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New Developments May Change Study Results
Submit responseGiven the FDA’s decision to include on warfarin labels a suggestion to consider genetic testing prior to dosing, we read with interest the thoughtful analysis of studies to date on genetic testing for warfarin sensitivity (“Cost- Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients With Nonvalvular Atrial Fibrillation,” 1/20/09, Volume 150, Issue 2, pp. 73-83). The authors’ finding that warfarin testing is not cost- effective is reasonable based on the studies they examined, and we appreciate the inclusion of caveats that could potentially change that conclusion. We would like to highlight a few of those points, based on rapidly emerging developments in this field.
Cost. The authors assumed that genetic tests would cost $400, the price that might be paid by a consumer who seeks an independent test from a lab. With more widespread use of the tests, costs for hospitals or clinics are now much lower, as low as $50-$75 per test, or about $150 to $225 if positive and negative controls are run with each test. As the authors note, a $50 test is in fact cost-effective. Given the advances in technology, we suspect the price point will drop further and therefore, make this test not only cost- effective but also beneficial (“clinically worthy”) to the patient.
Timing. In their analysis, the authors assume that it would take about three days to get a result from a genetic test. This time frame was reasonable when the underlying studies were done, given that few labs processed the tests at that time. Today, the tests can be turned around in as little as 45 minutes from patient to calculated dose, with most in the range of two to six hours and results obtainable in no more than 24 hours. While it is difficult to calculate the cost-effectiveness of a quicker test, some studies suggest that it will result in fewer adverse events, simply because patients could be given a more appropriate dose more quickly (1, 2, 3).
Finally, we are concerned that the underlying studies, among others, examine the number of bleeding events as a way of determining whether treatment is effective. Bleeding is a relatively rare event, even more so in many of these studies, since it is unlikely that caregivers in state-of-the-art anti- coagulation clinics or clinical research (academic medical centers of excellence) settings would have failed to adjust a patient’s warfarin dose before bleeding could occur. Alternative measurements, that are possibly superior, are the number of dose adjustments (times a patient must get a new prescription filled or visit a clinic for an INR measurement), change between initial and final warfarin dose, or time to stable INR, in order to measure whether the genetic test resulted in more accurate initial dosing.
As we are all aware, these are serious issues. Errors in warfarin dosing result in 17,000 strokes and 85,000 serious bleeding events each year, and as many as 43,000 emergency room visits. If the 2 million people who start taking warfarin each year are able to receive a more accurate dose more quickly, the benefit to patients might be immense, with substantial healthcare cost savings.
References
1. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mos Dis. 2009 Mar 16
2. Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy. Pharmacogenomics. 2008 Sept;9(9):1237-50
3. Frequency of adverse events in patients with poor anticoagulation: a meta-analysis. CMAJ. 2007 May 22; 176(11): 1589–1594
Conflict of Interest:
None declared
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Health Care System Issues & Patient Characteristics Impact Cost Effectiveness of PG-Guided Dosing
Submit responseWe appreciate the comments from your readers. In fact, we agree with many of their observations. The results of our analysis are more nuanced than a simple assertion that pharmacogenetic-guided (PG) dosing is not “cost effective.” Indeed, we used sensitivity analyses to explore how changes in either health care delivery systems or patient characteristics might affect the cost-effectiveness of PG-guided dosing. With regards to systems changes that might make this strategy “cost-effective,” we found that the marginal cost-effectiveness ratio drops below a societal willingness-to-pay threshold of $50K per quality adjusted life year (QALY), when the cost of genotyping is less than $200 and results were available at the time of warfarin initiation. Regarding patient characteristics, we found that patients at higher risk for bleeding would benefit more from PG-guided dosing. In particular, PG-guided dosing would cost less than $50K/QALY for patients having more than a two-fold increase, risk of major bleeding compared to a patient without risk factors for hemorrhage. This corresponds to a HEMORR2HAGES score between 1 and 2, or an absolute risk of major hemorrhage greater than ~4% per year(1). Note that all of these findings are predicated on the assumption that PG-guided dosing reduces adverse events. The 32% reduction in major hemorrhage that we estimated was not statistically significant [relative risk – 0.68, 95% CI, 0.22 to 2.06]. Thus, additional randomized trials are needed to quantify this reduction.
Finally, the point is made that use of genotype might be helpful in the future, such as if a patient requires a second course of warfarin therapy at a later date. However, in our experience when both genotype and a prior therapeutic dose are known, knowledge of the prior dose trumps genotype.
References:
1. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151(3):713-9.
Conflict of Interest:
None declared
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Is Cost-Effective Genotype-Informed Warfarin Dosing Closer Than We Think?
Submit responseWe read with interest the article by Eckman, et al and believe it provides a useful starting point for assessing the cost-effectiveness of genotype-informed warfarin dosing. While the authors are to be commended for their modeling effort, it should be emphasized that much work remains to be done before such assessments will be robust. As the authors note, there is considerable uncertainty about the impact of genotype-informed dosing on serious bleeding events during warfarin initiation that even large studies like the incipient NHLBI-sponsored COAG trial will not fully address.
All models are hostages to their assumptions and data, including the latter's timeliness; this model is no exception. In this case, the timeliness of genotyping costs and availability of real time test results, appear to significantly affect the author’s model. By their analysis as genotype costs and time to obtain genotype results decrease, the cost/QALY falls. When genotype results are available in real time and at a cost of about $200 the cost/QALY rapidly approximates the $50,000 gold standard of cost effectiveness. (See authors' Figure 1.)
Given the model's apparent sensitivity to these values and considering that genotype-related test costs have fallen since the inception of this paper, more attention should have been given to sensitivity analyses that included genotype costs below $200 and close to real time genotype availability. We note that such analyses would have been consistent with historical trends for genotype test costs; reflected costs that are more aligned with large scale production costs as opposed to nearer first-copy costs; reflected likely competitive market outcomes for about 300,000 annual genetic tests for individuals new to warfarin; and provided a more appropriate forward-looking assessment of the potential for cost-effective genotype-informed warfarin dosing. Our position on this issue is well reasoned and supported by current marketplace pricing for the required genetic tests, which range from $185 to $250 per test bundle (February 2009 Medicare Clinical Laboratory Fee Schedule) (1). (Table 1, vide infra).
In the end, the most important impact of these modeling choices is on the impressions of readers. We believe that many readers may limit their review to the abstract and thereby be left with the misconception that genotype-informed dosing is not cost-effective under any likely conditions. Since this does not appear to us to be a valid conclusion, we believe the article and its abstract should have included a more balanced summary of the potential for cost-effective genotype-informed warfarin dosing.
(1) http://www.cms.hhs.gov/ClinicalLabFeeSched/02_clinlab.asp#TopOfPage select 09CLAB.zip
Table 1
Code National Limit ($) Procedure
83891 5.85 Isolation or extraction of highly purified DNA
83892 5.85 Enzymatic digestion, each enzyme treatment
83900 48.95 Amplification, target, multiplex, first 2 nucleic acid sequences
83901 24.47 Amplification, target, multiplex, each additional nucleic acid sequence >2
83896 5.85 Nucleic acid probe, each
83908 24.47 Amplification, signal, each nucleic acid sequence
83912 5.85 Interpretation and report
83914 24.47 Mutation identification by enzymatic ligation or primer extension, single segment,
each segment (eg OLA, SBCE, ASPE)
Conflict of Interest:
Marshfield Clinic has a licensing agreement with Osmetech, Inc granting use rights to scientific discoveries by MC, JB and RB that have application to genotype-informed warfarin dosing. Third Wave Technologies, Inc, and Osmetech, Inc, provided supplemental funding to an AHRQ-funded study of genotype-informed dosing (#RO1 HS 016355) in which JS, RB, JB, SY and MC are investigators.
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Study Misinterpreted Meta-Data - Raises Concern on the Validity of the Findings
Submit responseTo the Editor:
There are several issues in the recent article on the cost-effectiveness of using pharmacogenetic information in warfarin dosing that raise concern about the adequacy of the analysis and hence the significance of the findings (1).
Dr. Anderson and his colleagues reported the proportion of patients with SERIOUS ADVERSE CLINICAL EVENTS in each group during the 90 days clinical study (2). Those clinical events included 7 different categories (INR>3.9, use of vitamin K, major bleeding events, thromboembolic events, stroke, myocardial infarction, and death). Dr. Eckman and his colleagues used those results as if they were all MAJOR BLEEDING EVENTS. This is clearly a mistake since 5 events in the control group and 4 events in the study group (5.1% and 4.0%, respectively, P=0.71, OR=0.78 [95% CI 0.20-2.98]) are much higher rates of major bleeding events reported in other clinical studies (3, 4).
Dr. Eckman and his colleagues also argue that if 300,000 patients start warfarin therapy each year in the U.S., a genotype-guided dosing would prevent 300 major bleeding events during the first year of therapy. This conclusion is contradicting their own meta-data analysis. Drs. Landefeld and Goldman reported that the first month risk of major bleeding events is 3% (3). A projected 32% reduction in major bleeding events from the use of genotype-guided dosing would suggest that the 3% first month risk would be reduced to 2% and 1% would be prevented, which is 3,000 major bleeding events. This is a factor of 10 mistake!
Analyzing the results of just the other two clinical studies by Caraco et al.(5) and Hillman et al.(6) used by Dr. Eckman and his colleagues in the meta-analysis suggest that genotype-guided dosing efficacy in preventing major bleeding is 100%. According to this article analysis, the marginal cost-effectiveness of testing in the base case would actually be below $50,000 per QALY. However, these cohorts are too small for the underlying statistics for a meaningful pharmacoeconomics analysis.
References
1. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients With Nonvalvular Atrial Fibrillation. Ann Intern Med. 2009;150:73-83.
2. Anderson JL, Horne BD, Stevens SM, Grove AS, et al. Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation. Circulation. 2007;116:2563-70.
3. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989;87(2):144-52.
4. Wadelius M, Chen LY, Lindh JD, Eriksson N, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2009;113:784-92.
5. Caraco Y, Blotnick S, Muszkat M. CYP2C9 Genotype-guided Warfarin Prescribing Enhances the Efficacy and Safety of Anticoagulation: A Prospective Randomized Controlled Study. Clin Pharmacol Ther. 2008;83:460-70.
6. Hillman MA, Wilke RA, Yale SH, Vidaillet HJ, et al. A Prospective, Randomized Pilot Trial of Model-Based Warfarin Dose Initiation using CYP2C9 Genotype and Clinical Data. Clin Med Res. 2005;3:137-45.
Conflict of Interest:
None declared
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Potential cost savings of fewer visits and less time for patients should be included in analysis
Submit responseTO THE EDITOR:
In their recent article on the cost-effectiveness of using pharmacogenetic information in warfarin dosing, Eckman and colleagues present the most complete and practical cost-effectiveness analysis of this issue to date (1). However, their model did not consider some cost savings that could result from pharmacogenetic testing. If genotype-guided warfarin dosing results in shorter time to stable anticoagulation or the need for fewer INR measurements and fewer visits, then important cost savings would result. There is some evidence to suggest this may be the case. First, a controlled trial in Israel comparing genotype-guided dosing with clinical management reported that stable anticoagulation was reached 18.1 days earlier for those in the genotype-guided group (2). Second, an RCT in the US comparing genotype-guided dosing with standard dosing reported no significant difference in their primary outcome (% out-of-range INRs), but reported fewer dose adjustments (mean 3.0 vs. 3.6, p=0.035) and fewer INRs needed (mean 7.2 vs. 8.1, p=0.06) for those in the genotype-guided group (3). The difference suggests that there could be an average savings of one visit with genotype-guided dosing. From the societal perspective, the value of this would include the cost savings of the visit and one INR ($18.95 and $5.49 according to the Eckman article, respectively) as well as the cost of patient time.
The Panel on Cost-effectiveness in Health and Medicine recommends including patient time costs in analyses conducted from the societal perspective (4). It has been estimated that one anticoagulation clinic visit requires an average of 147 minutes for travel, waiting, and visit time (5). Using the human capital method with the hourly wage rate of $19.29 (from the National Compensation Survey, June 2006), the time patients spend for one visit is worth $47.26 (5).
Inclusion of the potential cost savings of fewer visits and less time for patients would decrease the cost per QALY to less than $171,800 as calculated in their base case. In addition, for centers where in-hospital testing is available at a cost of less than $200 with a turnaround time under 24 hours, the more favorable marginal cost-effectiveness ratio of $51,000 per QALY (from their sensitivity analyses) could decrease to a number that would make genotype-guided dosing cost-effective, perhaps even if the efficacy for reduction in hemorrhage is worse than their base-case value of 32%. It is also worth noting that the cost-effectiveness threshold of $50,000 per QALY may significantly undervalue QALYs, with some economists estimating the value of a human life year around $129,000 (6).
References
1. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150(2):73-83.
2. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008;83(3):460-70.
3. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007;116(22):2563-70.
4. Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-Effectiveness in Health and Medicine. New York: Oxford University Press; 1996:xxiii, 425.
5. Jonas DE, Bryant Shilliday ME, Laundon WR, Pignone M. Patient Time Requirements for Anticoagulation Care. Society of General Internal Medicine, 31st Annual Meeting. Pittsburgh, Pennsylvania; 2008.
6. Kingsbury K. The Value of a Human Life: $129,000. Time.com May 20, 2008. Available at: http://www.time.com/time/health/article/0,8599,1808049,00.html.
Conflict of Interest:
None declared
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Clinical And Economic Factors That Might Change the ICER of Genotyping Before Warfarin Therapy
Submit responseWe were surprised that Eckman et al. found through comprehensive modeling (1) that genotyping before warfarin therapy instead of standard care without genotyping is not cost-effective when compared with other, well- accepted medical interventions.We suggest that additional factors may improve the cost-effectiveness of warfarin genotyping. For example, if patients with a short-term warfarin indication (i.e. uncomplicated deep vein thrombosis) had their genotype recorded in an interoperable electronic health record, this test would not need to be repeated prior to subsequent warfarin use. Because genotype testing is the largest component of costs, additional benefit would accrue with limited or no incremental costs. In addition, restricting testing to those most likely to have complications of supra-therapeutic warfarin levels (i.e. the elderly at a high risk for falls or patients with a known history of gastrointestinal bleeding), may improve cost-effectiveness. The incremental costs of avoiding complications may be lower and the incremental health benefits may be higher.
Although restricting testing to those most likely to benefit may improve cost-effectiveness, diagnostic tests tend to be used more broadly than the initial research indications, potentially diluting the average health benefits. However, widespread adoption of warfarin genotype testing or technologic advancements may decrease the unit cost of testing beyond the range evaluated in the sensitivity analysis. If so, the overall cost- effectiveness may improve. These clinical and economic factors may change the incremental cost- effectiveness ratio, although the direction and magnitude is unclear without full model evaluation.
References
1. Eckmann MH, Rosand J, Greenberg SM, Gage BF. Cost-Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients With Nonvalvular Atrial Fibrillation. Ann Intern Med. 2009;150(2):73-83.
Conflict of Interest:
None declared
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Alternate Reasons Why Genetic Testing Will Not Be Cost-Effective
Submit responseMany people starting warfarin have friends or relatives who are eager to tell "how it really is". This includes scaring the new warfarin patient with statements like, "You know it is really rat poison" or "Remember that Aunt Minnie bled to death on that drug". These are strong disincentives to properly starting warfarin therapy.
Many professional warfarin managers are overly cautious and as a result scare the new warfarin patient into being reluctant to start warfarin. Statements such as, "You have to be careful about green vegetables," "Shave only with an electric razor", "Be careful not to cut yourself" are powerful disincentives to taking warfarin that are of questionable value.
No amount of expensive testing will overcome what friends or relatives say. Until health-care professionals realize that the green vegetable statement is the equivalent of saying, "I have determined your proper warfarin dose and now it is your duty to change your lifestyle to prove that I am correct" we cannot expect people who need warfarin to be enthusiastic about initiating therapy. Thus genetic testing is unlikely to be cost effective in today's environment.
Conflict of Interest:
None declared