Warfarin loading dose guided by pharmacogenetics is effective and safe in cardioembolic stroke patients – a randomized, prospective study

Růžičková, Tereza; Šrámek, Martin; Kaplan, Vojtěch; Kumstýřová, Simona; Lacinová, Zuzana; Jánský, Petr; Magerova, Hana; Šarbochová, Ivana; Schwabová, Jaroslava Paulasová; Maťoška, Václav; Tomek, Aleš

doi:10.1038/s41397-019-0066-4

Cited by 8 publications

(4 citation statements)

References 35 publications

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“…Apart from atrial fibrillation (AF), indications studied include stroke, prophylaxis associated with the use of artificial heart valves and continuous‐flow left ventricular assist devices, deep venous thrombosis and pulmonary embolism . Patients studied came from diverse ethnic/racial backgrounds and included not only adult but also paediatric populations …”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

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

Shah

2020

J Clin Pharm Ther

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“…The potential value of warfarin pharmacogenomic testing is before warfarin initiation, when a lower starting dose could be selected and quicker adjustment to a therapeutic INR might be achieved. 58,59 On comprehensive reports that identify individual drugs that may present a risk for the patient, it is the clinician's responsibility to consider the risk vs benefit of prescribing that medication. An alternative drug may not have a pharmacogenomic interaction, but it might be an inappropriate drug choice for the clinical situation.…”

Section: What Are Some Of the Additional Clinical Considerations?mentioning

confidence: 99%

Considerations When Applying Pharmacogenomics to Your Practice

Nicholson

Formea

Matey

et al. 2021

Mayo Clinic Proceedings

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“…On the other hand, potential warfarin-drug interactions with a multitude of drugs and foods along with warfarin’s narrow therapeutic index raise serious safety concerns, with bleeding being the most serious and most frequent adverse effect of warfarin [ 3 ]. Moreover, inter-individual variations in dose requirements that ensure the stability of anticoagulation and minimal bleeding risk make warfarin dosing a challenging task [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hyper-responsiveness to warfarin in a young patient with the VKORC1 -1639GA/CYP2C9146 genotype: a case report

Aldiban

Altawil

Hussein³

et al. 2022

Thrombosis J

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Background Warfarin is the most widely used oral anticoagulant; nevertheless, dosing of warfarin is problematic for clinicians worldwide. Inter-individual variability in response to warfarin is attributed to genetic as well as non-genetic factors. Pharmacogenomics studies have identified variants in CYP2C9 and VKORC1 genes as significant predictors of warfarin dose, however, phenotypes of rare variants are not well characterized. Case presentation We report a case of hyper-responsiveness to warfarin in a 22-year-old outpatient with Crohn's disease who presented with a swollen, red, and painful left calf. Deep venous thrombosis (DVT) in the left lower extremity was confirmed via ultrasonography, and hence, anticoagulation therapy of heparin and concomitant warfarin was initiated. Warfarin dose of 7.5 mg/day was estimated by the physician based on clinical factors. Higher than the expected international normalized ratio (INR) value of 4.5 necessitated the reduction of the warfarin dose to 5 and eventually to 2.5 mg/day to reach a therapeutic INR value of 2.6. Pharmacogenetic profiling of the VKORC1 -1639G > A and CYP2C9 *2, *3, *4, *5, *8, *14, *20, *24, *26, *33, *40, *41, *42, *43, *45, *46, *55, *62, *63, *66, *68, *72, *73 and *78 revealed a VKORC1-1639GA/CYP2C9*1*46 genotype. The lower catalytic activity of the CYP2C9*46 (A149T) variant was previously reported in in vitro settings. Conclusions This is the first report on a case of warfarin hyper-responsive phenotype of a patient with the heterozygous CYP2C9*1*46 polymorphism.

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Warfarin loading dose guided by pharmacogenetics is effective and safe in cardioembolic stroke patients – a randomized, prospective study

Cited by 8 publications

References 35 publications

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

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

Considerations When Applying Pharmacogenomics to Your Practice

Hyper-responsiveness to warfarin in a young patient with the VKORC1 -1639GA/CYP2C9146 genotype: a case report

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Warfarin loading dose guided by pharmacogenetics is effective and safe in cardioembolic stroke patients – a randomized, prospective study

Cited by 8 publications

References 35 publications

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

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

Considerations When Applying Pharmacogenomics to Your Practice

Hyper-responsiveness to warfarin in a young patient with the VKORC1 -1639GA/CYP2C9*1*46 genotype: a case report

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Hyper-responsiveness to warfarin in a young patient with the VKORC1 -1639GA/CYP2C9146 genotype: a case report