NIH-funded study shows genotyping adds no benefit when added to clinically-guided dosing formula11/18/2013
When it comes to giving patients the appropriate dosage of warfarin, a blood thinner used to prevent blood clots in the circulatory system, researchers found that a less-costly clinical formula is equally as effective as using a more expensive genetic profile to base dosage levels, according to a new study.
The study is being presented today at the American Heart Association’s Scientific Session in Dallas, and simultaneously published in the New England Journal of Medicine.
Intermountain Medical Center in Murray was one of 18 hospitals in the nation involved in the study, which was funded by the National Institutes of Health.
Intermountain Medical Center enrolled 123 of the study’s 1,015 patients, and was the third-leading enroller in the country.
"This study shows that having expensive care doesn't lead to better care,” says Scott Stevens, MD, who served as site principal investigator at Intermountain Medical Center. “Patients will not have to go through time-intensive and expensive genetic profiling in order to receive the right dosing of warfarin.”
“The genetic plus clinical algorithm did predict individual maintenance doses better, as expected,” said Jeffrey Anderson, MD, who also serves as a member of the CAOG executive board. “However, this did not translate into a better overall time in therapeutic range, the primary endpoint.”
Gary H. Gibbons, MD, director of the NIH’s National Heart, Lung and Blood Institute agrees.
“The use of genetic data holds great promise for predicting disease risk or determining optimal therapies, but it must be put to the test through clinical trials like this one to determine how to best use that information. This is especially true for complex drugs like warfarin whose action in our bodies is influenced by a variety of genetic, clinical and environmental factors.”
Dr. Stevens and Dr. Anderson, associate chief of cardiology at the Intermountain Medical Center Heart Institute, contributed to the study, called the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, under the direction of Stephen Kimmel, MD, of the Perelman School of Medicine at the University of Pennsylvania, and principal investigator of the trial.
The study showed combining genetic data with clinical information to determine the initial dosage of warfarin was no more effective than using only clinical information.
Warfarin is the most commonly prescribed drug to prevent blood clots in conditions such as atrial fibrillation, deep vein thrombosis, or pulmonary embolism. Though warfarin is an effective therapy for many people with cardiovascular problems, the drug poses risks if improperly dosed. If dosed too high, warfarin can increase the risk of bleeding; if dosed too low, it can increase the risk of blood clots.
Proper dosing of warfarin is complicated because the drug interacts with many other common medications as well as some foods. When determining an initial dose, doctors often start with a standard dose and can take certain clinical indicators into account to alter that dose. These clinical measures include age, body size, smoking status, and use of certain medications. During the initial weeks of therapy, the warfarin activity is monitored closely through blood tests, and adjustments are made as needed.
Recent research has suggested that variants of two genes, CYP2C9 and VKORC1, may be important in selecting the dose of warfarin needed for individual patients. Based on these studies, dosing formulas have been developed that incorporate a person’s genetic profile along with the patient’s clinical characteristics to try and better predict the proper dose of warfarin – an approach known as pharmacogenetics.
However, the evidence supporting pharmacogenetics for warfarin has not been definitive; small clinical studies and some observational data have produced conflicting results. In addition, there have been differences noted in how accurate these dosing formulas are in different groups of patients. In particular, the formulas tend to be somewhat less accurate in African-Americans.
“Several years ago, Dr. Anderson conducted two similar studies with Warfarin – CoumaGen and CoumaGen II but with a smaller sample size,” says Dr. Stevens. “In order to get more substantial evidence that a clinical algorithm is just as effective as gene testing, more patients needed to be involved.”
The patients beginning warfarin therapy were randomly assigned to one of two dosing strategies. During the first five days of therapy, the participants would have their dosages determined and adjusted by a clinical formula or a pharmacogenetic formula. The participants were monitored for 23 additional days, and dosage changes were made using a standard approach. Participants and the treating physician were blinded to the strategy and the dose of warfarin.
Study investigators compared how much time the patients spent in their ideal therapeutic dosage range during the 28-day monitoring phase. Among all patients, the clinical and pharmacogenetic groups were virtually identical at 45.4 percent and 45.2 percent time in therapeutic range, respectively.
“Given the lack of definitive information on whether or not pharmacogenetics can improve the care of patients and the need to study a broad range of patients being treated with warfarin, we needed a large clinical trial like this to help resolve this important question,” said Dr. Kimmel.