percutaneous coronary intervention pharmacogenomics

Clopidogrel is the most commonly prescribed antiplatelet drug for patients following percutaneous coronary intervention (PCI) procedures to treat narrowing of the arteries. However, about 30% of Caucasians and African-Americans, and about 60% of Asians, have genetic variations in the cytochrome p450 2C19 (CYP2C19) gene that affect their metabolism of the drug, leaving them at about a two fold increased risk of developing a recurring cardiovascular event.

In March 2010, the Food and Drug Administration (FDA) added a black box warning to clopidogrel, advising clinicians that poor metabolizers of this drug could experience reduced effectiveness when taking it, that tests for CYP2C19 function are available, and that they might consider prescribing other medications in these high-risk patients.

Even before the FDA box warning, some medical centers had started clinically testing for CYP2C19 genotype in patients undergoing PCI to help guide selection of appropriate antiplatelet therapy, either with clopidogrel or other agents such as prasugrel or ticagrelor. More have followed suit over the past decade, including participants in the Implementing GeNomics In pracTicE (IGNITE) network, a National Institutes of Health-funded research group aimed at implementing genomics in practice. Twelve of these trailblazing institutions recently published their strategies for implementing CYP2C19 genotype-guided therapy (Clin Pharmacol Ther 2018;104:664-74).

“There has been considerable debate and uncertainty surrounding whether using CYP2C19 genetic testing clinically to guide antiplatelet therapy is the right thing to do given the amount of evidence,” said the study’s senior author, Craig Lee, PharmD, PhD, an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics at the University of North Carolina at Chapel Hill (UNC), one of the early adopters of CYP2C19 testing.

Guidelines from groups like the American Heart Association say genotyping high-risk PCI patients might make sense, but they don’t recommend it routinely for all patients. Data from a multicenter randomized clinical trial called TAILOR-PCI, seeking to discover if genetic testing can determine the best anti-platelet therapy, is expected to be released by September.

Meanwhile, evidence accruing through studies from IGNITE and previous pharmacogenomic networks, and a number of small clinical trials in Asia and Europe, are demonstrating improved patient outcomes using a genotype-guided strategy, and an increasing number of institutions have either implemented or sought to implement some CYP2C19 genetic testing, said Lee.

While other antiplatelet agents don’t carry the same interactions with CYP2C19, clopidogrel often is still favored, said the study’s first author, Philip Empey, PharmD, PhD, associate director for pharmacogenomics at the University of Pittsburgh/UPMC Institute of Precision Medicine (UPMC). “The higher potency agents have different side effect profiles and higher rates of bleeding events,” he said. Some older populations can’t take them, and they’re more expensive. “In our cost-focused world, clinicians must consider many factors when making prescribing decisions,” he added.

Which Alleles, Platforms?

Institutions participating in the recent IGNITE study noted several challenges in implementing their pharmacogenomic testing programs, such as selecting a testing platform, determining how to communicate test results, and educating patients and providers. The medical centers used a variety of platforms for genotyping, including Spartan Biosciences’ Spartan RX, GenMark Diagnostics’ eSensor XT-8, and custom TaqMan and QuantStudio assays from ThermoFisher.

UNC uses a TaqMan assay, said Karen Weck, MD, director of the institution’s molecular genetics laboratory. “We looked at a number of genotyping platforms and chose to use this for various reasons,” she said. “It works really well, it’s a fast test, and we have designed a separate assay for the CYP2C19*2 and *3 variants, which are the poor metabolism alleles, and for *17, which is a rapid metabolism allele.” All 12 institutions surveyed in the study said they report at least these three alleles, with some adding results for CYP2C19*4-*10, *12, and *13.

UPMC reports findings for 10 CYP2C19 variants employing the GenMark platform, Empey said. “It has coverage of the variants we think are important, and it made sense in our workflow for what we wanted to return.”

Accuracy and speed are critical factors to look for in platforms, said Empey and Alan Shuldiner, MD, associate dean for personalized and genomic medicine at the University of Maryland School of Medicine (UM) in Baltimore. At UM, results are reported in patients’ electronic medical records within 3-4 hours of tests being ordered. “The key is to make sure the genotype is returned before the patient is discharged,” Shuldiner said, “so that an appropriate therapeutic decision can be made.”

All sites in the IGNITE study report CYP2C19 test results in patients’ electronic health records, often listed as discrete genotype and phenotype results as well as a notation of how patients will metabolize the drug, with a linked text-based full report. Some centers use pharmacists or dedicated teams to provide genotype-informed drug therapy recommendations.

“Discrete results are critical to enabling clinical decision support and alerting appropriately within our health system,” said Empey. “It’s hard to do that solely from a PDF or text-based report.”

Institutional Champions

IGNITE study participants listed several key ingredients for success in implementing pharmacogenomics programs like this. Chief among them are identifying a physician champion and engaging key stakeholders.

UNC was able to encourage CYP2C19 testing more easily because the former head of the cardiac catheterization laboratory helped push for it, said Weck. “The most important issue of clinical success is having a clinical group interested in utilizing the results,” she emphasized.

Also important is to create clinical decision support tools to spur clinicians to order the tests and take appropriate medical action based on the results. After discovering at their own institution that use of the tests fluctuated over time, staff at UNC are in the process of creating automated clinical decision support for CYP2C19 testing, said Lee (Circ Genom Precis Med 2018;11:e002069).

In addition, he said, “Education is really key to assure that those ordering the tests and using the results understand the evidence behind it.” Interdisciplinary collaboration with clinicians and nurses also is crucial. “We really need to make sure everyone who’s involved in the process understands the goals and processes to make it successful,” Empey said.

Laboratorians might want to partner with pharmacists to educate providers, advised Petr Starostik, MD, director of molecular pathology at University of Florida Health (UFH) in Gainesville, “because they will send you samples only if they see there is a need for such testing.”

Future Targets

While CYP2C19-guided therapy for clopidogrel remains the “poster child and most broadly applicable” of the genotyping tests, said Shuldiner, some medical centers—including IGNITE participants—are considering or already running pharmacogenomic tests for additional genes and their drug interactions. “I think a lot’s going to happen over the next few years,” he predicted.

At UFH, for example, the lab also tests for CYP2D6, involved in the metabolism of many drugs, including opioids. Ultra-fast metabolizers of that gene may need higher doses to experience pain relief, Starostik said. In addition, the UFH lab plans to start using an All of Us microarray to study the whole genome. Clinically relevant genes like CYP2D6 and CYP2C19 will be reported per usual in patients’ electronic health records while the remaining data will be held in a biobank for subsequent research.

IGNITE participants emphasize the importance of working with clinicians in determining the need for and implementing any tests. “Pharmacogenomics has not been an example of ‘If you build it, they will come,’” said Weck. “We’ve had several such tests that we have brought online that have not been ordered because of lack of clinical uptake.”

Karen Blum is a freelance medical/science writer in Owings Mills, Maryland. +Email: [email protected]