This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time-varying covariates. Forty-four major and 203 minor hemorrhages occurred over 555 person-years among 446 patients (60.67±15.6 years, 50% men, 227 African Americans). The variant CYP2C9 genotype conferred an increased risk for major (hazard ratio (HR) 3.0; 95% confidence interval (CI): 1.1-8.0) but not minor (HR 1.3; 95% CI: 0.8-2.1) hemorrhage. The risk of major hemorrhage was 5.3-fold (95% CI: 0.4-64.0) higher before stabilization of therapy, 2.2-fold (95% CI: 0.7-6.5) after stabilization, and 2.4-fold (95% CI: 0.8-7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7-4.4) or minor (HR 0.8; 95% CI: 0.5-1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.Thromboembolic disorders are significant contributors to morbidity and mortality. 1 Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, 2-4 it is vastly underutilized, 5,6 with difficulties in management 5,7 and risk of complications being the main deterrents. 7,8 Recognition of genetic regulation of warfarin response has fueled Correspondence: NA Limdi (E-mail: nlimdi@uab.edu).
CONFLICT OF INTERESTThe authors declared no conflict of interest.
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NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript efforts aimed at quantifying this influence, but past efforts have focused on a few cytochrome P450 2C9 (CYP2C9) alleles in largely white populations. 9-13 Outcome definitions varied significantly, with several studies addressing risk of over-anticoagulation, 12,13 whereas others analyzed hemorrhagic complications retrospectively. 9-11 Exclusion of underrepresented ethnic groups and inability to address factors such as concurrent medications and comorbid conditions 9-13 limit the generalizability of study results. Although these studies have enhanced our understanding of the association of CYP2C9 and hemorrhagic complications, a prospective study in racially representative population is lacking. A recent report indicates the significance of 1173C/T polymorphism in the vitamin K epoxide reductase complex 1 (VKORC1) gene in explaining variability in warfarin dose requirements among both European-American and African-American patients. 14 However, the influence of VKORC1 polymorphisms in risk of hemorrhagic complications is lacking.Herein we present the association of CYP2C9 and VKORC1 1173C/T (rs9934438) genotypes and risk of hemorrhagic complications among African Americans and European Americans on warfarin therapy.
RESULTSAll patients meeting eligibility criteria (n=526) were asked to particip...
CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.
Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers Nita A. Limdi,
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