A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). WebSpecialties: At Twin Boro Physical Therapy, we aim to provide our patients with a very active approach to Telehealth PT through our one-on-one sessions. Use 65% of the standard initial dose. Post hoc pairwise comparisons were made using Tukeys HSD. Helenowski, I.B. presents characteristics of the 302 study participants who remained after application of these criteria. ). Despite the introduction of direct oral anticoagulants in 2010, warfarin remains the most widely prescribed anticoagulant We specifically chose a grouped analysis because our outcome variables reflect how often and with what magnitude a participants anticoagulation quality is perturbed from a stable baseline rather than reflecting directionality of that perturbation. CYP4F2 genetic variant alters required warfarin dose. AMIO, amiodarone; INB, CYP2C9inhibitors; IND, CYP2C9inducers; MET, metronidozole; SMX, suflamethoxazole. Unlike either the COAG or EU-PACT trial or the trial underway in Asians, GIFT is powered to detect a difference in thrombotic and major bleeding events with genotype-guided dosing.42 Data from GIFT may be helpful in resolving the discrepancy between similar TTR between dosing strategies in COAG, but a signal for more adverse outcomes with clinically-guided dosing. Boxandwhisker plots are shown. WebWhat is new and conclusion: Since 60% of inter-individual variability in warfarin dose/response is due to other factors (many of which are non-genetic), expectations of eliminating this variability simply by CYP2C9/VKORC1 genotyping are over-optimistic and efforts cost-ineffective. S4 They found that pharmacogenetic-guided dosing led to significantly fewer out of range INRs at 1 and 3 months and greater time in therapeutic range (TTR) over the same time periods (all p < 0.001). Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, Baird MF, Acton RT. Warfarin is a drug with narrow therapeutic index; thus, a small change in its plasma levels may result in concentration dependent adverse drug reactions or therapeutic failure. Center for Pharmacogenomics, Huang, S.M. The maximum perturbation is defined by peak INR after initiation of a CYP2C9 inhibitor, and by trough INR after initiation of a CYP2C9 inducer. Taken together, these results suggest that CYP2C9/VKORC1 genotype influences INR variability but not TTR. Feasibility of implementing a comprehensive warfarin pharmacogenetics service. Epub 2011 Sep 7. Wolf, W.A. Clinical and demographic features were recorded. 2 Division of Cardiology, Importantly, CYP2C9*2 and CYP2C9*3 did not have a significant association with warfarinrelated bleeding events in this African ancestry population. Celecoxib Therapy and. Multiple candidate gene studies have consistently demonstrated that the VKORC1 and CYP2C9 genotypes influence the inter-patient variability in warfarin dose requirements, together explaining 10% to 45% of the overall variance depending on the population studied and genotypes detected.1618 This has been confirmed by several genome-wide association studies (GWAS).12,19,20 The CYP4F2 SNP explains approximately 1% of the overall variability in warfarin dose requirements.12,20 Specific effects of these and other variants on dose are shown in Table 3. clinical algorithm), there were no differences in TTR. and M.H.). We were also unable to assess adherence to warfarin regimen, which may be a source of INR variability. Hernandez W, Gamazon ER, Aquino-Michaels K, Patel S, O'Brien TJ, Harralson AF, et al. Amiodarone analogdependent effects on CYP2C9mediated metabolism and kinetic profiles. However, in the context of genome or exome sequencing, the other CYP2C9 variants likely would be available. What is the impact of cytochrome P450 (CYP)2C9interacting drug exposure on longterm measures of warfarin anticoagulation when CYP2C9 andvitamin K epoxide reductase complex (VKORC)1 genotypes are taken into account? Carriers are defined as those with one (e.g. Warfarin Therapy and the Genotypes CYP2C9 and VKORC1 3 states that drugs that inhibit or induce CYP2C9, CYP1A2, and/or CYP3A4 have the potential to alter the effect (INR) of warfarin by altering the exposure of warfarin. 3 First, our sample size lacked power to discern associations with less common genotype groups, such as highly sensitive responders. There were no significant differences in clinical characteristics including age, sex, and body mass index among the three groups (Table Our findings emphasize the importance of considering an expanded range of drug interactions in pharmacogenomic studies of warfarin and potentially other medications. The study is estimated to be completed in 2014. 23 2 Variants shown in bold text were not included in either the COAG or EU-PACT study. 7 Genotyping methods for CYP2C9 and VKORC1 variants are described in the Supporting Information and Table Moreover, among African Americans, genotype-guided dosing was associated with a lower percentage TTR compared to the clinical algorithm arm (35% versus 43.5%) and a higher percent of time with an INR >3 (27% versus 22.5%). because some providers received clinical decision support that may have altered prescribing behavior. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Recommendation. Ormond, K.E. Department of Pharmacology, Hence, although CYP2C9/VKORC1 genotype was found to be a significant predictor of INR variability, overall it did not predict how often INR values were in the therapeutic range. Investigators E. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. Schelleman H, Chen J, Chen Z, Christie J, Newcomb CW, Brensinger CM, et al. Kumar, V. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. However, they do not include many of the variants important for African Americans and do not perform as well in African Americans compared to Europeans.7,26 The www.warfarindosing.org algorithm also includes is a formula for dose refinement so that therapy can be adjusted based on INR response to previous doses.27. The genotype of VKORC1 and CYP2C9 for all the patients was analyzed using PCR and biochip technology. 20 Stated another way, is it reasonable to ignore the warfarin pharmacogenetic data if it is available? A common variant, VKORC1, c.-1639G>A, is associated with an increased sensitivity to warfarin and lower dose requirements. In contrast to the EU-PACT results, the COAG trial showed no differences in percent TTR in the initial 4 weeks of therapy between genotype-guided and clinically-guided dosing algorithms (45% in both arms). 30 In conclusion, we observed that exposure to CYP2C9interacting drugs was more predictive of longterm warfarin anticoagulation efficacy and stability than CYP2C9/VKORC1 genotype in a selfidentified white population. The fact that many genotypes associated with lower dose requirements in African Americans were not accounted for in the COAG trial likely explains the greater time outside TTR and greater number of INRs over 3 with genotype-guided dosing in this population. This yielded 34 candidate CYP2C9interacting drugs (Tables We examined exposure to CYP2C9interacting drugs by counting the number of unique medications taken during warfarin therapy. ), MD009217 (M.A.P. Disclaimer. Thus, using warfarin pharmacogenetic data, if it is only the 3 variants above, should be avoided in African Americans, even when the data are available. CYP2C9 PM. Variants important for warfarin dosing are better defined for Asian populations. Hummel, M.A. Regional differences in anticoagulation care between the US and Europe may have also played a role, and such differences have certainly been evident in other cardiovascular trials. Two recent meta-analyses also provide insights. No additional IRB approval was required for this study. S2 Differential genotype dependent inhibition of CYP2C9 in humans, Genetic variants associated with warfarin dose in AfricanAmerican individuals: a genomewide association study, http://creativecommons.org/licenses/by-nc/4.0/, https://druginteractions.medicine.iu.edu/MainTable.aspx, https://www.ncbi.nlm.nih.gov/pubmed/28520347. Niinuma Y, Saito T, Takahashi M, Tsukada C, Ito M, Hirasawa N, Hiratsuka M. Functional characterization of 32 CYP2C9 allelic variants. Recommendation. Shahin MH, Khalifa SI, Gong Y, Hammad LN, Sallam MT, El Shafey M, et al. The CYP2C9 genotype has also been correlated with risk for over-anticoagulation and hemorrhage during warfarin therapy. A common variant, VKORC1, c.-1639G>A, is associated with an increased sensitivity to warfarin and lower dose requirements. The 2011 CPIC guidelines are freely available through the Pharmacogenomics Knowledgebase website (www.PharmGKB.org). CYP2C9 IM. Illinois, , Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study. Sham, Y.Y. wrote the manuscript. International normalized ratio (INR) differences before and after cytochrome P450 (CYP)2C9interacting drug exposure. S4 . Herein, we review the evidence for genetic associations with warfarin response, evaluate the design and results from clinical trials, and discuss evidence needed to further define the role for genotyping to guide warfarin dosing. Warfarin therapy and VKORC1 and CYP genotype In: Pharmacogenetics of warfarin elimination and its clinical implications, The largest prospective warfarintreated cohort supports genetic forecasting. However, a comparative effectiveness trial called COUMAGEN-II was published in 2012, and was the largest warfarin pharmacogenetics study at that time. INRvarA and INRvarB are measures of INR variability without regard for distance from the therapeutic range, whereas TTRa and TTRb rely only on whether INR values are within the therapeutic range. The second issue is whether warfarin pharmacogenetic data should be utilized if already available to the patient or in their electronic health record. The CYP4F2 V433M (rs2108622) SNP was first identified as a contributor to warfarin dose requirements in Europeans, with variant allele homozygotes requiring higher doses.11 The association was subsequently replicated in Asians, but not in African Americans, in whom the variant allele is much less common (Table 1).12,13 In functional studies, the 433M allele led to reduced hepatic concentrations of CYP4F2 and decreased vitamin K metabolism.14 As a consequence, variant allele carriers are expected to have higher vitamin K concentrations and require higher warfarin doses to inhibit vitamin K dependent clotting factor activation. that explain a significant amount of variance in stable warfarin dose. Several studies were conducted early on to help identify the potential clinical utility of warfarin pharmacogenetic testing, with mixed results, leading to the speculation that they were too small to draw meaningful conclusions. Telehealth physical therapy may be considered a more efficient and cost effective option for many by reducing travel time, increasing appointment flexibility, and minimizing missed work and school Stergiopoulos K, Brown DL. Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, et al. The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 and *3, are also associated with lower dose requirements. 2 19 We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9interacting drugs on longterm measures of warfarin anticoagulation. All variants tested in the cohort were in HardyWeinberg equilibrium and exhibited minor allele frequencies (Table Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a library, NLM provides access to scientific literature. Kumar, V. 3 USA, 4 The data suggesting improved effectiveness in dose prediction with use of genetic information, and the positive results from the comparative effectiveness trial COUMAGEN-II led to great anticipation of the results of several randomized controlled trials. 11 Verhoef TI, Redekop WK, Daly AK, van Schie RM, de Boer A, Maitland-van der Zee AH. Our study was designed to analyze participants in whom longterm warfarin anticoagulation could be assessed without sacrificing the power of our study, and an exclusion threshold of 14 INR measurements satisfied this goal. , government site. The risk for bleeding is highest in the initial 3 to 6 months following warfarin initiation, but continues with chronic therapy.6,21 In a meta-analysis of 22 studies including over 6,000 patients, the CYP2C9*2, *3, and VKORC1 1639A alleles were associated with an increased risk for over-anticoagulation, defined as an INR>4.22 Interestingly, the association between VKORC1 1639G>A genotype and over-anticoagulation was evident only in the initial month of therapy, whereas the risk conferred by CYP2C9 extended beyond this period, suggesting that the effects of the VKORC1 genotype are realized early on while the influence of CYP2C9 genotypes persists into chronic therapy. Yasuda, S.U. Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues: Meta-analysis of Randomized Clinical Trials. Bounds of the boxandwhisker plots are discussed in the Methods section. ). Abstract. Use 20% of the standard initial dose. Figure An official website of the United States government. Chisholm, R.L. 1 , Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, et al. Ninetysix were excluded because they had fewer than 14 INR measurements during the study period, and 3 were excluded because they were not genotyped successfully for CYP2C9 or VKORC1. Federal government websites often end in .gov or .mil. The VKORC1 and CYP2C9 genotypes are associated with overanticoagulation during initiation of warfarin therapy in children - BISS - 2013 - Journal of Thrombosis and Haemostasis - Wiley Online Library. So use of a clinical algorithm is not the only explanation for the differences in findings of the COAG and warfarin EU-PACT studies. Northwestern University Feinberg School of Medicine, The primary genes contributing to warfarin dose requirements are vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9). National Library of Medicine and Mol Diagn Ther. , WebFounded in 1998, Professional Physical Therapy is a leading provider of physical therapy and sports medicine services with clinic locations throughout New England. NUgene recruitment procedures and participant information have been described elsewhere. Zhang, L. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. 6 Use 65% of the standard initial dose. Figure *2/*2) copies of the variant allele. To quantify the impact of starting a CYP2C9interacting drug on INR, we examined INR values determined within a time period around the start date of a concurrent medication and then characterized the trend of INRs before and after starting the drug (see Methods for definition of the time period and parameters that were calculated). A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. 9 Pediatr Blood Cancer. This is likely an important difference between the two trials, particularly since there was suggestion of harm in the African Americans in COAG. The COAG trial had a diverse population, consisting of nearly 30% African Americans, while EU-PACT enrolled a homogeneous European population. Dean, L. There are two major sets of guidelines regarding warfarin pharmacogenetics, although both were published prior to publication of the most recent randomized controlled trials. Peter, I. Phenotype/diplotype. Accessibility WebWarfarin targets VKORC1, an enzyme involved in vitamin K recycling. 2 , WebThe DPWG (2017) Recommendations for Warfarin and CYP2C9 and VKORC1 Genotype. INR values obtained on the same day were not averaged for this analysis to lower the risk of masking shortlived peaks and troughs. Illinois, Telehealth physical therapy may be considered a more efficient and cost effective option for many by reducing travel time, increasing appointment flexibility, and minimizing missed work and school WebSpecialties: Physical therapy, occupational therapy, sports medicine, post-surgery care, orthopedic therapy, vestibular therapy, balance dysfunctions, hand therapy, pain management, neurokinetic therapy, SFMA, work compensation, lymphedema therapy, motor vehicle accidents. Dutch Pharmacogenetics Working Group (DPWG). & Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, et al. includes concurrent fluvastatin use. Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research. In other words, it becomes a question of non-inferiority, not superiority which many argue is needed to warrant ordering a genetic test. Neither TTRa nor TTRb was significantly associated with CYP2C9/VKORC1 genotype. and in vivo Therapeutic Recommendations based on Genotype. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ Group R-CS. 29 S.A., M.S.H., L.J.R.T, M.A.P., and A.L.G. Emergency hospitalizations for adverse drug events in older Americans. The FDA has published dosing and administration recommendations for warfarin based on VKORC1, CYP4F2, and CYP2C9 genotypes. 7 McLeod, H.L. . A pharmacogenetic versus a clinical algorithm for warfarin dosing, A randomized trial of genotypeguided dosing of warfarin, Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin, Estimation of the warfarin dose with clinical and pharmacogenetic data, Integration of genetic, clinical, and INR data to refine warfarin dosing, Genetic variation among 82 pharmacogenes: the PGRNseq data from the eMERGE network. Oneway ANOVA was then done with subgroups defined by combined genotype and medication exposure. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. and Recently, genetic variation in the CYP4F2 gene, and a variant near the CYP2C gene cluster, rs12777823, have been associated with influencing warfarin therapy. WebThe cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genes have recently been determined to be associated with warfarin dose requirements, with reduced doses of this drug being required in patients with the variant CYP2C9*2, CYP2C9*3, or VKORC1 -1639A allele. . Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Bethesda (MD): National Center for Biotechnology Information (US); 2012. In this study, the pharmacogenetic algorithm arm had significantly greater TTR than the clinical algorithm at 4 weeks, but not at 12 weeks. 21 ). A complete description of these variables is found in the Supporting Information. BMI, body mass index; CYP, cytochrome P450;HS, highly sensitive; NL, normal; SN, sensitive; VKORC,vitamin K epoxide reductase complex. S8 12 The possibility of population stratification confounding results of warfarin pharmacogenomics was evident in the COAG trial, in which 27% of the study population was categorized as African American. This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of Federal government websites often end in .gov or .mil. WebWarfarin targets VKORC1, an enzyme involved in vitamin K recycling. , S1 Celecoxib Therapy and. ) found that although the maximum change in INR shortly after starting each CYP2C9interacting drug was consistent with that drugs identity as an inhibitor or inducer, the difference in average INR shortly before and after starting that drug was not. WebVKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. We also sought evidence of drugdruggene interactions in this study population. Zhang, N. We identified drugs with potential CYP2C9mediated interactions with warfarin from two sources: the FDA label for warfarin, and the Flockhart Table of Drug Interactions. Chicago WebWarfarin targets VKORC1, an enzyme involved in vitamin K recycling. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. S3 CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. and transmitted securely. The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 and *3, are also associated with lower dose requirements. 22 The .gov means its official. Genotypepredicted warfarin responder groups were determined by cytochrome P450 (CYP)2C9 *1, *2, and *3 and VKORC1 c. 1639 G>A genotype. USA, 2 S2 The Cytochrome P450 Superfamily. Shaw K, Amstutz U, Hildebrand C, Rassekh SR, Hosking M, Neville K, Leeder JS, Hayden MR, Ross CJ, Carleton BC. Tracy, T.S. 8600 Rockville Pike sharing sensitive information, make sure youre on a federal Of those 11,416 participants, 401 met all inclusion criteria for our study. Our findings emphasize the importance of considering drug interactions in pharmacogenomic studies. As a service to our customers we are providing this early version of the manuscript. ) in accordance with the FDA drug label for warfarin. The https:// ensures that you are connecting to the Oneway analysis of variance (ANOVA) and 2 tests were utilized to compare descriptive variables, such as age and sex, across combined genotype categories (normal responder, sensitive responder, and highly sensitive responder), and medication exposure categories (0, 1, 2+). support the conclusion that any concurrent CYP2C9interacting drug exposure adversely affects a participants anticoagulation quality. 11 Our study cohort did not contain any participants who were genotyped as *3/*3 for CYP2C9. Chicago Before The 2017 Update of the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing, provides warfarin dosing recommendations for adults with and without African ancestry, and also for pediatric patients (see Therapeutic Recommendations). Among this subgroup, there were participants with CYP2C9 genotypes *1/*1 (n=75), *1/*2 (n=17), *1/*3 (n=10), and *2/*2 (n=3). , Dutch Pharmacogenetics Working Group (DPWG). Table 4 outlines the design and study population for each study. Flow diagram illustrating inclusion and exclusion criteria. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. The VKORC1 and CYP2C9 genotypes are associated with overanticoagulation during initiation of warfarin therapy in children - BISS - 2013 - Journal of Thrombosis and Haemostasis - Wiley Online Library. In addition, the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) has published recommendations for the initial standard dose of warfarin. The EU-PACT investigators reported a significant improvement in the primary endpoint of percent of time within the therapeutic INR range with genotype-guided dosing compared to standard dosing over the initial 12 weeks of therapy (67% versus 60%, p<0.001). In contrast, the data suggest that using just VKORC1 1639 and CYP2C9 *2 and *3, may be harmful in African Americans, likely because this approach ignores important genetic variants in the CYP2C9 cluster that lead to lower warfarin doses. VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. bleeding and thrombosis), which are more important for evaluating the benefit of warfarin pharmacogenomics. , 18. In this case, if a genotype associated with reduced warfarin dose requirements in African Americans is present, it seems reasonable to use lower than usual doses. Clinical and demographic features were recorded. The Clarification of Optimal Anticoagulation through Genetics (COAG) and European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trials were randomized, multi-center, controlled trials designed to assess the clinical utility of genotype-guided warfarin dosing, with results from each published in late 2013.29,30 WebThe cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. We also investigated the influence of interacting drugs in the subgroup without VKORC1 variants (n=105). Kornreich, R. The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 and *3, are also associated with lower dose requirements. The high frequency of variant CYP2C9 and VKORC1 alleles in AJ and SJ individuals indicates that clinical testing of these genes is warranted among individuals initiating warfarin therapy, as recently recommended by a Food and Drug Administration Advisory Committee (see Web Resources). , Use 65% of the standard initial dose. The other meta-analysis included warfarin only, and utilized 7 clinical trials that enrolled 1,910 patients.37 They considered control arms that were fixed dosed separately from non-fixed dose and found that the trials with fixed dosing of warfarin as the comparator (which essentially represents usual care in most settings) revealed significant improvements in TTR with genotype-guided dosing. 2 List of cytochrome P450 (CYP)2C9interacting drugs selected for this study (number of participants exposed given in parentheses).
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