Should we use pharmacogenetic testing when prescribing warfarin?
HOW SHOULD GENETIC INFORMATION BE USED TO GUIDE OR ALTER THERAPY?
Algorithms are available for estimating initial and maintenance warfarin doses based on genetic information (CYP2C9 and VKORC1), race or ethnicity, age, sex, body mass index, smoking status, and other medications taken. In addition, models incorporating the INR on day 4 and days 6 to 11 have been developed for dose refinement.15 The algorithms explain 30% to 60% of the variability of the data, with lower values for African Americans.7
A well-developed dosing model that includes traditional clinical factors and patient genetic status is publicly available online at www.warfarindosing.org.4
CPIC: A leader in applied pharmacogenetics
In late 2009, PharmGKB joined forces with the Pharmacogenomics Research Network of the National Institutes of Health to form the Clinical Pharmacogenetics Implementation Consortium (CPIC). This organization issues guidelines that are written by expert clinicians and scientists and then are peer-reviewed, published in leading journals, and simultaneously posted to the PharmGKB website along with supplemental information and updates.
CPIC’s goal is to review the current evidence and to address barriers to the adoption of pharmacogenetic testing into clinical practice. Its guidelines do not advise when or which pharmacogenetic tests should be ordered. Rather, they provide guidance on interpreting and applying such testing, should the test results be available.7
CPIC has guidelines on CYP2C9 and VKORC1 genotypes and warfarin dosing.8 If a patient’s genetic information is available, CPIC strongly recommends the use of pharmacogenetic algorithm-based dosing. If such an algorithm is not accessible, use of a genotype dosing table is recommended.8
Monitoring is still needed
Many factors can affect an individual’s response to warfarin above and beyond the above-noted clinical and genetic traits. These include diet, concomitant medications (both prescription and over-the-counter and herbal), and disease state. There may also be additional genetic polymorphisms not yet identified in various racial and ethnic groups that may affect dosing requirements. And as with all medications, patient compliance and dosing errors have a large potential to affect individual response. Therefore, clinicians should still be diligent about clinical monitoring.15
Most useful for initial dose
As with most pharmacogenetic information, the greatest benefit can be achieved when this information is used to guide the initial dose, although there is also some effect noted when this information is known and acted upon into the 2nd week of treatment.8
Patients on long-term warfarin treatment with stable doses and those unable to achieve stable dosing because of variable adherence or dietary vitamin K intake are less likely to benefit from genetic testing.
There are no published guidelines on the utility of pharmacogenetic testing if a patient is already on a stable dose of warfarin or has a known historical stable dose. There are also no published guidelines on changing the frequency of monitoring based on known genotype.
In children, the data are sparse at this time regarding the utility of pharmacogenetically informed dosing.
HOW DOES ONE ORDER TESTING, AND WHAT IS THE COST?
The FDA has approved four warfarin pharmacogenetic test kits. To be used in clinical decision-making, these tests must be done in a laboratory certified by the Clinical Laboratory Improvement Amendments (CLIA) program.
Testing typically costs a few hundred dollars and may take days for results to be returned if not available on site.15 At Cleveland Clinic, CYP2C9 and VKORC1 testing can be run in-house at a cost of about $700. Generally, many third-party payers do not reimburse for testing without a prior-approval process.
TO TEST OR NOT TO TEST
Pharmacogenetic testing is available and may help optimize warfarin dosing early in treatment, as well as help maintain therapeutic INRs more consistently. There is preliminary evidence that using this information to guide dosing improves clinical outcomes. Several large trials are under way to address additional questions of clinical utility, with results expected in the next year. There are also readily available decision-support tools to guide therapeutic dosing, and when pharmacogenetic test results are available, utilization of a warfarin dosing algorithm is recommended.
The largest barrier remaining appears to be cost (relative to perceived benefit), and until larger trials of clinical utility and cost-effectiveness are completed and analyzed, hurdles exist to obtaining coverage for such testing.
If it is readily available (and can be paid for by insurance companies or out-of-pocket) and test results can be obtained within 24 to 48 hours or before prescribing, pharmacogenetic testing can be a valuable tool to guide and manage warfarin dosing. Particularly for patients who want to be as proactive as possible, warfarin pharmacogenetic testing offers the ability to participate in this decision-making and to potentially reduce their risk of adverse drug events. And in view of the evidence and FDA recommendations, we propose that the discussion with our patients is not whether we should consider pharmacogenetic testing, but that we have considered pharmacogenetic testing, and why we have decided for or against it.
