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Pharmacogenomic anticoagulation

Paolo Emilio Puddu, Loredana Iannetta, Attilio Placanica, Domenico Cuturello, Michele Schiariti, Olivia Manfrini
The role played by glycoprotein (GP) IIb/IIIa inhibitors (GPI) has continuously evolved until the most recent Guidelines whereby they were stepped down from class I to class II recommendation for treating acute coronary syndromes (ACS). GPI compete with a wider use of ADP inhibitors and novel anticoagulant drugs although GPI use has greatly narrowed. However, GPI may still have a role. Several criteria were proposed to define post-PCI anemia which is strictly related to bleeding and transfusion. In ACS, it should be important to define anemia in comparative terms versus baseline levels: ≥ 15% of red blood cell decrease should be a practical cut-off value...
November 1, 2016: International Journal of Cardiology
Payman Shahabi, Laura B Scheinfeldt, Daniel E Lynch, Tara J Schmidlen, Sylvie Perreault, Margaret A Keller, Rachel Kasper, Lisa Wawak, Joseph P Jarvis, Norman P Gerry, Erynn S Gordon, Michael F Christman, Marie-Pierre Dubé, Neda Gharani
Pharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process...
August 1, 2016: Thrombosis and Haemostasis
Yuya Masuda, Kazuhiko Matsuno, Chikara Shimizu
In recent years, thrombotic disease, including myocardial infarction and ischemic stroke, has rapidly increased in Japan. To treat and prevent thromboembolism, warfarin has been commonly prescribed for a long period as an oral anticoagulant. However, it is difficult to define an appropriate warfarin dose because of large inter-individual variability in dose requirements and the narrow therapeutic range. Recent pharmacogenomic (PGx) studies have shown that several single nucleotide polymorphisms (SNPs) in CYP2C9 (warfarin metabolic enzyme) and VKORC1 (warfarin target enzyme) are responsible for an individual's warfarin sensitivity...
November 2015: Rinsho Byori. the Japanese Journal of Clinical Pathology
Larisa H Cavallari, Darius L Mason
CKD is an independent risk factor for cardiovascular disease (CVD). Thus, patients with CKD often require treatment with cardiovascular drugs, such as antiplatelet, antihypertensive, anticoagulant, and lipid-lowering agents. There is significant interpatient variability in response to cardiovascular therapies, which contributes to risk for treatment failure or adverse drug effects. Pharmacogenomics offers the potential to optimize cardiovascular pharmacotherapy and improve outcomes in patients with CVD, although data in patients with concomitant CKD are limited...
March 2016: Advances in Chronic Kidney Disease
J Liu, H H Jiang, D K Wu, Y X Zhou, H M Ye, X Li, Z Y Luo, Z Guo, Y L Zhang, Y C Wang, W Zhang, H H Zhou, L S Wang
The adverse reactions of warfarin that were found mainly occurred in the first month. This study was carried out to observe the effect of gene polymorphisms on the warfarin therapy at the initial stage. Four-hundred and sixty Chinese patients began warfarin treatment with daily 2.5 mg after heart valve replacement operations were enrolled. The daily international normalized ratio (INR) for anticoagulation were recorded till the seventh day. Blood samples were collected and used to detect genotypes for VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650...
December 8, 2015: Pharmacogenomics Journal
Flavia Storelli, Youssef Daali, Jules Desmeules, Jean-Luc Reny, Pierre Fontana
Pharmacogenomics is a relatively recent yet rapidly expanding field of study examining how genetic variations influence responses to drugs. Antithrombotic drugs include the anticoagulant and antiplatelet compounds widely prescribed for the treatment and prevention of cardiovascular diseases. However, there is a large variability in response to antithrombotics, and this can modify the benefit/risk ratio of taking such medications. This variability can be explained by clinical factors such as age, sex, and drug-drug interactions, but also by genetic variants...
2016: Current Pharmaceutical Design
S E Kimmel
The utility of using genetic information to guide warfarin dosing has remained unclear based on prior observational studies and small clinical trials. Two larger trials of warfarin and one of the acenocoumarol and phenprocoumon have recently been published. The COAG trial addressed the incremental benefit of adding genetic information to clinical information and demonstrated no benefit from the pharmacogenetic-based dosing strategy on the primary outcome. The EU-PACT UK trial compared an algorithm approach using genetic and clinical information to one that used a relatively fixed starting dose...
June 2015: Journal of Thrombosis and Haemostasis: JTH
Gwendolyn Spizz, Zongyuan Chen, Peng Li, I Cristina McGuire, Paulina Klimkiewicz, Devin Zysling, Rubina Yasmin, Whitney Hungerford, Benjamin Thomas, Gregory Wilding, Gregory Mouchka, Lincoln Young, Peng Zhou, Richard A Montagna
CONTEXT: Although the value of pharmacogenomics to improve patient outcomes has become increasingly clear, adoption in medical practice has been slow, which can be attributed to several factors, including complicated and expensive testing procedures and required equipment, lack of training by private practice physicians, and reluctance of both private and commercial payers to reimburse for such testing. OBJECTIVES: To evaluate a fully automated molecular detection system for human genotyping assays, starting with anticoagulated whole blood samples, and to perform all sample preparation, assay, and analysis steps automatically with actionable results reported by the system's software...
June 2015: Archives of Pathology & Laboratory Medicine
Amber L Beitelshees, Deepak Voora, Joshua P Lewis
In recent years, substantial effort has been made to better understand the influence of genetic factors on the efficacy and safety of numerous medications. These investigations suggest that the use of pharmacogenetic data to inform physician decision-making has great potential to enhance patient care by reducing on-treatment clinical events, adverse drug reactions, and health care-related costs. In fact, integration of such information into the clinical setting may be particularly applicable for antiplatelet and anticoagulation therapeutics, given the increasing body of evidence implicating genetic variation in variable drug response...
2015: Pharmacogenomics and Personalized Medicine
H L Tang, W L Shi, X G Li, T Zhang, S D Zhai, H G Xie
In terms of inconsistent conclusions across all relevant randomized controlled trials (RCTs) and available meta-analyses, we aimed to use a meta-analysis and trial sequential analysis (TSA) to evaluate whether clinical utility of a genotype-guided warfarin initiation dosing algorithm could be better than that of a standard therapy regimen, and whether currently relevant evidence could be reliable and conclusive. Overall, 11 eligible RCTs involving 2677 patients were included for further analyses. Compared with fixed dose or clinically adjusted warfarin initiation dosing regimens, genotype-guided algorithms significantly increased time in therapeutic range, shortened time to first therapeutic international normalized ratio (INR) and time to stable doses, but did not show any marked improvements in excessive anticoagulation, bleeding events, thromboembolism, or all-cause mortality...
December 2015: Pharmacogenomics Journal
Gaurav Thareja, Sumi Elsa John, Prashantha Hebbar, Kazem Behbehani, Thangavel Alphonse Thanaraj, Osama Alsmadi
BACKGROUND: The 1000 Genome project paved the way for sequencing diverse human populations. New genome projects are being established to sequence underrepresented populations helping in understanding human genetic diversity. The Kuwait Genome Project an initiative to sequence individual genomes from the three subgroups of Kuwaiti population namely, Saudi Arabian tribe; "tent-dwelling" Bedouin; and Persian, attributing their ancestry to different regions in Arabian Peninsula and to modern-day Iran (West Asia)...
2015: BMC Genomics
Jenna M Murray, Amy Hellinger, Roger Dionne, Loren Brown, Rosemary Galvin, Suzanne Griggs, Karen Mittler, Kathy Harney, Shannon Manzi, Christina VanderPluym, Annette Baker, Patricia O'Brien, Cheryl O'Connell, Christopher S Almond
Congenital heart disease is the leading cause of stroke in children. Warfarin therapy can be difficult to manage safely in this population because of its narrow therapeutic index, multiple drug and dietary interactions, small patient size, high-risk cardiac indications, and lack of data to support anticoagulation recommendations. We sought to describe our institution's effort to develop a dedicated cardiac anticoagulation service to address the special needs of this population and to review the literature. In 2009, in response to Joint Commission National Patient Safety Goals for Anticoagulation, Boston Children's Hospital created a dedicated pediatric Cardiac Anticoagulation Monitoring Program (CAMP)...
April 2015: Pediatric Cardiology
Luis Ángel Bermúdez Bosch
Warfarin is the current standard of care in oral anticoagulation therapy. It is commonly prescribed to treat venous thromboembolism, pulmonary embolism, acute myocardial infarction, and to decrease the risk of stroke in atrial fibrillation. Warfarin therapy is challenging because of marked and often unpredictable inter-individual dosing variations that effectively reach and maintain adequate anticoagulation. Several researchers have developed pharmacogenetic-guided maintenance dose algorithms that incorporate genetics and individual patient characteristics...
January 25, 2014: Journal of Pharmacogenomics & Pharmacoproteomics
Bridget L Morse, Richard B Kim
Personalized medicine is an emerging field with a goal of applying genomic information as a predictor of disease risk as well as individualization of drug therapy. For optimization of drug therapy, significant progress has been made in the past decade in linking genetic variation in genes associated with drug disposition to prediction of drug response and adverse reactions. For most drugs in clinical use, the interplay of many factors, including genetics, demographics, drug-drug interactions, disease states and the environment, result in the interindividual variability observed during drug therapy...
February 2015: Critical Reviews in Clinical Laboratory Sciences
W L Baker, K W Chamberlin
For patients requiring long-term anticoagulation, oral vitamin K antagonists (VKAs) such as warfarin have overwhelming efficacy data and present significant challenges. In addition to the potential exposure to numerous drug-drug and drug-food interactions, patients receiving warfarin require frequent monitoring. It had been hoped that the integration of pharmacogenomic with clinical information would improve anticoagulation control with warfarin, but trials have not supported this aim. Novel oral anticoagulants (NOACs) offer both advantages and disadvantages and deserve consideration in appropriate patients...
July 2014: Clinical Pharmacology and Therapeutics
Tejasvita Gaikwad, Kanjaksha Ghosh, Shrimati Shetty
BACKGROUND: Warfarin is the most widely used anticoagulant all over the world for prevention and treatment of different thrombotic conditions. Polymorphisms in two genes i.e. CYP2C9 (Cytochrome P450 2C9) and VKORC1 (Vitamin K epoxide reductase complex subunit 1) play a major role in warfarin dose variation and its related adverse effects. Different ethnic groups have shown significant differences in dose requirement. METHOD: A systematic electronic search was carried out in PUBMED and ScienceDirect using different key words like, 'warfarin', 'CYP2C9', 'VKORC1', 'pharmacokinetics', 'metabolites' and 'genetic'...
September 2014: Thrombosis Research
Vrinda Kulkarni, Abhay Bhave, Renuka Kulkarni Munshi, Supriya Bhalerao, Dhiraj Bhattad, Santosh Khude, Dnyneshwar Upase
We report an Indian adult female patient with Deep Vein Thrombosis (DVT), in whom it was difficult to achieve and maintain target INR on warfarin (oral anticoagulant) by conventional doses. Pharmacogenomics study for warfarin revealed that she had Homozygous mutant for CYP2C9 *3(CYP2C9 *3/*3) and Heterozygous mutant for VKORC 1(1639G >A) {genetic polymorphism double defect}. This conferred a greater sensitivity to her warfarin therapy in an otherwise conventional dose regime used in most patients, making her management challenging...
August 2013: Journal of the Association of Physicians of India
Paula Scibona, Federico Angriman, Ventura Simonovich, Martina M Heller, Waldo H Belloso
Cardiovascular disease remains a major cause of morbidity and mortality worldwide. Current medical practice takes into account information based on population studies and benefits observed in large populations or cohorts. However, individual patients present great differences in both toxicity and clinical efficacy that can be explained by variations in adherence, unknown drug to drug interactions and genetic variability. The latter seems to explain from 20% up to 95% of patient to patient variability. Treating patients with cardiovascular disorders faces the clinician with the challenge to include genomic analysis into daily practice...
January 2014: Archivos de Cardiología de México
J A Roth, D Boudreau, M M Fujii, F M Farin, A E Rettie, K E Thummel, D L Veenstra
The influence of warfarin pharmacogenomics on major bleeding risk has been little studied in long-term users and non-specialist care settings. We conducted a case-control study to evaluate associations between CYP2C9*2/*3, VKORC1(1173), and CYP4F2*3 variants and major bleeding among patients treated with warfarin in a community setting. We calculated major bleeding odds ratios, adjusting for race, duration of warfarin use, age, gender, and body mass index. In 265 cases and 305 controls with 3.4 and 3.7 mean years of warfarin use, respectively, CYP4F2*3 was associated with decreased major bleeding risk (odds ratio: 0...
June 2014: Clinical Pharmacology and Therapeutics
R M Turner, M Pirmohamed
Cardiovascular disease is a leading cause of morbidity and mortality worldwide. Pharmacogenomics is the study of genetic determinants of interindividual variation in drug response and aims to facilitate personalized medicine, through genotype-informed drug and dose selection, to maximize drug efficacy and/or minimize adverse drug reactions. Despite high expectations, no cardiovascular pharmacogenomic association is currently in widespread clinical practice; evidential, logistical, financial, and knowledge implementation barriers exist...
March 2014: Clinical Pharmacology and Therapeutics
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