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Gene-based Medicine - Prime Time Yet?
Abstract & Commentary
By Rahul Gupta, MD, MPH, FACP, Assistant Professor, Department of Internal Medicine, Meharry Medical College Nashville, TN; Assistant Clinical Professor, Division of General Internal Medicine and Public Health, Vanderbilt University Medical School, Nashville, TN. Dr. Gupta reports no financial relationship to this field of study.
Synopsis: Utilizing genotyping for warfarin therapy in patients with non-valvular atrial fibrillation may not be cost-effective.
Source: Eckman MH, et al. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with non-valvular atrial fibrillation. Ann Intern Med 2009; 150:73-83.
On Aug. 16, 2007, the FDA sent out an announcement titled, "New genetic information may help providers improve initial dosing estimates of the anticoagulant for individual patients."1 This labeling change for warfarin suggested that health care providers use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients. FDA claimed this change to be in support of the "personalized health program" spearheaded by the then Health and Human Services Secretary, Mike Leavitt.
Over the years, it has been learned that about 30 different genes may affect metabolism and sensitivity when dosing warfarin.2 Under-dosing can lead to delay in treatment and over-dosing can lead to increased risk for bleeding. However, 2 genes play the most important role: cytochrome P450 CYP2C9 and vitamin K epoxide reductase VKORC1. Patients who harbor certain alleles of these genes can be at higher risk of bleeding during the induction phase and, therefore, may benefit from such identification in advance. Currently, genetic testing costs approximately $400.
Eckman et al utilized existing data from MEDLINE and other searches. They developed a computer program (Markov state transition model) and considered 2 strategies - standard induction of warfarin therapy vs genotype-guided warfarin therapy (testing for CYP2C9 and VKORC1) - for a hypothetical man age 69 years with newly diagnosed non-valvular atrial fibrillation.
The authors found that there was minimal improvement in survival rates in patients with genotype-based dosing compared with traditional warfarin management. Additionally, there was a high cost to the former approach with a marginal cost-effectiveness ratio of almost $172,000 per quality-adjusted life-year (QALY). In simple population terms, the authors argue that if about 300,000 patients start warfarin treatment each year in the United States, the genotype-guided dosing would prevent 300 major bleeding events during the first year at a net cost of more than $113 million. A further sensitivity analysis suggests that for genetic testing to cost less than $50,000 per QALY (a generally accepted societal threshold), it would have to be restricted to patients at high risk for hemorrhage or cost less than $200.
I understand the wish to excel in the field of personalized medicine, both by researchers and politicians. In the 21st century, that's what makes us sound literate - when we speak of gene-based medicine, web-based medicine, and personalized medicine. However, in the field of gene-based testing, we must not forget that the same principles of a good screening test apply when it is being advocated to the mass population. This includes the test being inexpensive, low-risk, valid, and reliable when compared with a gold standard. Since the genotyping for warfarin dosing currently is highly expensive when administered at a population level, I would suggest that the FDA recommend narrowing the application of this test to those predicted to be at higher risk for bleeding.3
Perhaps in the future, costs of such tests would be reduced dramatically and the turnaround times will become much faster. Only in those circumstances would these tests become cost-effective enough for broader use. Also, there is much more research required in this field. Till such occurs, I may continue to use dosing guidance from web sites such as www.warfarindosing.org, but without adding the genotyping information when it is unavailable.
1. FDA Approves Updated Warfarin (Coumadin) Prescribing Information. Available at: www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed Jan. 23, 2009.
2. Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: Current status and future challenges. Pharmacogenomics J 2007;7:99-111.
3. Gage BF, et al. Clinical classification schemes for predicting hemorrhage: Results from the National Registry of Atrial Fibrillation. Am Heart J 2006;151:713-719.