Influence of CYP2C9 and VKORC1 on Patient Response to Warfarin: A Systematic Review and Meta-Analysis

Abstract

BackgroundWarfarin is a highly effective anticoagulant however its effectiveness relies on maintaining INR in therapeutic range. Finding the correct dose is difficult due to large inter-individual variability. Two genes, CYP2C9 and VKORC1, have been associated with this variability, leading to genotype-guided dosing tables in warfarin labeling. Nonetheless, it remains unclear how genotypic information should be used in practice. Navigating the literature to determine how genotype will influence warfarin response in a particular patient is difficult, due to significant variation in patient ethnicity, outcomes investigated, study design, and methodological rigor. Our systematic review was conducted to enable fair and accurate interpretation of which variants affect which outcomes, in which patients, and to what extent.Methodology/Principal FindingsA comprehensive search strategy was applied and 117 studies included. Primary outcomes were stable dose, time to stable dose and bleeding events. Methodological quality was assessed using criteria of Jorgensen and Williamson and data synthesized in meta-analyses using advanced methods. Pooled effect estimates were significant in most ethnic groups for CYP2C9*3 and stable dose (mutant types requiring between 1.1(0.7–1.5) and 2.3 (1.6–3.0)mg/day). Effect estimates were also significant for VKORC1 and stable dose for most ethnicities, although direction differed between asians and non-asians (mutant types requiring between 0.8(0.4–1.3) and 1.5(1.1–1.8)mg/day more in asians and between 1.5(0.7–2.2) and 3.1(2.7–3.6)mg/day less in non-asians). Several studies were excluded due to inadequate data reporting. Assessing study quality highlighted significant variability in methodological rigor. Notably, there was significant evidence of selective reporting, of outcomes and analysis approaches.Conclusions/SignificanceGenetic associations with warfarin response vary between ethnicities. In order to achieve unbiased estimates in different populations, a high level of methodological rigor must be maintained and studies should report sufficient data to enable inclusion in meta-analyses. We propose minimum reporting requirements, suggest methodological guidelines and provide recommendations for reducing the risk of selective reporting.

The influence of VKORC1 and CYP2C9 mutations on warfarin response after total hip and knee arthroplasty

“…1,[25][26][27] The PREDICT project, which was launched institutionally in 2010, provides patients with a pharmacogenomic profile of possible sensitivities to these specific medications. 25 There were over 14,000 genotyped patients within the PREDICT database, panels which included genotypes of both VKORC1 and CYP2C9.…”

“…One major factor is the individual's genetic makeup. 1 Debate has emerged as to whether genetic testing is indicated prior to initiation of warfarin therapy, as persistently subtherapeutic anticoagulation may lead to fatal thromboembolic events, while supratherapeutic anticoagulation can lead to bleeding. A recent prospective randomized trial of a clinical vs. genotype-guided warfarin-dosing algorithm has been reported in patients anticoagulated for atrial fibrillation or venous thromboembolic disease, revealing that genetic-based dosing leads to greater time spent in, and shorter time to reach therapeutic international normalized ratio (INR) range.…”

“…8 Most data assessing the benefit of genetic-based warfarin dosing have only considered patients requiring anticoagulation for a medical indication. 1 However, the postoperative patient represents a perturbed metabolic system due to whole-body inflammation, in which the genetic influence on warfarin response may vary considerably, and consequences of subtherapeutic or supratherapeutic dosing could be magnified. The total joint replacement represents a commonly performed operation after which patients generally receive thromboprophylaxis for as long as a month.…”

Polymorphisms in Genes Encoding Metalloproteinase 9 and Lymphotoxin- Alpha can Influence Warfarin Treatment

“…Interestingly, age, concomitant drugs, comorbidities, vitamin K intake and other environmental factors alongside genetic predispositions are responsible for almost half of warfarin dose variability [5].…”

The influence of VKORC1 3730 G > A polymorphism on warfarin dose: reply

“…Moreover, in a recent meta-analysis [4], Jorgensen et al showed that for the Caucasian ethnic group, the pooled effect estimate of the VKORC SNP rs 7294 on warfarin dosing was nonsignificant for heterozygotes versus wild-types, but was statistically significant for mutant-types versus wild-types.…”