These findings, published June 4 EDT in The Lancet, are the latest results from ongoing collaborative work by 42 researchers from 17 institutions in the International Warfarin Pharmacogenetics Consortium led by University of Florida Health researcher Julie A. Johnson, a distinguished professor of pharmacy and medicine and director of the UF Center for Pharmacogenomics.
A highly effective blood thinner taken by patients at risk for strokes caused by clotting, warfarin also contributes to nearly one-third of all hospital admissions for adverse drug events.
“Warfarin dose requirements vary substantially among all patients and the perfect dose is critical,” said Johnson, the V. Ravi Chandran professor of pharmaceutical sciences at the UF College of Pharmacy. “A little high might mean bleeding risk, a little low raises a danger of a clot that can cause pulmonary embolism or stroke.”
Also known as Coumadin, warfarin is a low-cost drug option that may be prescribed for short- or long-term blood-thinning therapy. Last month, the IMS Institute for Healthcare Informatics reported that more than 33 million U.S. prescriptions for warfarin were filled in 2012.
Among all patients, warfarin daily doses range anywhere from 1 milligram to 20 milligram, and even a small miscalculation can lead to complications. It may take a couple of weeks to several months to determine the right dose without the use of genetics, leaving patients vulnerable in the process. By compiling genetic data along with other factors that affect dosing, such as patients’ weight, age and other drugs being taken, doctors can prescribe a more accurate dosage for any patient from the start. For African-Americans, however, that wasn’t enough to predict the widely variable dose of warfarin, so the researchers began looking for additional factors. They discovered a difference in one part of the genome that strongly influences how people of African-American descent metabolize these drugs.
After adding this genetic marker to dosing algorithms, co-author Minoli Perera, an assistant professor of medicine at the University of Chicago, showed a 21 percent improved predictability of warfarin dosing for the at-risk population, who often require a higher dosage.
“This finding demonstrates the potential for genetic studies, especially those applied to minority groups, to make a substantial impact on both the population and the personal level,” Perera said. “Physicians will appreciate its impact on the management of this common and difficult-to-dose drug. Patients who carry this mutation will appreciate that their doctors can start them at a lower dose that is closer to what they really require.”
Studies conducted at the University of Illinois at Chicago and the University of Chicago identified novel genetic associations with warfarin dose requirements in African-Americans. Study co-author Larisa H. Cavallari, an associate professor in the UIC department of pharmacy practice, has been a member of the consortium since its early efforts to identify a dosing algorithm for warfarin.
Existing pharmacogenetic algorithms have not accurately predicted the best warfarin dose in African-Americans, said Brian F. Gage, an internist and a professor of medicine at Washington University in St. Louis whose work is independent of the consortium.
Gage developed a website, www.warfarindosing.org, that offers a calculator for his widely used warfarin dosing algorithm for clinicians evaluating new patients or seeking scientific resources, including patient education. Johnson and her colleagues, who also have contributed a dosing algorithm to the site, believe that doctors and their patients will benefit with the addition of the consortium’s newest findings.
The consortium obtained genetic samples African-American participants with an average age of 59. To compare the results of the new dosing predictions, researchers collected genetic samples from several clinical study sites. They analyzed 533 samples from the discovery group and compared them to a 432-validation group of African-American adult volunteers — all taking maintenance dose of warfarin.
“Incorporating this gene variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population and help more patients arrive at their optimal dose more quickly,” said Nita Limdi, an associate professor in the department of neurology at the University of Alabama at Birmingham School of Medicine, and a co-author of the study.
The UAB, with a large demographic population at risk for health care disparities, enrolled the largest number of patients in the study.
“This newly discovered polymorphism will improve prediction substantially,” Gage said. “Furthermore, because it affects warfarin metabolism, accounting for it should significantly decrease the risk of overdosing African-Americans who are initiating warfarin.”
The consortium researchers all hope to improve patients’ outcomes worldwide by taking the next steps to apply what they have learned.
“We are currently genotyping all patients newly starting warfarin at the University of Illinois Hospital & Health Sciences System. We plan to add the new variant, described in the Lancet paper, to our genotyping platform,” Cavallari said.
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