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Critical Path, AMA Debut Brochure to Educate Docs On Gene-Based Warfarin Testing

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Last week, the Critical Path Institute, the Arizona Center for Education and Research on Therapeutics, and the American Medical Association issued a new brochure to help educate physicians about gene-based warfarin dosing.
 
The brochure, called Personalized health care report 2008: Warfarin and genetic testing, “is designed for physicians and other healthcare providers who commonly prescribe warfarin but who may not have had exposure to pharmacogenomics and genetic testing,” the AMA states on its website.
 
The pamphlet discusses how variations in the genes CYP2C9 and VKORC1 affect patients’ ability to metabolize and respond to the anticoagulant; mentions the US Food and Drug Administration’s request for drug makers to update the drug’s label with genetic-testing information; and notes that an FDA-approved genetic test is available to determine which patients carry the gene variations.
 
In August, the FDA had pharmas update warfarin’s label to say that people with variations in the CYP2C9 and VKORC1 genes may respond differently to the drug. The agency, however, stopped short of including stronger language in the label that would require physicians to genetically test patients, noting the need for additional outcomes studies [see PGx Reporter 9-5-2007].
 
The brochure states that while genotyping patients for the CYP2C9 and VKORC1 variants may account for between 45 percent and 60 percent of the variation in their response to warfarin, “a large part of the variation is still unknown.” For this reason, genotyping patients should not be thought of as a panacea for warfarin’s dose variability between patients. 
 
“’Is genetic testing ready to replace what we’re doing today?’ That’s never been the question,” noted Raymond Woosley, president of the Critical Path Institute. “The question is, ‘Can genetic testing provide important, additional information?’”
 
“It’s just another very important piece of information that for some people can be life saving. And for others it won’t be as important,” he added.
 
Several academic and government institutions, including the University of Washington in Seattle, the University of Utah, the FDA in partnership with the principal investigators of the Harvard Creating an Optimal Warfarin Nomogram Trial, and the Warfarin Pharmacogenomics Consortium, are working to develop their own PGx-based dosing algorithm for warfarin.
 
Additionally, as reported in Pharmacogenomics Reporter’s sister publication BioInform, PGx Labs is developing a decision support system that combines a patient’s clinical and genotype information to determine the most appropriate maintenance dose for warfarin for a given patient.
 

“Those who have a dog in the fight, as they say, who are deciding whether they are going to pay for something, really need to start thinking about patients. Really, the science is overwhelming.”

While the AMA/Critical Path’s brochure doesn’t suggest a particular algorithm to dose warfarin, it does point physicians to visit www.warfarindosing.org, a website to help doctors initiate patients on warfarin therapy based on clinical factors and genotypes of the CYP2C9 and VKORC1 genes.
 
The recommendations on warfarindosing.org are based on data from more than 1,000 patients. Doctors enter patient information into the free site and immediately receive an initial estimate of a therapeutic dose that “explains 53 percent of the variability in a warfarin dose,” according to information on the site. “If you return to the website and enter an INR value after 3 and/or 4 warfarin doses, the dose refinement is even more accurate.”
 
Woosley noted that the Critical Path and the AMA plan to issue a second brochure on warfarin that will concentrate on dosing, drug interactions, or both. However, he noted that recommending “good dosing guidelines” for warfarin is challenging because there are so many clinical factors that can alter the dose from patient to patient.
 
The Critical Path Institute “and the FDA have gone back and forth on this,” Woosley said. “When you come right down to it, you can’t really give good dosing guidelines on warfarin.”
 
According to Woosley, even the distance a patient lives from the clinic factors into the dosing regimen. “For instance, if you’re seeing a patient who lives 20 miles from the clinic, and someone else lives one mile from the clinic, you may give them a different dose and a different regimen when they come back for INR,” he said. “You have to weigh in age and body weight. … If you don’t have any nurses or pharmacists to help the patient, and it’s just the doctor writing a prescription, it would be good if they weigh in the genetic information, but how much they weigh it in depends on how many resources they have to manage the patient.
 
“Every case is so different,” said Woosley. “It’s truly personalized medicine.”
 
Reimbursement Reservations
 
Meanwhile, although there have been numerous published studies and two FDA-approved genetic tests to gauge warfarin sensitivity [see PGx Reporter 01-30-2008], insurers remain uncertain about whether to reimburse for genetic tests designed to help doctors dose the commonly prescribed anticoagulant.
 
Recently, when a controversial PGx warfarin study, called Couma-Gen, by Anderson et al., failed to meet its endpoint, some payors interpreted it as a negative mark against genotyping to dose warfarin.
 
However, in the latest issue of Personalized Medicine, Lawrence Lesko, director of FDA’s Office of Pharmacology, and Brian Gage, associate professor of medicine at Washington University and the creator of warfarindosing.org, published an evaluation of Couma-Gen and how the study might improve the design of future PGx warfarin studies (see related article, this issue).
 
“Numerous studies have confirmed that a significant proportion of the variability in individual dose requirements and anticoagulation response to warfarin can be linked causally to polymorphisms in VKORC1 and CYP2C9,” Lesko and Gage wrote in the article, entitled “Couma-Gen: implications for future randomized trials of pharmacogenetic-based warfarin therapy.”
 
Woosley added: “Those who … are deciding whether they are going to pay for something really need to start thinking about patients. Really, the science is overwhelming.”

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