Real-Time Genetic Data Impacts Physician Prescribing Behavior Following Stent Procedures

Sony Tuteja, PharmD, MS

While it is unknown if physicians in real-world settings will utilize the data, the results of the ADAPT trial revealed that providing test results for Loss-of-Function (LOF) alleles in the CYP2C19 gene was shown to significantly influence the prescription of antiplatelet therapies.

While current ACC/AHA guidelines do not recommend routine CYP2C19 testing, the presence of LOF alleles impacts the body’s ability to process clopidogrel, a common antiplatelet therapy. As a result, clinical pharmacogenetics guidelines recommend the use of prasugrel or ticagrelor for patients that carry CYP2C19 LOF.

"One of the main things we aimed to do in this study was to integrate a clinical trial protocol into the physicians' daily practice, in order to provide the most beneficial medication regimens to patients based on their specific genetic needs, while also identifying what drives physician behavior when prescribing," senior author Jay Giri, MD, the associate director of the Penn Cardiovascular Outcomes, Quality, & Evaluative Research Center and an assistant professor of cardiovascular medicine, said in a statement.

Presented by lead author Sony Tuteja, PharmD, MS, a research assistant professor of translational medicine and human genetics at the University of Pennsylvania’s Perlman School of Medicine, at the 67^th American College of Cardiology Scientific Sessions in Orlando, Florida, the study randomized 504 patients that received percutaneous coronary intervention (PCI) to either be genotyped (n = 249) or receive the usual care (n = 255), with a primary endpoint seeking to know the proportion of patients receiving either prasugrel or ticagrelor.

The usual care group received a saliva swab to be genotyped for post-analysis.

Physicians treating those in the genotyped group received verbal guided recommendations for those with CYP2C19 *2 or *3 to receive prasugrel or ticagrelor, and those with CYP2C19 *1 or *17 to receive clopidogrel, although the choice was ultimately left up to the interventional cardiologist.

"Clinicians were provided with a real-time, rapid response genetic test and an appropriate level of education for using said test, which would identify patients' genetic mutation, CYP2C19 LOF alleles,” Giri said. “We thought this precision medicine approach would impact the medications being prescribed to patients following PCI."

In a 2013 study, it was found that CYP2C19 LOF is most common in those of South Asian (frequency, 35%) and East Asian descent (29%), followed by African and European descent (15% each). The ADAPT trial demographics revealed the genotyped group to be 78% (n = 194) white, and 19% (n = 48) black, with similar results in the usual care group (white, 77%, n = 197; black, 20%, n = 51).

Genetic data revealed that 28% of the total genotyped group carried the CYP2C19 *2 mutation (*1/*2, 20%; *2/*17, 5%; *2/*2, 3%). Prior to genotyping the anticipated rate of prasugrel/ticagrlor prescriptions was 30% to 35%, a mark that the genotyped group hit, at 30% (n = 75). The remaining 70% (n = 174) received clopidogrel. In the usual care group, 79% (n = 201) of patients received clopidogrel, while 21% (n = 54) received prasugrel/ticagrelor.

Prasugrel/ticagrelor was found to be utilized more frequently in those that carried LOF alleles in the genotyped group, being prescribed to 22% (n = 38) of the non-LOF carriers and 53% (n = 36) of the LOF carriers in the genotyped group (P <.001). Clopidogrel was administered to 47% (n = 32) of those carrying LOF alleles, and 78% (n = 136) of those without LOF alleles.

In the usual care group, 21% (n = 54) were prescribed prasugrel/ticagrelor, and 79% (n = 201) received clopidogrel.

The overall rate of guideline agreement in the genotyped group was high—71%&mdash;with only 43 cases not following recommendations for a number of reasons, but physician choice being the reasoning in only 3 instances. Other reasons included the presence of stable coronary artery disease (n = 9), cost (n = 6), disease characteristics (n = 6), current utilization of therapy (n = 6), acute coronary syndrome (n = 5), recurrent events (n = 5), and contraindications (n = 3).

"This implies that physicians consider factors beyond the genotype when deciding the most appropriate antiplatelet medication for their patients, which is the premise of precision medicine," Tuteja said. "Ultimately we concluded that access to pharmacogenetic test results significantly impacted antiplatelet prescribing behaviors. It remains to be seen whether a reduction in important clinical outcomes like heart attack, stroke, and cardiovascular-related death follow what is predicted by the genetics.”

One of the main results of the study, however, was not displayed in the form of data. It raised the question as to whether or not patient-specific genetic information will impact standards of care and the way that physicians behave in this developing age of precision medicine.

"Often times we have a situation where the data in large clinical trials will say one thing, but precision medicine data will say another, so we need to figure out what the physician will do in those situations and what drives their decisions," Giri said in a statement. "Are clinicians influenced more by a patients' genetic make-up, or by the population-based research they have access to? Ultimately more research is needed to really identify the impact and usefulness of real-time genetic testing for making clinical decisions, which we intend to evaluate for interventional patients. As it turns out, precision medicine is a lot more than just precise genetics."

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