SAN FRANCISCO – Using a rapid point-of-care test to identify patients likely to be poor metabolizers of clopidogrel and tailoring their antiplatelet therapy accordingly improves the biologic effectiveness of that therapy, concludes a trial reported at the annual Transcatheter Cardiovascular Therapeutics meeting.
Investigators conducted the open-label, randomized trial in 200 patients undergoing percutaneous coronary intervention with stenting, using a point-of-care test for the *2 allele of the CYP2C19 gene. The allele confers a loss of function of the CYP2C19 enzyme and thus reduced hepatic metabolic activation of clopidogrel and an increased risk of adverse cardiovascular events in this setting. Testing was performed by nurses at the bedside using buccal swabs and yielded results in about 1 hour.
Findings of the RAPID GENE (Reassessment of Antiplatelet Therapy Using an Individualized Strategy Based on Genetic Evaluation) trial showed that nearly a third of patients having the *2 allele had impaired platelet activity a week later if they had simply been given standard clopidogrel therapy. This compared with none of their counterparts who were instead given prasugrel, an agent that overcomes the problem of poor metabolism, on the basis of their point-of-care test results.
"What RAPID GENE has shown is that point-of-care genetic testing after stenting performed at the bedside by clinical nurses permits accurate identification of the *2 carrier status and facilitates a rapid, tailored approach to antiplatelet therapy," according to lead investigator Dr. Derek Y.F. So.
The findings are clinically important, given that up to one-fourth of the more than 2 million patients undergoing coronary stenting each year may have genetic variants increasing their risk of clopidogrel failure, he noted. "RAPID GENE is essentially a proof of concept that rapid genetic testing and adherence with tailored therapy is now feasible," he said at the meeting, which is sponsored by the Cardiovascular Research Foundation. "The other reason this is important is that this will be applicable to all other areas of medicine as well."
However, added Dr. So, a cardiologist at the University of Ottawa Heart Institute, such testing remains more of a research tool at present. "I do think that it’s premature right now to say that this is going to be routinely implemented in hospitals. But ... this is going to be a game-changer in the sense that it allows us to design other prospective studies to evaluate this on a more detailed basis," he elaborated.
And this genetic information is merely one piece of a complex puzzle, he noted. "I don’t think using genetics alone is going to allow us to select out all the patients, but it’s going to be a combination of genetics in association with clinical risk factors, in association with platelet function. And I think that [*2 allelic information] will be a potential risk factor that will be incorporated in any future model."
Discussant Dr. Paul A. Gurbel, director of the Sinai Center for Thrombosis Research in Baltimore, expressed reservations about the trial, noting that a previous genome-wide associated study suggested that only 12.5% of the variability in platelet reactivity on clopidogrel can be attributed to the *2 allele, suggesting many genetic influences on the response to this drug. "So I have to say, this is a bit surprising – for any thienopyridine actually, there are so many influences on the response to thienopyridine therapies – to see absolutely no high platelet activity on prasugrel therapy in the *2 carriers," he said.
Furthermore, other studies in patients undergoing PCI suggest that the rate of high platelet reactivity on prasugrel is not zero. "So this [trial’s result] is discordant with data that’s already out there in the literature," Dr. Gurbel maintained.
He also sounded a note of caution about making decisions about clopidogrel therapy based solely on this allele. "There are many patients on clopidogrel who are *2 carriers who respond very nicely to the drug. So [by making] your decision based on *2, a lot of patients who would have responded nicely to clopidogrel are given another agent," he said.
In the trial, patients were randomized in balanced fashion to either standard therapy or genetically tailored therapy.
All patients in the former group received clopidogrel (Plavix) 75 mg daily. All patients in the latter group were started on clopidogrel but had point-of-care genotyping at the time of PCI to determine their *2 carrier status (Spartan RX, Spartan Bioscience); those found to carry the *2 allele were immediately switched to prasugrel 10 mg daily, whereas those found to be noncarriers continued on clopidogrel.