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Letter to the Editor
Editor, – Dr Martin has comprehensively reviewed the genetic and environmental factors contributing to the large inter-individual variability in warfarin requirements (Aust Prescr 2009;32:76-80). These factors explain about 50% of such variability which is quite impressive considering that for most drugs, 100% of the dose variability cannot be explained. It is very unlikely that additional genetic factors will be uncovered, as whole genome association studies have clearly identified CYP2C9 and VKORC1 genotype as the major genetic contributors to dosage requirements with a very small contribution by CYP4F2.1 Other factors that need to be considered are drug-drug interactions, medication adherence, psychosocial factors and the less than optimal system of care for people prescribed warfarin.2
The Food and Drug Administration in the US refers to the genetic factors (CYP2C9 and VKORC1) which influence dosage requirements in the product information for warfarin, but Medicare and Medicaid will not pay for the genetic test (except as part of clinical trials) because of insufficient evidence of benefit. There is clearly a need for large scale prospective studies, including pharmacoeconomic studies, before any decisions are made to incorporate genetic testing into best practice guidelines.3
In Australia, the situation is complex as some pathology services already advertise the test, but there are no known large prospective multi centre trials being conducted to determine feasibility, interpretation, dosage recommendations and cost-benefit. It is timely that this be done so that Australia, with its different spread of ethnicities and diets, can contribute to the evidence and importantly, that Australian-based cost-benefit analyses and dosage recommendations can be made to determine whether or not warfarin genetic testing should become part of treatment guidelines.
Professor Andrew Somogyi
Discipline of Pharmacology
University of Adelaide
- Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 2009;5:e1000433. Epub 2009 Mar 20.
- Lowthian JA, Duig BO, Evans SM, Maxwell EL, Street AM, Piterman L, et al. Who is responsible for the care of patients treated with warfarin therapy? Med J Aust 2009;190:674-7.
- Daly AK. Pharmacogenomics of anticoagulants: steps towards personal dosage. Genome Med 2009;1:10.