Publication

Systematic review: influence of CYP2C9 and VKORC1 polymorphisms in warfarin dosing – clinical practice

Bibliographic Details
Summary:	Warfarin is a coumarin anticoagulant widely used in the world that has an important role in treatment and prevention of several thromboembolic diseases. However, there is a large inter-individual and intra-individual variability of the necessary dose for optimal anticoagulation, defined as an international normalized ratio (INR) of 2-3 for most indications. Additionally, owing to its narrow therapeutic window, warfarin is also a leading cause of serious adverse drug events, mainly in the beginning of the treatment. Therefore, treatment with this coumarin anticoagulant is extremely challenging. Beyond clinical factors, genotype is also an important factor in dosage requirements. This area is called pharmacogenetics and uses individual genetic information to predict the pharmacologic effect of a given drug. Through various studies it is possible to analyze that certain polymorphisms in two genes (CYP2C9 and VKORC1) can explain approximately one-third of warfarin dose variation and are associated with lower dose requirements. Regarding previous information, a search strategy was implemented and 19 studies (10 randomized controlled trials – RCTs - and 9 observational studies - OSs) were chosen considering specific inclusion and exclusion criteria. The objective was to find high quality RCTs and prospective OSs comparing a pharmacogenetics algorithm versus a clinical algorithm regarding specific outcomes of interest. To be eligible, original studies were required to meet all of the following criteria: RCTs or OSs; (2) to report at least one of the outcomes of interest: %TTR (percentage of time in therapeutic range), time to reach a stable dose or a stable therapeutic INR, over-anticoagulation with international normalized ratio (INR) more than 4 or 5, hemorrhagic or thromboembolic events; (3) pharmacogenetics warfarin algorithm should contain at least one of CYP2C9 or/and VKORC1 genotypes (CYP2C92, CYP2C93, VKORC1 c.−1639 G/A). Additionally, for each study was defined: population, genotype, measured outcomes, intervention/algorithm and results about outcomes of interest. After this step, several RCTs and OSs meta-analyses were performed and divided by outcomes. The current evidence found in meta-analyses does not support an incremental benefit on anticoagulation control of using CYP2C92, CYP2C93 and VKORC1 to determine the warfarin dosing above and beyond what is available from clinical information, despite some advantages on surrogate quality markers for anticoagulation control. In addition, in some cases (such as %TTR) the results were only more relevant when PG group was being compared with STD fixed dose regimen and an obvious difference was not observed when PG group was being compared with STD non-fixed dose regimen. Important points to consider were: the insufficient sample size and power of the studies, the genotyping platform (analytical validity) and some specific bias of RCTs and OSs. The cost-effectiveness is also extremely important to answer the critical question of whether to use genotyping in everyday clinical care can be afforded in relation to NOACs. While it is well documented that sequence variants in the VKORC1 and CYP2C9 genes predict therapeutic warfarin doses, the routine application of this biotechnology to clinical medical care is not well recognized to be clinically useful. Warfarin dosing based on pharmacogenetics in not yet the standard of care, although guidelines for its use are available and should the clinician choose to employ it when genotype data are available. Then, future research should be aimed to obtain reliable clinical event outcomes data to recommend with better evidence the use of pharmacogenetics in clinical warfarin dosing.
Main Authors:	Melo, Mafalda Bastos
Subject:	Warfarin Pharmacogenetics CYP2C9 VKORC1 Mestrado Integrado - 2016
Year:	2016
Country:	Portugal
Document type:	master thesis
Access type:	restricted access
Associated institution:	Universidade de Lisboa
Language:	English
Origin:	Repositório da Universidade de Lisboa

Description
Summary:	Warfarin is a coumarin anticoagulant widely used in the world that has an important role in treatment and prevention of several thromboembolic diseases. However, there is a large inter-individual and intra-individual variability of the necessary dose for optimal anticoagulation, defined as an international normalized ratio (INR) of 2-3 for most indications. Additionally, owing to its narrow therapeutic window, warfarin is also a leading cause of serious adverse drug events, mainly in the beginning of the treatment. Therefore, treatment with this coumarin anticoagulant is extremely challenging. Beyond clinical factors, genotype is also an important factor in dosage requirements. This area is called pharmacogenetics and uses individual genetic information to predict the pharmacologic effect of a given drug. Through various studies it is possible to analyze that certain polymorphisms in two genes (CYP2C9 and VKORC1) can explain approximately one-third of warfarin dose variation and are associated with lower dose requirements. Regarding previous information, a search strategy was implemented and 19 studies (10 randomized controlled trials – RCTs - and 9 observational studies - OSs) were chosen considering specific inclusion and exclusion criteria. The objective was to find high quality RCTs and prospective OSs comparing a pharmacogenetics algorithm versus a clinical algorithm regarding specific outcomes of interest. To be eligible, original studies were required to meet all of the following criteria: RCTs or OSs; (2) to report at least one of the outcomes of interest: %TTR (percentage of time in therapeutic range), time to reach a stable dose or a stable therapeutic INR, over-anticoagulation with international normalized ratio (INR) more than 4 or 5, hemorrhagic or thromboembolic events; (3) pharmacogenetics warfarin algorithm should contain at least one of CYP2C9 or/and VKORC1 genotypes (CYP2C92, CYP2C93, VKORC1 c.−1639 G/A). Additionally, for each study was defined: population, genotype, measured outcomes, intervention/algorithm and results about outcomes of interest. After this step, several RCTs and OSs meta-analyses were performed and divided by outcomes. The current evidence found in meta-analyses does not support an incremental benefit on anticoagulation control of using CYP2C92, CYP2C93 and VKORC1 to determine the warfarin dosing above and beyond what is available from clinical information, despite some advantages on surrogate quality markers for anticoagulation control. In addition, in some cases (such as %TTR) the results were only more relevant when PG group was being compared with STD fixed dose regimen and an obvious difference was not observed when PG group was being compared with STD non-fixed dose regimen. Important points to consider were: the insufficient sample size and power of the studies, the genotyping platform (analytical validity) and some specific bias of RCTs and OSs. The cost-effectiveness is also extremely important to answer the critical question of whether to use genotyping in everyday clinical care can be afforded in relation to NOACs. While it is well documented that sequence variants in the VKORC1 and CYP2C9 genes predict therapeutic warfarin doses, the routine application of this biotechnology to clinical medical care is not well recognized to be clinically useful. Warfarin dosing based on pharmacogenetics in not yet the standard of care, although guidelines for its use are available and should the clinician choose to employ it when genotype data are available. Then, future research should be aimed to obtain reliable clinical event outcomes data to recommend with better evidence the use of pharmacogenetics in clinical warfarin dosing.

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