Inside the Diagnostics Industry: Genotyping to Guide Antiplatelet Selection Feasible, Effective

Despite years of frustration that pharmacogenomic testing for antiplatelet therapy dosing has not been adopted as hoped in the field of cardiology, new evidence is emerging that genetic testing should be employed to guide therapy decisions.

CYP2C19 testing has not been adopted in widespread practice due to conflicting recommendations for its use, as well as uncertainty over its effectiveness its real-world feasibility to inform treatment decisions in a timely matter. Several recent studies are providing evidence to overcome these concerns.

Importantly, the recent studies show that genetic test results are significantly influencing cardiologists' treatment decisions, which may ultimately improve patient outcomes.

Genotyping Improves Patient Outcomes
Patients who receive genotyping to guide the choice of antiplatelet therapy are significantly less likely to experience a primary endpoint event—a composite of myocardial infarction, stroke, cardiovascular death, and major bleeding—compared with patients who did not receive the genetic test, according to the Italian PHARMCLO trial, published March 11 in the Journal of the American College of Cardiology, in conjunction with the American College of Cardiology (ACC) 2018 Annual Scientific Session.

Experts say the use of more potent antiplatelet drugs—prasugrel and ticagrelor—involves a fundamental trade-off between decreasing the risk of ischemia, but increasing the risk of bleeding. Experts believe this trade-off can be mitigated by adding genetic information to clinical decisionmaking.

Patients hospitalized for acute coronary syndromes were randomly assigned to standard of care (n=440) or the pharmacogenomic arm (n=448), which included the genotyping of ABCB1, CYP2C19*2, CYP2C19*17 using an ST Q3 system that uses real-time polymerase chain reaction technology at the point of care to provide results within 70 minutes at each patient's bedside. Treatment decisions were informed by a genetic algorithm that was designed to consider the three genes simultaneously, although the ultimate therapy decisions were left to the discretion of the physicians. In the standard of care group therapy decisions were based upon clinical considerations only. The patients were followed up one year.

Genotyping showed that 29.2 percent of patients had at least one copy of the loss-of-function CYP2C19*2 allele and 31.3 percent had at least one copy of the gain-of-function CYP2C19*17 allele. Genotyping significantly changed treatment decisions with clopidogrel was more significantly frequently in the standard of care arm, while ticagrelor was used significantly more frequently in the pharmacogenomic arm. Prasugrel was equally used in both arms. The primary endpoint occurred significantly more often in the standard of care arm versus the pharmacogenomics arm (25.9 percent versus 15.9 percent). Additionally, ischemic and bleeding endpoints occurred significantly more frequently in the standard of care arm.

"This prospective, randomized multicenter study provides evidence that the use of genomic medicine to select P2Y12 receptor antagonists can be successfully incorporated into the clinical care of patients with acute coronary syndromes," write the authors led by Diego Ardissino, M.D., from Azienda Ospedaliero-Universitaria di Parma, Italy. "This may be considered one of the most challenging clinical settings in which to use pharmacogenetic data to guide clinical practice because of the urgency of the situation and the need to start drug treatment promptly. In our case, this was made feasible by the development of a bedside instrument capable of providing genotype results within 70 minutes of blood sampling."

However, the Ardissino had to urge caution, as the trial was stopped after enrolling approximately one-quarter of the planned 3,600 patients. At the ACC meeting Ardissino explained that ethical committees decided to stop the trial because of the lack of in vitro diagnosis certification for the genetic testing instrument used, despite the same committee's initial approval of the study. 

Despite the fact they had a far smaller sample than planned, the PHARMCLO trial still showed quite a large beneficial effect on outcomes in the genetic tested group.

"These recent studies nicely highlight the potential value of genotyping in personalizing antiplatelet therapy," Deepak L. Bhatt, M.D., from Brigham & Women's Hospital in Boston, Mass., told Medscape Medical News at ACC. "There are a number of larger ongoing trials, such as TAILOR PCI, that will need to provide greater clarity to the field before we routinely change practice."

Testing is Feasible
In addition to mounting evidence that CYP2C19 genotype–guided antiplatelet therapy strategy is effective, it is also feasible and sustainable in a real-world clinical setting, according to a study published April 3 in Circulation: Genomic and Precision Medicine. Additionally, the study found a higher risk of major adverse events tied to use of clopidogrel in CYP2C19 loss-of-function (LOF) allele carriers, suggesting that use of genotype-guided prescribing may improve clinical outcomes.

Clopidogrel plus aspirin remains one of the most commonly prescribed blood thinners, but it is recognized that CYP2C19 loss-of-function alleles impair its effectiveness. Yet, there remains considerable debate about whether CYP2C19 genetic testing should be used clinically to guide antiplatelet therapy selection in patients undergoing percutaneous coronary intervention.

The University of North Carolina Cardiac Catheterization Laboratory implemented a clinical algorithm that recommends CYP2C19 testing in high-risk patients and alternative dual antiplatelet therapy (DAPT; prasugrel or ticagrelor) in LOF allele carriers. The study assessed use of the algorithm and subsequent clinical outcomes in 1,193 patients who underwent percutaneous coronary intervention (July 1, 2012 to June 30, 2014).

The researchers found that the median time from genotype order to return of results was 1 day, with 75 percent of results available by the day after the procedure. CYP2C19 genotyping was performed in just under three-quarters of patients (72.8 percent). However, the frequency of genotype testing significantly varied over time. The authors note that it is unclear what specific factors contributed to the fluctuations in fidelity.

Among genotyped patients, just under one-third of patients (30.2 percent) carried one or two LOF alleles. Alternative DAPT was prescribed in approximately 71 percent of LOF allele carriers. Like genotype testing, use of alternative therapy in CYP2C19 intermediate and poor metabolizers varied significantly over time. The authors note that while recurrent clinician education was used, automated clinical decision support within the electronic health record (EHR) system to alert clinicians about the genotype result was not available during the study period.

Clinical outcomes were assessed in 999 patients with available 1-year follow-up. There was a significantly higher (four-fold) risk for major adverse cardiovascular or cerebrovascular in LOF carriers prescribed clopidogrel versus those prescribed alternative DAPT. But, bleeding event rates were similar across groups.

"The feasible implementation and sustainable use of a genotype-guided algorithm … was possible because of several key factors that alleviated logistical barriers," write the authors led by Craig Lee, Pharm.D., Ph.D., from University of North Carolina, Chapel Hill. "Notably, in-house genotype testing with prompt turnaround of results in the EHR, and interdisciplinary collaboration and communication among physicians, clinical pharmacists, and nurses have proven critical."

Takeaway: While several large studies are still ongoing, implementation of a CYP2C19 genotyping strategy to guide antiplatelet selection is feasible and appears to have clinically meaningfully impact on outcomes.