Genetic Tests for Predicting Clopidogrel Response Gain Traction: AHA

It’s time for genetic testing of clopidogrel response to move into the mainstream, suggests a new scientific statement from the American Heart Association (AHA) that outlines the supporting evidence but also acknowledges the obstacles that still stand in the way of wider adoption.

Clopidogrel, the mainstay oral P2Y12 inhibitor, is a prodrug that’s metabolized by the enzyme CYP2C19 before becoming biologically active. But a substantial part of the population—the prevalence varies by race/ethnicity—has a loss-of-function variation in the CYP2C19 gene. For decades, it’s been known that patients with this allele have more platelet aggregation and ischemic events than noncarriers while on clopidogrel therapy.

Still, US and European guidelines addressing antiplatelet therapy in CAD haven’t gone so far as to recommend routine genetic testing, though a few of these documents did give a nod to selective use in situations like dual antiplatelet therapy (DAPT) de-escalation after PCI for ACS.

Writing group chair Naveen L. Pereira, MD (Mayo Clinic, Rochester, MN), told TCTMD that one driver of their new AHA statement is the fact that the guidelines haven’t yet addressed the latest published clinical trials (POPular Genetics, TAILOR-PCI, PHARMCLO, and IAC-PCI), observational studies, and meta-analyses.

“We felt that incorporating data from these studies and providing some guidance to clinicians by interpreting the data, which can be pretty complicated sometimes, would be helpful,” said Pereira, who served as a co-principal investigator for the TAILOR-PCI trial.

Beyond this, the authors also collected information on the pharmacology and pharmacokinetics of P2Y12 inhibitors, both genetic and nongenetic determinants of patients’ response to the drugs, as well as practicalities like reimbursement and how to choose among assays.

“Our conclusion was that the evidence to date supports genetic testing,” Pereira noted. “But in an AHA statement, we cannot directly say, ‘You should do genetic testing.’ That's up to the guidelines.”

As the document points out, “many clinicians have positive perceptions about pharmacogenetic testing and its clinical implications, [but fewer than] 10% adopt pharmacogenetic testing in their routine clinical practice, primarily because of a lack of clinical guidelines and pharmacogenetic education.”

Indeed, only “a very small fraction of practices preemptively genotype,” said Pereira. For patients who go on clopidogrel only to fare poorly and experience an event, genetic testing is moot by that point, he explained, since the answer would be to simply give an alternative antiplatelet drug.

Why Clopidogrel Shouldn’t Be Skipped

Increasingly, the oral P2Y12 inhibitor of choice isn’t clopidogrel but ticagrelor or prasugrel—neither of which are dependent on CYP2C19. Some clinicians wonder, why not just avoid the problem of clopidogrel response entirely?

“There are physicians who say, ‘I know that having a loss-of-function genotype is a problem when I give clopidogrel, but if I give ticagrelor or prasugrel to all my patients, I don't have to worry about genetic testing,’” Pereira commented. The problem with this blanket approach is that these drugs are more potent antiplatelets, so on the whole there will be an increase in bleeding incidence. “If you want to balance the ischemic and bleeding event risk, it appears that genetic-guided therapy [from the outset] would be an optimal strategy,” he added.

Pereira pointed out that multiple studies have shown the cost-effectiveness of using genetic testing to guide antiplatelet therapy. Both clopidogrel and prasugrel are now generic, but not ticagrelor (Brilinta; AstraZeneca), which is considerably more expensive. Medicare considers genetic testing for CYP2C19 loss-of-function alleles to be medically necessary in certain situations, such as when an ACS patient is undergoing PCI, and thus covers its cost. Some commercial payers also offer reimbursement for the testing.

With the availability of point-of-care assays, the logistical hurdles to widespread adoption are also less high. Previously, it could take 2 or 3 days to get results after sending a blood sample for analysis, he noted, but now the testing can be done at bedside with a buccal swab, producing results within an hour.

Naturally, the field loves to see data, Pereira said. While it would be ideal to have a clinical trial comparing genetic-guided therapy versus no testing, with that design, there would be a lot of overlap, since perhaps 70% of patients in the testing arm and 100% of those in the control arm would be taking clopidogrel—with any difference driven by the 30% in the testing arm on another P2Y12 inhibitor. “You're going to need tens of thousands of patients to show a difference, so I think doing a trial like that is very difficult at this point,” he said. It’s easier to see the impact of testing when, as he pointed out was done in a prespecified analysis of TAILOR-PCI, only patients found to have a loss-of-function variant are compared: those given clopidogrel versus those given ticagrelor or prasugrel.

In an AHA statement, we cannot directly say, ‘You should do genetic testing.’ That's up to the guidelines. Naveen L. Pereira

Overall, Pereira urged, “I think it's important to pay attention to evidence in a holistic way. . . . All the data, even though there's not that one big trial showing a difference, really points to [the need] to be careful giving loss-of-function patients clopidogrel.” This is especially true when talking about the monotherapy that’s happening with newer stents after DAPT de-escalation.

What he’d like to see next, said Pereira, is for guidelines to give specific advice on how to use CYP2C19 testing. “Clinicians in the meantime should consider looking at [point-of-care] platforms and see how they can incorporate that in their practices so it becomes easy and intuitive.” Implementation, the statement adds, depends on the ease not only of performing the tests but also of interpreting their results, as well as knowledge about how to adjust therapy accordingly and the ability to integrate each patient’s genetic status into the electronic health record for care teams to access.

But What About Platelet Function?

In a commentary published on the AHA’s Professional Heart Daily website, Mark B. Effron, MD (John Ochsner Heart and Vascular Institute, New Orleans, LA), highlights the fact that platelet function testing (PFT) is another option for predicting who will benefit from a more-potent antiplatelet agent versus clopidogrel, or from de-escalation of therapy.

“In most institutions in the United States, it is easier to obtain results of a platelet aggregation test using VerifyNow than it is to obtain genomics on the patient,” he writes. “Until . . . there are studies evaluating the benefit of an all-comers genomic strategy versus a directed PFT, there will still be controversy as to which is more appropriate in the management of patients receiving P2Y12 inhibitor therapy.”

In their statement, Pereira and colleagues point out that platelet function testing and genetic testing each “has advantages and disadvantages.”

The key advantage of PFT lies in “directly defining the intermediate phenotype of interest (ie, levels of on-treatment platelet reactivity) for which studies have shown an association with clinical outcomes (ie, increased thrombotic and bleeding risks with high and low platelet reactivity, respectively),” they say. “Nevertheless, its clinical implementation has been challenging given the need for multiple repeated assessments due to potential of variability of results over time and the need for a patient to be on treatment for a certain length of time with a given antiplatelet agent (eg, for at least 1–2 weeks with clopidogrel) to be able to assess antiplatelet effects and define responsiveness adequately.”

Effron agrees that a tailored approach is the way forward, though the exact strategy is still being debated. “Whether directed P2Y12 therapy is accomplished through genotype-guided antiplatelet therapy or through PFT,” he says, “it is becoming clear that patient profiling is needed to determine the best therapy for the patient.”