By Terri Malloy
Heart patients who undergo percutaneous coronary intervention (PCI) or stent placement― nonsurgical procedures to improve blood flow to the heart ― are typically prescribed anti-platelet therapy to avoid blood clots that can lead to a heart attack or stroke. New research from the international TAILOR-PCI trial, the largest pharmacogenetics clinical trial in cardiology, suggests that genetic testing could potentially be a useful tool to help select antiplatelet medication. Pharmacogenetics is the use of a patient's genetic makeup in prescribing treatments that are likely to be most successful.
The trial, led by Naveen Pereira, M.D., and Michael Farkouh, M.D., is published in JAMA. Dr. Pereira is a cardiovascular disease specialist at Mayo Clinic and Dr. Farkouh is a cardiologist from the Peter Munk Cardiac Centre, University Health Network. The trial originated from a Mayo Clinic study catalyzed by Mayo Clinic's Center for Individualized Medicine and Department of Cardiovascular Diseases in 2012.
Clopidogrel is the most commonly used antiplatelet drug, but about 30% of Americans carry variants in the CYP2C19 gene, which interfere with the metabolism of clopidogrel. These patients are in a high-risk category due to their genetic makeup, but they can be identified with a simple point-of-care genetic test. Patients who have the CYP2C19 gene variants may be good candidates for alternative anti-platelet therapy.
The trial focused on people with the loss of function CYP2C19 gene variants who underwent percutaneous coronary intervention to see if genotype-guided therapy in that group would be more beneficial than giving clopidogrel to all. Mayo Clinic was the clinical coordinating center and data coordinating center for the five-year clinical trial, which spanned 40 centers in Canada, Mexico, South Korea and the U.S. The data coordinating center was led by Kent Bailey, Ph.D., a Mayo Clinic statistician, and the chair of the steering committee was Charanjit Rihal, M.D., a Mayo Clinic interventional cardiologist.
"Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetic testing, with approximately one-third fewer adverse events in the patients who received genetically guided treatment, compared with those who did not." - Dr. Pereira.
The trial enrolled 5,302 patients who had been treated for artery blockage with one or more stents, and followed them for one year. Half of the group was randomized to be tested for the CYP2C19 gene variation and the carriers (35%) were treated with the alternative anti-platelet medication, ticagrelor. The remainder of the group was given clopidogrel, as was the entire other randomized half that consisted of the control group of patients who did not receive genetic testing.
The results showed a statistically not significant 34% reduction in blood clotting events in the loss of function CYP2C19 gene carrier patients assigned to ticagrelor in the genotype-guided group. The loss of function CYP2C19 gene carrier patients that received clopidogrel showed a 5.9% event rate versus a 4.4% event rate in those who received genotype-guided ticagrelor treatment. The study narrowly missed its statistical goal, which was a 50% reduction in blood clotting events.
"Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetic testing, with approximately one-third fewer adverse events in the patients who received genetically guided treatment, compared with those who did not," says Dr. Pereira.
Dr. Pereira explains that the standard of care following coronary angioplasty and stent placement has evolved and greatly improved since the study was designed in 2012. The advent of drug-coated stents and other medical treatments improved care by reducing the expected rate of adverse events for patients in a year, but at the same time made it more difficult for the trial to reach its goal. The National Heart, Lung and Blood Institute has funded an extended follow-up study of TAILOR-PCI to determine if genetic-guided treatment will benefit longer-term outcomes.
"TAILOR PCI represents an important public-private partnership in advancing science and therapeutics for the benefit of patients. We will continue to seek more follow-up data and ascertain clinical endpoints." - Dr. Rihal.
The trial was positioned for patient evaluation at one year and just missed statistical significance. However, data at the three-month mark hold important implications for pharmacogenetics. In the first three months after the procedure, TAILOR-PCI showed an 80% risk reduction in patients with the CYP2C19 gene variation who were given ticagrelor. Furthermore, when evaluating the total number of events experienced per patient, genetic-guided treatment showed a statistically significant 40% reduction in events, compared to those who received standard treatment.
"Clopidogrel offers many advantages, but for those who can't metabolize the drug, this trial demonstrates the potential effectiveness of a personalized medicine approach," says Dr. Farkouh. "For patients who do not have a loss of function variation, it may be cost-effective to use clopidogrel, as it's widely available and has a favorable safety profile. We plan to report a cost-effective analysis in a separate manuscript."
"TAILOR PCI represents an important public-private partnership in advancing science and therapeutics for the benefit of patients. We will continue to seek more follow-up data and ascertain clinical endpoints," says Dr. Rihal.
"The TAILOR-PCI trial is an example of the rigorous testing needed to explore personalized, genetic-guided treatment and whether it can improve patients’ outcomes," says Yves Rosenberg, M.D. "The results suggest potential value of a personalized, pharmacogenomic approach to the management of patients with heart disease undergoing coronary stenting." Dr. Rosenberg leads the National Heart, Lung, and Blood Institute's Atherothrombosis and Coronary Artery Disease Branch and is a co-author on the study.
The study was funded by Mayo Clinic, Mayo Clinic Center for Individualized Medicine and the National Heart, Lung and Blood Institute, which is part of the National Institutes of Health. Spartan Bioscience Inc. supplied the point-of-care genetic tests used.
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