Simon Sanderson1, Jon Emery, Julian Higgins. 1. Department of Public Health and Primary Care, University of Cambridge and Cambridge Genetics Knowledge Park, Cambridge, UK.
Abstract
PURPOSE: Two common variant alleles of the cytochrome CYP2C9 (CYP2C9*2 and CYP2C9*3) lead to reduced warfarin metabolism in vitro and in vivo. The study objective was to examine the strength and quality of existing evidence about CYP2C9 gene variants and clinical outcomes in warfarin-treated patients. METHODS: The study was a systematic review and meta-analysis. Multiple electronic databases were searched, references identified from bibliographies were sought, and experts and authors of primary studies were also contacted. Strict review inclusion criteria were determined. Three reviewers independently extracted data using prepiloted proformas. RESULTS: In all, 11 studies meeting review inclusion criteria were identified (3029 patients). Nine were included in the meta-analyses (2775 patients). Random effects meta-analyses were performed; statistical heterogeneity and inconsistency was assessed. Twenty percent of patients studied carry a variant allele: CYP2C9*2 12.2% (9.7%-15.0%) and CYP2C9*3, 7.9% (6.5%-9.7%). Mean difference in daily warfarin dose: for CYP2C9*2, the reduction was 0.85 mg (0.60-1.11 mg), a 17% reduction. For CYP2C9*3, the reduction was 1.92 mg (1.37-2.47 mg), a 37% reduction. For CYP2C9*2 or *3, the reduction was 1.47 mg (1.24-1.71 mg), a 27% reduction. The relative bleeding risk for CYP2C9*2 was 1.91 (1.16-3.17) and for CYP2C9*3 1.77 (1.07-2.91). For either variant, the relative risk was 2.26 (1.36-3.75). CONCLUSIONS: Patients with CYP2C9*2 and CYP2C9*3 alleles have lower mean daily warfarin doses and a greater risk of bleeding. Testing for gene variants could potentially alter clinical management in patients commencing warfarin. Evidence for the clinical utility and cost-effectiveness of genotyping is needed before routine testing can be recommended.
PURPOSE: Two common variant alleles of the cytochrome CYP2C9 (CYP2C9*2 and CYP2C9*3) lead to reduced warfarin metabolism in vitro and in vivo. The study objective was to examine the strength and quality of existing evidence about CYP2C9 gene variants and clinical outcomes in warfarin-treated patients. METHODS: The study was a systematic review and meta-analysis. Multiple electronic databases were searched, references identified from bibliographies were sought, and experts and authors of primary studies were also contacted. Strict review inclusion criteria were determined. Three reviewers independently extracted data using prepiloted proformas. RESULTS: In all, 11 studies meeting review inclusion criteria were identified (3029 patients). Nine were included in the meta-analyses (2775 patients). Random effects meta-analyses were performed; statistical heterogeneity and inconsistency was assessed. Twenty percent of patients studied carry a variant allele: CYP2C9*2 12.2% (9.7%-15.0%) and CYP2C9*3, 7.9% (6.5%-9.7%). Mean difference in daily warfarin dose: for CYP2C9*2, the reduction was 0.85 mg (0.60-1.11 mg), a 17% reduction. For CYP2C9*3, the reduction was 1.92 mg (1.37-2.47 mg), a 37% reduction. For CYP2C9*2 or *3, the reduction was 1.47 mg (1.24-1.71 mg), a 27% reduction. The relative bleeding risk for CYP2C9*2 was 1.91 (1.16-3.17) and for CYP2C9*3 1.77 (1.07-2.91). For either variant, the relative risk was 2.26 (1.36-3.75). CONCLUSIONS:Patients with CYP2C9*2 and CYP2C9*3 alleles have lower mean daily warfarin doses and a greater risk of bleeding. Testing for gene variants could potentially alter clinical management in patients commencing warfarin. Evidence for the clinical utility and cost-effectiveness of genotyping is needed before routine testing can be recommended.
Authors: John F Carlquist; Benjamin D Horne; Joseph B Muhlestein; Donald L Lappé; Bryant M Whiting; Matthew J Kolek; Jessica L Clarke; Brent C James; Jeffrey L Anderson Journal: J Thromb Thrombolysis Date: 2006-12 Impact factor: 2.300
Authors: A Cecile J W Janssens; Marta Gwinn; Linda A Bradley; Ben A Oostra; Cornelia M van Duijn; Muin J Khoury Journal: Am J Hum Genet Date: 2008-03 Impact factor: 11.025
Authors: Thomas P Moyer; Dennis J O'Kane; Linnea M Baudhuin; Carmen L Wiley; Alexandre Fortini; Pamela K Fisher; Denise M Dupras; Rajeev Chaudhry; Prabin Thapa; Alan R Zinsmeister; John A Heit Journal: Mayo Clin Proc Date: 2009-12 Impact factor: 7.616
Authors: Tanima De; Cristina Alarcon; Wenndy Hernandez; Ina Liko; Larisa H Cavallari; Julio D Duarte; Minoli A Perera Journal: JAMA Date: 2018-10-23 Impact factor: 56.272