Published 10/1/2007
Starr McCaffery

Making personalized medicine practical

In August, the U.S. Food and Drug Administration (FDA) announced a labeling change for the widely used blood-thinning drug warfarin (Coumadin®), designed to increase patient safety. The change is a recommendation for prescribing physicians to use genetic test results to optimize warfarin dosage.

Although genetic tests are not required by the new FDA labeling, the change highlights the opportunity for orthopaedic surgeons, as well as for other healthcare providers who prescribe warfarin, to lower patients’ risk of bleeding complications.

With the labeling change comes the launch of a new, interactive Web site—www.WarfarinDosing.org—designed to make it practical for physicians to use genetic data in dosing recommendations.

Orthopaedic research helped determine doses
Researchers at Washington University in St. Louis studied patients undergoing total hip or knee arthroplasty who were prescribed warfarin in an effort to “develop a dose-refinement nomogram to guide clinicians in adjusting warfarin doses.” They ultimately hoped to “simplify and standardize warfarin initiation.” The study appears in the Sept. 1 issue of the journal Blood (full text available at
http://bloodjournal.org). The dosing model is available at the Web site, which is supported by Barnes-Jewish Hospital at Washington University, the National Institutes of Health, and donations.

“Our main collaborator, Brian F. Gage, MD, has made major contributions to the monitoring of Coumadin with pharmacogenetic strategies,” said study coauthor John C. Clohisy, MD, of the department of orthopaedic surgery at Washington University. “Our collaboration with Dr. Gage has underscored the potential benefits of pharmacogenetic monitoring techniques in the perioperative care of our total joint replacement patients. He will continue to validate and refine warfarin pharmacogenetic dosing algorithms that will enhance the safety and efficacy of this commonly utilized prophylactic agent for deep venous thrombosis.”

Estimating and refining the estimates
The interactive Web site allows physicians to enter patient-specific data and receive an estimated loading dose and estimated therapeutic dose of warfarin for each individual patient. In addition, a patient number is provided so a prescribing physician can return to the site with updated international normalized ratio (INR) values and receive adjusted dosing estimates.

In providing the dosing estimates, the site considers the patient’s genotype information for the CYP2C9 and VKORC1 genes, as well as a number of other patient-specific factors known to affect optimal warfarin dosage. These include age, gender, height and weight, ethnicity and race, use of other prescription medications commonly taken by patients prescribed warfarin, and lifestyle factors, such as smoking.

Dosing recommendations on the site are based on data from more than 1,000 patients. Using patient-specific information entered by the prescribing physician, the initial estimate of therapeutic dose explains 53 percent of the variability in a warfarin dose. When a physician returns to the site and enters a patient’s INR value after three or four warfarin doses, the dose refinement is even more accurate.

Starr McCaffery is a communications consultant working with the AAOS Washington, D.C., office.