Researchers have launched the WARFARIN study to determine if genetic testing could improve the safety and effectiveness of warfarin, which could lead to estimated savings to the U.S. healthcare system of approximately $1.1 billion.
The Centers for Medicare & Medicaid Services (CMS) approved the study, initiated by Iverson Genetic Diagnostics, under Coverage with Evidence Development and will cover pharmacogenetic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness.
The WARFARIN (Warfarin Adverse event Reduction For Adults Receiving genetic testing at therapy INitiation) study intends to include more than 7,000 patients at up to 50 study sites in the U.S. for a duration of 18 months.
Patients with CYP2C9 or VKORC1 gene variants could have their warfarin dose adjusted to accommodate their body's individual dosing requirements.
"The WARFARIN study is the first major personalized medicine study approved by CMS," principal investigator Elizabeth Ofili, MD, MPH, chief of cardiology at Morehouse School of Medicine in Atlanta, told Cardiovascular Business News. "CMS wants to gather data on the potential impact of a pharmacogenetic test to reduce serious bleeding and clotting episodes in patients. "
Warfarin is difficult to dose as patients respond to it differently according to their genetic makeup—too much warfarin can result in severe bleeding, and too little can cause clot formation and increased risk of stroke. Warfarin dosing relies on trial and error, which exposes patients to serious medical risks. And it is the second most frequent cause of drug-related emergency room visits, according to Ofili.
Over the past few years, researchers have identified two genetic variants that predict an individual's response to warfarin—VKORC1 (for warfarin sensitivity) and CYP2C9 (for warfarin metabolism), which contribute up to 40 percent of an individual patient's variations in response to using warfarin.
"Using INR [international normalized ratio] testing for patients without these gene variants should be fine," said Ofili. "In those with the gene variants, however, even after they get average doses and go home, they could have huge jumps in their INR—up to 7, 8, 10 or even 12, where the normal is 3, and that is a risk for hemorrhage."
The WARFARIN study will compare dosing guided by genetic testing for these two genes with standard INR dosing.
Previous smaller studies examining warfarin response to patients with these gene variants have been conflicting. CMS would like to resolve this problem, hence the agency called for a well designed study in the context of coverage with evidence development. This means that CMS will cover the cost of the genetic test for this trial, with the potential to reimburse for the test depending on the findings.
It is important to have test results within 24 hours. "We don't want to give patients several doses before the genetic results are known," she said. "In that scenario, we would have missed the timeline to impact the INR."
The gene variants can result in a patient needing more or less warfarin. The degree of reduction depends on the mutation and some mutations require very little drug that has to be carefully titrated, she said.
The VKORC1 gene reduces levels of vitamin K, which leads to clotting. If this gene is not working properly, the body will not adequately reduce levels of vitamin K, therefore putting the patient at risk for stroke. Even knowing that a patient has a mutation of this gene, however, will not obviate the need for INR testing. "There are many factors that influence vitamin K levels, including food and drugs," Ofili said. "There also are other gene variants that interact with this gene pathway."
Variants of the CYP2C9 gene retard the body's ability to break down warfarin, helping it linger longer in the bloodstream, which means the patient needs less of the drug or will be at risk of hemorrhage.
Other drugs that don't require INR monitoring also are being used to prevent clotting, such as clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Aventis) and dabigatran (Pradaxa, Boehringer Ingelheim). Whether these gene variants affect the responsiveness of clopidogrel or dabigatran is not yet known, Ofili said.
In the WARFARIN study, researchers will catalogue patients' response to other factors that affect warfarin efficacy, such as environmental, dietary and other drug interactions. "The question we want to answer is, How can genetic