Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy

Abstract

Objective: To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results?Methods: A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus.Results: Testing of VKORC1 (21639G.A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose.Significance: This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotypeguided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.

VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

“…Published data on the increased risk of side effects associated with genetic variants among VKA users is controversial, as highlighted by recently published guidelines concerning the appropriateness of genetic testing in warfarin therapy. [34] A recent meta-analysis showed that only the CYP2C9∗3 allele, but not the CYP2C9∗2 allele, was associated with a significant risk of bleeding. [35] However, another meta-analysis concluded that CYP2C9∗2 and CYP2C9∗3 , but not VKORC1 genotypes, were associated with warfarin hemorrhagic complications.…”

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

“…Compared to CYP4F2*1 / *1 genotype, 3 / *3 genotype is reported to be associated with a statistically significant increase in dose (13.2%), a trend towards a lower risk of over‐anticoagulation and lower incidence of haemorrhage . Thus, though the current data suggests an overall effect which is lower than those of CYP2C9 and VKORC1 , the effect of CYP4F2 polymorphism in different ethnic groups requires further investigations.…”

Analyses of Adverse Drug Reactions–Nationwide Active Surveillance Network: Canadian Pharmacogenomics Network for Drug Safety Database

“…The Clinical Recommendations Group has published clinical practice recommendations regarding anthracycline-induced cardiotoxicity, 35 carbamazepine-induced hypersensitivity reactions, 36 cisplatin-induced ototoxicity, 37 the safety and effectiveness of codeine, 38 and warfarin therapy. 39 The CPNDS is 1 of 3 pharmacogenomic clinical practice guideline groups cited by The Pharmacogenomics Knowledgebase (PharmGKB) 40 along with the Dutch Pharmacogenomic Working Group and the Clinical Pharmacogenetics Implementation Consortium in the United States. The clinical recommendations aid incorporation of pharmacogenomic biomarkers into clinical practice.…”