Marshfield Clinic investigators contribute to international pharmacogenetics study

Research improves estimation of warfarin dose

Michael Caldwell, M.D.

The International Warfarin Pharmacogenetics Consortium (IWPC) reported in the February 19 issue of the New England Journal of Medicine the results of a study to improve estimation of warfarin dose with clinical and pharmacogenetic data.

Three Marshfield Clinic investigators contributed to the study: Michael Caldwell, M.D., Ph.D.; James Burmester, Ph.D.; and Dick Berg.

Warfarin is a frequently used anticoagulant prescribed to patients to prevent clotting.

The major issue for patients who need this drug is that optimum dosage varies widely from patient to patient and is difficult to predict. It also has a narrow therapeutic window.

If too much warfarin is used, the patient could develop bleeding problems. If too low a dose is used, complications from clotting could occur.

“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.

James Burmester, Ph.D.

“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 IWPC consists of investigators from 21 institutions.

All participants in the study contributed de-identified data (information that cannot be traced to the individual, safeguarding privacy) to a secure Web-based site (PharmGKB), where it was aggregated and curated.

“The aggregate data, which represents the largest collection of data on warfarin, is an incredible resource. Now it is available to researchers for other warfarin investigations,” Dr. Caldwell said.

“The study looked at developing a dose algorithm that considers age, body size and gender, along with the interactions of two genes identified with metabolizing warfarin, to come up with a way to get the right dose the first time,” Dr. Burmester said.

The proper warfarin dosage can vary greatly among individuals and the process of determining proper warfarin dosage can be somewhat lengthy.

Physicians currently prescribe an initial dosage to patients based on clinical information and follow up with blood tests to determine the degree of anticoagulation.

Dick Berg

The amount prescribed may be altered several times, each time followed by blood tests, until the correct dosage is achieved. Investigators concluded that the new algorithm could make dosing more effective and reduce risks.

“The study has been a labor of love on the part of many people to solve a real problem. Warfarin is the only oral anticoagulant currently available and we need to make it safer,” Dr. Caldwell said.

“Equally as important, it has been an excellent learning process, as well as a reassuring process, to see how science can be accomplished for the better good. We hope it can be a prototype for future pharmacogenetic studies.”

The National Institutes of Health announced it will follow up these findings by initiating a large, randomized clinical trial to test the IWPC algorithm to see if it will improve the outcomes of patients who require the anticoagulant.