Abstract
BackgroundDespite its shortcomings, warfarin is still the most commonly prescribed anticoagulant to prevent thromboembolism in children. In adults, numerous studies confirmed the robust relationship between warfarin maintenance doses and single nucleotide polymorphisms of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase (VKORC1), and cytochrome P450 4F2 (CYP4F2). However, their effect in children still remains to be determined. The primary objective of the present systematic review and meta-analysis is to assess the effect of genotypes of CYP2C9, VKORC1, and CYP4F2 on warfarin maintenance dose in children.Methods/designA comprehensive literature review search using the OVID platform will be conducted by a specialized librarian, without language restrictions (i.e., MEDLINE/EMBASE/Cochrane Central Register of Controlled Trials), and all abstracts will be reviewed by two authors. Data abstraction from each eligible study will be extracted individually by two authors (MT and TK), and disagreements will be resolved through discussion with a third person (SI). Critical appraisal of the included analysis of the primary objective will follow the Newcastle–Ottawa Scale, in addition to the Strengthening the Reporting of Genetic Association study (STREGA) statement, and data reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. For the meta-analysis, the presence vs. absence of each genetic polymorphism will be pursued, respectively, using a random effect model with effect size expressed as a mean difference plus 95 % confidence interval.DiscussionOur study will provide a comprehensive systematic review and meta-analysis on the potential effects of CYP2C9, VKORC1, or CYP4F2 on the warfarin maintenance dose in children, exploring the feasibility of the development of pharmacogenetic-guided warfarin dosing algorithm for children on oral vitamin K antagonists.Systematic review registrationThe review has been registered with PROSPERO (registration number CRD42015016172).Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-016-0280-y) contains supplementary material, which is available to authorized users.
Highlights
Despite its shortcomings, warfarin is still the most commonly prescribed anticoagulant to prevent thromboembolism in children
We hope that our systematic review and meta-analysis will appropriately evaluate the effects of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) on warfarin maintenance dose in children
VKORC1 and CYP2C9 affected the maintenance dose in 120 pediatric patients receiving warfarin, in addition to Shaw et al [28], who has reported that warfarin dose variability was attributed to VKORC1 and CYP2C9 polymorphisms in 93 pediatric patients
Summary
We hope that our systematic review and meta-analysis will appropriately evaluate the effects of CYP2C9, VKORC1, and CYP4F2 on warfarin maintenance dose in children. Zhang et al [42] conducted a meta-analysis and have reported that VKORC1-1639 polymorphism had an effect on warfarin dose in pediatric patients in 2015 They did not follow the Cochrane Handbook for Systematic Reviews of Intervention or the PRISMA guidelines considered the current gold standard guideline in the systematic review field. The patients in the two literatures they selected may overlap and they did not include data of some literature meeting the eligibility criteria in the metaanalysis To avoid these flaws, we will conduct the systematic review and meta-analysis officially following to the principle of the Cochrane Handbook for Systematic Reviews of Intervention and PRISMA guideline. Abbreviations CI, confidence interval; CYP2C9, cytochrome P450 2C9; CYP4F2, cytochrome P450 4F2e; GRADE, Grading of Recommendations Assessment, Development and Evaluation; INR, international normalized ratio NOS, the Newcastle–Ottawa Scale; PRISMA, Preferred Reporting Items for Systematic Reviews and Metaanalyses; PRISMA-C, Preferred Reporting Items for Systematic Reviews and Meta-analyses—Reporting for Children; PRISMA-P, Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocol; PROSPERO, international prospective register of systematic reviews; SNPs, single nucleotide polymorphisms; STREGA, Strengthening the Reporting of Genetic Association study; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; VKORC1, vitamin K epoxide reductase
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