New Platelet Function, Genetic Testing Consensus Seeks to Fill Gaps—Again

Randomized trials of platelet function and genetic testing to guide antiplatelet decisions following PCI have produced notoriously mixed results: now, an updated consensus document aims to fill some gaps by providing real-world-based scenarios to guide clinical choices.

Tests of platelet function and genetic predisposition have been designed to identify the up to 30% of patients with loss-of-function variations in the CYP2C19 gene that limit their ability to metabolize the P2Y12 inhibitor clopidogrel. To date, trials like POPular Genetics, TAILOR-PCI, and PHARMCLO of gene tests, as well as TROPICAL-ACS, ARCTIC, and ANTARCTIC of platelet function, have failed to provide the slam-dunk evidence needed to support routine use of the tests in all patients. As a result, their use has become dependent on operator preference and institutional availability with neither US nor European guidelines recommending routine use of the tests.

“The practice guidelines continue to either not provide strong recommendations or overall completely fail to acknowledge the topic, which, in my opinion, has sufficient evidence to support its use, not routinely in all patients but definitely in a number of patients,” lead author Dominick J. Angiolillo, MD (University of Florida College of Medicine, Jacksonville), told TCTMD.

The latest consensus document, last updated in 2019, was published online this week in JACC: Cardiovascular Interventions, and follows a similar review paper published in 2023 as well as a scientific statement by the American Heart Association (AHA) published in June.

Speaking with TCTMD, Geoff Barnes, MD (University of Michigan, Ann Arbor), said the new document is timely given the scientific progress made in the last 5 years regarding the use of antiplatelet monotherapy and de-escalation, even if the data supporting platelet function and genetic testing haven’t made similar strides. “Most of the evidence around these tests is a little bit older,” he said. “But because the way in which we use antiplatelet agents has evolved so much, this document, to me, now provides a very state-of-the-art framework for when a clinician would consider either platelet function or genetic testing to help them make the best decision for an individual patient.”

I think there’s solid evidence out there, so let’s focus on making it easy to do in clinical practice. Deepak Voora

Barring a change in guidelines, what the field has been missing is “a strong endorsement for guided therapy using either platelet function testing or genetic testing,” Deepak Voora, MD (Duke University School of Medicine, Durham, NC), commented to TCTMD, adding that he isn’t sure the field will ever “get there.”

This paper, coupled with the AHA statement, however, “is the next best thing,” he said. “These are the people that often write those guidelines getting together and basically saying: ‘Here’s an approach that is proven to improve outcomes.’”

Algorithms in Context

The central focus of the document is finding the balance between bleeding and ischemic risk in patients who need P2Y12 inhibitor therapy and using that as the basis for moving forward.

“There is large and consistent evidence supporting the prognostic relevance of different levels of platelet reactivity in response to clopidogrel, suggesting a potential ‘therapeutic window’ of platelet inhibition in PCI patients,” the authors write.

They offer several decision-making algorithms to help guide when platelet function or genetic testing might offer benefit, and in which patients, enumerating the advantages and drawbacks associated with each specific test. While both are now available as a rapid bedside assay, platelet function testing one-ups genetic testing by measuring the direct response to antiplatelet therapy and assessing both genetic and nongenetic factors. That said, genetic testing isn’t hindered by interindividual variability or changing findings over time and doesn’t require patients to be on antiplatelet therapy to provide a result.

This document, to me, now provides a very state-of-the-art framework for when a clinician would consider either platelet function or genetic testing to help them make the best decision for an individual patient. Geoff Barnes

New in this iteration of the consensus is a “clear distinction between escalation and de-escalation strategies, who are the target populations, and what these strategies are intended to do in terms of impact on ischemic events and bleeding events,” Angiolillo said. “A lot of the confusion that has occurred in the past was related to how you actually interpret the data, and obviously, the approaches need to be put into context based on the patient population being tested and the strategies being used.”

Data Aligning

He hopes this latest contribution, alongside the AHA statement published earlier this year, will give writing committees something to chew on when considering future iterations of the guidelines. “I also believe that this document provides the foundations to see how we can design future studies to move the needle a little bit more in favor of testing,” Angiolillo said.

All the data from randomized trials, real-world registries, and meta-analyses “point in the same direction,” he continued. “By using testing, we have an opportunity to optimize outcomes rather than the approach of one-size-fits-all. One of the hesitations of integrating these more frequently in clinical practice is that guidelines either do not provide strong recommendations or do not acknowledge them at all.”

Paul Gurbel, MD (LifeBridge Health, Baltimore, MD), who was the first author of a 2003 paper that first introduced the concept of clopidogrel resistance, told TCTMD “it’s still incredible to me . . . that we’re still debating whether [platelet function testing] is useful or not. Here we are, 21 years after the seminal paper that came out in Circulation, and we still don’t know what to do with it.”

He attributes this to the lack of a “well-designed, adequately-sized clinical trial to prove the utility of platelet function testing,” acknowledging that there have been efforts to do such a trial.

Regardless, Gurbel, who was a co-author on the new statement, said: “I never stopped measuring platelet function. I would never, ever put a stent in a patient’s coronary artery and have that patient on clopidogrel and just assume that the drug is effective.” For patients not yet on antiplatelet therapy, he uses genetic testing.

We’re at a point right now where we need to make sure that when we’re doing this strategy, we do it with the right drugs and the drugs that actually work. Dominick J. Angiolillo

Voora said the question now turns to exploring implementation strategies. “It’s not like an individual practitioner can just do this,” he said. “You need the lab to participate, you need the pharmacy to participate, you need help from the health system and the EMRs to participate.

“The evidence for clinical utility is there and is solid,” Voora continued. “It may not be as solid as you want it, and it may not be as robust as you want it, but I think there’s solid evidence out there, so let’s focus on making it easy to do in clinical practice.”

The emergence of P2Y12 monotherapy has led physicians to be more open to testing to ensure that their patients aren’t going without therapy, Angiolillo said. “We’re at a point right now where we need to make sure that when we’re doing this strategy, we do it with the right drugs and the drugs that actually work.”

For Barnes, the main take-home message from the paper “is that platelet function testing or genetic testing is not recommended for all patients. In fact, I think it is going to be a minority of patients in whom this is going to be very useful.”

But for those patients, in particular those at increased thrombotic risk or who are being considered for P2Y12 monotherapy, testing could specifically guide the decision between clopidogrel or a more potent agent like ticagrelor or prasugrel, he said.

Future Directions

While Angiolillo argues that the existing data should be sufficient to support greater use of platelet function and genetic testing, he’s open to more “pragmatic trials” that include newer antithrombotic regimens.

I would never, ever put a stent in a patient’s coronary artery and have that patient on clopidogrel and just assume that the drug is effective. Paul Gurbel

Gurbel, however, wasn’t optimistic that testing strategies will be studied in another large, randomized trial, primarily due to the lack of interested funders. “To me, the totality of the evidence base would support selective use of P2Y12 inhibitors dependent upon genotype,” he said. “I hope we can move the field forward, but my plea would be to get clinicians to understand that one out of three times, in effect, they’re giving a placebo to their patient when they give them clopidogrel.”

While Angiolillo sees pros and cons to each kind of test, he argued that “genetic testing has more potential” given that it’s less subject to variability and more practical. “Your genetics do not change. We have the opportunity to enrich them with clinical factors. And you can do genetic testing at any point in time and store these data in the patients’ electronic medical records.”

Barnes said he tends to prefer platelet function testing, primarily because that is the “cultural norm” at his center and how he was trained. What is the most important, though, is that the results from whichever test is used are appropriately communicated between hospitals and physicians.

“This is particularly true for platelet function testing, where the different assays are reporting out different values,” he explained. “What I may be used to as a normal range at my center may not be the same as the hospital down the street. And so, moving to a model where there’s more standardization so that everyone is speaking the same language would, I think, help all of us at a public health level.”

Another hurdle to overcome in this space is better quantifying bleeding and thrombotic risk, according to Barnes. “The more we can make that standard in the way it’s approached, then the easier it will be to apply this framework and determine when either platelet function testing or genetic testing is going to be most useful,” he said.

For now, Barnes said he recommends clinicians review the algorithms in this paper and “ask themselves, ‘While most of the time I don’t need to do this, when are the select times I do need to do it?’ I think this framework really outlines that clearly.”

“I hope interventional cardiologists read this with an open mind,” Voora said. “And for those who haven’t been convinced yet, [that they] consider changing their clinical practice.”