Browsing by Author "Coons, James C."

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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 implementation of CYP2C19 genotype-guided antiplatelet therapy
    (Wiley, 2018) Empey, Philip E.; Stevenson, James M.; Tuteja, Sony; Weitzel, Kristin W.; Angiolillo, Dominick J.; Beitelshees, Amber L.; Coons, James C.; Duarte, Julio D.; Franchi, Francesco; Jeng, Linda J. B.; Johnson, Julie A.; Kreutz, Rolf P.; Limdi, Nita A.; Maloney, Kristin A.; Obeng, Aniwaa Owusu; Peterson, Josh F.; Petry, Natasha; Pratt, Victoria M.; Rollini, Fabiana; Scott, Stuart A.; Skaar, Todd C.; Vesely, Mark R.; Stouffer, George A.; Wilke, Russell A.; Cavallari, Larisa H.; Lee, Craig R.; Medicine, School of Medicine
    CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes which are both related to CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. This article is protected by copyright.
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    Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention
    (Elsevier, 2018-01-22) Cavallari, Larisa H.; Lee, Craig R.; Beitelshees, Amber L.; Cooper-DeHoff, Rhonda M.; Duarte, Julio D.; Voora, Deepak; Kimmel, Stephen E.; McDonough, Caitrin W.; Gong, Yan; Dave, Chintan V.; Pratt, Victoria M.; Alestock, Tameka D.; Anderson, R. David; Alsip, Jorge; Ardati, Amer K.; Brott, Brigitta C.; Brown, Lawrence; Chumnumwat, Supatat; Clare-Salzler, Michael J.; Coons, James C.; Denny, Joshua C.; Dillon, Chrisly; Elsey, Amanda R.; Hamadeh, Issam; Harada, Shuko; Hillegass, William B.; Hines, Lindsay; Horenstein, Richard B.; Howell, Lucius A.; Jeng, Linda J.B.; Kelemen, Mark D.; Lee, Y.M.; Magvanjav, Oyunbileg; Montasser, May; Nelson, David R.; Nutescu, Edith A.; Nwaba, Devon C.; Pakyz, Ruth E.; Palmer, Kathleen; Peterson, Josh F.; Pollin, Toni I.; Quinn, Alison H.; Robinson, Shawn W.; Schub, Jamie; Skaar, Todd C.; Smith, Donald M.; Sriramoju, Vindhya B.; Starostik, Petr; Stys, Tomasz P.; Stevenson, James M.; Varunok, Nicholas; Vesely, Mark R.; Wake, Dyson T.; Weck, Karen E.; Weitzel, Kristin W.; Wilke, Russell A.; Willig, James; Zhao, Richard Y.; Kreutz, Rolf P.; Stouffer, George A.; Empey, Philip E.; Limdi, Nita A.; Shuldiner, Alan R.; Winterstein, Almut G.; Johnson, Julie A.; Medical and Molecular Genetics, School of Medicine
    OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
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    Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy
    (Wiley, 2018-10) Empey, Philip E.; Stevenson, James M.; Tuteja, Sony; Weitzel, Kristin W.; Angiolillo, Dominick J.; Beitelshees, Amber L.; Coons, James C.; Duarte, Julio D.; Franchi, Francesco; Jeng, Linda J.B.; Johnson, Julie A.; Kreutz, Rolf P.; Limdi, Nita A.; Maloney, Kristin A.; Obeng, Aniwaa Owusu; Peterson, Josh F.; Petry, Natasha; Pratt, Victoria M.; Rollini, Fabiana; Scott, Stuart A.; Skaar, Todd C.; Vesely, Mark R.; Stouffer, George A.; Wilke, Russell A.; Cavallari, Larisa H.; Lee, Craig R.; IGNITE Network; Medicine, School of Medicine
    CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions