Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update
Icahn School of Medicine at Mount Sinai1, Stanford University2, Vanderbilt University3, Pierre-and-Marie-Curie University4, Brigham and Women's Hospital5, University of Florida6, American Association of Colleges of Pharmacy7, University of Maryland, Baltimore8, United States Department of Veterans Affairs9
TL;DR: In this article, an expanded literature review showed that CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI).
Abstract: Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).
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Cleveland Clinic Lerner College of Medicine1, University of Minnesota2, Stanford University3, Centre for Addiction and Mental Health4, Mayo Clinic5, University of Montana6, Children's Mercy Hospital7, Veterans Health Administration8, Indiana University9, Icahn School of Medicine at Mount Sinai10, St. Jude Children's Research Hospital11
TL;DR: Evidence from the published literature supporting associations between CYP2D6 and CYC19 polymorphisms and SSRIs efficacy and safety is summarized and dosing recommendations for fluvoxamine, paroxetine, citalopram, escitaloprams, and sertraline based on CYP1C19 genotype are provided.
Abstract: Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
700 citations
TL;DR: The use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings.
Abstract: Importance Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. Objectives To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. Design, Setting, and Participants An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. Main Outcomes and Measures Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. Results Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P Conclusions and Relevance In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.
413 citations
TL;DR: Current programs that use preemptive genotyping to optimize the pharmacotherapy of patients are discussed and key processes for implementation are highlighted, including clinical decision support.
Abstract: Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support.
366 citations
Semmelweis University1, National and Kapodistrian University of Athens2, Brigham and Women's Hospital3, Aix-Marseille University4, University of Paris5, University of Florida6, Gyeongsang National University7, Icahn School of Medicine at Mount Sinai8, University of Kentucky9, University of Freiburg10, Mayo Clinic11, Scripps Health12, University of Ottawa13, Columbia University Medical Center14, University of Sheffield15, University of Bern16, MedStar Washington Hospital Center17
TL;DR: An international expert consensus group of key leaders from North America, Asia, and Europe with expertise in the field of antiplatelet treatment was convened and summarizes the contemporary updated expert consensus recommendations for the selective use of PFT or genotyping in patients undergoing percutaneous coronary intervention.
Abstract: Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention. The availability of different P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor) with varying levels of potency has enabled physicians to contemplate individualized treatment regimens, which may include escalation or de-escalation of P2Y12-inhibiting therapy. Indeed, individualized and alternative DAPT strategies may be chosen according to the clinical setting (stable coronary artery disease vs. acute coronary syndrome), the stage of the disease (early- vs. long-term treatment), and patient risk for ischemic and bleeding complications. A tailored DAPT approach may be potentially guided by platelet function testing (PFT) or genetic testing. Although the routine use of PFT or genetic testing in percutaneous coronary intervention-treated patients is not recommended, recent data have led to an update in guideline recommendations that allow considering selective use of PFT for DAPT de-escalation. However, guidelines do not expand on when to implement the selective use of such assays into decision making for personalized treatment approaches. Therefore, an international expert consensus group of key leaders from North America, Asia, and Europe with expertise in the field of antiplatelet treatment was convened. This document updates 2 prior consensus papers on this topic and summarizes the contemporary updated expert consensus recommendations for the selective use of PFT or genotyping in patients undergoing percutaneous coronary intervention.
346 citations
Stanford University1, University of Toronto2, University of Tübingen3, Bosch4, University of Extremadura5, National Institutes of Health6, Academia Sinica7, China Medical University (Taiwan)8, Vanderbilt University9, Icahn School of Medicine at Mount Sinai10, Uppsala University11, Leiden University12, Geisinger Medical Center13
TL;DR: This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.
Abstract: The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
329 citations
References
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TL;DR: The four articles in this special section onMeta-analysis illustrate some of the complexities entailed in meta-analysis methods and contributes both to advancing this methodology and to the increasing complexities that can befuddle researchers.
Abstract: During the past 30 years, meta-analysis has been an indispensable tool for revealing the hidden meaning of our research literatures. The four articles in this special section on meta-analysis illus...
20,272 citations
TL;DR: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding.
Abstract: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Conclusions In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591.)
6,021 citations
TL;DR: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rates of overall major bleeding but with an increase of non-procedure-related bleeding.
Abstract: At 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% vs. 5.1%, P = 0.001) but not stroke alone (1.5% vs. 1.3%, P = 0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopid ogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. Conclusions In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non– procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)
5,898 citations
01 Jan 2010
TL;DR: A systematic review of studies published from January 1, 1950, through November 31, 2008 using PubMed, EMBASE, Web of Knowledge, CINAHL, and all Evidence-Based Medicine Reviews found that randomized clinical trials and prospective studies of RRTs that reported data on changes in the primary outcome of hospital mortality or the secondary outcome of cardiopulmonary arrest cases were included.
Abstract: Methods: We conducted a systematic review of studies published from January 1, 1950, through November 31, 2008, using PubMed, EMBASE, Web of Knowledge, CINAHL, and all Evidence-Based Medicine Reviews. Randomized clinical trials and prospective studies of RRTs that reported data on changes in the primary outcome of hospital mortality or the secondary outcome of cardiopulmonary arrest cases were included.
2,958 citations
TL;DR: General agreement of genetic and predefined populations suggests that self-reported ancestry can facilitate assessments of epidemiological risks but does not obviate the need to use genetic information in genetic association studies.
Abstract: We studied human population structure using genotypes at 377 autosomal microsatellite loci in 1056 individuals from 52 populations. Within-population differences among individuals account for 93 to 95% of genetic variation; differences among major groups constitute only 3 to 5%. Nevertheless, without using prior information about the origins of individuals, we identified six main genetic clusters, five of which correspond to major geographic regions, and subclusters that often correspond to individual populations. General agreement of genetic and predefined populations suggests that self-reported ancestry can facilitate assessments of epidemiological risks but does not obviate the need to use genetic information in genetic association studies.
2,661 citations