Rapid Bedside Genotyping May Help Guide Antiplatelet Strategy After PCI

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Point-of-care genetic testing can be easily performed after percutaneous coronary intervention (PCI) and, when used to guide antiplatelet therapy, reduces the prevalence of high on-treatment platelet reactivity. But whether this strategy, described in a paper published online March 29, 2012, ahead of print in the Lancet, also improves clinical outcomes has yet to be determined.

Results from the RAPID GENE study were previously presented November 2011 at the annual Transcatheter Cardiovascular Therapeutics scientific symposium in San Francisco, CA.

For the trial, Derek Y.F. So, MD, of the University of Ottawa Heart Institute (Ottawa, Canada), and colleagues enrolled 200 patients undergoing PCI for ACS or stable angina. Subjects were randomized to upfront genetic testing with the Spartan RX CYP2C19 assay (Spartan Biosciences, Ottawa, Canada) or to standard therapy. Those identified as having the CYP2C19*2 allele received prasugrel (10 mg daily), while noncarriers and those in the standard therapy arm received clopidogrel (75 daily). Both groups underwent standard DNA sequencing in order to validate the results of the new test.

For rapid genotyping, nurses required only a 30-minute instructional course beforehand. The test, which uses a buccal swab to obtain samples, can be performed in fewer than 8 minutes and identifies CYP2C19*2 carrier status—heterozygous or homozygous–within 1 hour.

Focusing on Carriers

In all, 187 patients completed follow-up (91 assigned to rapid genotyping and 96 to standard treatment). Twenty-three patients in each group were carriers of CYP2C19*2, amounting to an overall prevalence of 24.6%.

At 1 week after antiplatelet therapy, the primary endpoint of high-on treatment platelet reactivity (defined as P2Y12 reactivity unit [PRU] value > 234) among *2 carriers was significantly lower in those who had undergone testing than in those receiving standard treatment. The difference was even larger when using the cutoff of 208 PRUs, as had been suggested by results of the GRAVITAS trial (table 1).

Table 1. Platelet Reactivity After 7 Days of Antiplatelet Therapy in CYP2C19*2 Carriers

No MACE occurred in either group at 7 or 30 days, and TIMI major bleeding occurred in 2 of the rapid genotyping patients (2.2%) and 1 of the standard therapy patients (1%; P = 0.6134). Compared with conventional DNA sequencing, rapid genotyping had a sensitivity of 100% and a specificity of 99.3%.

Moving Forward from Proof of Concept

“As far as we are aware, we have reported the successful validation and clinical application of the first point-of-care genetic test in medicine,” the investigators conclude. “We have shown that a rapid genetic test coupled with subsequent personalized treatment reduces the number of CYP2C19*2 carriers treated with PCI that have high on-treatment platelet reactivity.”

In a telephone interview with TCTMD, Dr. So reported that the RAPID GENE researchers are now doing another proof-of-concept study on a test that looks at several CYP2C19 alleles as well as focusing their attention on STEMI patients, who require particularly quick decision making.

Considering multiple genetic factors as well as testing platelet function is the way forward, he said. “I think that’s what most people would agree is the most likely scenario in terms of personalization of antiplatelet therapy on a large-scale basis in the future, because the 2 pieces of information could be used coherently to make decisions in a more effective manner.”

Study co-author Jason D. Roberts, MD, also of the University of Ottawa Heart Institute, told TCTMD in the same interview that testing for carriers of the CYP2C19*2 variant allele offers the most “bang for your buck.”

“The other alleles, like *3, are relatively rare, whereas *2 . . . is present in 30% of those with Western European ancestry and in 50% of Asians,” he explained.

Clinical Evidence Still Absent

In an editorial accompanying the paper, Amber L. Beitelshees, PharmD, MPH, of the University of Maryland School of Medicine (Baltimore, MD), said that the researchers are the first to meet the need for quick turnaround when genotyping patients who have experienced a cardiovascular event.

However, Dr. Beitelshees pointed out that “[n]o randomized controlled trials have assessed the superiority of genotype-guided care over routine practice. The RAPID GENE study had a surrogate endpoint of ex-vivo platelet aggregation, so whether genotype-guided treatment will indeed improve major adverse cardiovascular outcomes is yet to be established.”

She stresses that the researchers “provide a valuable first step” toward that goal, which is currently being realized in the PAPI-2 (Pharmacogenomics of Anti-Platelet Intervention-2) trial. The study is looking at how altering antiplatelet therapy based on CYP2C19 genotype—including the *3 and *17 alleles as well as *2—might affect 1-year clinical outcomes in over 7,000 patients.

But those results “will take time to complete and analyze, and many clinicians do not know what action to take, if any, in the meantime,” Dr. Beitelshees adds.

Some Caveats

Paul A. Gurbel, MD, of the Sinai Hospital of Baltimore (Baltimore, MD), told TCTMD in a telephone interview that this is not in fact the first time that point-of-care genetic testing has been validated and used in a clinical setting. He cited a study he presented at the 2011 American College of Cardiology/i2 Scientific Session in New Orleans, LA, that evaluated the Verigene 2C19/CBS nucleic acid assay (Nonosphere, Northbrook, IL) but did not use results to alter antiplatelet therapy.

Nor should they have, because a gene-based strategy does not take into account the possibility that genotype does not necessarily equal phenotype, Dr. Gurbel explained.

“In my mind, the goal would be to eliminate high platelet reactivity in all patients,” he said, noting that 9 patients in the rapid genotyping group who were noncarriers—10% of that treatment arm—stayed on clopidogrel and still had high platelet reactivity.

“Genotyping is good when you haven’t given the therapy yet,” because it can help predict clopidogrel response, he acknowledged. “But to really personalize therapy, be sure to follow-up by measuring phenotype [with platelet function testing].”

In an e-mail communication with TCTMD, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), also expressed some skepticism about RAPID GENE: “We still have no signal that changing therapy in poor responders because of an abnormal [genetic] test result leads to improved clinical outcomes.”

Moreover, he said, because the risk of stent thrombosis is decreasing with newer stents, a very large study would be needed to show clinical benefit.

Cost will play a large part in how genotyping is received by clinicians, Dr. Bates predicted. “Prasugrel and clopidogrel are the same price. Generic clopidogrel will have to be much cheaper to make this strategy important,” he said. “If that happens, it may be the payers that bring pharmacogenomics into clinical medicine instead of the scientists.”

 

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Sources:
1. Roberts JD, Wells GA, LeMay MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): A prospective, randomised proof-of-concept trial. Lancet. 2012;Epub ahead of print.

2. Beitelshees AL. Personalised antiplatelet treatment: A RAPIDly moving target. Lancet. 2012;Epub ahead of print.

 

 

Related Stories:

• RAPID GENE: Validation of Point-of-Care Genetic Testing
• Meta-analysis: Data Do Not Support Genotyping for Clopidogrel Response
• Cases Made For, Against Genotyping to Guide Antiplatelet Therapy

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