Publications by authors named "Craig R Lee"

90 Publications

The impact of pregnancy on antihypertensive drug metabolism and pharmacokinetics: current status and future directions.

Expert Opin Drug Metab Toxicol 2021 Nov 5. Epub 2021 Nov 5.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Introduction: Hypertensive disorders of pregnancy (HDP) are rising in prevalence, and increase risk of adverse maternal and fetal outcomes. Physiologic changes occur during pregnancy that alter drug pharmacokinetics. However, antihypertensive drugs lack pregnancy-specific dosing recommendations due to critical knowledge gaps surrounding the extent of gestational changes in antihypertensive drug pharmacokinetics and underlying mechanisms.

Areas Covered: This review (1) summarizes currently recommended medications and dosing strategies for non-emergent HDP treatment, (2) reviews and synthesizes existing literature identified via a comprehensive Pubmed search evaluating gestational changes in the maternal pharmacokinetics of commonly prescribed HDP drugs (notably labetalol and nifedipine), and (3) offers insight into the metabolism and clearance mechanisms underlying altered HDP drug pharmacokinetics during pregnancy. Remaining knowledge gaps and future research directions are summarized.

Expert Opinion: A series of small pharmacokinetic studies illustrate higher oral clearance of labetalol and nifedipine during pregnancy. Pharmacokinetic modeling and preclinical studies suggest these effects are likely due to pregnancy-associated increases in hepatic UGT1A1- and CYP3A4-mediated first-pass metabolism and lower bioavailability. Accordingly, higher and/or more frequent doses may be needed to lower blood pressure during pregnancy. Future research is needed to address various evidence gaps and inform the development of more precise antihypertensive drug dosing strategies.
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http://dx.doi.org/10.1080/17425255.2021.2002845DOI Listing
November 2021

How-To Guide for Overcoming Barriers of Research and Scholarship Training in Pharm.D. and Pharmacy Residency Programs.

J Am Coll Clin Pharm 2021 Jun 13;4(6):743-753. Epub 2021 Mar 13.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Accrediting bodies for Doctor of Pharmacy (Pharm.D.) and postgraduate residency training programs recognize the importance of research and scholarship training. However, specific guidance on how research and scholarship fundamentals should be delivered to trainees have not been provided. As a result, competing priorities often create barriers for trainees to develop research and scholarship skills and limit the trainees' ability to conduct and participate in high-quality, meaningful research experiences. The purpose of this "how-to" guide is to assist pharmacy school faculty and pharmacy residency program directors with strategies to overcome programmatic, trainee, and project barriers to providing a high-quality training experience in research and scholarship. Programmatic topics addressed include institutional support and program oversight, expertise and number of research mentors, incentives for mentor engagement, and competing priorities that diminish time for research activities. Trainee topics include lack of trainee interest in the assigned project, trainee departure prior to project completion, lack of knowledge of the publication process, and time constraints to work on the project. Project topics addressed include time needed to initiate a project, training on methodology relevant to a project, selection of projects that lack rigor, depth, or feasibility, and resource constraints to disseminate project results. A summary of specific recommended actions is provided to effectively overcome these common barriers encountered in research and scholarship training programs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330697PMC
June 2021

Implementation and Initial Evaluation of a Research and Scholarship Training Pathway in a Doctor of Pharmacy Curriculum.

Am J Pharm Educ 2021 01 2;85(1):8079. Epub 2020 Oct 2.

University of North Carolina at Chapel Hill, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina

To design, implement, and assess the initial impact of a pharmacy student research and scholarship training pathway. The Research and Scholarship in Pharmacy (RASP) pathway was designed to create a longitudinal, elective pathway within a Doctor of Pharmacy (PharmD) curriculum at a single institution. The pathway consisted of three elective courses built around a faculty-mentored scholarly project where students framed an answerable question, generated and interpreted relevant data, and communicated their findings in oral and written form. Following implementation, a retrospective, multi-method analysis was conducted to evaluate the impact of the program on the initial two student cohorts that completed it and assess their perceptions of the value of the pathway. Fifty students (25 in each of two cohorts) completed the three-course sequence. Students were supported by 33 distinct faculty mentors. Thirty-eight (76%) students presented an abstract derived from their project at a national meeting. The first cohort exit survey (96% response rate) revealed positive student perceptions regarding the value of and satisfaction with the research pathway. Twenty-three (96%) students were satisfied with their research experience, 21 (88%) were satisfied with their faculty mentor, and 24 (100%) were satisfied with their development of project management skills. In the first cohort, 10 (40%) students published an original research manuscript within one year of graduation. The Research and Scholarship in Pharmacy pathway feasibly and effectively provided a mechanism for students to engage in a faculty-mentored longitudinal research experience within a PharmD curriculum that promoted skill development and opportunities for scholarship. Initial implementation demonstrated high rates of student satisfaction, low rates of student attrition, and high rates of scholarly output.
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http://dx.doi.org/10.5688/ajpe8079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829690PMC
January 2021

Effects of aging on clinical outcomes in patients receiving genotype-guided P2Y12 inhibitor selection after percutaneous coronary intervention.

Pharmacotherapy 2021 Jul 9. Epub 2021 Jul 9.

Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Study Objective: To compare the clinical effectiveness of genotype-guided P2Y12 inhibitor selection following PCI in older patients (≥70 years) and younger patients (<70 years).

Design And Setting: Single-center, retrospective, cohort study. Risk of major adverse cardiovascular or cerebrovascular events (MACCE), defined as stent thrombosis, ischemic stroke, transient ischemic attack, non-fatal acute coronary syndrome, or cardiovascular death during 12 months after PCI, was compared across genotype and antiplatelet therapy groups by proportional hazards regression in patients ≥70 years and <70 years.

Patients: 1,469 patients who underwent PCI and had CYP2C19 genotype testing at a single academic medical center.

Measurements And Main Results: The study population was comprised of 402 (27.4%) ≥70 years (older group) and 1067 (72.6%) <70 years (younger group). Alternative P2Y12 inhibitors (prasugrel or ticagrelor) were used less often in the older group than the younger group in patients with a CYP2C19 no function allele (55% vs. 67%; p = 0.02) and in patients without a no function allele (10% vs. 35%, p < 0.001). For patients treated with clopidogrel, MACCE was significantly higher in no function allele carriers compared to those without a no function allele in the older group (19.2% vs. 12.7%; adjusted HR 2.32; 95% CI 1.07-5.05; p = 0.03) and the younger group (17.4% vs. 10.4%; adjusted HR 2.01; 95% CI 1.17-3.46; p = 0.01). In patients without a no function allele, MACCE risk was similar with clopidogrel compared to prasugrel or ticagrelor in the older group (adjusted HR 0.99; 95% CI 0.44-2.21; p = 0.98) and the younger group (adjusted HR 1.12; 95% CI 0.72-1.74; p = 0.61).

Conclusion: This study suggests important clinical benefits of CYP2C19 genotype-guided antiplatelet therapy after PCI in both younger and older patients.
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http://dx.doi.org/10.1002/phar.2611DOI Listing
July 2021

Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes.

Front Pharmacol 2021 15;12:655320. Epub 2021 Apr 15.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Pregnancy-related hormones (PRH) are recognized as important regulators of hepatic cytochrome P450 enzyme expression and function. However, the impact of PRH on the hepatic expression and function of uridine diphosphate glucuronosyltransferases (UGTs) remains unclear. Using primary human hepatocytes, we evaluated the effect of PRH exposure on mRNA levels and protein concentrations of UGT1A1, UGT2B7, and other key UGT enzymes, and on the metabolism of labetalol (a UGT1A1 and UGT2B7 substrate commonly prescribed to treat hypertensive disorders of pregnancy). Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to the PRH estradiol, estriol, estetrol, progesterone, and cortisol individually or in combination. We quantified protein concentrations of UGT1A1, UGT2B7, and four additional UGT1A isoforms in SCHH membrane fractions and evaluated the metabolism of labetalol to its glucuronide metabolites in SCHH. PRH exposure increased mRNA levels and protein concentrations of UGT1A1 and UGT1A4 in SCHH. PRH exposure also significantly increased labetalol metabolism to its UGT1A1-derived glucuronide metabolite in a concentration-dependent manner, which positively correlated with PRH-induced changes in UGT1A1 protein concentrations. In contrast, PRH did not alter UGT2B7 mRNA levels or protein concentrations in SCHH, and formation of the UGT2B7-derived labetalol glucuronide metabolite was decreased following PRH exposure. Our findings demonstrate that PRH alter expression and function of UGT proteins in an isoform-specific manner and increase UGT1A1-mediated labetalol metabolism in human hepatocytes by inducing UGT1A1 protein concentrations. These results provide mechanistic insight into the increases in labetalol clearance observed in pregnant individuals.
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http://dx.doi.org/10.3389/fphar.2021.655320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115026PMC
April 2021

Pregnancy-Related Hormones Increase Nifedipine Metabolism in Human Hepatocytes by Inducing CYP3A4 Expression.

J Pharm Sci 2021 01 12;110(1):412-421. Epub 2020 Sep 12.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Pregnancy-related hormones (PRH) have emerged as key regulators of hepatic cytochrome P450 (CYP) enzyme expression and function. The impact of PRH on protein levels of CYP3A4 and other key CYP enzymes, and the metabolism of nifedipine (a CYP3A4 substrate commonly prescribed during pregnancy), was evaluated in primary human hepatocytes. Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRH (estradiol, estriol, estetrol, progesterone, and cortisol), individually or in combination as a cocktail. Absolute protein concentrations of twelve CYP isoforms in SCHH membrane fractions were quantified by nanoLC-MS/MS, and metabolism of nifedipine to dehydronifedipine in SCHH was evaluated. PRH significantly increased CYP3A4 protein concentrations and nifedipine metabolism to dehydronifedipine in a concentration-dependent manner. CYP3A4 mRNA levels in hepatocyte-derived exosomes positively correlated with CYP3A4 protein levels and dehydronifedipine formation in SCHH. PRH also increased CYP2B6, CYP2C8 and CYP2A6 levels. Our findings demonstrate that PRH increase nifedipine metabolism in SCHH by inducing CYP3A4 expression and alter expression of other key CYP proteins in an isoform-specific manner, and suggest that hepatocyte-derived exosomes warrant further investigation as biomarkers of hepatic CYP3A4 metabolism. Together, these results offer mechanistic insight into the increases in nifedipine metabolism and clearance observed in pregnant women.
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http://dx.doi.org/10.1016/j.xphs.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750305PMC
January 2021

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Clin Pharmacol Ther 2021 03 2;109(3):705-715. Epub 2020 Oct 2.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

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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http://dx.doi.org/10.1002/cpt.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902344PMC
March 2021

Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence.

Pharmgenomics Pers Med 2020 27;13:239-252. Epub 2020 Jul 27.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.

In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke. Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. It has been shown that clopidogrel use in patients who are CYP2C19 no function allele carriers are associated with impaired antiplatelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Compared to clopidogrel, prasugrel and ticagrelor clinical response is not impacted by CYP2C19 genotype. Even with a demonstrated increased risk of adverse outcomes in CYP2C19 no function allele carriers treated with clopidogrel, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial and has not been widely adopted. Recent results from multiple prospective randomized and nonrandomized clinical trials investigating the use of CYP2C19 genotype-guided antiplatelet therapy following PCI have advanced the evidence base demonstrating the clinical utility of this strategy. Multiple recent studies have examined the effects of CYP2C19 genotype on clopidogrel outcomes in the setting of stroke and neurointerventional procedures. In this review, we discern the clinical utility of using CYP2C19 genotype testing to guide antiplatelet therapy prescribing by evaluating the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes, summarizing emerging data from cardiovascular and neurology clinical studies, and discussing implications for clinical practice guidelines, remaining knowledge gaps and future research directions.
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http://dx.doi.org/10.2147/PGPM.S231475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419635PMC
July 2020

Projected impact of pharmacogenomic testing on medications beyond antiplatelet therapy in percutaneous coronary intervention patients.

Pharmacogenomics 2020 05 28;21(7):431-441. Epub 2020 Apr 28.

Division of Pharmacotherapy & Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

genotyping is used to guide antiplatelet therapy after percutaneous coronary intervention (PCI). This study evaluated the potential impact of and multigene pharmacogenomics (PGx) testing on medications beyond antiplatelet therapy in a real-world cohort of PCI patients that underwent testing. Multiple medications with actionable PGx recommendations, including proton pump inhibitors, antidepressants and opioids, were commonly prescribed. Approximately 50% received a CYP2C19 metabolized medication beyond clopidogrel and 7% met criteria for a genotype-guided intervention. A simulation analysis projected that 17.5 PGx-guided medication interventions per 100 PCI patients could have been made if multigene PGx results were available. This suggests that and multigene PGx results could be used to optimize medication prescribing beyond antiplatelet therapy in PCI patients.
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http://dx.doi.org/10.2217/pgs-2019-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252508PMC
May 2020

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs.

Clin Pharmacol Ther 2020 08 28;108(2):191-200. Epub 2020 Apr 28.

Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to cause serious gastrointestinal, renal, and cardiovascular adverse events. CYP2C9 polymorphisms influence metabolism and clearance of several drugs in this class, thereby affecting drug exposure and potentially safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for NSAIDs based on CYP2C9 genotype (updates at www.cpicpgx.org).
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http://dx.doi.org/10.1002/cpt.1830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080882PMC
August 2020

Cost-effectiveness of CYP2C19-guided antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention informed by real-world data.

Pharmacogenomics J 2020 10 11;20(5):724-735. Epub 2020 Feb 11.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.
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http://dx.doi.org/10.1038/s41397-020-0162-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417282PMC
October 2020

Cost-Effectiveness of Multigene Pharmacogenetic Testing in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Value Health 2020 01 25;23(1):61-73. Epub 2019 Sep 25.

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Objective: To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with single-gene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare's perspective.

Methods: A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained.

Results: Base-case-discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%).

Conclusions: On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.
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http://dx.doi.org/10.1016/j.jval.2019.08.002DOI Listing
January 2020

Logistical Challenges Associated With Implementing Precision Medicine.

JAMA Cardiol 2019 12;4(12):1300

McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill.

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http://dx.doi.org/10.1001/jamacardio.2019.4157DOI Listing
December 2019

A case for genotype-guided de-escalation of antiplatelet therapy after percutaneous coronary angioplasty.

Future Cardiol 2019 07 6;15(4):251-254. Epub 2019 Aug 6.

Division of Pharmacotherapy & Experimental Therapeutics, Eshelman School of Pharmacy & McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7569, USA.

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http://dx.doi.org/10.2217/fca-2019-0017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270838PMC
July 2019

Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting.

Genet Med 2020 01 18;22(1):160-169. Epub 2019 Jul 18.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Purpose: To evaluate the frequency and clinical impact of switches in antiplatelet therapy following implementation of CYP2C19 genotyping after percutaneous coronary intervention (PCI).

Methods: The frequency of escalation (clopidogrel switched to prasugrel/ticagrelor) and de-escalation (prasugrel/ticagrelor switched to clopidogrel) was evaluated in 1063 PCI patients who underwent CYP2C19 genotyping. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and bleeding events over one year was evaluated.

Results: Antiplatelet therapy switches were common (19%), with escalation (101/115: 88%) and de-escalation (77/84: 92%) occurring predominantly in patients with and without a CYP2C19 nonfunctional allele, respectively. Nonfunctional allele carriers initiated and continued on clopidogrel had a significantly higher risk of experiencing either a MACCE or bleeding event compared with those escalated to prasugrel/ticagrelor (52 vs. 19 events/100 patient-years; adjusted hazard ratio [HR] 2.89 [1.44-6.13], p = 0.003). Patients without a nonfunctional allele de-escalated to clopidogrel had no difference in risk compared with those initiated and continued on prasugrel/ticagrelor (21 vs. 19 events/100 patient-years; adjusted HR 1.13 [0.51-2.34], p = 0.751).

Conclusion: CYP2C19-guided escalation and de-escalation is common in a real-world setting. Continuation of clopidogrel in nonfunctional allele carriers is associated with adverse outcomes. De-escalation to clopidogrel in patients without a nonfunctional allele appears safe and warrants prospective study.
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http://dx.doi.org/10.1038/s41436-019-0611-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946839PMC
January 2020

Targeted quantitative proteomic analysis of drug metabolizing enzymes and transporters by nano LC-MS/MS in the sandwich cultured human hepatocyte model.

J Pharmacol Toxicol Methods 2019 Jul - Aug;98:106590. Epub 2019 May 31.

Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States of America. Electronic address:

Introduction: Sandwich-cultured human hepatocytes (SCHHs) are the most common in vitro hepatocyte model used for studying hepatic drug disposition and hepatotoxicity. Targeted quantification of key DME and transporter protein expression is useful for in vitro-in vivo extrapolation of drug and xenobiotic clearance and developing corresponding PBPK models. However, established methods for comprehensive quantification of drug metabolizing enzyme (DMEs) and transporter expression in SCHHs are lacking. In this study, a targeted quantitative proteomic isotope dilution nanoLC-MS/MS method developed in our laboratory was adapted to quantify a panel of phase I & II DMEs and transporter proteins in SCHHs under basal and induced conditions.

Methods: SCHHs were treated with known inducers of DMEs (Rifampin: PXR activator, CITCO: CAR activator) and transporters (CDCA: FXR activator) or with vehicle control (DMSO) for 72 h. Membrane protein was isolated from the SCHHs using a membrane extraction kit and 30 μg membrane protein was digested with trypsin. The resulting peptides were analyzed by isotope dilution nanoLC-MS/MS to quantify the DMEs and transporters.

Results: Using the method, we could quantify fourteen phase I and ten phase II DMEs, and twelve uptake/efflux transporters, under basal and induced conditions in the SCHHs. Analysis showed donor to donor variation in basal protein levels of CYP450s, UGTs and transporters, and that basal protein expression of CYP450s and UGTs was higher than that of transporters. In addition, induction of key proteins in response to rifampin, CITCO and CDCA was observed.

Discussion: We have successfully quantified protein abundance of multiple phase I and II DMEs and uptake and efflux transporters in SCHHs using a method previously developed in our laboratory. Our method is sufficiently sensitive to quantify inter-donor differences in protein concentrations at the basal level as well as changes in protein expression in response to endogenous and exogenous stimuli.
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http://dx.doi.org/10.1016/j.vascn.2019.106590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701468PMC
January 2020

CYP2C19 Genotype-Guided Antiplatelet Therapy and 30-Day Outcomes After Percutaneous Coronary Intervention.

Circ Genom Precis Med 2019 02;12(2):e002441

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy (A.K.W., J.M., C.R.L.), School of Medicine, University of North Carolina at Chapel Hill.

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http://dx.doi.org/10.1161/CIRCGEN.119.002441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014555PMC
February 2019

Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

Arterioscler Thromb Vasc Biol 2019 04;39(4):647-652

From the Division of Cardiology (M.D.K., G.A.S.).

Current guidelines recommend dual antiplatelet therapy-a P2Y inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.
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http://dx.doi.org/10.1161/ATVBAHA.118.311963DOI Listing
April 2019

Association between the EPHX2 p.Lys55Arg polymorphism and prognosis following an acute coronary syndrome.

Prostaglandins Other Lipid Mediat 2018 09 7;138:15-22. Epub 2018 Aug 7.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Inhibition of soluble epoxide hydrolase (sEH, EPHX2) elicits potent cardiovascular protective effects in preclinical models of ischemic cardiovascular disease (CVD), and genetic polymorphisms in EPHX2 have been associated with developing ischemic CVD in humans. However, it remains unknown whether EPHX2 variants are associated with prognosis following an ischemic CVD event. We evaluated the association between EPHX2 p.Lys55Arg and p.Arg287Gln genotype with survival in 667 acute coronary syndrome (ACS) patients. No association with p.Arg287Gln genotype was observed (P = 0.598). Caucasian EPHX2 Arg55 carriers (Lys/Arg or Arg/Arg) had a significantly higher risk of 5-year mortality (adjusted hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.01-2.55, P = 0.045). In an independent population of 2712 ACS patients, this association was not replicated (adjusted HR 0.92, 95% CI 0.70-1.21, P = 0.559). In a secondary analysis, Caucasian homozygous Arg55 allele carriers (Arg/Arg) appeared to exhibit a higher risk of cardiovascular mortality (adjusted HR 2.60, 95% CI 1.09-6.17). These results demonstrate that EPHX2 p.Lys55Arg and p.Arg287Gln polymorphisms do not significantly modify survival after an ACS event. Investigation of other sEH metabolism biomarkers in ischemic CVD appears warranted.
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http://dx.doi.org/10.1016/j.prostaglandins.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162147PMC
September 2018

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

Pharmacogenomics 2018 08 20;19(13):1039-1046. Epub 2018 Jul 20.

Division of Cardiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

It is well established that the CYP2C19 nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.
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http://dx.doi.org/10.2217/pgs-2018-0072DOI Listing
August 2018

Response by Lee and Stouffer to Letter Regarding Article, "Clinical Outcomes and Sustainability of Using Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention".

Circ Genom Precis Med 2018 07;11(7):e002258

Division of Cardiology, UNC School of Medicine (G.A.S.) University of North Carolina at Chapel Hill.

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http://dx.doi.org/10.1161/CIRCGEN.118.002258DOI Listing
July 2018

Projected impact of a multigene pharmacogenetic test to optimize medication prescribing in cardiovascular patients.

Pharmacogenomics 2018 06 25;19(9):771-782. Epub 2018 May 25.

Division of Pharmacotherapy & Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Aim: To determine the projected impact of a multigene pharmacogenetic (PGx) test on medication prescribing.

Materials & Methods: A retrospective analysis was conducted with 122 cardiac catheterization laboratory patients undergoing angiography for eligibility of potential PGx-guided interventions that could have occurred if multigene PGx information was pre-emptively available at the time of the procedure. Medication data and presence of actionable at-risk genotypes were used to determine eligibility of a PGx intervention.

Results: 20% of the study population (n = 24) would have qualified for at least one PGx-based medication intervention per US FDA or Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines within 6 months of their cardiac catheterization procedure. Commonly encountered gene-drug pairs for these interventions included: CYP2C19 for clopidogrel and antidepressants, CYP2D6 for antidepressants and codeine, SLCO1B1 for simvastatin, and VKORC1/CYP2C9 for warfarin.

Conclusion: Pre-emptive use of a multigene PGx test in the cardiac catheterization laboratory offers potential to reduce adverse medication outcomes.
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http://dx.doi.org/10.2217/pgs-2018-0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367721PMC
June 2018

Clinical Outcomes and Sustainability of Using Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Circ Genom Precis Med 2018 04;11(4):e002069

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (C.R.L., A.C., K.H., M.J.P., J.A.L.), UNC Center for Pharmacogenomics and Individualized Therapy (C.R.L., K.E.W.), UNC McAllister Heart Institute (C.R.L., G.A.S.), Division of Cardiology, UNC School of Medicine (V.B.S., L.A.H., N.V., S.M., G.A.S.), Department of Pharmacy, UNC HealthCare Medical Center (M.C., J.D.C.), and Department of Pathology and Laboratory Medicine, UNC School of Medicine (K.E.W.), University of North Carolina at Chapel Hill.

Background: loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear.

Methods: A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation end points. Risk of major adverse cardiovascular or cerebrovascular and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression.

Results: genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. testing (<0.001) and alternative DAPT use in LOF allele carriers (=0.001) varied over time. Risk for major adverse cardiovascular or cerebrovascular was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio, 4.65; 95% confidence interval, 2.22-10.0; <0.001), whereas no significant difference was observed in those without a LOF allele (adjusted hazard ratio, 1.37; 95% confidence interval, 0.72-2.85; =0.347). Bleeding event rates were similar across groups (log-rank =0.816).

Conclusions: Implementing genotype-guided DAPT is feasible and sustainable in a real-world setting but challenging to maintain at a consistently high level of fidelity. The higher risk of major adverse cardiovascular or cerebrovascular associated with clopidogrel use in LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes.
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http://dx.doi.org/10.1161/CIRCGEN.117.002069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889089PMC
April 2018

Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

Clin Pharmacol Ther 2018 10 30;104(4):664-674. Epub 2018 Jan 30.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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.
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http://dx.doi.org/10.1002/cpt.1006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019555PMC
October 2018

Urinary 11-dehydro-thromboxane B2 levels are associated with vascular inflammation and prognosis in atherosclerotic cardiovascular disease.

Prostaglandins Other Lipid Mediat 2018 01 16;134:24-31. Epub 2017 Nov 16.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address:

Cyclooxygenase-derived thromboxane (TxA2) and prostacyclin (PGI2) regulate atherogenesis in preclinical models. However, the relationship between TxA2 and PGI2 biosynthesis, vascular inflammation, and atherosclerotic cardiovascular disease (ASCVD) progression in humans remains unclear. The association between stable urine metabolites of thromboxane (TxA2-M) and prostacyclin (PGI2-M), circulating levels of cellular adhesion molecules (CAMs: E-selectin, P-selectin), chemokines and C-reactive protein, and the incidence of major adverse cardiovascular events (MACE) were evaluated in 120 patients with stable ASCVD on aspirin therapy. Urinary TxA2-M levels were significantly correlated with circulating P-selectin (r=0.319, p<0.001) and E-selectin (r=0.245, p=0.007) levels, and associated with higher risk of MACE (p=0.043). In contrast, PGI2-M levels were not significantly associated with CAM levels or MACE. These results provide insight into the contribution of TxA2 biosynthesis to ASCVD progression in humans, and suggest that patients with elevated TxA2-M levels may be predisposed to advanced platelet and endothelial activation and higher risk of adverse cardiovascular outcomes.
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http://dx.doi.org/10.1016/j.prostaglandins.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803431PMC
January 2018

Clinical Evidence Supports a Protective Role for CXCL5 in Coronary Artery Disease.

Am J Pathol 2017 Dec 16;187(12):2895-2911. Epub 2017 Nov 16.

McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address:

Our goal was to measure the association of CXCL5 and molecular phenotypes associated with coronary atherosclerosis severity in patients at least 65 years old. CXCL5 is classically defined as a proinflammatory chemokine, but its role in chronic inflammatory diseases, such as coronary atherosclerosis, is not well defined. We enrolled individuals who were at least 65 years old and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating CXCL5 levels were measured from plasma, and both DNA genotyping and mRNA expression levels in peripheral blood mononuclear cells were quantified via microarray gene chips. We observed a negative association of CXCL5 levels with CAD at an odds ratio (OR) of 0.46 (95% CI, 0.27-0.75). Controlling for covariates, including sex, statin use, hypertension, hyperlipidemia, obesity, self-reported race, smoking, and diabetes, the OR was not significantly affected [OR, 0.54 (95% CI, 0.31-0.96)], consistent with a protective role for CXCL5 in coronary atherosclerosis. We also identified 18 genomic regions with expression quantitative trait loci of genes correlated with both CAD severity and circulating CXCL5 levels. Our clinical findings are consistent with the emerging link between chemokines and atherosclerosis and suggest new therapeutic targets for CAD.
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http://dx.doi.org/10.1016/j.ajpath.2017.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718092PMC
December 2017

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

JACC Cardiovasc Interv 2018 01 1;11(2):181-191. Epub 2017 Nov 1.

Department of Medicine, University of Maryland, Baltimore, Maryland.

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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http://dx.doi.org/10.1016/j.jcin.2017.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775044PMC
January 2018

Precision Dosing: Public Health Need, Proposed Framework, and Anticipated Impact.

Clin Transl Sci 2017 11 10;10(6):443-454. Epub 2017 Aug 10.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.

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http://dx.doi.org/10.1111/cts.12490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698804PMC
November 2017

CYP2C19-guided antiplatelet therapy: a cost-effectiveness analysis of 30-day and 1-year outcomes following percutaneous coronary intervention.

Pharmacogenomics 2017 Aug 26;18(12):1155-1166. Epub 2017 Jul 26.

Division of Pharmacotherapy & Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Aim: Determine whether using CYP2C19 genotype to optimize antiplatelet therapy selection is cost effective over the initial 30 days and 1-year following percutaneous coronary intervention.

Materials & Methods: A cost-effectiveness analysis compared 30-day and 1-year outcomes and cost across three treatment strategies (universal clopidogrel, universal prasugrel, genotype-guided) in a hypothetical cohort.

Results: Base-case scenario results at 30 days indicated that the incremental cost per major cardiovascular or bleeding event avoided for genotype-guided treatment was US$8525 and US$42,198 compared with universal clopidogrel and prasugrel, respectively. Probabilistic sensitivity analysis demonstrated that genotype-guided treatment was cost effective over 30 days and 1 year in 62 and 70% of simulations, respectively.

Conclusion: Implementing a CYP2C19 genotype-guided approach to antiplatelet therapy could have a positive economic impact by preventing readmissions following percutaneous coronary intervention.
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http://dx.doi.org/10.2217/pgs-2017-0075DOI Listing
August 2017
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