Genetic information can improve administration of anticoagulant

Each year in the United States, doctors start about 2 million patients on warfarin (Coumadin™), an anticoagulant drug that’s notoriously hard to administer. Now a study from the International Warfarin Pharmacogenetics Consortium (IWPC), which includes researchers from Washington University School of Medicine in St. Louis, confirms that using a patient’s genetic information can make it easier to get the warfarin dose right.

“If the warfarin dose is too high, patients are at risk of hemorrhage, and if it’s too low, they risk blood clots that can lead to stroke, heart attack or even death,” says Brian F. Gage, M.D., associate professor of medicine at the School of Medicine and director of the outpatient Anticoagulation Service at Barnes-Jewish Hospital. “Unfortunately, getting the warfarin dose right is like walking a tightrope — it’s very easy to give too little or too much.”

Doctors prescribe warfarin to prevent blood clots or reduce the risk of stroke in patients with atrial fibrillation or artificial heart valves and those with a history of blood clots in the legs or lungs. It is also helpful in preventing blood clot formation after certain orthopedic surgeries such as knee or hip replacement.

Recently, Gage, Charles Eby, M.D., associate professor of pathology and immunology, and colleagues at the School of Medicine developed improved dosing formulas. They calculate the warfarin dose by taking into account the effect of two genes involved in warfarin sensitivity and metabolism. Their research demonstrated that gene-based dosing could more quickly and accurately estimate the appropriate dose of warfarin.

The current study, published in the Feb. 19, 2009, issue of the New England Journal of Medicine, gave gene-based dosing a rigorous test in an international collaboration that included more than 5,000 patients. The patients had been prescribed warfarin in the past and had achieved a stable effective dose.

For the study, the researchers calculated a warfarin dose for each of these patients with the gene-based dosing algorithm and with a formula based only on clinical data. Both formulas incorporate data such as age, body size, medications and race to estimate appropriate warfarin dose, but only the gene-based formula includes genetic information.

Using both formulas, the IWPC researchers checked how closely the calculated dose matched the dose actually used for each patient. In 60 percent of the patients, the gene-based formula got closer to the actual dose than did the clinical formula.

Almost half of the patients studied had either low or high warfarin dose requirements. Patients in these categories would be at high risk if given the wrong dose. The researchers showed that the gene-based formula was better than the clinical formula at identifying the patients at the low and high ends of the dosing spectrum. It provided significantly fewer overestimations in the low-dose group and significantly fewer underestimations in the high-dose group.

“This research study has made an important advance toward personalizing medicine—it uses data from countries around the world to develop a gene-based strategy for warfarin dosing that could benefit a wide range of patients,” said Jeremy M. Berg, Ph.D., director of the National Institute of General Medical Sciences, which partially funded the study. “This is a wonderful example of international cooperation and the results are especially valuable for the United States, since our population is so genetically diverse.”

The research lays important groundwork for a new clinical trial, the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. The trial, sponsored by the National Heart, Lung, and Blood Institute, one of the National Institutes of Health, will compare gene-based warfarin dosing to the traditional dosing approach in a prospective, randomized trial. Scheduled to open at the end of March, the trial will enroll 1,200 participants of diverse backgrounds and ethnicities at 12 clinical sites in the United States including Washington University School of Medicine. Eby will lead the COAG Central Genotyping Lab located at the School of Medicine. To enroll a patient beginning warfarin in this trial, doctors can contact Gage.

The IWPC comprises 21 research groups from nine countries and four continents. Each group contributed clinical and genetic data and submitted data for this study.

The International Warfarin Pharmacogenetics Consortium. Improved warfarin dosing with a global pharmacogenetic algorithm. New England Journal of Medicine. Feb. 19, 2009.

Funding from the National Institutes of Health and other groups supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.