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

Abstract

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.

Randomized controlled trial of genotype‐guided warfarin anticoagulation in Chinese elderly patients with nonvalvular atrial fibrillation

“…But the clinical benefit of this is uncertain. Real‐world studies have not always corroborated trials‐based claims of clinical benefit 18 …”

Potential of Whole-Genome Sequencing-Based Pharmacogenetic Profiling

“…In spite of largely accepted scientific evidence for PGx, some points of discussion still exist, most of which originate from the fact that, currently, PGx fails to explain 100% of variability in drug response. This could partly be explained by other factors affecting drug response, such as age, sex, co-medication, disease state, kidney and liver function, which may explain up to 60% of the interindividual variability in drug response [93]. In addition, our current understanding of PGx is still incomplete.…”

A network meta‐analysis ofCYP2C9,CYP2C9withVKORC1andCYP2C9withVKORC1andCYP4F2genotype‐based warfarin dosing strategies compared to traditional

“…More randomized clinical trials are needed for delineating the additional therapeutic benefit of CYP4F2 compared to CYP2C9 and VKORC1 combination. The result of this meta‐analysis needs to be interpreted with greater caution as the majority of the benefits observed with genotyping‐based strategies were in surrogate outcomes, and non‐genetic factors play a significant role in the inter‐individual response to warfarin 43…”