A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding.
OBJECTIVE
Summarize evidence regarding genetic testing in adults to inform warfarin dosing to reduce adverse drug events such as serious bleeding.


METHODS
Review published (and selected gray) literature using the Rapid-ACCE structure that addresses analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications.


RESULTS
Preliminary data suggest overall analytic sensitivity and specificity will be 98% or higher for CYP2C9 genotyping, but strength of evidence for analytic validity is low, especially for VKORC1 testing. Strength of evidence is high for the clinical validity of both genes in predicting stable warfarin dose, an intermediate outcome, but is low for the association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (95% CI 32-60%); specificity 69% (95% CI 62-75%) and absent for bleeding events associated with VKORC1 testing. No data are available to document clinical utility of genotyping before warfarin dosing.


CONCLUSIONS
The most important gaps identified are: which variants should be included in a testing panel, lack of data from external proficiency testing, lack of validated dosing algorithm incorporating genetic and nongenetic factors, evidence of clinical utility, reliable economic analyses, and methods to address several ethical, legal, and social implications issues.
McClain
Monica R
MR
Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Warren Alpert School of Medicine of Brown University, Providence, Rhode Island 02903, USA. mmcclain@ipmms.org
Palomaki
Glenn E
GE
Piper
Margaret
M
Haddow
James E
JE
D000483:Alleles; D000925:Anticoagulants / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases