Warfarin (Coumadin®) is a blood thinner given to people at high risk for the formation of blood clots due to conditions such as deep vein thrombosis, heart valve disease or replacement, and irregular heart beat. The drug is also given to prevent recurrence of pulmonary embolism, heart attack and stroke.

If too little warfarin is prescribed, the threat of blood clots will remain. But if too much drug is given, uncontrolled bleeding can result. Add to this the fact that “too little” and “too much” can vary significantly between people, and it’s no wonder that complications from incorrect warfarin dosing are one of the most common reasons for emergency room visits due to adverse drug reactions.

In 2007, the FDA updated the labeling information for warfarin to include information about how variations in two genes, CYP2C9 and VKORC1, can impact a patient’s optimal dose of the drug.  But the FDA did not make specific dosing recommendations at that time.

Now the FDA has updated warfarin’s label once again, this time specifically saying that a “patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose.”  The agency also provides initial dosage recommendations for patients with different variant combinations.  The FDA does not, however, require that genetic testing be done before prescribing warfarin.

The warfarin label lists non-genetic factors that can impact warfarin dosing, including age, race, body weight, sex, other medications and other medical problems.  These factors are accounted for in the dosing recommendations given in the label.

The Centers for Medicare and Medicaid Services, the federal agency that makes decisions about what Medicare, Medicaid and the Children’s Health Insurance Program will cover, decided last year that there was not sufficient evidence to justify covering genetic testing before warfarin administration for Medicare beneficiaries.  They did say, however, that they would pay for testing in patients who are part of clinical studies aimed at gathering more data on how outcomes are influenced by the availability of genetic information.

Many physicians are still not comfortable incorporating genetics into their prescription decisions.  The Pharmacogenomics Reporter quoted Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, as saying, “Doctors tell us all the time, don’t tell us about VKORC1, just tell us what the right dose is for patients,” at a recent conference.

The American Medical Association has produced a booklet to help doctors understand the science behind genetics and warfarin dosing.

23andMe Health Edition and Complete Edition customers can view their data for the genetic variations in CYP2C9 and VKORC1 considered in the FDA labeling update in the Warfarin (Coumadin®) Sensitivity Drug Response Report.

A downloadable PDF version of the Warfarin Sensitivity report is available to help customers share their results with their doctors.

Only a physician can determine whether warfarin is the right medication for a particular patient and at what dosage it should be given.  The information contained in 23andMe Drug Response reports should not be used to independently establish a drug regimen or abolish or adjust an existing course of treatment.

The Spittoon previously reported on one of the studies that contributed to the FDA’s new labeling decision.

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Each time a doctor writes a prescription for warfarin (Coumadin®), a blood thinner given to about two million people each year in the United States, it’s a guessing game.  There is no “right” dose of the drug.  Everyone is different and it can take weeks of adjustment to find a patient’s ideal amount of the medication.  Too much puts the patient at risk for bleeding.  Too little can lead to clots and in turn, heart attack, stroke or even death.

In addition to clinical factors such as age, body size, other medications and ethnicity, genetic factors can affect a patient’s ideal dose of warfarin.  In 2007 the FDA added to warfarin’s label information about the importance of these genetic factors, but stopped short of directing doctors to carry out testing before prescribing the drug.  This may change, however, based on the results of a large international study published yesterday in the New England Journal of Medicine. The study shows that dosing decisions based on genetic information in addition to clinical data come significantly closer to the ideal dose for almost half of all patients.

Scientists from the International Warfarin Pharmacogenetics Consortium, comprised of research centers in Taiwan, Japan, Korea, Singapore, Sweden, Israel, Brazil, Britain and the United States, used the medical records and genetic information of about 4,000 patients who had been prescribed warfarin to develop a “pharmacogenetic” method for predicting the ideal dose. They then tested their method by applying it to the information from an additional 1,000 patients who had taken warfarin.

Compared to initial warfarin dosing decisions made with clinical data alone or based on a fixed starting dose of 35 mg per week for every patient, the pharmacogenetic method provided significantly better predictions of the final, ideal dose for many people.

“The greatest differences among the dose-prediction approaches were noted among patients whose stable therapeutic warfarin doses were 21 mg or less per week and among those whose stable doses were 49 mg or more per week, representing 46% of the cohort. These are the patients for whom an underdose or an overdose could have adverse clinical consequences,” the authors write.

The dosing method developed by the researchers did not provide a significantly better approximation for the 54% of patients whose ideal dose fell between 21 and 49 mg per week.

While the current study does show that genetic information can better predict the ideal dose of warfarin for a patient, it does not address whether this translates into less risk for bleeding or clotting. This question will be addressed by a soon-to-be-launched NIH-sponsored clinical trial called “Clarification of Optimal Anticoagulation through Genetics” (COAG).  This large study being conducted at 12 sites will evaluate how a gene-based dosing strategy affects a patient’s ability to maintain the correct level of blood thinning, the risk for bleeding problems, quality of life and cost of therapy.

“A better understanding of individual differences in the response, either positive or negative, to medicines should be an overarching goal for pharmacotherapy over the next decade. Pharmacogenetics has the potential to increase benefit and reduce harm in people whose drug responses are not ‘average’,” write Janet Woodcock and Lawrence Lesko, of the Center for Drug Evaluation and Research at the Food and Drug Administration, in an editorial that accompanies the study.

But, they warn, the move toward using genetic information to make prescription decisions must be made prudently.

“Given the expected volume of genetic information and the relative paucity of randomized, controlled trials involving marketed drugs, we need clear thinking about what is required for the adoption of pharmacogenetic testing.”

23andMe scientific advisor Russ Altman is a lead investigator for the International Warfarin Pharmacogenetics Consortium.

An article about the genetic influences on warfarin dosing is expected to be added to the Health and Traits section of 23andMe soon.  In the meantime, customers can use the Browse Raw Data feature to find out about their data as it relates to the study discussed in this post.  The study indicated that the ideal warfarin dose for people with the SNPs listed below may be lower than the average dose. As a reminder, 23andMe does not provide medical advice and this information should not be used to choose or adjust an already prescribed dose of warfarin.

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