American Association for Clinical Chemistry
Better health through laboratory medicine
April 2011 Clinical Laboratory News: Online Extra

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April 2011: Volume 37, Number 4

Pharmacogenomics Faces Complex Hurdles
Warfarin Genotyping Illustrates Uncertainty
By Bill Malone

Chief among the boons expected from the genomic era has been personalized medicine, in which molecular diagnostics enable medical interventions tailored to individual patients. However, like all things genomic, questions persist about exactly how this new depth of knowledge regarding patients’ genotypes can be translated into better care.

The debate about warfarin sensitivity genotyping is a case in point, a controversy that remains unresolved as 2 million Americans each year enter the dangerous initiation phase of this anticoagulant therapy. After studies confirmed that CYP2C9 and VKORC1 polymorphisms could predict a person’s response to the drug, the Food and Drug Administration (FDA) updated the drug’s label in 2007 with a suggestion that physicians consider lower initiation doses for patients with variations in these genes. FDA updated the label again in January 2010, referring prescribers to a table of stable maintenance doses recommended for genetic variants.

Yet clinical practice guidelines have remained unchanged for warfarin, and warfarin sensitivity testing is performed infrequently. Since FDA’s label changes, a study showing a dramatic reduction in hospitalization for genotyped patients has drawn increased attention to the issue (J Am Coll Cardiol 2010;55:2804–2812). A collaboration of Mayo Clinic and pharmacy benefit firm Medco, the study was the first national, prospective, comparative effectiveness study of the impact of warfarin sensitivity genotyping on patients who initiated therapy in an outpatient setting. The study evaluated the impact of testing on hospitalization rates in the first 6 months of treatment with the drug compared to traditional care and found that, compared to the control group, patients in the genotyping arm had 31% fewer hospitalizations overall and 28% fewer hospitalizations for bleeding or thromboembolism.

An NIH-funded double-blind, randomized, multicenter clinical trial of warfarin sensitivity genotyping is underway, with preliminary results about 3-5 years out. In the mean time, physicians’ uncertainty about the test and the lack of reimbursement under the Centers for Medicare and Medicaid Services (CMS) has thwarted widespread utilization, explained Thomas Moyer, PhD, an author of the study. “The Mayo-Medco warfarin study clearly demonstrated significant benefit to patients through reduced morbidity and hospital utilization. However, with FDA saying yes and CMS saying no, most physicians are waiting for clearer guidance,” he said. “Contrast the lack of support for warfarin sensitivity genotyping with clopidogrel genotyping, testing that is heavily promoted and used, but based on much less definitive information than warfarin sensitivity genotyping.  What’s the difference?  Warfarin is a generic drug while clopidogrel is a proprietary drug.  Profit, rather than patient safety, seems to be the primary motivator.” Moyer is professor of laboratory medicine in the Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minn.