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Clopidogrel Pharmacogenetics - Why the Wait?
Roden DM
(2019) N Engl J Med 381: 1677-1678
MeSH Terms: Clopidogrel, Genotype, Percutaneous Coronary Intervention, Pharmacogenetics, Platelet Aggregation Inhibitors, Ticlopidine
Added March 24, 2020
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1 Members
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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
A prognostic model based on readily available clinical data enriched a pre-emptive pharmacogenetic testing program.
Schildcrout JS, Shi Y, Danciu I, Bowton E, Field JR, Pulley JM, Basford MA, Gregg W, Cowan JD, Harrell FE, Roden DM, Peterson JF, Denny JC
(2016) J Clin Epidemiol 72: 107-15
MeSH Terms: Adult, Age Factors, Aged, Clopidogrel, Decision Support Systems, Clinical, Drug Utilization, Electronic Health Records, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Longitudinal Studies, Male, Middle Aged, Models, Statistical, Pharmacogenetics, Predictive Value of Tests, Prognosis, Program Evaluation, Proportional Hazards Models, Reproducibility of Results, Risk Factors, Sex Factors, Ticlopidine, United States, Warfarin
Show Abstract · Added March 14, 2018
OBJECTIVES - We describe the development, implementation, and evaluation of a model to pre-emptively select patients for genotyping based on medication exposure risk.
STUDY DESIGN AND SETTING - Using deidentified electronic health records, we derived a prognostic model for the prescription of statins, warfarin, or clopidogrel. The model was implemented into a clinical decision support (CDS) tool to recommend pre-emptive genotyping for patients exceeding a prescription risk threshold. We evaluated the rule on an independent validation cohort and on an implementation cohort, representing the population in which the CDS tool was deployed.
RESULTS - The model exhibited moderate discrimination with area under the receiver operator characteristic curves ranging from 0.68 to 0.75 at 1 and 2 years after index dates. Risk estimates tended to underestimate true risk. The cumulative incidences of medication prescriptions at 1 and 2 years were 0.35 and 0.48, respectively, among 1,673 patients flagged by the model. The cumulative incidences in the same number of randomly sampled subjects were 0.12 and 0.19, and in patients over 50 years with the highest body mass indices, they were 0.22 and 0.34.
CONCLUSION - We demonstrate that prognostic algorithms can guide pre-emptive pharmacogenetic testing toward those likely to benefit from it.
Copyright © 2016 Elsevier Inc. All rights reserved.
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25 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
Cardiovascular pharmacogenomics: current status and future directions.
Roden DM
(2016) J Hum Genet 61: 79-85
MeSH Terms: Arrhythmias, Cardiac, Cardiovascular Agents, Clopidogrel, Genetic Variation, Genomics, Hematologic Agents, Heparin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Ticlopidine, Warfarin
Show Abstract · Added March 24, 2020
Drugs are widely used and highly effective in the treatment of heart disease. Nevertheless, in some instances, even drugs effective in a population display lack of efficacy or adverse drug reactions in individual patients, often in an apparently unpredictable fashion. This review summarizes the genomic factors now known to influence variability in responses to widely used cardiovascular drugs such as clopidogrel, warfarin, heparin and statins. Genomic approaches being used to discover new pathways in common cardiovascular diseases and thus potential new targets for drug development are described. Finally, the way in which this new information is likely to be used in an electronic medical record environment is discussed.
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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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1 Members
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18 MeSH Terms
Pharmacogenomics and cardiovascular disease.
Weeke P, Roden DM
(2013) Curr Cardiol Rep 15: 376
MeSH Terms: Adrenergic beta-Antagonists, Cardiovascular Agents, Cardiovascular Diseases, Clopidogrel, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Polymorphism, Genetic, Practice Guidelines as Topic, Ticlopidine, Warfarin
Show Abstract · Added March 7, 2014
Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the genomic basis for variable responses to cardiovascular therapies has been a model for pharmacogenomics in general and has established critical pathways and specific loci modulating therapeutic responses to commonly used drugs such as clopidogrel, warfarin, and statins. In addition, genomic approaches have defined mechanisms and genetic variants underlying important toxicities with these and other drugs. These findings have not only resulted in changes to the product labels but also have led to development of initial clinical guidelines that consider how to facilitate incorporating genetic information to the bedside. This review summarizes the state of knowledge in cardiovascular pharmacogenomics and considers how variants described to date might be deployed in clinical decision making.
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10 MeSH Terms
A huge coronary artery aneurysm in osteogenesis imperfecta: a case report.
Hajsadeghi S, Jafarian Kerman SR, Pouraliakbar H, Mohammadi R
(2012) Acta Med Iran 50: 785-8
MeSH Terms: Adult, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Clopidogrel, Coronary Aneurysm, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Hypotension, Inferior Wall Myocardial Infarction, Osteogenesis Imperfecta, Platelet Aggregation Inhibitors, Rare Diseases, Ticlopidine, Treatment Outcome, Ultrasonography
Show Abstract · Added April 25, 2016
Osteogenesis imperfecta (OI) as an inherited connective tissue disorder can affect all tissues that contains type I collagen. Well-known cardiac complications of this disease such as aortic root dilatation, aortic regurgitation and mitral valve prolapse have been rarely reported in the literature. Coronary artery aneurysm is a rare cardiac complication in OI, as reported in a 19 year old female presenting with myocardial infarction and hypotension.
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17 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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6 Members
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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