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School of Medicine Scientist Awarded $11.4 Million to Study Effectiveness of Gene-Directed Therapy for Cardiac Patients

Wednesday, September 08, 2010

 Dr. Shuldiner is studying the effectiveness of Plavix in treating cardiac patients with certain gene variants.

Research to gauge value of prescribing Plavix, other anti-clotting drugs, based on genetic makeup

The National Institutes of Health has awarded Alan R. Shuldiner, M.D., an $11.4 million five-year grant to lead a multi-center study to gauge the effectiveness of treating cardiac patients with anti-platelet drugs to prevent blood clots, based on their genetic makeup. Dr. Shuldiner is a professor of medicine and director of the Program in Genetics and Genomic Medicine at the University of Maryland School of Medicine. The program focuses on "translational research" to move discoveries out of the lab and into clinical practice to improve patient care.

The year-long study of 2,400 cardiac patients at five sites will build on previous research by Dr. Shuldiner and others that showed that Plavix, which is also called clopidogrel, is not as effective for people who have a common variant of the CYP2C19 gene. The variant, CYP2C19/*2, appears to affect people’s ability to activate the drug, which is designed to prevent platelets from clumping together and causing blood clots that may lead to heart attacks and strokes. Approximately one-third of the U.S. population carries at least one copy of this abnormal CYP2C19 variant.

"People with this gene variant who take Plavix after undergoing angioplasty and having a stent implanted have more than twice the risk of dying or having a serious cardiac event resulting  from a blocked artery than those on the medication who don't have the mutation," Dr. Shuldiner says. In March, the U.S. Food and Drug Administration issued a warning to physicians and patients about the reduced effectiveness of the drug in patients with the CYP2C19/*2 variant.

The new study will look at whether therapy geared to an individual’s genetic makeup, or  genotype, is more effective than the current standard of care. Patients who have the CYP2C19/*2 gene variant will receive a new anti-clotting medication called prasugrel, which is not as dependent on CYP2C19 for activation. Those who have the normal CYP2C19 gene, called CYP2C19/*1, will receive the standard dose of 75 mg of clopidogrel, and a third group will receive the standard dose of clopidogrel regardless of their genetic makeup.

"We want to learn whether treatment based on the CYP2C19 gene variant is more effective than standard treatment with clopidogrel in preventing future cardiac events. We believe that a gene-based approach is superior, but a randomized clinical trial will provide hard evidence. We also hope to identify common and rare variants in other genes that may play a role in people’s response to clopidogrel therapy," Dr. Shuldiner says.

In the earlier study, the University of Maryland researchers identified the gene variant by studying the DNA of members of the Old Order Amish community in Lancaster County, Pa. They confirmed their findings by studying a group of 227 cardiovascular patients at Sinai Hospital of Baltimore who received Plavix after having stents implanted to open blocked coronary arteries.

E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the School of Medicine, says, "This is a critically important area of research given the hundreds of thousands of people with cardiovascular disease who depend on clopidogrel to prevent future heart attacks and strokes. We need to determine the efficacy of genotype-directed
anti-platelet therapy in our clinical practice so that patients receive the most effective treatment for their particular genetic profile. The University of Maryland School of Medicine has made
personalized medicine, such as this, a major part of its translational research and clinical portfolio."

The funding for the new study comes from the NIH’s National Heart, Lung, and Blood Institute (NHLBI). The NIH announced that it is expanding a nationwide group of scientists focused on understanding how genes affect a person’s response to medicines. The expanded Pharmacogenomics Research Network (PGRN) consists of 14 research groups and seven resource networks. Dr. Shuldiner heads one of the research groups. NIH expects to spend an estimated $161.3 million on the grants over the next five years.

NIH Director Francis S. Collins, M.D., Ph.D., says, "Thanks to breakthroughs in genome-
sequencing technologies and our growing understanding of genetic variation among individuals,
there has never been a better time to propel the field of pharmacogenomics. Through these studies, we are moving closer to the goal of using genetic information to help prescribe the safest, most effective medicine for each patient."

In the new study, Dr. Shuldiner and his team will work with researchers at other institutions, including Johns Hopkins University in Baltimore, Sinai Hospital of Baltimore, Geisinger Health System in Danville, Pa., and Christiana Care Health Services in Wilmington, Del. The study will be called the Pharmacogenomics of Anti-Platelet Intervention-2 (PAPI-2) Study.

The project also will bring together an international team of investigators to search for other
genes responsible for clopidogrel response using a method called a genome-wide association study
(GWAS). GWAS refers to a sophisticated technique to rapidly scan hundreds of thousands of genetic markers. Dr. Shuldiner’s research group will use this technique and another genome-sequencing approach to look at DNA samples from more than 20,000 patients treated with clopidogrel to search for common and rare variants that also play a role in clopidogrel response.

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