Platelet inhibition is an essential treatment element for acute coronary syndrome (ACS), but patient response to the leading therapy, clopidogrel, is quite variable. CYP2C19*2 carrier status is a key factor in this variability; however, conventional DNA testing is not practical for routine clinical practice. Canadian researchers recently evaluated a point-of-care (POC) rapid genetic test for CYP2C19*2 carrier status, and their findings are the subject of this issue of Strategies.
The standard of care for ACS includes use of aspirin and other medications to inhibit platelet activity, most notably clopidogrel, which blocks the ADP platelet receptor. This approach has proven to decrease major cardiovascular events in ACS, but patient response to clopidogrel is highly variable, with some patients achieving only low or incomplete platelet inhibition. Although multiple mechanisms have been proposed for this variable response, genetics is a key factor. Since clopidogrel is a prodrug that is biotransformed in the liver, patients with the loss-of-function CYP2C19*2 allele—present in about 30% of individuals of European ancestry, and approximately half of those of Asian descent—are considered poor metabolizers. After two large meta-analyses showed that patients with one copy of this allele remained at significantly increased risk for adverse cardiovascular events, the U.S. Food and Drug Administration (FDA) issued a boxed warning for clopidogrel describing the relationship between CYP2C19 pharmacogenetics and drug response.
The mechanism of action for newer platelet-inhibiting therapies, such as prasugrel and ticagrelor, is not affected by CYP2C19*2 carrier status, but these agents have been associated with increased bleeding complications. Given the challenges involved in balancing the risk of adverse cardiovascular events on the one hand with risk of bleeding complications on the other, testing patients with ACS for CYP2C19*2 carrier status has considerable appeal, according to Derek So, MD, FRCPC, MSc, a staff interventional cardiologist at the University of Ottawa Heart Institute and assistant professor of medicine at the University of Ottawa, Canada.
“These medications are there to keep coronary stents open. What has come to light in the last couple of years is that some people don’t respond to clopidogrel as well as they should, because of an impaired metabolism in their liver,” he explained. “Prasugrel and ticagrelor inhibit the P2Y receptor on the platelets differently than clopidogrel, and are better at inhibiting the platelets. However, the trade-off is that patients taking either of these drugs have a higher chance of bleeding. So there’s always a balance between the risk of bleeding and the risk of thrombosis. By having personalized therapy based on CYP2C19*2 carrier status, we hope we can balance this bleed risk against the thrombosis risk.” So added that such genetic information is needed rapidly at the time cardiologists place stents, so they can prescribe the most appropriate medication for each patient. Yet genetic testing takes much longer to perform, making it impractical for current clinical practice. This led So and his colleagues to evaluate a novel genetic POCT developed by Spartan Biosciences to determine whether it would facilitate personalized antiplatelet treatment (Lancet 2012;379:1705-11).
Before embarking on this proof-of-concept study, the authors validated the POCT device by comparing its performance against conventional DNA sequencing. In 267 tests with 37 healthy volunteers, they found 100% concordance between the methods. The study itself involved 200 prospectively enrolled ACS and stable coronary artery disease patients about to undergo percutaneous coronary intervention (PCI). The patients were randomly assigned to rapid POCT genotyping or to standard care, which involved a 600 mg bolus of clopidogrel within 24 hours before PCI, followed by a daily 75 mg dose. Those assigned to rapid POCT genotyping also received a 600 mg bolus of clopidogrel prior to PCI, but patients determined to carry a CYP2C19*2 allele received 10 mg prasugrel daily instead of clopidogrel. All patients underwent platelet function testing immediately after PCI and 1 week later. The authors confirmed CYP2C19*2 carrier status of POCT-assigned patients using conventional DNA sequencing. Likewise, at the 1-week follow-up the researchers investigated carrier status in the standard care group by both POCT and conventional DNA sequencing. The study’s primary endpoint was the proportion of CYP2C19*2 carriers with a P2Y12 reactivity units (PRU) value >234 after 1 week of antiplatelet therapy.
Nurses who had participated in a 30-minute training session but without other laboratory training performed the test. The process involved taking a buccal swab, inserting it in the device, and pressing a button to start the genetic analysis, which took approximately 1 hour.
The authors found that equal numbers of POCT and standard therapy patients had at least one copy of the CYP2C19*2 allele. One case in the POCT group was incorrectly identified as a CYP2C19*2 carrier, giving the device a sensitivity of 100% and specificity of 99.3% in comparison to conventional DNA testing. Although mean baseline PRU was not significantly different between the two groups, none of the CYP2C19*2 carriers in the POCT group had a PRU value >234 at day 7, compared with 30% who received standard therapy. These proof-of-concept results—perhaps the first successful validation and clinical application of a POCT genetic test—demonstrate the feasibility of using the test in patient care, according to So.
“One of the obstacles in pharmacogenetics is we need the information rapidly, but often hospitals either don’t perform genetic testing or it’s not readily available. Our proof-of-concept is that we have a technology that will enable us to immediately identify whether someone is a CYP219*2 carrier, and if so, rather than continuing with clopidogrel we would change to prasugrel and essentially offer personalized therapy,” So said. “We demonstrated that this can be done without a genetics lab, performed by nurses with no prior genetic training, as a bedside test with a machine that’s the size of a toaster.” The device has European Union CE Marks and the manufacturer is working towards FDA clearance.
The findings are an important step in achieving personalized antithrombotic therapy, according to Jean-Sebastien Hulot, MD, PhD, associate professor of medicine and director of pharmacogenomics and personalized therapeutics at Mount Sinai School of Medicine’s Cardiovascular Research Center in New York City. “This study had to be done, and it’s great that it has been done now because we were waiting for this evidence,” he said. “With the use of genetic information in cardiology, most of the time it comes many days later or from a retrospective evaluation, so it’s not something useful in clinical care. But now with this study we have the evidence that we can do it in under an hour, which is absolutely fantastic. We can use this information to make medication adjustments to the patient, at least it seems so in this paper.”
Hulot earlier this year co-authored an opinion piece in Clinical Chemistry identifying four issues that need to be addressed before CYP2C19 testing can be implemented in clinical practice, including whom to test, how to test, how to interpret results, and how to respond to genotype results (Clin Chem 2012;58:154-157). Even though So’s work goes a long way towards answering these questions, Hulot suggested further research would be needed for a POCT genetic testing to be used routinely. “In our opinion piece, that was one of the issues we raised—how to test but also how to interpret the results. Whether we should rely on only one genetic test that assesses one variant—as has been done here—is an issue because the predictive value is a little bit low. So the question is, do we want to come with a set of genetic variants to have a better determination of the genetic background of our patients?” he said.
So agreed and explained that the Ottawa Heart Institute already is in process with another study involving rapid identification of three genetic variants in patients with ST-elevation myocardial infarction. Both he and Hulot argued that ultimately the best means of identifying at-risk individuals probably will be to incorporate rapid genetic results as a part of an overall risk profile. So also suggested that even as further evidence about this particular methodology becomes available, laboratorians should be on the look out for many more advances in rapid genetic testing. “This study opens the door to say that point-of-care or bedside genetics testing is now available. It doesn’t just have to be in the world of coronary stenting or even in cardiology. We hope this proof-of-concept study is going to allow other areas of medicine to apply their knowledge in genetics and pharmacogenetics.”
Dr. So discloses that he has unrestricted research grants for physician initiated studies from Spartan Biosciences and that Spartan Biosciences funded the study profiled in this issue of Strategies.