Clinical Impact of Pharmacogenomic Testing on Antiplatelet Therapy

Background

Pharmacogenomics (PGx) is changing the use of P2Y12 inhibitors (antiplatelet drugs), which are widely used in the treatment of acute coronary syndrome (ACS), neurovascular problems, and vascular diseases. Among them, clopidogrel is a commonly used P2Y12 inhibitor. This prodrug relies on multiple pathways to convert into active metabolites, mainly through the cytochrome P450 2C19 (CYP2C19) enzyme. However, individuals carrying loss-of-function (LOF) alleles in the CYP2C19 gene have lower clopidogrel efficacy, putting some patients at a higher risk of major adverse cardiovascular events (MACE).

CYP2C19 genotyping can identify patients with LOF alleles and recommend switching from clopidogrel to ticagrelor or prasugrel, which do not rely on the CYP2C19 pathway. Existing studies have mostly focused on reactive genotyping to guide antiplatelet drug selection after the need arises. Preemptive PGx testing refers to genotyping patients in a healthy state to avoid potential delays in waiting for test results when drug needs arise, which could lead to adverse consequences.

Research Source

This study was conducted by Amanda Massmann, Kurt D. Christensen, et al., with main collaborating institutions including Sanford Imagenetics, Harvard Medical School, and South Dakota State University School of Medicine. The research findings were published in the European Journal of Human Genetics in 2024.

Research Content

Research Process

This study is a retrospective cohort study analyzing data from patients who received P2Y12 inhibitor treatment and PGx testing after ACS or PCI within the Sanford Health system from January 2018 to September 2021. These patients were divided into preemptive genotyping, early genotyping, and late genotyping groups based on when they obtained CYP2C19 genotyping results.

Data Collection

Candidates were selected from new antiplatelet drug orders between January 2018 and September 2020. Selected antiplatelet drugs included clopidogrel, ticagrelor, and prasugrel. New drug orders were defined as data showing no P2Y12 inhibitor use for over 1 year or no P2Y12 inhibitor orders for over 2 years, aiming to prevent misclassifying drug renewals as new starts.

Experimental and Computational Methods

The study used Propensity Score matching to reduce confounding bias, analyzed data using R software, and used logistic regression to compare preemptive and early genotyping PGx testing strategies. Cluster-robust variance was used in statistical models to estimate standard errors. The analysis included all patients, regardless of the duration of antiplatelet drug use.

Research Results

The study analyzed 274 patients, with 67 in the preemptive genotyping group, 67 in the early genotyping group (through Propensity Score matching), and 140 in the late genotyping group. The study found that for patients with CYP2C19 loss-of-function alleles, only 18.2% of those receiving preemptive genotyping were initiated on clopidogrel, compared to 66.7% and 73.2% for those receiving early and late genotyping, respectively.

Preemptive genotyping significantly reduced the proportion of clopidogrel initiation, but it was also found that patients using preemptive genotyping did not have a significantly higher proportion of subsequent cardiovascular adverse events or bleeding events after starting ticagrelor or prasugrel compared to other genotyping strategies. Additionally, analysis showed that the genomic testing strategy had no significant impact on cardiology, neurology, or emergency department visit rates.

Research Conclusions

The study shows that preemptive PGx testing has a significant impact on initial P2Y12 inhibitor selection, making treatment more in line with Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations. However, comparative results showed no significant difference in patient outcomes between preemptive CYP2C19 genotyping and early genotyping, possibly due to healthcare providers’ rapid response to early genotyping results.

Research Significance

This study provides preliminary evidence that preemptive CYP2C19 genotyping has a significant impact on P2Y12 inhibitor selection but no significant improvement or deterioration in ultimate patient outcomes. This provides valuable empirical data for policymakers and health systems to help evaluate the risks and benefits of preemptive PGx testing. It also highlights the potential value of preemptive testing in clinical workflow efficiency, such as reducing resource waste and redundancy in drug prescriptions.

Research Highlights

1. Emphasizes the key role of preemptive PGx testing in optimizing antiplatelet drug selection.
2. Provides preliminary analysis and comparison of different PGx testing strategies on patient medical outcomes and healthcare resource utilization.
3. Data comes from real-world healthcare systems, offering high practical reference value.

Although preemptive PGx testing shows more advantages in initial antiplatelet drug selection, its impact on patient outcomes needs further research for verification. This study provides a strong foundation of baseline data for future exploration of clinical applications of preemptive PGx testing strategies.