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Release issued 7th March 2008
Medicine gets Personal
Study helps doctors give better care to patients
It is estimated that there are currently more than 200,000 Canadians on the blood thinner warfarin. However, dosing of warfarin is challenging as there is a wide variation in how a patient's body will respond. Variations in a gene involved in blood clotting can cause the medication to be highly effective in some people while, in others, the same dose may cause fatal side effects.
Drs. Ute Schwarz and Richard Kim, researchers at Lawson Health Research Institute are using a patient's genetics to map out their dose requirements of warfarin. By pinpointing how a person will respond to the drug before it is administered doctors may be able to decrease the risk of adverse side effects. Their findings have been published in this week's New England Journal of Medicine.
Warfarin is prescribed for people with an irregular heartbeat, prosthetic heart valves, or for people who have suffered a heart attack. It is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). At least 30 genes have been associated with the metabolism and action of Warfarin, making dosing very challenging. One gene, CYP2C9, codes for an enzyme that breaks down warfarin in the body. The other, VKORC1, encodes the enzyme that warfarin blocks in order to prevent blood clot formation. What was not known was the relative impact of these genetic variants when warfarin therapy was first initiated.
"Each individual's needs (of warfarin) is different," says Dr. Schwarz, lead author and Research Scientist in the Department of Medicine at London Health Sciences Centre "The first few days of initiating warfarin therapy are very important because this is when we find out how the patient will respond. Because of the risk of bleeding, and warfarin's narrow therapeutic index, it is necessary and important to frequently monitor the blood so that the dosage can be appropriately adjusted."
Current practice for finding the proper dose of warfarin is based on trial and error. Doctor's monitor the dose by checking a person's International Normalized Ratio(INR), the standard unit for reporting the clotting time of blood. A common target INR level for a person taking anticoagulants is 2.0 to 3.0.
Drs. Schwarz and Kim's study focused on the relationship between VKORC1 and CYP2C9 and the INR responses. Their findings suggest variations in a person's VKORC1 gene is a major determinant of whether a patient's initial INR values would be high or low in patients starting warfarin, as well as predicted both the time to the first goal (therapeutic) INR and time to the first INR of more than 4, that is associated with an increased risk of bleeding.
Adverse drug reactions are thought to account for the death of nearly 10,000 Canadian patients each year, and each year we see newly released drugs with great hopes of alleviating patient suffering withdrawn from the market because unexpected side effects or toxicity. "It seems that by understanding our genetic makeup and testing for such differences, we may be able to better adjust the dose of drugs that have important clinical utility, but also serious side effects such as warfarin," says Dr. Schwarz.
The bulk of Dr. Schwarz and Kim's research on warfarin was done with colleagues at Vanderbilt University School of Medicine, in Nashville, Tennessee. When Dr. Kim, a Canadian physician-scientist and leading researcher in the field of personalized medicine, decided to relocate his lab and his research team from Vanderbilt to London, Dr. Schwarz moved with him.
Together, Drs. Kim and Schwarz will be working at the new Centre for Clinical Investigation & Therapeutics (CCIT) at London Health Sciences Centre. Dr. Kim is the inaugural Medical Director of the CCIT, as well as a Clinical Pharmacologist and Chair/Chief in the Division of Clinical Pharmacology at the London Health Sciences Centre; and Professor, Department of Medicine at the Schulich School of Medicine & Dentistry at The University of Western Ontario.
The CCIT is one of the first centres of its kind in Canada for bench to bedside research and clinical trials. According to Dr. Kim, Dr. Schwarz's research is a prime example of the relevant work the team is doing and the group is planning to use her findings to move forward genotype-based warfarin dosing research at the CCIT.
Translation of knowledge from Dr. Schwarz's study into clinical practice may mean that in the near future doctors would be able to use DNA analysis to prescribe the right dose of warfarin for each individual. The outcome will be more effective treatments with fewer complications, unnecessary hospitalizations, saving the patient time and the health system money.
The study was supported by the National Heart, Lung, and Blood Institute, the National Institute of General Medical Studies, and the NIH-funded Pharmacogenetics Research Network.
Lawson Health Research Institute
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