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Iverson Begins CMS-Funded Warfarin PGx Study; Plans to Return Test Results Within 24 Hours

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By Turna Ray

Iverson Genetics will attempt to avoid the pitfalls of past warfarin PGx studies by returning genetic testing results within 24 hours to doctors involved in a large trial funded by the Centers for Medicare & Medicaid Services.

Iverson Genetic Diagnostics announced on March 1 that its Warfarin Adverse Event Reduction for Adults Receiving Genetic Testing at Therapy Initiation, or WARFARIN, study has begun at 50 sites nationwide. The 7,000-patient study will assess whether testing patients for polymorphisms that might impact how they metabolize warfarin reduces the rate of adverse events more than when the drug is dosed without genetic testing data.

While past studies that have attempted to gauge the clinical utility of warfarin PGx testing have been hampered by slow test turnaround times, Iverson is promising to provide genetic test results within 24 hours.

For example, a warfarin PGx study conducted by the Mayo Clinic and the pharmacy-benefit manager Medco reported that hospitalizations due to blood clots or excessive bleeding for heart patients taking warfarin dropped by approximately 28 percent when genetic information was available to doctors.

However, a major limitation of the study was that the median turnaround time for getting genetic test results back to the doctor was 32 days — a disadvantage in the acute setting, where physicians must make dosing decisions within a few hours. Researchers involved with the Medco/Mayo study observed, however, that the closer the genotyping was to warfarin initiation, the better patient outcomes were (PGx Reporter 03/17/10).

Iverson will attempt to avoid the drawbacks of prior trials by generating test results much faster. The company will conduct testing for the study at its Atlanta lab located within Morehouse School of Medicine's clinical research center and will determine dosing through warfarindosing.org, a website that calculates warfarin doses for healthcare providers using genetics and clinical factors.

After patients agree to participate in the trial, they will get their first warfarin dose and will submit a sample for testing. Iverson aims to report the test results to the physician before the patient is due for another warfarin dose.

"All the participating sites will be trained on warfarindosing.org, because that's how the dosing gets calculated," Elizabeth Ofili, lead study investigator and cardiology chief at Morehouse School of Medicine, said.

Iverson is currently using the eSensor Warfarin Sensitivity Test, which was developed by GenMark Diagnostics and cleared by the US Food and Drug Administration in 2008, in the WARFARIN Study. However, the company also has an agreement with TrimGen to use its 510(k) cleared test, called eQ-PCR LC Warfarin Genotyping kit, which runs on Roche's LightCycler system. According to Iverson CEO Dean Sproles both tests gauge the same SNPs.

Sproles added that the study has been launched in at least two hospitals so far, WellStar Health System in Marietta, Ga., and Overlake Hospital Medical Center in Bellevue, Was. In total, the WARFARIN Study will be conducted in 30 hospitals across the country. Iverson is aiming to have the study started at 10 sites by the American College of Cardiology's annual meeting in New Orleans, April 2-5.

Iverson Genetics is being reimbursed for the genetic testing conducted as part of the WARFARIN study by CMS under a "coverage with evidence development" scheme (PGx Reporter 07/28/10).

Last year, when CMS found insufficient evidence demonstrating that PGx-guided warfarin dosing improves health outcomes for Medicare beneficiaries, the government payor decided not to cover such testing for Medicare recipients, except when it is performed as part of a prospective, randomized controlled trial (PGx Reporter 05/06/09).

The Genetics Informatics Trial of Warfarin, another PGx study in which Washington University's Brian Gage is looking at the utility of genetic testing to personalize warfarin dosing for orthopedic patients, is also funded through CMS's CED program. Gage is one of the developers of warfarindosing.org.

Iverson's randomized and blinded WARFARIN study will run for 18 months and will enroll more than 7,000 patients at various sites across the country. Researchers will compare the rate of warfarin-related adverse events — mainly bleeding and thromboembolism — that patients experience after receiving warfarin with the aid of PGx testing to the rate of such events in those who are dosed with standard methods. Researchers will track adverse events at 30 days, 60 days, and 90 days after initiating patients on the anticoagulant.

As many as 2 million new patients are initiated on warfarin each year in the US, and 21 percent of them experience adverse events due to getting too much or too little of the drug. Prior research suggests that two genetic polymorphisms, VKORC1 and CYP2C9, account for up to 40 percent of the variability in warfarin response.

Currently, warfarin dosing is adjusted by trial and error and by monitoring how fast a patient's blood clots with a prothrombin international normalized ratio test.

For the WARFARIN study, Iverson is planning to screen all 7,000 study participants for the VKORC1 and CYP2C9 polymorphisms. Ofili anticipates that of those who have these polymorphisms, approximately 1,650 will be enrolled in the PGx testing arm of the study and around the same number of patients will be dosed via standard methods.

"These two groups will receive everything in parallel," Ofili told PGx Reporter. "So they both will have their doses adjusted by the clinician who is caring for them. The difference is that those in the PGx arm will get dosing guidance after genetic testing."

The primary study endpoint will be to see if PGx testing reduces the rate of hemorrhagic and thromboembolic events after 30 days of receiving warfarin compared to dosing by standard methods. Researchers will also investigate whether PGx testing compared to standard dosing methods reduces the number of INR tests for a patient and whether it reduces the time it takes for a patient to reach a stable INR. In the study, investigators will also compare bleeding and clotting adverse events with PGx testing and standard methods at 60 and 90 days.

Although CMS doesn't currently reimburse for genetic testing related to warfarin administration, the results from this and other studies funded by CMS could impact the government payor's reimbursement policy toward this intervention. "Upon review of the [WARFARIN] study … the agency may establish reimbursement for [Iverson's] genetic warfarin test," the company said in a statement.

Since CMS initiated its CED for warfarin PGx testing and approved Iverson's study for funding under the program, a new antigoagulant called Pradaxa has come on the market that doesn't have the dosing variability of warfarin (PGx Reporter 10/27/10). Ofili noted, however, that the availability of Boehringer Ingelheim's Pradaxa shouldn't negatively impact CMS's cost-benefit calculations against PGx wafarin testing.

"Pradaxa is approved for atrial fibrillation patients, and while there are a significant number of individuals that require warfarin, you still have a lot of other people that need warfarin who are currently not eligible for Pradaxa because the drug is not indicated for those conditions," Ofili said.

She added that Iverson's study will allow CMS to consider whether generic warfarin with the added cost of genetic testing is cheaper than and improves patient outcomes better than Pradaxa, particularly in atrial fibrillation patients.

In Iverson's study, investigators will enroll all comers who have received warfarin for at least 30 days for any medical condition. "So, we expect to enroll people who have just had surgery, whose doctors think they will need warfarin for more than 30 days," Ofili said. "A big number of participants will be those who have atrial fibrillation, deep vein thrombosis, and those who have received a heart valve."


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