Browsing by Author "Lee, James C."

Now showing 1 - 6 of 6
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    CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.
    (Journal of the American Heart Association, 2022-02-15) Beitelshees, Amber L.; Thomas, Cameron D.; Empey, Philip E.; Stouffer, George A.; Angiolillo, Dominick J.; Franchi, Francesco; Tuteja, Sony; Limdi, Nita A.; Lee, James C.; Duarte, Julio D.; Kreutz, Rolf P.; Skaar, Todd C.; Coons, James C.; Giri, Jay; McDonough, Caitrin W.; Rowland, Rachel; Stevenson, James M.; Thai, Thuy; Vesely, Mark R.; Wellen, Jacob T.; Johnson, Julie A.; Winterstein, Almut G.; Cavallari, Larisa H.; Lee, Craig R.
    Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.
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    Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention
    (Wiley, 2023) Cavallari, Larisa H.; Limdi, Nita A.; Beitelshees, Amber L.; Lee, James C.; Duarte, Julio D.; Franchi, Francesco; Tuteja, Sony; Giri, Jay; Empey, Philip E.; Kreutz, Rolf P.; Skaar, Todd C.; Allen, John M.; Coons, James C.; Gong, Yan; McDonough, Caitrin W.; Stevenson, James M.; Thomas, Cameron D.; Johnson, Julie A.; Stouffer, George A.; Angiolillo, Dominick J.; Lee, Craig R.; IGNITE Network; Pharmacology and Toxicology, School of Medicine
    Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.
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    Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.
    (Wiley, 2021-03) Lee, Craig R.; Thomas, Cameron D.; Beitelshees, Amber L.; Tuteja, Sony; Empey, Philip E.; Lee, James C.; Limdi, Nita A.; Duarte, Julio D.; Skaar, Todd C.; Chen, Yiqing; Cook, Kelsey J.; Coons, James C.; Dillon, Chrisly; Franchi, Francesco; Giri, Jay; Gong, Yan; Kreutz, Rolf P.; McDonough, Caitrin W.; Stevenson, James M.; Weck, Karen E.; Angiolillo, Dominick J.; Johnson, Julie A.; Stouffer, George A.; Cavallari, Larisa H.
    Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.
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    Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing
    (Springer Nature, 2019-10) Cavallari, Larisa H.; Van Driest, Sara L.; Prows, Cynthia A.; Bishop, Jeffrey R.; Limdi, Nita A.; Pratt, Victoria M.; Ramsey, Laura B.; Smith, D. Max; Tuteja, Sony; Duong, Benjamin Q.; Hicks, J. Kevin; Lee, James C.; Obeng, Aniwaa Owusu; Beitelshees, Amber L.; Bell, Gillian C.; Blake, Kathryn; Crona, Daniel J.; Dressler, Lynn; Gregg, Ryan A.; Hines, Lindsay J.; Scott, Stuart A.; Shelton, Richard C.; Weitzel, Kristin Wiisanen; Johnson, Julie A.; Peterson, Josh F.; Empey, Philip E.; Skaar, Todd C.; Medical and Molecular Genetics, School of Medicine
    PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
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    Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing
    (Elsevier, 2021) Duarte, Julio D.; Dalton, Rachel; Elchynski, Amanda L.; Smith, D. Max; Cicali, Emily J.; Lee, James C.; Duong, Benjamin Q.; Petry, Natasha J.; Aquilante, Christina L.; Beitelshees, Amber L.; Empey, Philip E.; Johnson, Julie A.; Obeng, Aniwaa Owusu; Pasternak, Amy L.; Pratt, Victoria M.; Ramsey, Laura B.; Tuteja, Sony; Van Driest, Sara L.; Wiisanen, Kristin; Hicks, J. Kevin; Cavallari, Larisa H.; IGNITE Network Pharmacogenetics Working Group; Medical and Molecular Genetics, School of Medicine
    Purpose: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear. Methods: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates. Results: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low. Conclusion: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.
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    The Pharmacogenomics Global Research Network Implementation Working Group: global collaboration to advance pharmacogenetic implementation
    (Wolters Kluwer, 2025) Cavallari, Larisa H.; Hicks, J. Kevin; Patel, Jai N.; Elchynski, Amanda L.; Smith, D. Max; Bargal, Salma A.; Fleck, Ashley; Aquilante, Christina L.; Killam, Shayna R.; Lemke, Lauren; Ochi, Taichi; Ramsey, Laura B.; Haidar, Cyrine E.; Ho, Teresa; El Rouby, Nihal; Monte, Andrew A.; Allen, Josiah D.; Beitelshees, Amber L.; Bishop, Jeffrey R.; Bousman, Chad; Campbell, Ronald; Cicali, Emily J.; Cook, Kelsey J.; Duong, Benjamin; Tsermpini, Evangelia Eirini; Girdwood, Sonya Tang; Gregornik, David B.; Grimsrud, Kristin N.; Lamb, Nathan; Lee, James C.; Lopez, Rocio Ortiz; Mazhindu, Tinashe Adrian; Morris, Sarah A.; Nagy, Mohamed; Nguyen, Jenny; Pasternak, Amy L.; Petry, Natasha; van Schaik, Ron H. N.; Schultz, April; Skaar, Todd C.; Al Alshaykh, Hana; Stevenson, James M.; Stone, Rachael M.; Tran, Nam K.; Tuteja, Sony; Woodahl, Erica L.; Yuan, Li-Chi; Lee, Craig R.; Medicine, School of Medicine
    Pharmacogenetics promises to optimize treatment-related outcomes by informing optimal drug selection and dosing based on an individual's genotype in conjunction with other important clinical factors. Despite significant evidence of genetic associations with drug response, pharmacogenetic testing has not been widely implemented into clinical practice. Among the barriers to broad implementation are limited guidance for how to successfully integrate testing into clinical workflows and limited data on outcomes with pharmacogenetic implementation in clinical practice. The Pharmacogenomics Global Research Network Implementation Working Group seeks to engage institutions globally that have implemented pharmacogenetic testing into clinical practice or are in the process or planning stages of implementing testing to collectively disseminate data on implementation strategies, metrics, and health-related outcomes with the use of genotype-guided drug therapy to ultimately help advance pharmacogenetic implementation. This paper describes the goals, structure, and initial projects of the group in addition to implementation priorities across sites and future collaborative opportunities.