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Genetic Testing for Warfarin (Coumadin) Dosing? - Not Yet Ready for Prime Time
Henry I. Bussey, Pharm.D., FCCP, FAHA
Ann K Wittkowsky, PharmD, CACP, FASHP, FCCP
Elaine M. Hylek, MD, MPH
Marie B. Walker
July, 2007
Recently, a lot of media attention (1-4) has been focused on genetic testing as a means to determine the right warfarin dose for an individual patient and thereby substantially reduce the risk of bleeding or clotting events. For those of you who attended the Anticoagulation Forum meeting in Chicago this past May, you know that genetic testing for warfarin dosing was a hot topic. Even the FDA has weighed in on this issue (5). In addition, the American Enterprise Institute-Brookings Joint Center (with input from the FDA) has published a document that reached some very impressive conclusions. Specifically, the report concludes: "We estimate that formally integrating genetic testing into routine warfarin therapy could allow American warfarin users to avoid 85,000 serious bleeding events and 17,000 strokes annually. We estimate the reduced health care spending from integrating genetic testing into warfarin therapy to be $1.1 billion annually, with a range of about $100 million to $2 billion." (6)
So, what's the story? Can genetic testing be used to determine the right warfarin dose? Dose such an approach reduce clinical complications and save the healthcare industry billions of dollars annually? The answer, quite simply, is maybe, but no one knows for sure. While the concept may be attractive and this evolving area needs to be researched, good clinical data to support the use of genetic testing for warfarin dosing are not yet available. Also, it is important to realize that the impressive conclusions from the Brookings report mentioned above are based on supposition and projections; not on solid clinical outcome data. Further, some experienced clinicians question whether genetic testing adds significantly to the information one may discern by carefully monitoring the INR (International Normalized Ratio, the blood test used to monitor the effect of warfarin) and by taking into consideration the numerous patient-specific factors that influence warfarin dosing requirements, including age, underlying disease states, concomitant medications, and other factors.
The Scientific Basis Behind the Concept of Genetic Testing for Warfarin Dosing
The genetic tests in question are useful in assessing an individual patient's sensitivity to warfarin and his/her rate of warfarin metabolism (i.e. how fast the body gets rid of warfarin).
The test that can estimate a patient's sensitivity to warfarin is referred to as the VKORC1 (vitamin K epoxide reductase) test. VKORC1 is the gene that codes for the enzyme that is the site of action where warfarin exerts its effect. Genetic testing can indicate whether the patient may be more sensitive or less sensitive to warfarin than "average". Patients who are found to have the "sensitive" genotype (often referred to as "AA" genotype) typically require a lower dose than average. Those who are expected to be resistant to the effects of warfarin are referred to as "GG" genotype and typically require larger doses of warfarin to reach a therapeutic INR. Those with the "usual" genotype are referred to as "AG" genotype.
The test that can estimate a patient's rate of warfarin metabolism is referred to as the 2C9 or CYP2C9 test. CYP2C9 refers to the particular liver enzyme that is primarily responsible for metabolizing (breaking down) the most active component of warfarin. Some patients have genetic variation in the CYP2C9 enzyme so that they metabolize warfarin more slowly than usual. Patients who metabolize warfarin more slowly will continue to accumulate warfarin in the blood over a longer period of time and will take longer for the INR to reach a stable level. Slow metabolizers typically require a lower dose of warfarin than those who metabolize warfarin faster.
Potential Benefits of Genetic Testing for Warfarin Dosing
The argument for genetic testing is that a clinician can use this information to achieve the correct INR sooner, to maintain the INR in range, and thus to prevent complications. For example, if the patient has the AA genotype (warfarin sensitive), the clinician would logically start therapy with a lower warfarin dose and/or would expect to see an earlier and larger increase in the INR than usual. For the GG genotype (warfarin resistant), the clinician might start with a larger than usual warfarin dose. For the patient with a CYP2C9 variant that indicates slow metabolism, the clinician might start the patient on a typical initial warfarin dose to reach the target INR range quickly, but would then need to adjust the dose downward over time to keep the INR in the target range as the patient accumulates more and more warfarin in the blood.
Another potential benefit suggested by some is that the results of these genetic tests may be put into a mathematical formula to determine a patient's specific warfarin dose and time needed to reach a steady state. Sconce and colleagues have derived a formula to utilize such genetic testing to predict the warfarin dose and the time required to get to a steady state INR. (7)
Limitations & Risks of Genetic Testing for Warfarin Dosing
The use of genetic testing for warfarin dosing may have no significant benefit in practice and may significantly increase healthcare costs. Additionally, the misuse of genetic information may increase the risk of warfarin therapy.
Genetic Testing May Have no Significant Benefit in Practice
Although genetic testing has theoretical benefits, there are no good clinical data to show that providing clinicians with this genetic information will make any difference in practice. In fact, studies looking at this issue have found genetic testing to account for only 39 to 56% of the variability in the warfarin dose (8-14). One thorough study by Aquilante et. al. from the University of Florida used a linear regression model which included the CYP2C9 and VKORC1 genetic testing together with various other patient-specific factors (such as weight, smoking status, factor X genotype, factor VII genotype, and vitamin K intake) and found that a combination of all the factors they utilized explained only 51.4% of the variability in warfarin dose (14).
Careful monitoring of the INR (as is necessary for safe and effective therapy) along with other clinical observations (such as race) can provide the information necessary for optimal dosing. Before the VKORC1 was identified, clinicians recognized that Asians (who tend to have the AA genotype) tend to be more sensitive to warfarin, and blacks (who tend to have the GG genotype) tend to be warfarin resistant. However, in the absence of a clear racial effect, if the patient has an early and rapid increase after starting a reasonable dose of warfarin, that patient is likely to have the sensitive (AA) VKORC1 genotype. If the patient requires a prolonged period of time before the INR stabilizes, then that patient is likely to have a CYP2C9 variant that leads to a slower rate of warfarin metabolism. Additionally, careful monitoring of the INR allows the clinician to identify and assess the impact on the INR of several other important variables that are not identified with genetic testing. Such variables include (but are not limited to) smoking habits, use of alcohol, other medical conditions (such as heart failure), exercise routines, medications, and routine vitamin K intake. Consequently, close monitoring of the INR may provide insight into the patient's probable genetic profile and also will provide additional useful information of the composite effect of various other factors. Clearly, there is no substitute for close INR monitoring of warfarin treated patients.
Genetic Testing May Significantly Increase Healthcare Costs
Another potential limitation of genetic testing for warfarin dosing is the cost associated with these tests. The genetic tests in question cost approximately $250 per test or $500 for both tests. The American Enterprise Institute-Brookings Joint Center report estimated that 2 million people in the U.S. start warfarin every year. Consequently, the cost of performing genetic testing on these 2 million patients would be approximately one billion dollars. Whether genetic testing adds a significant level of additional useful information and whether that additional level of useful information is worth the costs remains to be determined.
Misuse of Genetic Information May Increase the Risk of Warfarin Therapy
There is the potential for the misuse of genetic information to be dangerous to the patient's care. For example, if the clinician relies too heavily on equation-based estimates of warfarin dosage, he/she may not follow the patient's INR as closely as he/she should.
In the experience of at least one author of this write up (HIB), the equation (7) can accurately predict the warfarin dose in some patients, but in other patients the required dose may be twice as large or only one-half as large as the equation-calculated warfarin dose. If the clinician relies on the equation-calculated dose and time to steady state, he/she may conclude that the usual frequency of INR monitoring is not needed. In those patients in whom the estimated dose is only one-half of what is really needed - or twice the dose that is actually right for a given patient - the result of less frequent INR monitoring could be a catastrophic blood clot or bleeding complication. For example, if the equation tells the clinician that the daily dose will be 4.63 mg per day and that the patient will be at steady state in 12 to 15 days, then the clinician may rely on that information and not monitor the INR as often as is necessary. In reality, that same patient may require only 2.32 mg per day and may reach a steady state in 10 days. If the patient is receiving 4.63 mg per day and the INR is not followed closely, the INR could be dangerously high after 8 days of dosing. It is critical for clinicians to understand that the genetic-based dosing equations are assessing only 2 of numerous factors that may influence the patient's response to warfarin.
Bottom Line
The bottom line is that genetic testing for warfarin dosing may hold promise, but its time has not yet arrived. Clearly, more research is needed in this area, and solid clinical data demonstrating a clear benefit of such testing should be required before such testing is recommended on a routine basis.
References
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Palca, J. "Genome Project Begins Paying Dividends to Patients." 2005 NPR. 27 July 2007. <http://www.npr.org/templates/story/story.php?storyId=4675941>.
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"Genetic test offered at West Penn lessens dangers of Coumadin/warfarin." 2007 The Western Pennsylvania Hospital. 27 July 2007. <http://www.wpahs.org/wph/news/index.cfm?hera=590A5150&zeus=5B05>.
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Johnson, L. "DNA Tests to Determine Warfarin Dose." Washington Post. 2007 Associated Press. 27 July 2007. <http://www.washingtonpost.com/wp-
dyn/content/article/2007/01/12/AR2007011201331.html>.
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Winslow, R and Matthews, A. "New genetic tests boost impact of drugs." 2005 Post-Gazette. 27 July 2007. <http://www.post-gazette.com/pg/05355/625848.stm>.
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Critical Path Initiative: Warfarin Dosing. 27 July 2007. <http://www.fda.gov/oc/initiatives/
criticalpath/warfarin.html>.
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McWilliam A, Lutter R, Nardinelli C. "Health Care Savings from Personalizing Medicine Using Genetic Testing: The Case of Warfarin." 2006 AEI-Brookings Joint Center. 27 July 2007. <http://aei-brookings.org/publications/abstract.php?pid=1127>.
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Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329-33.
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Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost. 2004 Jan;91(1):87-94.
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Hillman MA, Wilke RA, Yale SH, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res. 2005 Aug;3(3):137-45.
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Millican E, Jacobsen-Lenzini PA, Milligan PE, et al. Genetic-Based Dosing in Orthopedic Patients Beginning Warfarin Therapy. Blood. 2007 Mar 26; [Epub ahead of print]
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Voora D, Eby C, Linder MW, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost. 2005 Apr;93(4):700-5.
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Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet. 2007 Mar;121(1):23-34. Epub 2006 Oct 18.
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WarfarinDosing.org. 27 July 2007. <http://www.warfarindosing.org>.
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Aquilante CL, Langaee TY, Lopez LM, et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther. 2006 Apr;79(4):291-302. Epub 2006 Feb 28.
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