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Warfarin-Dose Dx May Not Be Cost-Effective for 'Typical' Patient; May Be for At-Risk Cohort

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It may not be cost-effective to perform genetic tests to guide initial warfarin dosing in "typical" patients with atrial fibrillation, though it may be cost-effective to test individuals at high risk for hemorrhage, according to a meta-analysis from the University of Cincinnati.

The study, which appears in this week's issue of Annals of Internal Medicine, comes two weeks before the Centers of Medicare and Medicaid is slated to make a national coverage decision on pharmacogenetics-guided warfarin dosing.

The researchers said that in the "typical" case, described as a 69-year-old man with newly diagnosed nonvalvular atrial fibrillation and no contraindications to warfarin therapy, "genotype-guided dosing resulted in better outcomes, but at a relatively high cost."

Consequently, in this population the overall cost-effectiveness of gene testing exceeded $170,000 per quality-adjusted life year, or QALY. "On the basis of current data and cost of testing (about $400), there is only a 10 percent chance that genotype-guided dosing is likely to be cost effective (that is,

However, the study suggests the test may be cost-effective if it is given to patients who are at high risk of hemorrhage, and if the test prevents 32 percent of major bleeding events, is available within 24 hours, and costs less than $200.

Mark Eckman, professor of medicine at the University of Cincinnati and lead investigator of the study, noted that cheaper and faster testing could be accomplished if hospitals carry out the sample analysis in-house. Currently, most hospitals have to send sample to outside labs for analyses, "which can lead to delays in starting treatment and increased cost," Eckman told Pharmacogenomics Reporter this week.

Currently most genetic tests for warfarin dosing cost between $200 and $500, and the turnaround time from sample collection to result delivery varies from same-day turnaround to up to a week.

Since updating the label for warfarin in 2007 with genetic risk-association data, the US Food and Drug Administration has approved a handful of genetic tests from several companies, including ParagonDx, Nanosphere, Autogenomics, and Osmetech.

However, the relative dearth of clinical-utility data for such tests has kept physicians from widely adopting genetic testing into their practices and many payors have decided not to cover the technology [see PGx Reporter 09-26-2007].

It was not immediately clear whether the cost-effectiveness study published in the Annals of Internal Medicine would influence how gene-based warfarin-dosing tests would be covered by the Centers for Medicare and Medicaid Services. CMS has gathered public comments on the issue and is slated to make a national coverage decision on Feb. 4 [see PGx Reporter 08-13-2008].

Whatever CMS' decision is on PGx-guided warfarin dosing, it is likely that many private insurers will likely follow CMS' lead.

"Personalized, predictive medicine offers great promise, but we need to carefully examine the benefits and understand the cost-effectiveness of such strategies before we spend a lot of money on very expensive tests," Eckman said in a statement.

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Specific Populations

To arrive at their findings, Eckman and his team combined the results of the only three randomized trials published to date that have analyzed the extent to which pharmacogenetic-guided dosing decreases the risk of major bleeds when compared with standard warfarin induction.

The three studies included in the meta-analyses were the COUMAGEN study by Anderson et al. published in Circulation in 2007; a study published by Hillman et al. in Clinical Medicine & Research in 2005, and a study by Caraco et al. published in Clinical Pharmacology & Therapeutics in 2008.

Eckman's team modeled cost-effectiveness of a genotype-guided dosing strategy by using the Markov transition-state decision model and provided probabilistic sensitivity analyses using second-order Monte Carlo simulations.

The study by Eckman et al. showed a trend that genetic testing may reduce the risk of major bleeding during the initiation phase of warfarin treatment, though the claim was not statistically significant since there were a small number of bleeding events in the three studies.

Ultimately, the final answer to whether genetic testing is cost-effective for all patients starting warfarin treatment will "depend upon future clinical trial data, and whether this trend towards decreased bleeding risk is maintained or not," Eckman said.

Eckman emphasized to Pharmacogenomics Reporter this week that since the study only looked at the cost-effectiveness of PGx-guided dosing for patients with atrial fibrillation, the results are not generalizeable with regard to whether genetic testing is cost-effective for all patients starting warfarin treatment.

"I would be careful about generalizing the results to all patients starting treatment with warfarin," he said. "A very large assumption in our analysis is that PGx-guided dosing does in fact decrease the risk of major bleeding during the initiation phase of warfarin treatment."

Two years ago, the FDA updated the label for warfarin to note that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. At the time, agency officials also pointed out that approximately 2 million people are initiated on warfarin therapy each year to prevent blood clots, heart attacks, and stroke. According to the FDA's adverse events reporting database, complications from warfarin are the second-most common reason for emergency room visits, behind adverse reactions from insulin [see PGx Reporter 9-5-2007].

Proponents of warfarin genetic testing often cite these figures to urge greater adoption of the technology into medical practice.

Cost Conscious

The findings of this current study suggest that genetic testing may be worth the high costs of genetic testing, if the patient is at high risk of hemorrhage, if the test prevents 32 percent of major bleeding events, if test results are available within 24 hours, and if the cost of the test is under $200.

However, cost-effectiveness estimates on PGx-guided warfarin dosing may differ based on the parameters being looked at.

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For instance, in comments to CMS' national coverage-assessment announcement for PGx-guided warfarin dosing, Brian Gage, medical director of the Barnes-Jewish Hospital's Blood Thinner Clinic, suggested that the technology should be reimbursed under certain conditions but outlined somewhat different criteria for coverage.

In his recommendations to CMS, Gage, who is also a co-author on the Annals of Internal Medicine paper, said coverage should be provided under the following conditions: (1) the patient is starting warfarin for the first time; (2) the genotype results will be available before the fourth dose is prescribed; (3) the patient would be at high risk of hemorrhage if the INR is elevated; and (4) the patient requires parental anticoagulant therapy (e.g. fondaparinux or intravenous or low-molecular-weight heparin) while his/her INR is subtherapeutic.

Gage, one of the creators of the online dosing calculator WarfarinDosing.org, has previously told Pharmacogenomics Reporter that CMS and private insurers are most likely to cover this technology "only when [it] would be cost-neutral or cost-saving."

In his estimation, genetic testing could show a cost-saving for patients who require intravenous or low-molecular-weight heparin while their INR is subtherapeutic.

Eckman pointed out that some of Gage's recommendations to CMS are still consistent with the cost-effectiveness study findings, such as the recommendation regarding patients at higher risk of hemorrhage.

In an article published in Clinical Pharmacology & Therapeutics last year entitled "The Critical Path of Warfarin Dosing: Finding an Optimal Dosing Strategy Using Pharmacogenetics," Lawrence Lesko, director of FDA's Office of Clinical Pharmacology, pointed out that the per-patient savings has been projected in one study to be around $900.

However Lesko notes in the article that "more work must be done to obtain greater precision in estimating the cost-effectiveness" for warfarin genetic testing.

An oft-cited cost-effectiveness analyses by the American Enterprise Institute-Brookings Joint Center for Regulatory Studies, published in 2006, before any randomized controlled trials on warfarin genetic testing were conducted, concluded that genetic testing to dose the anticoagulant would save up to $1.1 billion per year in the US.

"However, many of the assumptions made in this analysis were optimistic, [such as] very high rate of serious bleeding among patients with the variant alleles (almost 28 percent), 100 percent efficacy of PGx-guided dosing in preventing these bleeds, including prevention of bleeding even during the maintenance phase of anticoagulant therapy," Eckman pointed out.

Future Directions

According to Eckman, future studies should focus on gauging the impact of PGx-guided warfarin on bleeding risk and follow patients for a period that allows researchers to monitor outcomes and determine "the true duration of benefit."

Eckman also suggests that instead of excluding patients at higher risk for bleeding, these patients should be enrolled in studies if it has been determined they need warfarin.

The Harvard-Partners Center for Genetics and Genomics is developing a nomogram for PGx-guided warfarin dosing with the FDA, and the HPCGG is also looking the pharmacoeconomic benefits of incorporating such technology into clinical practice [see PGx Reporter 11-29-2006].

Lesko points out in his Clinical Pharmacology & Therapeutics article that future studies should capture the potential savings from a reduction in the number of dosing adjustments and a decrease in the number of INR measurements.

"These could translate into lower health-care costs meaningful to physicians and patients and related to the costs of INR testing, laboratory personnel time, providers' care time, and patients' time and inconvenience," Lesko wrote in the article.

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