Genetic tests to guide warfarin dosing could avert 85,000 serious bleeding events and 17,000 strokes annually, according to a report from the AEI-Brookings Joint Center for Regulatory Studies, a Washington, DC, think tank. The report further suggests that by integrating genetic testing into warfarin therapy, American health care spending could be reduced by $1.1 billion annually.1 Unfortunately, the promise of using genetic testing to guide such pharmacological treatment has largely gone unfulfilled.2
Case in point: Genetic testing can tell us whether a patient is likely to be an ultra-rapid metabolizer of warfarin (and need larger doses) or a poor metabolizer (and need lower doses), but there are no guidelines to tell us how to dose accordingly. International normalized ratios (INRs) still need to be ordered and the patient will likely have to pick up the tab for the genetic test ($250), since Medicare and private insurers don’t cover the cost. (See “Warfarin: An ideal, but far from ready, candidate”)
Hints that change may be on the horizon. The government—specifically the Department of Health and Human Services—created the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) to assess how genetic and genomic technologies are being integrated into health care and to identify opportunities and gaps in research. To that end, SACGHS issued a draft report earlier this year that notes that genetic-based treatment has “the potential to yield significant gains in personal health, population health, and cost-effective resource allocation.” Among its many recommendations, SACGHS calls for greater collaboration between the public and private sectors to expand our knowledge of the clinical validity and utility of using genetics to guide treatment.3
A standard of care, potentially. Readying ourselves for the ways that genetics is likely to shape the way we prescribe such drugs as anticoagulants, antidepressants, and antiarrhythmics requires that we step back and assess the progress made so far, and the work that still needs to be done before genetic testing becomes a common occurrence, and perhaps even a standard of care.
The goal: Avert adverse events
The wide variation in the way different people respond to the same dose of medications is a major contributor to the problem of adverse drug reactions. Lazarou and colleagues estimated that 6.7% of hospitalized patients—over 2 million patients in the US—experienced an adverse drug reaction and 0.32% (106,000) had a fatal adverse drug reaction.4
Warfarin: An ideal, but far from ready, candidate
It would appear that warfarin dosing would be a perfect candidate for the clinical use of a pharmacogenetic test. Studies have shown that about 7% of the Caucasian population are poor metabolizers and at increased risk of bleeding from over coagulation and 1% are ultra-rapid metabolizers.4 Despite what we know about the polymorphisms to the CYP2C9 enzyme, which is the primary route of metabolism for warfarin, the package insert on Coumadin still doesn’t contain a recommendation for determining a patient’s genetic profile before initiating treatment.30 Similarly, the chapter on anticoagulation in Applied Therapeutics, a commonly used medical textbook, says nothing about the use of CYP polymorphisms for dosing decisions.13
At issue: Genotyping to guide dosing has not been tested in comparison to the usual monitoring using the international normalized ratio (INR).31 Specifically, the outcomes of bleeding complications and adequate anticoagulation of the 2 methods have not been compared in a clinical trial.
Here’s what we do know: In one study, the presence of specific polymorphisms was associated with a lower maintenance warfarin dose, but not with over-anticoagulation.32 In a review of 4 studies on CYP2C9 polymorphisms and warfarin daily dose, Lee and colleagues found that between the slowest and fastest metabolizers, the difference in dose was, at most, 4 mg/day. These studies did not explore if dosing decisions could accurately be made on genetic classifications and it is unlikely they could because of the wide overlap in maintenance dosages in the different classes.7
To complicate things further, the future use of warfarin in some conditions is problematic because fractionated heparin has been proven in many situations to be as effective and less risky than warfarin, and does not require frequent monitoring with blood tests. All of these unknowns make it unclear how useful genetic tests will be, and whether insurers will pay for them.
Individual response to medications is determined by a host of factors including age, environment, other medications being taken, and genetic differences in drug absorption and metabolism. These genetic differences have spawned the fields of pharmacogenomics and pharmacogenetics.
Pharmacogenomics is the biotechnological science that combines the techniques of medicine, pharmacology, and genomics and is concerned with developing drug therapies to compensate for genetic differences in patients, which cause varied responses to a single therapeutic regimen.