RAPID GENE: Point-of-Care Genetic Test Singles Out Clopidogrel Nonresponders

Shelley Wood

March 29, 2012

March 29, 2012 (Ottawa, Ontario) — Canadian researchers say their study is the first published evidence of "successful validation and clinical application" of a point-of-care genetic test in medicine: a rapid, bedside test for identifying carriers of the CYP2C19*2 allele before undergoing PCI [1].

In the RAPID GENE study, patients randomized to undergo bedside testing and who were identified as carriers of the allele were then treated with prasugrel (Effient, Lilly/Daiichi) instead of clopidogrel post-PCI. Seven days postprocedure, those singled out by testing (and treated differently as a result) were significantly less likely to have high on-treatment platelet reactivity than patients who did not undergo point-of-care testing but who were also carriers of the CYP2C19*2 allele.

"RAPID GENE introduces and validates the first point-of-care genetic testing device in clinical medicine," senior author Dr Derek So (University of Ottawa Heart Institute, ON) told heartwire in an email. "Genetic testing has previously been viewed as a laborious procedure requiring highly trained personnel and expensive equipment; its time-consuming nature and its relatively limited availability have restricted its use in both clinical practice and research studies. The development of a simple bedside genetic test that can be performed by nurses with no prior training in genetics promises to overcome many of these previous obstacles."

RAPID GENE results were first presented at TCT 2011 and reported at the time by heartwire . Published results are largely in keeping with the results first reported by So in San Francisco last year.

RAPID GENE Leads to Different Treatment Choices

For the study, So, with first author Dr Jason D Roberts (University of Ottawa Heart Institute), randomized 200 patients to bedside testing or standard treatment. The point-of-care test is based on a buccal swab and was developed by Spartan Biosciences (it is not available in the US). Carriers identified in the bedside-testing group received 10-mg prasugrel daily following PCI, while noncarriers as well as patients randomized to standard treatment received 75-mg clopidogrel daily. Prasugrel, like another novel P2Y12 inhibitor, ticagrelor (Brilinta, AstraZeneca), is unaffected by the CYP2C19*2 allele.

At follow-up, 23 patients in each group were found to carry at least one CYP2C19*2 allele. But while none of the carriers in the genotyping group (who'd been switched to prasugrel) had high platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234), seven of those in the standard-therapy group had PRUs >234 by day seven.

To heartwire , So explained that platelet-function tests like VerifyNow (Accumetrics) and the vasodilator-stimulated phosphoprotein (VASP) assay have also been used to measure clopidogrel-mediated platelet inhibition at a single moment in time, but, by contrast, the new genetic test identifies people whose response to clopidogrel is fixed, unrelated to steady-state levels of the drug.

"Both platelet-function testing and the CYP2C19*2 allele serve as independent predictors of [major adverse cardiac events] MACE following PCI in patients treated with clopidogrel, and hence a hybrid approach that combines the use of both modalities may ultimately prove most effective for identifying at-risk patients," So said.

According to So, Roberts, et al, large randomized trials using clinical outcomes as end points are already under way--the use of platelet reactivity as a surrogate in RAPID GENE is the key shortcoming in this proof-of-concept study. But as So pointed out to heartwire , with robust evidence linking genotype to adverse clinical outcomes, "an obvious question arises: Will physicians and patients be willing to undergo randomization if they are informed that they are homozygous for CYP2C19*2?"

In their paper, So and Roberts also point out that the big trials will take time and, in the meantime, many clinicians "do not know what action to take, if any."

A Glimpse of the Future

Commenting on RAPID GENE for heartwire , Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) called the study "exceptionally important . . . for two main reasons."

For one, he said, "it is the first point-of-care rapid genotyping study--a randomized trial, in fact--that has yet to be performed in medicine. Furthermore, it shows unequivocally that knowledge of the key gene variant for Plavix [clopidogrel] metabolism leads to improved platelet suppression . . . a surrogate marker that has consistently tracked closely with clinical outcomes in PCI studies.

"Of particular note, the rapid, point-of-care genotyping has been a missing link in the interventional cardiology application, since the usual case was only being able to ascertain the genotype for CYP2C19 a few days after the PCI was already accomplished. This up-front, pre-PCI knowledge of a patient’s response to the standard medication--Plavix--makes it highly actionable."

Both So and Topol highlighted the implications beyond the ACS setting, with Topol heralding RAPID GENE as "progress for a specific path in genomics in real-world medicine, [with] big implications for the future well beyond this application."

So, likewise, stressed, "Findings from RAPID GENE and the development of a simple bedside genetic test will likely facilitate future clinical investigations examining the efficacy of pharmacogenetic strategies in all areas of medicine."

So's group is now looking at whether point-of-care genetic testing can be done with a multiple single-nucleotide-polymorphism (SNP) approach in STEMI patients. "We are now recruiting for the RAPID STEMI study, which will be based on three separate SNPs in STEMI patients," he said. "This will lay the groundwork for personalizing antiplatelet therapy in STEMI patients."

So disclosed receiving unrestricted research grants for physician-initiated studies from Sanofi Canada, Abbott Vascular Canada, and Spartan Biosciences and honoraria from Eli Lilly Canada. Topol is the editor in chief of theheart.org .

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