Personalized Medicine in Cath Lab Targets Best Blood Thinner for Patients
The promise of individualized medicine — where tests and therapies are tailored to each patient’s precise genetic makeup — is becoming a reality for cardiology patients at the University of Maryland Medical Center (UMMC), the culmination of efforts to determine which blood thinner will work best for each patient at preventing blood clots that cause heart attacks and sustaining health.
Physician-scientist Alan R. Shuldiner, M.D., associate dean and director of the Program in Personalized and Genomic Medicine (PPGM) and the John L. Whitehurst Endowed Professor of Medicine at the UM School of Medicine, helped launch PPGM nearly two years ago with a mission to advance personalized and genomic medicine from discovery through clinical trials through implementation in the patient care at UMMC and beyond.
“For more than the last year and a half since its inception,” he explains, “PPGM has been investing in building infrastructure to accomplish our mission — to develop a conduit through which we can rapidly advance genomic discoveries to improved patient care.”
In the new, federally accredited Translational Genomics Laboratory — funded with the help of a $1 million Department of Defense grant — UM physicians are able to test cardiology patients before undergoing cardiac catheterization procedures to determine which drug may be optimal for them to prevent clotting that may result in a recurrent heart attack. Within four hours of a simple blood draw, vital genetic information is gathered that informs doctors if a patient should be given something other than clopidogrel (Plavix) —statistically approximately one-quarter of patients may do better on an alternative medication — to stave off clotting.
Gene variation tips off doctors
Between 10 and 15 UMMC cardiac catheterization patients — most receiving drug-eluting stents — should benefit each week from the testing, which began in early March. The soon-to-be routine test, currently done only at a few other major medical centers in the United States, aims to tease out which patients have a variation in the CYP2C19 gene, which is involved in metabolizing clopidogrel.
For about 25% of cardiac catheterization patients, their genetic makeup renders them less responsive to the drug’s effects, leaving them with higher residual platelet activity and a greater risk of cardiovascular events. If doctors know this information before catheterization, these patients can be prescribed one of two newer anti-platelet agents, which include prasugrel (Effient) and ticagrelor (Brilinta). On the downside, prasugrel is associated with greater bleeding risks than clopidogrel, which is known commercially as Plavix but is now available generically and therefore much less costly than its alternatives.
“There are a lot of different angles to figuring out the best drug for a particular person,” says Mark R. Vesely, M.D., assistant professor of medicine in the interventional cardiology section of the Division of Cardiology and associate program director of the Interventional Cardiology Fellowship. “For some patients who have cost issues, if we know their metabolism of clopidogrel is sufficient, then we are less likely to utilize the more expensive newer agents. This is the core of personalized medicine. Maybe this person will do well on ‘Medicine Y,’ but let’s check it and personalize it.”
CYP2C19 testing can be done by some of the large commercial laboratories, Dr. Shuldiner notes, but UMMC handily beats the one- or two-week turnaround for results — a time frame that can be problematic for cardiac patients needing to start antiplatelet therapy immediately after catheterization.
“Many patients who have complications with their stents and catheterizations will have those complications within one to two weeks, so having that information back early is important and a distinguishing characteristic of our program,” he says. “The literature suggests we’ll be able to maximize efficacy and minimize risks of antiplatelet therapy by prescribing these medications in a more individualized way based on genetic makeup. We also believe this approach will be more cost-effective. Most patients will still get clopidogrel and we’ll reserve the more expensive medications for those who need it. We’ll minimize each patient’s bleeding risk … so there will be less opportunity for adverse side effects.”
Influential research in genomic medicine
Clopidogrel was the antiplatelet drug nearly always prescribed for cardiac catheterization patients until a flurry of research published between 2007 and 2009 indicated that it wouldn’t work optimally for a substantial percentage of patients, Dr. Shuldiner says. One of the most influential of those studies — the only one to perform a genome-wide search for clopidogrel-response genes — was authored by University of Maryland School of Medicine scientists and published in the Journal of the American Medical Association. The U.S. Food and Drug Administration took note, deciding to add a boxed warning on clopidogrel’s labeling detailing the issue and recommending alternative treatments be considered in patients categorized as genetically resistant.
“I can’t say we were the only ones to discover this,” Dr. Shuldiner says, “and we weren’t the first, but our study was one of the more influential papers that led to the FDA-mandated label change.”
But obstacles remain in implementing CYP2C19 technology, in part, Dr. Shuldiner says, because many cardiologists remain leery of genetic testing. “There are many reasons for this,” he adds, “but it’s not being adopted very widely and that’s been frustrating.” A multi-site, prospective clinical trial is needed, he notes, but finding private or public funding for such an endeavor is extremely difficult.
That doesn’t mean, however, that personalized medicine doesn’t have a bright future. Drs. Shuldiner and Vesely point out that genetic and genomic testing is also being used to great effect in the cancer field — where, for instance, the immune-targeted therapy trastuzumab (Herceptin) can hinder tumors in patients identified as HER2-positive — and with other drug types where genes predict response or chances of adverse events.
“Nobody knows where this is going, but we can hypothesize,” Dr. Shuldiner says. “One of the really exciting prospects is that sequencing of a whole human genome is becoming really inexpensive, projected to cost about $1,000 or less within the next year. In the not-too-distant future, I envision all humans will have their entire genomes sequenced … and this information will be embedded in their electronic health records and used pre-emptively over their lifespans to prevent various diseases and predict which medications will be most effective if they are required.”
ALAN SHULDINER, M.D., left, and MARK VESELY, M.D., are partnering to bring personalized medicine to the cardiac cath lab. To schedule an appointment, please call 1-866-408-6885.