8. CrossrefCASPubMedWeb of Science®Google Scholar 4 Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, Wallerman O, Melhus H, Wadelius C, Bentley D, Deloukas P. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5: 262– 70. CrossrefCASPubMedWeb of Science®Google Scholar 5 Tham LS, Goh BC, Nafziger A, Guo JY, Wang LZ, Soong R, Lee SC. A warfarin-dosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9. Clin Pharmacol Ther 2006; 80: 346– 55. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 6 Wu A. Use of genetic and nongenetic factors in warfain dosing algorithms. Pharmacogenomics 2007; 8: 851– 61. CrossrefCASPubMedWeb of Science®Google Scholar 7 Zhu Y, Shennan M, Reynolds KK, Johnson NA, Herrnberger MR, Valdes R Jr, Linder MW. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes. Clin Chem 2007; 53: 1199– 205. CrossrefCASPubMedWeb of Science®Google Scholar 8 Carlquist JF, Horne BD, Muhlestein JB, Lappe DL, Whiting BM, Kolek MJ, Clarke JL, James BC, Anderson JL. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis 2006; 22: 191– 7. CrossrefCASPubMedWeb of Science®Google Scholar 9 Millican EA, Lenzini PA, Milligan PE, Grosso L, Eby C, Deych E, Grice G, Clohisy JC, Barrack RL, Burnett RS, Voora D, Gatchel S, Tiemeier A, Gage BF. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood 2007; 110: 1511– 5. CrossrefCASPubMedWeb of Science®Google Scholar 10 Sconce EA, Daly AK, Khan TI, Wynne HA, Kamali F. APOE genotype makes a small contribution to warfarin dose requirements. Pharmacogenet Genomics 2006; 16: 609– 11. CrossrefCASPubMedWeb of Science®Google Scholar 11 Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, Bentley D, McGinnis R, Deloukas P. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 2007; 121: 23– 34. CrossrefCASPubMedWeb of Science®Google Scholar 12 Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690– 8. CrossrefCASPubMedWeb of Science®Google Scholar Citing Literature Volume6, Issue6June 2008Pages 1038-1040 FiguresReferencesRelatedInformation