Warfarin: The End or the End of One Size Fits All Therapy?

Pirmohamed, Munir

doi:10.3390/jpm8030022

Cited by 28 publications

(30 citation statements)

References 55 publications

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“…To date, more than 60 variant alleles in CYP2C9 have been described and the most common allele of CYP2C9 is ⁎ 1, usually considered as the wild-type genotype. CYP2C9 ⁎ 2 and CYP2C9 ⁎ 3 have been examined with respect to warfarin dosing ( Flora et al., 2017 ; Johnson et al., 2017 ; Pirmohamed, 2018 ) and it is found that patients who have one or two copies of CYP2C9 * 2 or * 3 require lower warfarin dose to achieve anticoagulation effect than those with CYP2C9 * 1 homozygous and have a greater risk of bleeding during therapy ( Johnson et al., 2011 ; Takeuchi et al., 2016 ; Cullell et al., 2018 ). Furthermore, warfarin is a specific inhibitor of the vitamin K epoxide reductase, encoded by the vitamin K epoxide reductase complex subunit 1 ( VKORC1 ) gene.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population

et al. 2020

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Objectives: To verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics. Methods: According to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. The basic data and clinical information of 360 elderly people were collected for statistical analysis and the genotypes of VKORC1-G1639A and CYP2C9 were detected by Sanger sequencing. The new algorithm of the elder pharmacogenetics warfarin dosing was obtained by stepwise multiple regression. The determination coefficient (R2), root mean squared error (RMSE), and the proportion of the predicted value within the true value range of ±20%(20%-p) were used to evaluate the accuracy of the IWPC algorithm and the new algorithm. Results: Among the three different age groups, the warfarin stable dose predictive accuracy of IWPC algorithm was the lowest in the elderly patients above 65-year-old. In this study, the important factors influencing the stable dose of warfarin in the elderly Han-Chinese were height, weight, body surface area, serum creatinine level, amiodarone usage, CYP2C9 (*1*2, *1*3), and VKORC1 (GG/GA) genotypes. By means of stepwise multiple regression analysis, we established a new elder warfarin dosing algorithm (R 2 =0.3714) containing height, creatinine, amiodarone usage, CYP2C9 (*1*2 or *1*3), and VKORC1 (GA or GG) genotypes. The prediction accuracy and clinical availability of the Elderly algorithm was significantly better than that of IWPC algorithm verified by RMSE, R2, and (20%-p) methods.

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Section: Introductionmentioning

confidence: 99%

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population

et al. 2020

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“…However, their current high price restricts access to them in many healthcare systems, and concerns over long term adherence [ 152 ], as well as patient choice, mean they are not suitable for all patients. Interestingly, bleeding risk appears equivalent between DOACs and warfarin in patients who have no VKORC1 / CYP2C9 warfarin risk alleles [ 153 ] or their anticoagulation centre-based TTR is ≥ 66% [ 154 ], and thus anticoagulant stratification based on VKORC1 / CYP2C9 genotypes has been posited [ 155 ]. Moreover, no DOAC is indicated following mechanical heart valve surgery or in those with a creatinine clearance < 15mL/min; thus, further research into the utility of warfarin PGx in these specific settings is warranted.…”

Section: Warfarinmentioning

confidence: 99%

Pharmacogenomics for Primary Care: An Overview

Rollinson

Turner

Pirmohamed

2020

Genes

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Most of the prescribing and dispensing of medicines happens in primary care. Pharmacogenomics (PGx) is the study and clinical application of the role of genetic variation on drug response. Mounting evidence suggests PGx can improve the safety and/or efficacy of several medications commonly prescribed in primary care. However, implementation of PGx has generally been limited to a relatively few academic hospital centres, with little adoption in primary care. Despite this, many primary healthcare providers are optimistic about the role of PGx in their future practice. The increasing prevalence of direct-to-consumer genetic testing and primary care PGx studies herald the plausible gradual introduction of PGx into primary care and highlight the changes needed for optimal translation. In this article, the potential utility of PGx in primary care will be explored and on-going barriers to implementation discussed. The evidence base of several drug-gene pairs relevant to primary care will be outlined with a focus on antidepressants, codeine and tramadol, statins, clopidogrel, warfarin, metoprolol and allopurinol. This review is intended to provide both a general introduction to PGx with a more in-depth overview of elements relevant to primary care.

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“…Warfarin, a coumarin anticoagulant and one of the most widely used drugs in clinical medicine, is used to prevent or reduce the risks of thromboembolism. Its daily dose for satisfactory anticoagulation displays wide inter‐individual variability, ranging from 0.5 to 20 mg daily . The intensity of anticoagulation by warfarin, determined by a number of genetic and non‐genetic factors which include age and dietary and environmental factors, is measured by the international normalised ratio (INR).…”

Section: What Is Known and Objectivementioning

confidence: 99%

“…The roles of CYP2C9 and VKORC1 polymorphisms have now been studied sufficiently exhaustively and further studies focussing on them will likely provide more of the same. While it is certainly premature to write an obituary for warfarin, now may well be an appropriate time to reconsider the justification of allocating further scarce resources to the study of its pharmacogenetics.…”

Section: What Is New and Conclusionmentioning

confidence: 99%

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Shah

2020

J Clin Pharm Ther

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What is known and objective: Despite an apparently sound pharmacological basis, clinical studies of genotype-guided warfarin dosing have yielded mixed and conflicting results, leading to reluctance in its clinical implementation. The objective of this critique is to re-evaluate key warfarin pharmacogenetic studies with a view to explaining why this may be so. Methods:Major widely-cited warfarin pharmacogenetic studies as well as recent meta-analyses were identified and a critical analysis of these was undertaken to identify factors that may account for poor clinical implementation of pre-treatment genotyping. Results and discussion: Critical examination of major warfarin pharmacogenetic studies identified a number of methodological concerns such as marked variations in study designs with different variously-defined measures of outcome. Genotype testing involved only a limited number of CYP2C9/VKORC1 alleles. Claims of benefits of genotyping are based almost exclusively on INR-related parameters which are known to be highly time-labile and of limited value in predicting clinical risk orbenefit. This is evidenced by lack of any significant effect of genotyping on rates of bleeding or thromboembolic events. Neither have the effects of potential phenoconversion or medication non-adherence in study populations been adequately investigated. Although the effect of ethnicity/race is now better characterised, studies lack the power to determine whether any benefits claimed are indication-sensitive. What 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. Real-world studies have not always corroborated trialsbased claims of clinical benefit. It is time to consider redirecting scarce resources away from the study of warfarin pharmacogenetics to pharmacogenetic research of potentially greater clinical relevance.

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Warfarin: The End or the End of One Size Fits All Therapy?

Cited by 28 publications

References 55 publications

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population

Pharmacogenomics for Primary Care: An Overview

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

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