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Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.
Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, Kimmel SE, McDonough CW, Gong Y, Dave CV, Pratt VM, Alestock TD, Anderson RD, Alsip J, Ardati AK, Brott BC, Brown L, Chumnumwat S, Clare-Salzler MJ, Coons JC, Denny JC, Dillon C, Elsey AR, Hamadeh IS, Harada S, Hillegass WB, Hines L, Horenstein RB, Howell LA, Jeng LJB, Kelemen MD, Lee YM, Magvanjav O, Montasser M, Nelson DR, Nutescu EA, Nwaba DC, Pakyz RE, Palmer K, Peterson JF, Pollin TI, Quinn AH, Robinson SW, Schub J, Skaar TC, Smith DM, Sriramoju VB, Starostik P, Stys TP, Stevenson JM, Varunok N, Vesely MR, Wake DT, Weck KE, Weitzel KW, Wilke RA, Willig J, Zhao RY, Kreutz RP, Stouffer GA, Empey PE, Limdi NA, Shuldiner AR, Winterstein AG, Johnson JA, IGNITE Network
(2018) JACC Cardiovasc Interv 11: 181-191
MeSH Terms: Aged, Clinical Decision-Making, Clopidogrel, Cytochrome P-450 CYP2C19, Drug Resistance, Female, Humans, Male, Middle Aged, Patient Selection, Percutaneous Coronary Intervention, Pharmacogenetics, Pharmacogenomic Testing, Pharmacogenomic Variants, Platelet Aggregation Inhibitors, Prasugrel Hydrochloride, Predictive Value of Tests, Risk Assessment, Risk Factors, Ticagrelor, Time Factors, Treatment Outcome, United States
Show Abstract · Added March 14, 2018
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.
Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Evidence for extensive pleiotropy among pharmacogenes.
Oetjens MT, Bush WS, Denny JC, Birdwell K, Kodaman N, Verma A, Dilks HH, Pendergrass SA, Ritchie MD, Crawford DC
(2016) Pharmacogenomics 17: 853-66
MeSH Terms: Adult, African Americans, Cytochrome P-450 CYP2C19, Female, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Pharmacogenetics, Phenotype, Symporters
Show Abstract · Added March 14, 2018
AIM - We sought to identify potential pleiotropy involving pharmacogenes.
METHODS - We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients.
RESULTS - We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10(-7); odds ratio [OR]: 1.73; 95% CI: 1.40-2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10(-4); OR: 1.67; 95% CI: 1.27-2.20).
CONCLUSION - In this systematic screen for phenotypic associations with functional variants, several novel genotype-phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10(-) (6); OR: 0.61; 95% CI: 0.49-0.75).
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13 MeSH Terms
Physician response to implementation of genotype-tailored antiplatelet therapy.
Peterson JF, Field JR, Unertl KM, Schildcrout JS, Johnson DC, Shi Y, Danciu I, Cleator JH, Pulley JM, McPherson JA, Denny JC, Laposata M, Roden DM, Johnson KB
(2016) Clin Pharmacol Ther 100: 67-74
MeSH Terms: Age Factors, Aged, Clinical Decision-Making, Clopidogrel, Cytochrome P-450 CYP2C19, Female, Genetic Variation, Genotype, Humans, Male, Middle Aged, Pharmacogenetics, Platelet Aggregation Inhibitors, Practice Patterns, Physicians', Precision Medicine, Prospective Studies, Stents, Ticlopidine
Show Abstract · Added March 14, 2018
Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.
© 2015 American Society for Clinical Pharmacology and Therapeutics.
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18 MeSH Terms
CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease.
Hoh BL, Gong Y, McDonough CW, Waters MF, Royster AJ, Sheehan TO, Burkley B, Langaee TY, Mocco J, Zuckerman SL, Mummareddy N, Stephens ML, Ingram C, Shaffer CM, Denny JC, Brilliant MH, Kitchner TE, Linneman JG, Roden DM, Johnson JA
(2016) J Neurosurg 124: 1746-51
MeSH Terms: Aged, Aspirin, Carboxylic Ester Hydrolases, Clopidogrel, Cytochrome P-450 CYP2C19, Female, Gene Frequency, Genotyping Techniques, Heterozygote, Humans, Intracranial Arteriosclerosis, Ischemic Attack, Transient, Kaplan-Meier Estimate, Male, Myocardial Infarction, Platelet Aggregation Inhibitors, Polymorphism, Single Nucleotide, Prospective Studies, Stroke, Ticlopidine
Show Abstract · Added March 14, 2018
OBJECT Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients. METHODS Genotype testing for CYP2C19*2, (*)3, (*)8, (*)17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months. RESULTS The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03-0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08-0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06-1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05-1.04, p = 0.056). CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.
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20 MeSH Terms
Applied pharmacogenomics in cardiovascular medicine.
Weeke P, Roden DM
(2014) Annu Rev Med 65: 81-94
MeSH Terms: Adrenergic beta-Antagonists, Antihypertensive Agents, Antithrombins, Aryl Hydrocarbon Hydroxylases, Cardiovascular Diseases, Clopidogrel, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP2C9, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver-Specific Organic Anion Transporter 1, Organic Anion Transporters, Pharmacogenetics, Polymorphism, Single Nucleotide, Precision Medicine, Ticlopidine, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added March 7, 2014
Interindividual heterogeneity in drug response is a central feature of all drug therapies. Studies in individual patients, families, and populations over the past several decades have identified variants in genes encoding drug elimination or drug target pathways that in some cases contribute substantially to variable efficacy and toxicity. Important associations of pharmacogenomics in cardiovascular medicine include clopidogrel and risk for in-stent thrombosis, steady-state warfarin dose, myotoxicity with simvastatin, and certain drug-induced arrhythmias. This review describes methods used to accumulate and validate these findings and points to approaches--now being put in place at some centers--to implementing them in clinical care.
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18 MeSH Terms
Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project.
Pulley JM, Denny JC, Peterson JF, Bernard GR, Vnencak-Jones CL, Ramirez AH, Delaney JT, Bowton E, Brothers K, Johnson K, Crawford DC, Schildcrout J, Masys DR, Dilks HH, Wilke RA, Clayton EW, Shultz E, Laposata M, McPherson J, Jirjis JN, Roden DM
(2012) Clin Pharmacol Ther 92: 87-95
MeSH Terms: Aryl Hydrocarbon Hydroxylases, Cardiac Catheterization, Clopidogrel, Computer-Aided Design, Cytochrome P-450 CYP2C19, Decision Support Systems, Clinical, Genetic Variation, Genotyping Techniques, Humans, Patient Selection, Pharmacogenetics, Platelet Aggregation Inhibitors, Precision Medicine, Ticlopidine
Show Abstract · Added December 10, 2013
The promise of "personalized medicine" guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision-support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health-care provider, identification of relevant genetic variations for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.
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14 MeSH Terms
Clopidogrel: a case for indication-specific pharmacogenetics.
Johnson JA, Roden DM, Lesko LJ, Ashley E, Klein TE, Shuldiner AR
(2012) Clin Pharmacol Ther 91: 774-6
MeSH Terms: Angioplasty, Balloon, Coronary, Aryl Hydrocarbon Hydroxylases, Clopidogrel, Cytochrome P-450 CYP2C19, Genotype, Humans, Pharmacogenetics, Platelet Aggregation Inhibitors, Ticlopidine
Show Abstract · Added June 26, 2014
The CYP2C19*2 loss-of-function allele is associated with reduced generation of active metabolites of clopidogrel. However, meta-analyses have supported or discounted the impact of genotype on adverse cardiovascular outcomes during clopidogrel therapy, depending on studies included in the analysis. Here we review these data and conclude that evidence supports a differential effect of genotype on protection from major adverse cardiovascular outcomes following percutaneous coronary intervention (PCI), but not for other clopidogrel indications.
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9 MeSH Terms
A surveillance tool to support quality assurance and research in personalized medicine.
Khan NA, Peterson JF
(2011) AMIA Annu Symp Proc 2011: 701-8
MeSH Terms: Aryl Hydrocarbon Hydroxylases, Biomedical Research, Clopidogrel, Cytochrome P-450 CYP2C19, Drug Therapy, Computer-Assisted, Drug-Eluting Stents, Genotype, Humans, Pharmacogenetics, Pilot Projects, Platelet Aggregation Inhibitors, Precision Medicine, Quality Assurance, Health Care, Ticlopidine, User-Computer Interface
Show Abstract · Added May 19, 2014
Developing effective methods to enable the practice of personalized medicine is a national priority for translational science. By leveraging modern genotyping technology and health information technologies, prescribing therapies based on genotype becomes an achievable goal. Within this manuscript, we describe the development, implementation, and piloting of a surveillance tool to assure the quality of clinical decision making in the context of new pharmacogenetic information. The surveillance tool allows a quality assurance (QA) team to review significant genotyping results and deliver focused educational interventions to providers. We report on the first eight patients undergoing genotyping to support antiplatelet therapy selection after drug-eluting stent placement. The collected pilot data supports an informatics approach to QA process management, as our tool delivered actionable patient information. It also enabled providers to tailor antiplatelet therapy to individual patients' genotypes. Our expectation is to continue collecting surveillance reports to perform an in-depth analysis of our tool.
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15 MeSH Terms
Predicting clopidogrel response using DNA samples linked to an electronic health record.
Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, Shi Y, Zink R, Oetjens M, Xu H, Cleator JH, Jahangir E, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC
(2012) Clin Pharmacol Ther 91: 257-63
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Aged, Aryl Hydrocarbon Hydroxylases, Aryldialkylphosphatase, Clopidogrel, Cytochrome P-450 CYP2C19, Databases, Nucleic Acid, Electronic Health Records, Female, Genotype, Humans, Male, Myocardial Infarction, Pharmacogenetics, Platelet Aggregation Inhibitors, Polymorphism, Genetic, Stents, Thrombosis, Ticlopidine, Treatment Outcome
Show Abstract · Added December 10, 2013
Variants in ABCB1 and CYP2C19 have been identified as predictors of cardiac events during clopidogrel therapy initiated after myocardial infarction (MI) or percutaneous coronary intervention (PCI). In addition, PON1 has recently been associated with stent thrombosis. The reported effects of these variants have not yet been replicated in a real-world setting. We used BioVU, the Vanderbilt DNA repository linked to de-identified electronic health records (EHRs), to find data on patients who were on clopidogrel treatment after an MI and/or a PCI; among these, we identified those who had experienced one or more recurrent cardiac events while on treatment (cases, n = 225) and those who had not experienced any cardiac event while on treatment (controls, n = 468). We found that CYP2C19*2 (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.16-2.06, P = 0.003) and ABCB1 (HR 1.28, 95% CI 1.04-1.57, P = 0.018), but not PON1 (HR 0.91, 95% CI 0.73-1.12, P = 0.370), were associated with recurrent events. In this population, genetic signals for clopidogrel resistance in ABCB1 and CYP2C19 were replicated, supporting the use of EHRs for pharmacogenomic studies. Our data do not show an association between PON1 and recurrent cardiovascular events.
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21 MeSH Terms
Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults.
Driscoll TA, Yu LC, Frangoul H, Krance RA, Nemecek E, Blumer J, Arrieta A, Graham ML, Bradfield SM, Baruch A, Liu P
(2011) Antimicrob Agents Chemother 55: 5770-9
MeSH Terms: Administration, Oral, Adolescent, Adult, Antifungal Agents, Aryl Hydrocarbon Hydroxylases, Child, Child, Preschool, Cytochrome P-450 CYP2C19, Dose-Response Relationship, Drug, Female, Genotype, Humans, Immunocompromised Host, Infusions, Intravenous, Liver Function Tests, Male, Middle Aged, Pyrimidines, Treatment Outcome, Triazoles, Voriconazole, Young Adult
Show Abstract · Added March 27, 2014
Voriconazole pharmacokinetics are not well characterized in children despite prior studies. To assess the appropriate pediatric dosing, a study was conducted in 40 immunocompromised children aged 2 to <12 years to evaluate the pharmacokinetics and safety of voriconazole following intravenous (IV)-to-oral (PO) switch regimens based on a previous population pharmacokinetic modeling: 7 mg/kg IV every 12 h (q12h) and 200 mg PO q12h. Area under the curve over the 12-h dosing interval (AUC(0-12)) was calculated using the noncompartmental method and compared to that for adults receiving approved dosing regimens (6 → 4 mg/kg IV q12h, 200 mg PO q12h). On average, the AUC(0-12) in children receiving 7 mg/kg IV q12h on day 1 and at IV steady state were 7.85 and 21.4 μg · h/ml, respectively, and approximately 44% and 40% lower, respectively, than those for adults at 6 → 4 mg/kg IV q12h. Large intersubject variability was observed. At steady state during oral treatment (200 mg q12h), children had higher average exposure than adults, with much larger intersubject variability. The exposure achieved with oral dosing in children tended to decrease as weight and age increased. The most common treatment-related adverse events were transient elevated liver function tests. No clear threshold of voriconazole exposure was identified that would predict the occurrence of treatment-related hepatic events. Overall, voriconazole IV doses higher than 7 mg/kg are needed in children to closely match adult exposures, and a weight-based oral dose may be more appropriate for children than a fixed dose. Safety of voriconazole in children was consistent with the known safety profile of voriconazole.
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22 MeSH Terms